PIDSOG HANDBOOK:

A GUIDANCE FOR CLINICIANS ON

THE OBSTETRIC MANAGEMENT OF
PATIENTS WITH CORONAVIRUS
DISEASE 2019 (COVID-19)

Philippine Obstetrical and Gynecological Society (Foundation), Inc.

Philippine Infectious Diseases Society for

Obstetrics and Gynecology, Inc.

© April 2020
 EDITORS
Katherine A. Angelo-Dela Cruz, MD
Jhorose R. Gementiza, MD
Florida F. Taladtad, MD
Cheryl T. Tiuseco, MD

TECHNICAL WORKING GROUP

PIDSOG Handbook: Guidance for Clinicians on the Obstetric
Management of Patients with COVID-19
Catherine Jane R. Costa, MD
Analyn F. Fallarme, MD
Maria Lorena L. Santos, MD
Valiant L. See, MD
 CONTRIBUTORS

BACKGROUND ON COVID-19
Sybil Lizanne R. Bravo, MD

DIAGNOSIS OF COVID-19 IN PREGNANCY

Head: Maria Lorena L. Santos, MD
Members:
Maria Meden P. Cortero, MD
Josefa Dawn V. Martin, MD
Sharon Faith B. Pagunsan, MD

MANAGEMENT OF COVID-19 IN PREGNANCY

Head: Catherine Jane R. Costa, MD
Members:
Louella P. Aquino, MD Analyn F. Fallarme, MD
Martha Monette A. Aquino, MD Patricia M. Kho, MD
May G. Asis, MD Henrietta S. Lucasan, MD
Ma. Angela R. Bandola, MD Judith R. Peralta, MD
Sigrid A. Barinaga, MD Maria Lorena L. Santos, MD
Erwin R. De Mesa, MD Guadalupe N. Villanueva, MD

INVESTIGATIONAL DRUGS USED IN COVID-19

Head: Analyn F. Fallarme, MD
Members:
Katherine A. Angelo-Dela Cruz, MD Josefa Dawn V. Martin, MD
Sybil Lizanne R. Bravo, MD Mariles H. Nazal, MD
Mary Judith Q. Clemente, MD Rojannah T. Sahagun, MD
Lorina Q. Esteban, MD Florida F. Taladtad, MD
Jhorose R. Gementiza, MD Cheryl T. Tiuseco, MD
Helen V. Madamba, MD

RECOMMENDED PPE USE FOR HEALTHCARE WORKERS CARING FOR

SUSPECTED AND CONFIRMED COVID-19 PREGNANT WOMEN
Head: Valiant L. See, MD
Members:
Sybil Lizanne R. Bravo, MD Christine D. Dizon, MD
Jennifer T. Co, MD Shareza B. Nadal, MD
Catherine Jane R. Costa, MD Mary Jane B. Noble, MD

COVER DESIGN
Ariel B. Vinarao, MD
 FOREWORD

The Philippine Infectious Diseases Society for Obstetrics and Gynecology, Inc.
(PIDSOG) 2019-2020 Board of Directors and its members, were tasked to come up
with the appropriate algorithm for managing pregnant patients during this COVID-19
pandemic. This handbook will provide the best available strategy in the diagnosis,
management, treatment and prevention of COVID-19 among pregnant women.

The immediate development of this handbook was done with extensive search of
available literature and quality evidence of data gathered in a short period of time. The
COVID-19 disease is still in its early phase – constantly progressing and data on the
disease is dynamic. Real knowledge on its causative agent, SARS-CoV-2, is still
insufficient. As updates are ongoing, expect constant changes on recommendations
in the near future as we learn more about this evolving disease.

The PIDSOG 2019-2020 Board of Directors would like to commend all the members
of the technical working group for their efforts and dedication in the completion of this
handbook amidst these unprecedented times. We are in deep gratitude to the different
stakeholders who have contributed and supported the cause for which this handbook
was formulated.

Lastly, we hope that this handbook will be of great help to our fellow colleagues –
obstetricians, residents and fellows-in-training and allied medical practitioners – as we
fight our elusive opponent. Always remember that there is NO EMERGENCY in a
pandemic. Keep safe and God bless the Philippines!
Philippine Infectious Diseases Society for Obstetrics and
Gynecology (PIDSOG), Inc.

2019 – 2020 BOARD OF DIRECTORS

Erwin R. De Mesa, MD
President

Sybil Lizanne R. Bravo, MD

Internal Vice President

Maria Lu D. Andal, MD
External Vice President

Analyn F. Fallarme, MD
Secretary

Louella P. Aquino, MD
Assistant Secretary

Catherine Jane R. Costa, MD

Treasurer

Valiant L. See, MD
Assistant Treasurer

Christine D. Dizon, MD
Auditor

Maria Lorena L. Santos, MD

P.R.O

Maria Angela R. Bandola, MD

Immediate Past President
 TABLE OF CONTENTS

I. Background on COVID-19
1
Sybil Lizanne R. Bravo, MD

II. Diagnosis of COVID-19 in Pregnancy – updated as of May 16, 2020

Maria Lorena L. Santos, MD / Maria Meden P. Cortero, MD / 3

Josefa Dawn V. Martin, MD / Sharon Faith B. Pagunsan, MD

III. Management of COVID-19 in Pregnancy

Catherine Jane R. Costa, MD / Louella P. Aquino, MD /

Martha M. Aquino, MD / May G. Asis, MD / Maria Angela R. Bandola, MD /
32
Sigrid A. Barinaga, MD / Erwin R. De Mesa, MD / Analyn F. Fallarme, MD /
Patricia M. Kho, MD / Henrietta S. Lucasan, MD / Judith R. Peralta, MD /
Maria Lorena L. Santos, MD / Guadalupe N. Villanueva, MD

IV. Investigational Drugs Used in COVID-19

Analyn F. Fallarme, MD / Katherine A. Angelo-Dela Cruz, MD /

Sybil Lizanne R. Bravo, MD / Mary Judith C. Clemente, MD /
Lorina Q. Esteban, MD / Jhorose R. Gementiza, MD / 57
Helen V. Madamba MD / Josefa Dawn V. Martin MD /
Mariles H. Nazal, MD / Rojannah T. Sahagun, MD /
Florida F. Taladtad, MD / Cheryl T. Tiuseco, MD

V. Recommended PPE Use for Healthcare Workers Caring for Suspected

and Confirmed COVID-19 Pregnant Women

Valiant L. See, MD / Sybil Lizanne R. Bravo, MD / Jennifer T. Co, MD / 117

Catherine Jane R. Costa, MD / Christine D. Dizon, MD /
Shareza B. Nadal, MD / Mary Jane B. Noble, MD

VI. Appendices

APPENDIX A: 140
Algorithm on Screening Pregnant Patients for SARS-CoV-2
APPENDIX B1-B3: 141
Empiric Antimicrobial Therapy for Community Acquired Pneumonia
APPENDIX C1-C4: 145
NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary
APPENDIX D: 146
Algorithm on the Clinical Approach to the Management of COVID-19 in
Pregnancy and the Newborn
APPENDIX E1: 150
Different Kinds of Face Mask
APPENDIX E2: 151
Different Kinds of N95 Face Mask
APPENDIX F: 152
PGH-HICU Risk-Based Personal Protective Equipment (PPE) Levels Infographic
APPENDICES G1-G2: 153
Components of Level 3 PPE for Ob-Gyn Procedures
APPENDICES H1-H3: 155
Components of Level 4 PPE for Ob-Gyn Procedures
 BACKGROUND ON COVID-19
Sybil Lizanne R. Bravo, RPh, MD, MSc

WHAT IS A PANDEMIC?

Pandemic is defined as “an outbreak of a disease that occurs over a wide

geographical area and affects an exceptionally high proportion of the population,1”
or as defined by the World Health Organization (WHO), “is the worldwide spread of
a new disease.2”

The world has suffered a number of pandemics. There was the 1918 Spanish flu
wherein millions died. About eighteen years ago, we had the 2002-2004 severe
acute respiratory syndrome (SARS), which was also caused by a coronavirus. And
of course, there is the Ebola contagion which has originated in the African region
but made its way to some countries and which has baffled scientists all over.

Who would have thought that, indeed, in our lifetime, we would experience a
pandemic? This current COVID-19 pandemic has indeed been a conundrum for
men of science.

COVID-19 AND SARS-CoV-2

As detailed by the World Health Organization (WHO), there are two official names
for this pathogen – COVID-19 refers to the coronavirus disease, while severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) is used when referring to the
virus itself.3

Last February 11, 2020, the International Committee on Taxonomy of Viruses

(ICTV) announced the term SARS-CoV-2, because this current virus is genetically
related to the coronavirus that caused the SARS outbreak in year 2003.

CLINICAL PRESENTATION OF COVID-19?

As of current knowledge and with global experience, a substantial proportion of

severely ill patients may require intensive care. The main reason for admission into
an intensive care unit is mainly due to viral pneumonitis that evolves into acute
respiratory distress syndrome (ARDS). The usual symptoms are fever, cough, sore
throat, and malaise. The onset of difficulty of breathing is on day 5 to day 7, though
progression into ARDS may be fast thereafter, about 2-3 days from difficulty of
breathing. Almost half to all who are critically ill would eventually require mechanical

PIDSOG Handbook: A Guidance for Clinicians on the Obstetric Management of Patients with Coronavirus Disease 2019
Version 3.0 -- Released May 28, 2020
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 ventilation. Complications include acute renal failure, liver enzyme elevation,
cardiac pathologies such as cardiomyopathy, arrhythmia and sudden cardiac
death, septic shock, secondary bacterial pneumonia, altered lung compliance, and
encephalopathy. In lieu of these complications, it is imperative that healthcare
providers offer what they think and believe are best supportive forms of
management including the use of some investigational pharmacological therapies.

In these past few months, risk factors have been identified and most healthcare
providers agreed that there are at-risk or vulnerable populations, such as the
elderly, the young, and those with immunocompromising conditions. Pregnant
women, in any disease state, are considered a vulnerable population.

As such, this handbook will function as guidance for obstetrician-gynecologists and

other healthcare providers who tirelessly devote much of their time and effort in
making sure our Filipino gravidas and their unborn children will be given, if not the
definitive, but as of current situation, the most ideal and applicable management.

While it is true that knowledge of the pathophysiology, the virulence of this

contagion, and the therapy of this infection are very much in evolution, the authors
of this guidance hope that this will be of assistance to everyone involved in the care
of our pregnant women as the following are discussed: diagnosis, management,
treatment and prevention including proper use of personal protective equipment.

REFERENCES:
1. https://www.merriam-webster.com/dictionary/pandemic
2. https://www.who.int/csr/disease/swineflu/frequently_asked_questions/pandemic/en/
3. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/naming-the-coronavirus-
disease-(covid-2019)-and-the-virus-that-causes-it

PIDSOG Handbook: A Guidance for Clinicians on the Obstetric Management of Patients with Coronavirus Disease 2019
Version 3.0 -- Released May 28, 2020
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 DIAGNOSIS OF COVID-19 IN PREGNANCY
Maria Lorena L. Santos, MD
Maria Meden P. Cortero, MD / Josefa Dawn V. Martin, MD
Sharon Faith B. Pagunsan, MD, MMPM

WHAT ARE THE CASE DEFINITIONS FOR COVID-19 IN PREGNANT WOMEN?

STATEMENT:
The case definitions for COVID-19 in pregnant women are no different from that
of the general population. The terms SUSPECTED case, PROBABLE case and
CONFIRMED case are used.

SUPPORTING STATEMENTS:
Suspected case
A patient with acute respiratory tract infection (i.e. sudden onset of at least one of the
following: fever, cough, shortness of breath) AND with no other etiology that fully
explains the clinical presentation AND with a history of travel or residence in a
country/area reporting local or community transmission during the 14 days prior to
symptom onset;
OR
A patient with any acute respiratory illness AND having been in close contact with a
confirmed or probable COVID-19 case in the last 14 days prior to onset of symptoms;
OR
A patient with severe acute respiratory illness (fever and at least one sign/symptom
of respiratory disease, e.g., cough, shortness of breath; AND requiring
hospitalization) AND in the absence of an alternative diagnosis that fully explains the
clinical presentation.

Probable Case
A suspected case for whom testing for virus causing COVID-19 is inconclusive
(according to the test results reported by the laboratory) or for whom testing was
positive on a pan-coronavirus assay.
Confirmed Case
A person with laboratory confirmation of virus causing COVID-19 infection,
irrespective of clinical signs and symptoms.

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Version 3.0 -- Released May 28, 2020
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 Close Contact
A close contact of a probable or confirmed case is defined as:
• A person living in the same household as a COVID-19 case;
• A person having had direct physical contact with a COVID-19 case (e.g. shaking
hands);
• A person having unprotected direct contact with infectious secretions of a COVID-
19
case (e.g. being coughed on, touching used paper tissues with a bare hand);
• A person having had face-to-face contact with a COVID-19 case within 2 meters
and > 15 minutes;
• A person who was in a closed environment (e.g. classroom, meeting room, hospital
waiting room, etc.) with a COVID-19 case for 15 minutes or more and at a distance
of less than 2 meters;
• A healthcare worker (HCW) or other person providing direct care for a COVID-19
case, or laboratory workers handling specimens from a COVID-19 case without
recommended personal protective equipment (PPE) or with a possible breach of
PPE;
• A contact in an aircraft sitting within two seats (in any direction) of the COVID-19
case, travel companions or persons providing care, and crew members serving in
the section of the aircraft where the index case was seated (if severity of symptoms
or movement of the case indicate more extensive exposure, passengers seated in
the entire section or all passengers on the aircraft may be considered close
contacts).

REFERENCES:
1. https://www.who.int/docs/default-source/coronaviruse/who-china-joint-missionon-covid-19-final-report.pdf
2. https://www.ecdc.europa.eu/en/case-definition-and-europe an-surveillance-human-infection-novel-coronavirus-2019-ncov

PIDSOG Handbook: A Guidance for Clinicians on the Obstetric Management of Patients with Coronavirus Disease 2019
Version 3.0 -- Released May 28, 2020
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 WHEN DO YOU SUSPECT THAT A PREGNANT PATIENT HAS COVID-19?
STATEMENT:
The possibility of COVID-19 infection is suspected in a pregnant woman with
new-onset fever and/or respiratory symptoms. It should also be considered in
a pregnant woman with severe lower respiratory tract illness without any clear
cause.

SUPPORTING STATEMENTS:
Clinical findings
The clinical characteristics reported among pregnant women with confirmed COVID-
19 infection are similar to those reported in non-pregnant adults in the general
population. There are no specific clinical features that can reliably distinguish COVID-
19 infection from other viral respiratory infections.

Pneumonia appears to be the most frequent serious manifestation of the infection,

characterized by fever, cough, dyspnea, and bilateral infiltrates on chest imaging.1-4
In a study describing 138 patients with COVID-19 pneumonia in Wuhan, the most
common clinical features at the onset of illness were fever, cough, and dyspnea.4

Similarly, other cohort studies of patients from Wuhan with confirmed COVID-19
infection have reported a similar range of clinical findings.2,3
Table 2.1 COVID-19 Common Clinical Features

Nonetheless, the symptoms expressed by COVID-19 patients are nonspecific and

cannot be used for an accurate diagnosis.

Other less common symptoms include headache, sore throat, and rhinorrhea. In
addition to respiratory symptoms, gastrointestinal symptoms (e.g. nausea and
diarrhea) have also been reported; and in some patients, these may be the
presenting complaint.2,4

PIDSOG Handbook: A Guidance for Clinicians on the Obstetric Management of Patients with Coronavirus Disease 2019
Version 3.0 -- Released May 28, 2020
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 Reports of cohorts in locations outside of Wuhan have described similar clinical
findings, although some have suggested that milder illness may be more common.5-
7
As an example, in a study of 62 patients with COVID-19 infection in the Zhejiang
province of China, all but one had pneumonia, but only two developed dyspnea, and
only one warranted mechanical ventilation.6

Anosmia has been anecdotally reported as a distinguishing symptom in patients who

were ultimately diagnosed with COVID-19.8 However, published cohort studies have
not highlighted this symptom, and its frequency and utility in suspecting COVID-19
infection is uncertain.

Laboratory findings
In patients with COVID-19 infection, the white blood cell count can vary. Leukopenia,
leukocytosis, and lymphopenia have been reported, although lymphopenia appears
most common.9 Elevated lactate dehydrogenase and ferritin levels are common, and
elevated aminotransferase levels have also been described. On admission, many
patients with pneumonia have normal serum procalcitonin levels. However, in those
requiring ICU care, they are more likely to be elevated.2-4 High D-dimer levels and
more severe lymphopenia have been associated with mortality.3

Inflammatory Markers
Serum Procalcitonin
Serum procalcitonin is often normal on admission, however, it increases in patients
who require ICU care.
C-reactive protein (CRP)
COVID-19 infection increases CRP. This seems to track with disease severity and
prognosis. In patients suffering from with severe respiratory failure with a normal CRP
level an alternative diagnosis should always be sought.10

REFERENCES:
1. Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 2020.
2. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet
2020; 395:497.
3. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus
pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395:507.
4. Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected
Pneumonia in Wuhan, China. JAMA 2020.
5. Chang, Lin M, Wei L, et al. Epidemiologic and Clinical Characteristics of Novel Coronavirus Infections Involving 13 Patients
Outside Wuhan, China. JAMA 2020.
6. Xu XW, Wu XX, Jiang XG, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-
Cov-2) outside of Wuhan, China: retrospective case series. BMJ 2020; 368:m606.
7. Wu J, Liu J, Zhao X, et al. Clinical Characteristics of Imported Cases of COVID-19 in Jiangsu Province: A Multicenter
Descriptive Study. Clin Infect Dis 2020.
8. https://www.entnet.org/content/coronavirus-disease-2019-resources (Accessed on March 28, 2020).
9. Centers for Disease Control and Prevention. Interim Clinical Guidance for Management of Patients with Confirmed 2019
Novel Coronavirus (2019-nCoV) Infection
10. Guan W, Ni Z, Yu Hu W, Liang, C. Ou, J He, Liu L, Shan H, Lei C, Hui D.S.C., Du B, Li L, Zeng G, Yuen K.Y., Chen R.
Clinical Characteristics of Coronavirus Disease 2019 in China.

PIDSOG Handbook: A Guidance for Clinicians on the Obstetric Management of Patients with Coronavirus Disease 2019
Version 3.0 -- Released May 28, 2020
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 WHO SHOULD BE TESTED FOR COVID-19?
STATEMENT:
All pregnant women with symptoms associated to COVID-19 infection should
be tested. Testing should also be considered in pregnant women with
increased of exposure to the diseases, such as those who reside in or has a
history of travel within the prior 14 days to a location with community
transmission or those who had close contact with a confirmed or suspected
case of COVID-19.

SUPPORTING STATEMENTS:
Testing is done based on approved
local protocols. Current guidelines do
not recommend testing for
asymptomatic individuals with no
comorbidities.1

Although the DOH has recognized the

pregnant population as a “vulnerable”
group, the evidence, so far, have shown
that pregnant women are still no more
likely to contract the infection than the
general population. In fact, the
Infectious Disease Society of America
(IDSA) classified pregnant women
under “Tier 3” for COVID-19
2
Prioritization Testing. However,
pregnancy in a small proportion of
Figure 2.1 Case Definition Classification
women, may alter the response of the
body to severe viral infections, and as such, some pregnant women may be at a
greater risk for severe illness, morbidity or mortality compared with the general
population.

Hence, pregnancy alone in the setting of new-flu like symptoms is sufficient to

warrant COVID-19 testing, especially if additional risk factors (e.g. close contact with
a known COVID-19 case, immunocompromised, with comorbidities such as
hypertension, diabetes, etc.) are identified in the patient.
The possibility of COVID-19 should be considered primarily in patients with new
onset fever and/or respiratory tract symptoms. It should also be considered in
patients with severe lower respiratory tract illness without any clear cause.

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Version 3.0 -- Released May 28, 2020
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 Although these syndromes can occur with other viral respiratory illnesses, the
likelihood of COVID-19 is increased if the patient:

• Resides in or has traveled within the prior 14 days to a location where there is
community transmission of COVID-19 (i.e. large numbers of cases that cannot
be linked to specific transmission chains) OR
• Has had close contact with a confirmed or suspected case of COVID-19 in the
prior 14 days, including those who work in health care settings.

Close contact includes being within approximately six feet (about two meters) of a
patient for a prolonged period of time while not wearing personal protective
equipment or having direct contact with infectious secretions while not wearing
personal protective equipment.

REFERENCES:
1. Philippine Society for Microbiology and Infectious Diseases Interim Guidelines On The Clinical Management Of Adult
Patients With Suspected Or Confirmed Covid-19 Infection Version 2.0, as of 26 March 2020
2. Infectious Diseases Society of America. COVID-19 Prioritization of Diagnostic Testing.
https://www.idsociety.org/globalassets/idsa/public-health/covid-19-prioritization-of-dx-testing.pdf

PIDSOG Handbook: A Guidance for Clinicians on the Obstetric Management of Patients with Coronavirus Disease 2019
Version 3.0 -- Released May 28, 2020
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 SHOULD ASYMPTOMATIC PREGNANT WOMEN BE SCREENED FOR SARS-
CoV-2 PRIOR TO DELIVERY?

STATEMENT:
Asymptomatic individuals play a role in the transmission of COVID-19. Hence,
screening for SARS-CoV-2 should be considered among pregnant women at
37 – 38 weeks to give time for the release of the results prior to delivery.

SUPPORTING STATEMENTS:
Experience with COVID-19 in pregnancy is limited. To date, data is based on case-
series that are not controlled. The background comorbidities in the population, local
testing policies, and obstetric care practices may limit generalizability to our
population.

Identifying pregnant women with COVID-19 infection has several goals:

1. To tailor frequency and location of prenatal care for identified COVID-19
confirmed women and COVID suspects and probable cases.
2. To decrease risk of transmission to other patients, healthcare personnel, and
family living in the same space
3. To plan for labor and delivery care
4. To plan for mother-infant separation strategies, if necessary

Rate of Asymptomatic Women with Positive

SARS-CoV-2 Results
Pregnancy alone in the setting of new flu-like
symptoms is sufficient to warrant COVID-19
testing especially if with additional risk factors
(e.g. close contact with known COVID-19 case,
immunocompromised, with co-morbidities e.g.,
hypertension, diabetes). However, patients
may present early in their infectious course
prior to symptoms or may have asymptomatic
viral carriage.
Figure 2.2 Symptom status and SARS-CoV-2 test
results among 215 obstetrical patients presenting for
delivery. (SOURCE: Adapted from Sutton NEJM)

In a series of 43 COVID-19 infected pregnant women in New York, 32.6% of them

presented WITHOUT symptoms. Of these, 46.2% developed symptoms within 7
days after the positive test.1

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Version 3.0 -- Released May 28, 2020
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 A recent series (by Sutton et al.) of 215 pregnant patients from New York
demonstrated a 13.7% rate of positive testing for SARS-CoV-2 amongst
asymptomatic women (4/215 had fever, while 211/215 were asymptomatic).
Nasopharyngeal swabs were obtained from 210 of the 211 women (99.5%) who did
not have symptoms of COVID-19. Of these women, 29 (13.7%) were positive for
SARS-CoV-2. Thus, 4 out of 33 patients who were positive for SARS-CoV-2 on
admission were symptomatic (12.1%), while 29 of the 33 patients who were positive
for SARS-CoV-2 at admission (87.9%) had no symptoms of COVID-19 at
presentation.2

Sutton et al. said that “use of universal SARS-CoV-2 testing in all pregnant patients
presenting for delivery revealed that at this point in the pandemic in New York City,
most of the patients who were positive for SARS-CoV-2 at delivery were
asymptomatic”. This highlights the risk of COVID-19 infection in asymptomatic
pregnant women. Hence, they concluded that the potential benefits of a universal
testing approach include the ability to use COVID-19 status to determine hospital
isolation practices and bed assignments, inform neonatal care, and guide the use of
personal protective equipment.2 This report in a high prevalence area demonstrated
1 out of 8 asymptomatic pregnant patients presenting for delivery were SARS-CoV-
2 positive, illustrating a need for universal screening.

Another New York study was done by Vintzileos et al. with the primary objective of
determining the accuracy of maternal symptomatology in predicting the COVID-19
infection as confirmed by rapid laboratory testing using GeneXpert SARS-CoV-2
Nasopharyngeal Sample Collection Kit.3 A total of 161 patients underwent routine
COVID-19 testing on admission to labor and delivery room. Of the 161 patients
tested, 32 (19.9%) were COVID-19 positive and of these, 11 (34%) were
symptomatic and 21 (66%) were asymptomatic.3

Table 2.2 Accuracy of maternal symptomatology in predicting the COVID-19 infection.3

Positive COVID- Negative COVID-19 Total
19
Symptomatic 11 5 16
Asymptomatic 21 124 145
Total 32 129 161
Note. Sensitivity = 11/32 (34.4%); specificity = 124/129 (96.1%); positive predictive value = 11/16 (68.7%); negative predictive
value = 124/145 (85.5%); positive likelihood ratio = 8.8; negative likelihood ratio = 0.68.

Can these numbers be generalizable to areas with lower infection rates like the
Philippines? It would be good to know how transmission rates differ between
symptomatic carriers and those who are asymptomatic. As this pandemic evolves,
we are learning more and more, and it is important to expand our understanding of
asymptomatic transmission and the risk this may pose.

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Version 3.0 -- Released May 28, 2020
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 Key benefits to screening are the capability for labor and delivery units to implement
best hospital practices in their care of mothers and babies, such as admitting
confirmed patients to cohort units. Such units would allow for closer monitoring of
mothers and babies, as well as ensuring proper use of personal protective equipment
by health care teams and also would help preserve supplies of personal protective
equipment.

Hospital testing capacity is an obvious barrier to screening of pregnant

women, as well as factors like the need for additional protective equipment to
be used during swab collection. Also, if you get a negative result and there is
a strong suspicion for COVID-19 infection, when do you retest? These are key
questions or areas of assessment that should be considered before embarking
on screening for pregnant women. In addition, some patients may refuse
testing out of fear of stigma or separation from their newborn.

Implementing an ‘opt out’ approach to screening may be encouraged, whereby a

patient is informed that a test will be included in standard preventive screening, and
they may decline the test. Routine, opt-out screening approaches have proven to be
highly effective as it removes the stigma associated with testing, fosters earlier
diagnosis and treatment, reduces risk of transmission, and has proven to be cost
effective. Pregnant women should be reassured that screening is beneficial for their
care and the care of their newborn baby.

Traditional infection control and public health strategies rely heavily on early
detection of disease to contain spread. When COVID-19 burst onto the global scene,
public health officials initially deployed interventions that were used to control severe
acute respiratory syndrome (SARS) in 2003, including symptom-based case
detection and subsequent testing to guide isolation and quarantine.

This initial approach was justified by the many similarities between SARS-CoV-1 and
SARS-CoV-2, including high genetic relatedness, transmission primarily through
respiratory droplets, and the frequency of lower respiratory symptoms with both
infections developing a median of 5 days after exposure. However, despite the
deployment of similar control interventions, the trajectories of the two epidemics have
veered in dramatically different directions.

What explains these differences in transmission and spread? A key factor in the
transmissibility of Covid-19 is the high level of SARS-CoV-2 shedding in the upper
respiratory tract, even among pre-symptomatic patients, which distinguishes it from
SARS-CoV-1, where replication occurs mainly in the lower respiratory tract.4,5 Viral
loads with SARS-CoV-1, which are associated with symptom onset, peak a median
of 5 days later than viral loads with SARS-CoV-2, which makes symptom-based
detection of infection more effective in the case of SARS CoV-1.6

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Version 3.0 -- Released May 28, 2020
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 Ultimately, the rapid spread of COVID-19 across the globe, the clear evidence of
SARS-CoV-2 transmission from asymptomatic persons, and the eventual need to
relax current social distancing practices argue for broadened SARS-CoV-2 testing to
include asymptomatic persons even in low epidemics.

Depending on the availability of testing capacity and resources, institutions

should consider implementing screening on labor and delivery as several
geographic areas are predicted to reach their peak time of COVID-19
transmission, and it is clear that asymptomatic individuals continue to play a
role in its transmission. It may be more prudent to conduct the testing at 37-38
weeks, giving a lead time for the release of results prior to delivery. If labor
ensues >14 days from the last testing, repeat testing may be done, if resources
would allow (Appendix A).

REFERENCES:
1. Breslin N, Baptiste C, Gyamfi-Bannerman C, Miller R, Martinez R, Bernstein K, Ring L, Landau R, Purisch S, Friedman AM,
Fuchs K, Sutton D, Andrikopoulou M, Rupley D, Sheen JJ, Aubey J, Zork N, Moroz L, Mourad M, Wapner R, Simpson LL,
D’Alton ME, Goffman D. COVID-19 infection among asymptomatic and symptomatic pregnant women: Two weeks of
confirmed presentations to an affiliated pair of New York City hospitals
2. Sutton D, Fuchs K, D’Alton M, Goffman D. Correspondence: Universal Screening for SARS-CoV-2 in Women Admitted for
Delivery. N Engl J Med. 2020 Apr 13. doi: 10.1056/NEJMc2009316.
3. Vintzileos W, Muscat J, Hoffman E, Vo D, John N, Vertichio R, Vintzileos A. Screening all pregnant women admitted to labor
and delivery for the virus responsible for COVID-19. American Journal of Obstetrics and Gynecology. www.ajog.org
4. Wölfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized patients with COVID-2019. Nature 2020
April 1.
5. Cheng PK, Wong DA, Tong LK, et al. Viral shedding patterns of coronavirus in patients with probable severe acute respiratory
syndrome. Lancet 2004; 363: 1699-700.
6. To KK-W, Tsang OT-Y, Leung W-S, et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and
serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect Dis 2020 March
23

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 WHAT IS THE GOLD STANDARD IN THE DIAGNOSIS OF COVID-19
INFECTION?

STATEMENT:
Reverse Transcription-Polymerase Chain Reaction (RT-PCR) test is the gold
standard to identify COVID-19 infection.

SUPPORTING STATEMENTS:
Thus far, the most commonly used and reliable test for diagnosis of COVID-19 has
been the RT-PCR test performed using nasopharyngeal swabs or other upper
respiratory tract specimens, including throat swab or, more recently, saliva. Test
results are generally available within a few hours to 2 days.

Table 2.3 Detection Rate from Different Biological Sources

Furthermore, the accuracy
and reliability of RT-PCR for
diagnosing SARS-CoV-2
infection depends on many
biological and technical
15
variables. Beside the
influence of procedures used
for collecting, transporting
and storing the specimens, as
well as from concomitant
antiviral therapy,16 virus
detection is largely influenced
by the biological source. Wang et al, for example, recently showed that the rate of
RT-PCR detection of SARS-CoV-2 in patients diagnosed with COVID-19 is as high
as 93% in bronchoalveolar lavage (BAL) fluid, but then decreases to 72% in sputum
and 63% in nasal swabs, respectively, whilst it is only 32% in pharyngeal swabs and
29% in stool. To et al also reported that the positive rate of RT-PCR for SARS-CoV-
2 is 15-30% in blood and 14-38% in rectal swabs, respectively.

False-negative result, on the other hand, ranges of 17-63% for nasopharyngeal

SARS-CoV2 RT-PCR have been reported in non-pregnant patients; however,
without clear gold standard tests available, diagnostic test characteristics including
sensitivity, specificity, positive and negative predictive values of SARS-CoV2 RT-
PCR assays are difficult to determine.19-21 Sensitivity of BAL samples appear to
be higher than nasopharyngeal or oropharyngeal swabs, but requires invasive and
high-risk aerosolizing bronchoscopy to obtain a sample.20,21

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 Given these, the most prudent strategy may be to presume that all patients are
infected and use the best available infection prevention possible during the duration
of this pandemic.

Then again, there are issues that have arisen with RT-PCR. First, the availability
of RT-PCR reagent kits has not kept up with demand. Second, community or
provincial hospitals outside of urban cities (NCR or laboratories other than
those identified as subnational laboratories) lack the PCR infrastructure to
accommodate high sample output. Lastly, RT-PCR relies on the presence of
detectable SARS-CoV-2 in the sample collected. If an asymptomatic patient
was infected with SARS-CoV-2 but has since recovered, RT-PCR would not
identify this prior infection, and control measures would not be enforced.
Despite these issues, given the lack of effective vaccines or treatments as of
writing, the only currently available lever to reduce SARS-CoV-2 transmission
is to identify and isolate persons who are contagious.

Reverse Transcription Polymerase Chain Reaction (RT-PCR)

RT-PCR assays have been designed to detect SARS-CoV-2 genetically. RT-PCR

involves the reverse transcription of SARS-CoV-2 RNA into complementary DNA
(cDNA) strands, followed by amplification of specific regions of the cDNA.1,2

RT-PCR is the most predominantly used method for diagnosing COVID-19 using
respiratory sample.8 Upper respiratory samples are broadly recommended, although
lower respiratory samples are recommended for patients exhibiting productive
cough.9 Upper respiratory tract samples include nasopharyngeal swabs,
oropharyngeal swabs, nasopharyngeal washes, and nasal aspirates. Lower
respiratory tract samples include sputum, bronchoalveolar lavage (BAL) fluid, and
tracheal aspirates. Both BAL and tracheal aspirates can be high risk for aerosol
generation.

The detectable viral load depends on the days after illness onset. In the first 14 days
after onset, SARS-CoV-2 could most reliably be detected in sputum followed by nasal
swabs, whereas throat swabs were unreliable 8 days after symptom onset.10 Given
the variability in the viral loads, a negative test result from respiratory samples does
not rule out the disease. These negatives could result from improper sampling
techniques, low viral load in the area sampled, or mutations in the viral genome.11
Moreover, a “positive” PCR result reflects only the detection of viral RNA and does
not necessarily indicate presence of viable virus.12

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 In some cases, viral RNA
has been detected by RT-
PCR even beyond week 6
following the first positive
test.14 A few cases have
also been reported positive
after 2 consecutive
negative PCR tests
performed 24 hours apart.
It is unclear if this is a
testing error, reinfection, or
reactivation. In a study of 9
Figure 2.3 Estimated Variation Over Time in Diagnostic Tests for Detection patients, attempts to isolate
of SARS-CoV-2 Infection Relative to Symptom Onset (Source: Sethuraman, et al.)
the virus in culture were not
successful beyond day 8 of illness onset, which correlates with the decline of
infectivity beyond the first week. 12 That is in part why the “symptom-based strategy”
of the Centers for Disease Control and Prevention (CDC) indicates that health care
workers can return to work, if “at least 3 days (72 hours) have passed since recovery
defined as resolution of fever without the use of fever-reducing medications and
improvement in respiratory symptoms (e.g., cough, shortness of breath); and, at least
10 days have passed since symptoms first appeared.”13

Bronchoscopy

Bronchoscopy helps in obtaining BAL samples in patients who are unable to

expectorate sputum for bacterial culture studies, AFB smear, or GeneXpert.1 It can
also be used to clear out mucus plugs in ventilated patients. However, it may cause
some deterioration in clinical condition, especially in patients who are on high oxygen
support. Likewise, there is high risk of infection transmission to providers resulting
from high aerosol production during the procedure. Moreover, there will be significant
utilization of valuable resources during bronchoscopy, which will be limited in supply
during a pandemic. Hence, bronchoscopy should not be done only for the purpose
of ruling COVID-19.4,5

If bronchoscopy is warranted, consider the use of a disposable bronchoscope if

available. Consider performing bronchoscopy in the patient’s place of care to
minimize the exposure and contamination. Minimize staff inside the room during
procedure; use a negative pressure room if available. Complete personal protective
equipment should be used. Standard disinfection protocols should be followed for
cleaning your flexible bronchoscopes and video monitors.

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 REFERENCES:
1. Freeman, W.M.; Walker, S.J.; Vrana, K.E. Quantitative RTPCR: Pitfalls and Poternial. BioTechniques 1999, 26 (1), 124-
125.
2. Kageyama, t.; Kojima,S.; Shinohara.; Uchida, K.; Fukushi, s.; Hoshino, F.B.; Takeda, n.; Katayama, K.; Broadly Reactive
ang Highly Sensitive Assay for Norwalk-like Viruses Based on Real-Time Qunatitative Reverse Transcription-PCR. J. Clin.
Microbiol. 2003, 41(4), 1548-1557.
3. Bouadma L, Lescure FX, Lucet JC, Yazdanpanah Y and Timsit JF. Severe SARS-CoV-2 infections: practical
considerations and management strategy for intensivists. https://link.springer.com/content/pdf/10.1007/s00134-020-
05967-x.pdf.
4. Momen M. Wahidi MM, Lamb C, Murgu S, MD. American Association for Bronchology and Interventional Pulmonology
(AABIP) Statement on the Use of Bronchoscopy and Respiratory Specimen Collection in Patients with Suspected or
Confirmed COVID-19 Infection.
5. Buonsenso D, Piano A, Raffaelli F, Bonadia N. Point-of-Care Lung Ultrasound findings in novel coronavirus disease-19
pnemoniae: a case report and potential applications during COVID-19 outbreak. Eur Rev Med Pharmacol Sci. 2020;
24:2776–80.
6. Rothe C, Schunk M, Sothmann P, et al. Transmission of 2019-nCoV Infection from an Asymptomatic Contact in Germany.
N Engl J Med 2020; 382:970.17.
7. Kupferschmidt K. Study claiming new coronavirus can be transmitted by people without symptoms was flawed. Science.
February 3, 2020. https://www.science mag.org/news/2020/02/paper-non-symptomatic-patient-transmitting-coronavirus-
wrong
8. Laboratory Testing for Coronavirus Disease 2019 (COVID-19) in Suspected Human Cases; World Health Organization:
Geneva, 2020.
9. Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens from Persons Under Investigation (PUIs) for
Coronavirus Disease 2019 (COVID-19); Centers for Disease Control and Prevention.
10. Yang, Y.; Yang, M.; Shen, C.; Wang, F.; Yuan, J.; Li, J.; Zhang, M.; Wang, Z.; Xing, L.; Wei, J.; et al. Laboratory Diagnosis
and Monitoring the Viral Shedding of 2019-nCoV Infections. medRxiv, February 17, 2020.
11. Winichakoon, P.; Chaiwarith, R.; Liwsrisakun, C.; Salee, P.; Goonna, A.; Limsukon, A.; Kaewpoowat, Q. Negative
Nasopharyngeal and Oropharyngeal Swab Does Not Rule Out COVID-19. J. Clin. Microbiol. 2020
12. Wölfel R, Corman VM, GuggemosW, et al. Virological assessment of hospitalized patients with COVID-2019. Nature.
2020. Published online April 1, 2020.
13. CDC. Return-to-work criteria for healthcare workers. Updated April 30, 2020. Accessed May 3, 2020.
14. Sethuraman N, Jeremiah SS, Ryo A. Interpreting Diagnostic Tests for SARS-CoV-2. JAMA, Published Online:May 6,
2020. doi:10.1001/jama.2020.8259
15. Galli C, Plebani M. Clinical laboratory and SARS-CoV-2 infection: where do we stand? Clin Chem Lab Med. 2020 Apr 2.
16. Lippi G, Simundic AM, Plebani M. Potential preanalytical and analytical vulnerabilities in the laboratory diagnosis of
coronavirus disease 2019 (COVID-19). Clin Chem Lab Med. 2020 Mar 16.
17. Wang W, Xu Y, Gao R, et al. Detection of SARS-CoV-2 in Different Types of Clinical Specimens. JAMA. 2020 Mar 11.
doi: 10.1001/jama.2020.3786.
18. To KK, Tsang OT, Leung WS, et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum
antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect Dis. 2020 Mar 23.
19. Xiao AT, Tong YX, Zhang S. False-negative of RT-PCR and prolonged nucleic acid conversion in COVID-19: Rather than
recurrence. Journal of Medical Virology. doi:10.1002/jmv.25855
20. Ai T, Yang Z, Hou H, et al. Correlation of Chest CT and RT-PCR Testing in Coronavirus Disease 2019 (COVID-19) in
China: A Report of 1014 Cases. Radiology. February 2020:200642. doi:10.1148/radiol.2020200642
21. Long C, Xu H, Shen Q, et al. Diagnosis of the Coronavirus disease (COVID-19): rRT-PCR or CT? Eur J Radiol.
2020;126:108961. doi:10.1016/j.ejrad.2020.108961

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 WHAT IS THE ROLE OF ANTIBODY TESTING IN THE DIAGNOSIS AND
MANAGEMENT OF COVID-19 INFECTION?

STATEMENT:
The rapid antibody-based (IgM/IgG) tests may be used as an adjunct to RT-PCR
and must not be used as a stand-alone test.

SUPPORTING STATEMENTS:
Serology, or antibody testing, is the latest entry in the COVID-19 testing landscape.
Serological diagnosis is especially important for patients with mild to moderate illness
who may present late, beyond the first 2 weeks of illness onset. Serological diagnosis
also is becoming an important tool to understand the extent of COVID-19 in the
community and to identify individuals who are immune and potentially “protected”
from becoming infected.

Serology testing is used to detect antibodies against SARS-COV-2 in the blood and
provides evidence that the patient has been exposed to the virus. Serology testing
alone is not recommended for COVID-19 diagnosis due to the kinetics of infection.
In the majority of individuals infected with SARS-CoV-2, we would expect to see a
peak in viral replication that coincides with the development of symptoms. This is
followed by the development of antibodies several days later (known as
seroconversion). Testing a patient too early in the course of infection may yield a
false-negative result because the patient has not yet seroconverted. Moreover, even
when patients have seroconverted, they still may be infectious and continue to shed
virus.

But, any antibody test, whether performed in the laboratory (e.g., laboratory-based
enzyme immunoassays on high throughput automated platforms) or at the rapid
point-of-care, as is the case with finger stick antibody testing at primary health
facilities, must be validated to ensure accuracy, consistency, reliability, and
reproducibility.

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 COVID-19 Rapid Diagnostic Test qualitatively detects the
presence of IgG and IgM antibodies to SARS-CoV-2 in human
whole blood, serum, plasma samples of people believed to have
been infected with COVID-19.6,7

This test applies lateral flow immuno-chromatography and is a tool

to assist in the diagnosis of SARS-CoV-2 infections. The IgM-IgG
combined assay has better utility and sensitivity compared with a
single IgM or IgG test. It can be used for the rapid screening of
SARS-CoV-2 carriers, symptomatic or asymptomatic, in hospitals,
clinics, and test laboratories.1

These point-of-care tests are used to diagnose patients without sending samples to
centralized facilities, thereby enabling communities without laboratory infrastructure
to detect infected patients. Despite the promise, there is no definitive evidence
regarding the utility of rapid kits for testing COVID 19 suspected patients
respiratory/serum samples.

Studies suggest that the majority of patients develop antibody response only in the
second week after onset of symptoms.6 This means that a diagnosis of COVID-19
infection based on antibody response will often only be possible in the recovery
phase, when many of the opportunities for clinical intervention or interruption of
disease transmission have already passed.

Moreover, antibody detection tests targeting COVID-19 may also cross-react with
other pathogens, including other human coronaviruses and give false-positive
results.8

Lastly, there has been discussion about whether rapid diagnostic tests could predict
whether an individual was immune to reinfection with the COVID-19 virus. There is
no evidence to date to support this.

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 COVID-19 Expanded Testing in the Philippines

With the increasing COVID-19 cases in the

Philippines, there is also a concomitant
increase in the demand for RT-PCR testing
all over the country. In order to maximize
the limited testing capacity, the Department
of Health (DOH) issued guidelines on risk-
based testing for COVID-19, which includes
the following groups: 1) suspect cases or 2)
individuals with relevant history of travel and
exposure (or contact), whether
asymptomatic or symptomatic, and 3)
healthcare workers with possible exposure,
whether asymptomatic or symptomatic.

The guidelines emphasized that based on

current available evidence, RT-PCR testing
is the confirmatory test, which are FDA- Figure 2.4 (above) Use of rapid antibody tests as
adjunct test for testing COVID-19 among
approved and validated by the Research SYMPTOMATIC patients and healthcare workers
with relevant history or travel exposure
Institute of Tropical Medicine (RITM). The
guidelines also made mention of the use of
rapid antibody tests and reiterated that
such shall not be used as standalone tests
to definitely diagnose or rule out COVID-19.

The DOH guidelines further mentions that

rapid antibody-based testing may be used
for ASYMPTOMATIC non-healthcare
workers who are close contacts of
confirmed COVID-19 cases, provided that
rapid antibody-based test kits are validated.
The table to the left is a helpful summary of
recommended actions depending on the
result of the rapid antibody-based test.

Figure 2.5 (right) Use of rapid antibody tests among

ASYMPTOMATIC patients and healthcare workers with relevant
history and travel exposure

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 Table 2.4: Recommended Actions based on Rapid Antibody Test

REFERENCES:
1. https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.25727 Development and Clinical Application of A Rapid IgM/IgG
Combined Antibody Test for SARSCoV2 Infection Diagnosis
2. Bouadma L, Lescure FX, Lucet JC, Yazdanpanah Y and Timsit JF. Severe SARS-CoV-2 infections: practical
considerations and management strategy for intensivists. https://link.springer.com/content/pdf/10.1007/s00134-020-
05967-x.pdf.
3. Momen M. Wahidi MM, Lamb C, Murgu S, MD. American Association for Bronchology and Interventional Pulmonology
(AABIP) Statement on the Use of Bronchoscopy and Respiratory Specimen Collection in Patients with Suspected or
Confirmed COVID-19 Infection.
4. Buonsenso D, Piano A, Raffaelli F, Bonadia N. Point-of-Care Lung Ultrasound findings in novel coronavirus disease-19
pnemoniae: a case report and potential applications during COVID-19 outbreak. Eur Rev Med Pharmacol Sci.
2020;24:2776–80.
5. FDA Advisory No. 2020-483
6. Liu Y, Liu Y, Diao B, Ren Feifei, et al. Diagnostic indexes of a rapid IgG/IgM combined antibody test for SARS-CoV-2.
7. Pan, Y.; Zhang, D.; Yang, P.; Poon, L. L. M.; Wang, Q. Viral Load of SARS-CoV-2 in Clinical Samples. Lancet Infect. Dis.
2020, 20, 411.
8. Che X, Qiu L, Liao Z, Wang Y, et al. Antigenic cross-reactivity between severe acute respiratory syndrome-associated
coronavirus and human coronaviruses 229E and OC43. The Journal of Infectious Diseases, Volume 191, Issue 12, 15
June 2005, Pages 2033–2037.
9. DOH Department Memorandum 2020-0180, Subject: Revised Interim Guidelines on Expanded Testing for COVID-19
(April 16, 2020).

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 HOW SHOULD WE INTERPRET SARS-CoV-2 IgM/IgG SEROLOGIC TEST
RESULTS?

STATEMENT:
The interpretation of serologic tests (IgM/IgG) for SARS-CoV-2 is dependent on
the phase of illness of the patient. It should not be used as a stand-alone test
and is best correlated with RT-PCR results. Only medical doctors should
interpret these serologic tests.

SUPPORTING STATEMENTS:

Table 2.5 Rapid Test Sensitivity

Antibodies are produced over days to
weeks after infection with the virus. The
strength of antibody response depends
on several factors, including age,
nutritional status, severity of disease, and
certain medications or infections like HIV
that suppress the immune system.1-3

Compared to PCR, serological testing is

advantageous with faster turn-around
time, high output and less workload.

However, the clinical value of antibodies largely depends on the understanding of

host antibody responses during infection. Given that SARS-CoV-2 is a newly
emerging virus, the antibody response in COVID-19 patients remains largely
unknown.

The present IgM/IgG serological assay is designed to complement RT-PCR in the

diagnosis of SARS-CoV-2 infections.

The table below shows the clinical interpretation of all possible scenarios that can be
encountered when testing a patient with both RT-PCR and an IgM/IgG serological
test.

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 Table 2.6 Clinical Significance of an IgM/IgG Serological Test Result 5,7

The table above is based on the

current knowledge about the rise and
fall of SARS-CoV-2 RNA and antigens,
IgM antibody and IgG antibody (Figure
2) and the correlation of these level
variations with the initial time of
infection, onset of symptoms and
recovery phase. As shown in Figure 2,
serological tests are recommended to
be used on patients at least 3 days
after onset of symptoms or 7-10 days Figure 2.6 Variation of the Levels of SARS-CoV-2 RNA and
after infection with the virus.5,7 Antigen, IgM and IgG after infection (SOURCE: Lauer, et al)

The key takeaway is that the results of RT-PCR and IgM/IgG serological tests do not
necessarily need to agree. A disagreement between the two tests, if any, can often
be traced to the after-infection time points at which the tests were performed. Overall,
while RT-PCR testing may be appropriate for the detection of the SARS-CoV-2 virus
during the acute phase, IgM/IgG is an appropriate test during the chronic phase.
Since the exact time of infection is often unknown, combining RT-PCR and IgM/IgG
testing can improve the accuracy of the COVID-19 diagnosis.

The Philippine FDA, in support of all efforts to address this pandemic, has recently
approved Rapid Test Kits for COVID-19. Provided, however, that:
1. Only Food and Drug Administration (FDA) approved kits should be used.
2. A COVID-19 antibody test CANNOT be used as a standalone test to definitively
diagnose COVID-19 and CANNOT be used for mass testing.
3. The COVID-19 RDT can only be used in people who had onset of symptoms for
at least 5 days (i.e. for IgM) and 21 days (i.e. for IgG). Most kits include both IgM
and IgG, so they can be used by day 5.

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 4. Anyone who tests positive for IgM should be tested with a RT-PCR to confirm the
positive test.
5. A negative IgM test DOES NOT rule out COVID-19 and the symptomatic patient
should REMAIN ISOLATED and swabbed using RT-PCR for confirmation.
6. IgG-only positive individuals without RT-PCR should be labeled as presumptive
past COVID-19 and not be officially counted as confirmed unless there is a further
validation test in the future, or if validated with a PRNT (Plaque reduction
neutralization test) or viral culture by a third party.
• If a patient is symptomatic, a RT-PCR should be done, and the patient should
be quarantined.
• If a patient is asymptomatic, there is no need to test using an RT-PCR.
7. The IgG antibody can be used as an adjunct test to clear quarantined patients
who remain asymptomatic at 14 days post discharge. The presence of antibodies
typically indicates viral clearance. If IgG is positive, the patient can be released
from self-quarantine. If IgG is negative, a repeat RT-PCR should be performed
8. ONLY medical doctors can prescribe and interpret the use of the antibody-based
test kits. These kits will not be available over the counter.

REFERENCES:
1. Zhao J, Yuan Q, Wang H, Liu W, Liao X, Su Y, et al. Antibody responses to SARS-CoV-2 in patients of novel coronavirus
disease 2019.
2. Okba N.M.A, Muller M.A., Li W, Wang C, et al. SARS-COV-2 specific antibody responses in COVID-19 patients.
3. Gorse GJ, Donovan MM, Patel GB. Antibodies to coronaviruses are higher in older compared with younger adults and
binding antibodies are more sensitive than neutralizing antibodies identifying coronavirus-associated illnesses. Journal of
medical virology.
4. FDA Advisory No. 2020-483
5. Lauer, S. et al., 2020. The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed
Cases: Estimation and Application. Annals of Internal Medicine.
6. National Health Commission of the People’s Republic of China, New Coronavirus Pneumonia Diagnosis and Treatment
Program (Trial Version 7).
7. To KK, Tsang OT, Leung WS, Tam AR, Wu TC, Lung DC et al. (2020). Temporal profiles of viral load in posterior
oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort
study. Lancet Infect Dis. 2020 Mar 23. pii: S1473-3099(20)30196-1.

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 WHAT IS THE ROLE OF RADIOLOGIC IMAGING IN COVID-19?

STATEMENT:
The use to radiologic imaging (CXR, chest CT and lung ultrasound) is not
recommended as a screening tool in asymptomatic to mild cases. Radiologic
imaging in COVID-19 is indicated in moderate to severe cases of the disease
and in cases with deterioration of respiratory function.

SUPPORTING STATEMENTS:
The findings on chest imaging are not specific of the infection, and could overlap with
other entities, such as influenza. There are also recommendations about the
performance of the chest radiography, including the fact that it is better to avoid the
movement of the patient within the hospital.

The value of an imaging test relates to the generation of results that are clinically
actionable either for establishing a diagnosis or for guiding management, triage, or
therapy. That value is diminished by costs that include the risk of radiation exposure
to the patient, risk of COVID-19 transmission to uninfected healthcare workers and
other patients, consumption of PPE, and need for cleaning and downtime of radiology
rooms in resource-constrained environments.

Chest x-ray (CXR) is insensitive in mild or early COVID-19 infection.5 However, with
respect to the relative value of CXR or computed tomography (CT) for detecting the
presence of viral pneumonia, the experience is vastly different dependent upon
community norms and public health directives. When patients are encouraged to
present early in the course of their disease, as was the case in Wuhan, China, CXR
has little value. The greater sensitivity of CT for early pneumonic changes is more
relevant in the setting of a public health approach that required isolation of all infected
patients within an environment where the reliability of COVID-19 testing was limited
and turnaround times were long.12 Alternatively, in New York City where patients were
instructed to stay at home until they experienced advanced symptoms, CXR was
often abnormal at the time of presentation. While ultrasound has been suggested as
a potential triage and diagnostic tool for COVID-19 given the predilection for the
disease in subpleural regions, there is limited experience at this time,1 as well as
infection control issues.

Thoracic imaging using CXR and CT are key tools for pulmonary disease diagnosis
and management, but their role in the management of COVID-19 has not been
considered within the multivariable context of the severity of respiratory disease, pre-
test probability, risk factors for disease progression, and critical resource constraints.
To address this deficit, a multidisciplinary panel comprised principally of radiologists
and pulmonologists from 10 countries with experience managing COVID-19 patients

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 across a spectrum of healthcare environments evaluated the utility of imaging within
three scenarios representing varying risk factors, community conditions, and resource
constraints.2

The Fleischner Statement 2

Written from multidisciplinary and multinational perspectives, the Fleischner

Statement is intended to provide context for the use of imaging to direct patient
management during the COVID-19 pandemic in different practice settings, different
phases of epidemic outbreak, and environments of varying critical resource
availability. The consensus statement is structured around three clinical scenarios
and three additional situations in which chest imaging is often considered in the
evaluation of patients with potential COVID-19 infection.

The scenarios apply only to patients presenting with features consistent with COVID-
19 infection. The scenarios distinguish mild respiratory disease from moderate-to-
severe respiratory disease based on the absence vs. presence of significant
pulmonary dysfunction or damage. Pre-test probability is defined by the background
prevalence of infection and can be estimated by observed transmission patterns: low
by sporadic transmission; moderate by clustered transmission; and high by
community transmission.

Scenario 1: Mild Features of COVID-19

The first scenario addresses a patient presenting for evaluation at an outpatient clinic
or via telehealth with mild respiratory features consistent with COVID-19 infection,
any pre-test probability of COVID-19 infection, and no significant critical resource
constraints.

Figure 2.7 Clinical Scenario 1

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 When COVID-19 test results are unavailable, patients with moderate-to-high pre-test
probability should be initially managed as if COVID-19 testing is positive, while
patients with low pre-test probability should be initially managed as if COVID-19
testing is negative. Imaging is advised for patients with risk factors for COVID-19
progression and either positive COVID-19 testing or moderate-to-high pre-test
probability in the absence of COVID-19 testing. Imaging provides a baseline for future
comparison, may establish manifestations of important comorbidities in patients with
risk factors for disease progression, and may influence the intensity of monitoring for
clinical worsening. Imaging is not advised for patients with mild features who are
COVID-19 positive without accompanying risk factors for disease progression, or for
patients with mild features who are COVID-19 negative. The panel felt that the yield
of imaging in these settings would be very low and that it was safe for most patients
to self-monitor for clinical worsening. Regardless of COVID-19 test results and risk
factors, imaging is advised for patients with mild clinical features who subsequently
develop clinical worsening. In the absence of clinical worsening, management
involves support and isolation of patients with positive COVID-19 testing or patients
with moderate to high pre-test probability without COVID-19 test results available.
Although not specifically addressed by this scenario, in the presence of significant
resources constraints, there is no role for imaging of patients with mild features
of COVID-19.

Scenario 2: Moderate to Severe Features of COVID-19

The second scenario addresses a patient presenting with moderate-to-severe
features consistent with COVID-19 infection, any pre-test probability of COVID-19
infection, and no significant critical resource constraints.

Figure 2.8 Clinical Scenario 2

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 Imaging is advised regardless of the results or availability of COVID-19 testing given
the impact of imaging in both circumstances.

For COVID-19 positive patients, imaging establishes baseline pulmonary status and
identifies underlying cardiopulmonary abnormalities that may facilitate risk
stratification for clinical worsening. In the presence of clinical worsening, imaging is
again advised to assess for COVID- 19 progression or secondary cardiopulmonary
abnormalities such as pulmonary embolism, superimposed bacterial pneumonia, or
heart failure that can potentially be secondary to COVID-19 myocardial injury.

For COVID-19 negative patients or any patient for whom testing is not performed,
imaging may reveal an alternative diagnosis to explain the patient’s clinical features,
which should direct patent care as per existing clinical guidelines or standard clinical
practice. If an alternative diagnosis is not revealed or images demonstrate features
of COVID-19 infection, then subsequent clinical evaluation would depend upon the
pre-test probability of COVID-19 infection and COVID-19 test availability. False-
negative COVID-19 testing is more prevalent in high pre-test probability
circumstances and repeat COVID-19 testing is therefore advised if available.
Depending upon the imaging findings, other clinical investigations may be pursued.

Scenario 3: Moderate-to-Severe Features of COVID-19 in a Resource Constrained Environment

The third scenario addresses a patient presenting with moderate-to-severe features
consistent with COVID-19 infection within an environment of high community disease
burden and critical resource limitations (as seen in Wuhan, China, in regions of Italy
and Spain, and in New York City, but not in the Philippines, as of yet). Because
healthcare personnel and infrastructure may be overwhelmed by a high influx of new
patients and resources are limited to provide critical care, urgent decision-making and
triage are of primary importance.

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 Figure 2.9 Clinical Scenario 3

At the time of this writing, turnaround time for COVID-19 test results range from 3
days (72 hours) to over 7 days. This is an impractically long time period to consider
triage to limited hospital beds and ventilators. However, rapid point-of-care (PoC)
COVID-19 tests are expected to be released into clinical environments during the first
week of April 2020, providing routine turnaround times of less than an hour and
potentially as little as 5 minutes. While the initial availability and sample processing
capacity of PoC COVID-19 testing is expected to be limited, this should increase over
time.

The third scenario first considers the potential availability of PoC COVID-19 testing.
Imaging is advised when PoC COVID-19 testing is available and positive for the same
reasons as described for Scenario 2. Based upon imaging findings and clinical
features, patients are subsequently supported and monitored with a level of intensity
consistent with clinical features. Imaging is again indicated if patients subsequently
clinically worsen.

Imaging is advised to support more rapid triage of patients in a resource-constrained

setting when point-of-care COVID-19 testing is not available or negative. Imaging
may reveal features of COVID-19, which within this scenario may be taken as a
presumptive diagnosis of COVID-19 for medical triage and associated decisions
regarding disposition, infection control, and clinical management. In this high pre-test
probability environment, and as described for Scenario 2, the possibility of falsely
negative COVID-19 testing creates a circumstance where a COVID-19 diagnosis may
be presumed when imaging findings are strongly suggestive of COVID-19 despite
negative COVID-19 testing.

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 This guidance represents a variance from other published recommendations which
advise against the use of imaging for the initial diagnosis of COVID-19 and was
supported by direct experience amongst panelists providing care within the conditions
described for this scenario. The relationship between disease severity and triage may
need to be fluid depending upon resources and case load. When imaging reveals an
alternative diagnosis to COVID-19, management is based upon established
guidelines or standard clinical practice.4

Summary of Recommendations for Imaging:

• Imaging is not routinely recommended as a screening test for COVID-19 in
asymptomatic individuals.
• Imaging is not indicated for patients with mild features of COVID-19 unless they
are at risk for disease progression (Scenario 1)
• Imaging is indicated for patients with moderate to severe features of COVID-19
regardless of COVID-19 test results (Scenarios 2 and 3)
• Imaging is indicated for patients with COVID-19 and evidence of worsening
respiratory status (Scenarios 1, 2, and 3)
• In a resource constrained environment where access to CT is limited, CXR may
be preferred for patients with COVID-19 unless features of respiratory worsening
warrant the use of CT (Scenarios 2 and 3)

Chest Radiography (CXR)

The findings on CXR are not specific, and in the initial phases of the disease the
studies could be normal. The most common features include lobar, multi-lobar, or
bilateral lung consolidation.3

Chest Computed Tomography (CT)

CT can play a vital role in the early detection and management of COVID-19.3,9
However, it is worth emphasizing that a patient with RT-PCR confirmed COVID-19
infection may have normal chest CT at admission. Bernheim et al. reported 20 (56%)
of 36 patients imaged 0–2 days after symptom onset had normal CT. Fang et al.
reported one of 51 (2%) patient imaged 3 days 6 3 after symptom onset with normal
CT. Ai et al. reported 21 of 601 (3%) RTPCR- positive patients with clinical symptoms
had normal CT scans.

In contrast, Pan et al. reported four of 21 (19%) patients with first normal CT had lung
abnormalities on the follow-up CT approximately 4 days later. Furthermore, Yang et
al. reported that among 17 of 149 (11.4%) symptomatic patients with normal chest
CT on admission, 12 remained negative 10 days later with two to three follow-up CT
examinations and the chest CT of the other five patients became positive over an
average of 7 days. These reports confirm that a normal chest CT scan cannot

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 exclude the diagnosis of COVID-19, especially for patients with early onset of
symptoms.

Recent studies have reported the features on CT imaging. Pan et al. described the
tomographic changes of 21 patients with mild to moderate disease who recovered
from the disease, and they described four stages:

• Early stage (0-4 days after the onset of the symptoms), in which ground glass
opacities (GGO) are frequent, with sub-pleural distribution and involving
predominantly the lower lobes. Some patients in this stage could have a normal
CT.
• Progressive stage (5-8 days after the onset of the symptoms), the findings usually
evolved to rapidly involvement of the two lungs or multi-lobe distribution with
GGO, crazy-paving and consolidation of airspaces.
• Peak stage (9-13 days after the onset of the symptoms), the consolidation
becomes denser and it was present in almost all of the cases. Other finding was
residual parenchymal bands.
• Absorption stage (>14 days after the onset of the symptoms), no crazy paving
pattern was observed, the GGO could remain.

Shi et al. also described the CT findings in 81 patients in Wuhan, China. All of the
patients had an abnormal CT, and the features include: GGO, smooth and irregular
interlobular septal thickening, crazy paving pattern, air bronchogram and irregular
pleural thickening. Usually affecting the subpleural regions and the lower lobes.

Lung ultrasound

The lung ultrasound findings are also not specific for COVID-19 infection. Little
information is available to date on this matter. The findings include irregular pleural
lines, sub-pleural areas of consolidation, areas of white lung and thick B lines.14 It is
a tool that could be used at bed side avoiding the need for shifting infected patients
to a Radiology suite.8
REFERENCES:
1. Soldati G, Smargiassi A, Inchingolo R, Buonsenso D, Perrone T, Briganti DF, Perlini S, Torri E, Mariani A, Mossolani EE,
Tursi F, Mento F, Demi L. Is there a role for lung ultrasound during the COVID-19 pandemic? J Ultrasound Med 2020.
2. Rubin GD, Rverson CJ, Haramat LB, Sverzellati N, Kanne JP, Raoof S, Schluger NW, Volpi A, Yim JJ, Martin IBK,
Anderson DJ, Kong C, Altes T, Bush A, Desai SR, Goldin J, Jin MoGoo Jin Mo, Humbert M, Leung AN. The Role of Chest
Imaging in Patient Management during the COVID-19 Pandemic: A Multinational Consensus Statement from the Fleischner
Society. Chest, 7 April 2020.
3. Kanne JP, Little BP, Chung JH, Elicker BM, Ketai LH. Essentials for Radiologists on COVID-19: An Update-Radiology
Scientific Expert Panel. Radiology [Internet]. 2020;200527.
4. American College of Radiology: ACR Recommendations for the use of Chest Radiography and Computed Tomography
(CT) for Suspected COVID-19 Infection.
5. Wong HYF, Lam HYS, Fong AH, Leung ST, Chin TW, Lo CSY, Lui MM, Lee JCY, Chiu KW, Chung T, Lee EYP, Wan EYF,
Hung FNI, Lam TPW, Kuo M, Ng MY. Frequency and Distribution of Chest Radiographic Findings in COVID-19 Positive
Patients. Radiology 2020:201160. doi: 10.1148/radiol.2020201160
6. Pan, Fen; Ye, Tianhe; Sun, Peng; Gui, Shan; Liang, Bo; Li, Lingli; Zheng, Dandan; Wang, Jiazheng; Hesketh, Richard;
Yang, Lian; Zheng C. Time Course of Lung Changes On Chest CT During Recovery From 2019 Novel Coronavirus
(COVID-19) Pneumonia. Radiology. 2020;77(8):1–15.

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 7. Shi H, Han X, Jiang N, Cao Y, Alwalid O, Gu J, et al. Radiological findings from 81 patients with COVID-19 pneumonia in
Wuhan, China: a descriptive study. Lancet Infect Dis. 2020;3099(20):1–10.
8. Peng QY, Wang XT, Zhang LN, Critical C, Ultrasound C, Group S. Findings of lung ultrasonography of novel corona virus
pneumonia during the 2019 – 2020 epidemic. Intensive Care Med. 2020;(87):6–7.
9. Zu ZY, Jiang MD, Xu PP, et al. Coronavirus Disease 2019 (COVID-19): A Perspective from China. Radiology 2020 Feb
21:200490.
10. Bernheim A, Mei X, Huang M, et al. Chest CT Findings in Coronavirus Disease-19 (COVID-19): Relationship to Duration
of Infection. Radiology 2020 Feb 20:200463.
11. Fang Y, Zhang H, Xie J, et al. Sensitivity of Chest CT for COVID-19: Comparison to RT-PCR. Radiology 2020 Feb
19:200432.
12. Ai T, Yang Z, Hou H, et al. Correlation of Chest CT and RT-PCR Testing in Coronavirus Disease 2019 (COVID-19) in
China: A Report of 1014 Cases. Radiology 2020 Feb 26:200642.
13. Yang W, Cao Q, Qin L, et al. Clinical characteristics and imaging manifestations of the 2019 novel coronavirus disease
(COVID-19): A multi-center study in Wenzhou city, Zhejiang, China. J Infect 2020 Feb 26.
14. Buonsenso D, Piano A, Raffaelli F, Bonadia N. Point-of-Care Lung Ultrasound findings in novel coronavirus disease-19
pnemoniae: a case report and potential applications during COVID-19 outbreak. Eur Rev Med Pharmacol Sci.
2020;24:2776–80.

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 MANAGEMENT OF PREGNANT PATIENTS
WITH COVID-19

Catherine Jane R. Costa, MD, MHA

Louella P. Aquino, MD / Martha Monette M. Aquino, MD / May G. Asis, MD
Maria Angela R. Bandola, MD / Sigrid A. Barinaga, MD
Erwin R. De Mesa, MD / Analyn F. Fallarme, MD, MPH / Patricia M. Kho, MD
Henrietta S. Lucasan, MD / Judith R. Peralta, MD
Maria Lorena L. Santos, MD / Guadalupe N. Villanueva, MD

ARE PREGNANT PATIENTS AT HIGHER RISK OF GETTING COVID-19?

STATEMENT:
Pregnant women do not appear to have an increased risk for COVID-19
infection.
SUPPORTING STATEMENTS:
COVID-19, the disease caused by a new coronavirus, SARS-CoV-2 is now a
pandemic according to the World Health Organization.1 There are limited data about
the clinical characteristics of pregnant women with the disease.2 Currently available
data do not indicate that pregnant individuals are at an increased risk of infection or
severe morbidity compared with non-pregnant individuals in the general population.3

Data extracted from the National Health Commission of China from Dec 8, 2019 to
March 20, 2020 identified 118 pregnant women in Wuhan who met the criteria for
COVID-19 set by the Chinese Clinical Guidance for COVID-19 Pneumonia
Diagnosis and Treatment. Eighty-four women (71%) had positive polymerase-chain-
reaction (PCR) testing for SARS-CoV-2, and the remaining 34 (29%) had suggestive
findings on computed tomography (CT) of the chest. Out of 118 women, 109 (92%)
had mild disease, and 9 (8%) had severe disease (hypoxemia). Severe disease
developed in 6 of the 9 women after delivery. By the end of the study, a total of 109
of 116 women (94%) had been discharged, including all women with severe or
critical disease. There were no reported deaths. The above data showed that the
risk of severe disease in the pregnant population (8%) compared favorably with the
risk reported in the general population of patients presenting with COVID-19 across
mainland China (15.7%).4

A large study of 16,749 individuals hospitalized in the UK with COVID-19, showed

that the proportion of pregnant women hospitalized (6%) was similar to the

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 proportion in the general population, and pregnancy was not associated with
increased mortality, unlike in influenza.5

However, pregnant patients with comorbidities may be at increased risk for severe
illness consistent with the general population with similar comorbidities. In a
retrospective study by Ruan, predictors of a fatal outcome in COVID-19 cases
included age, the presence of underlying diseases, the presence of secondary
infection and elevated inflammatory indicators in the blood.6 The relationship of
cardiovascular disease and drug therapy with in-hospital death among hospitalized
patients with COVID-19 who were admitted between December 20, 2019, and
March 15, 2020 was evaluated using an observational database from 169 hospitals
in Asia, Europe, and North America. Non -survivors were older, more likely to be
white, and more often men. Non-survivors also had a greater prevalence of diabetes
mellitus, hyperlipidemia, coronary artery disease, heart failure, and cardiac
arrhythmias.7

Emerging evidence suggests that individuals admitted to hospitals with COVID-19

are hypercoagulable. Considering that pregnancy is also known to be a
hypercoagulable state8 it follows that infection with COVID-19 is likely to be
associated with an increased risk of maternal venous-thromboembolism.9
REFERENCES:
1. World Health Organization. Coronavirus (COVID-19). 2020 (https://who.sprinklr.com.
2. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; 382:1708-
1720 DOI: 10.1056/NEJMoa2002032.
3. Yu N, Li W, Kang Q, et al. Clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19 in
Wuhan, China: a retrospective, single-centre, descriptive study. Lancet Infect Dis 2020 March 24 (Epub ahead of print).
4. Lian Chen, Qin Li et al. Clinical Characteristics of Pregnant Women with Covid-19 in Wuhan, China (Correspondence)
NEJM April 17, 2020 1-3.
5. Docherty AB, Harrison EM, Green CA, et al. Features of 16,749 hospitalised UK patients with COVID-19 using the
ISARIC WHO Clinical Characterisation Protocol. medRxiv 2020:2020.04.23.20076042.
doi:10.1101/2020.04.23.20076042
6. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of
data of 150 patients from Wuhan, China. Intensive Care Med 2020 March 3 (Epub ahead of print).
7. Mehra MR, Desai SS et al. Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19.2020 May 1
8. Royal College of Obstetricians & Gynaecologists. Reducing the Risk of Venous Thromboembolism during Pregnancy
and the Puerperium for 2015 [updated April, 2015.
Available from: https://www.rcog.org.uk/globalassets/documents/guidelines/gtg-37a.pdf].
9. Thrombosis UK. Practical guidance for the prevention of thrombosis and management of coagulopathy and disseminated
intravascular coagulation of patients infected with COVID-19. 2020 [Available from: https:// thrombosisuk.org/covid-19-
thrombosis.php] accessed 07 April 2020.

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 WHAT ARE THE KNOWN OBSTETRIC COMPLICATIONS OF COVID-19
INFECTION?
STATEMENT:
Preterm delivery, preterm prelabor rupture of membranes (PPROM) and
intrauterine fetal distress are potential complications of maternal COVID-19
infection, possibly caused by maternal hypoxemia. Further research is
needed to confirm a causal relation. Cesarean section rates are vastly higher
than in the general population, possibly indicating iatrogenic reasons.
SUPPORTING STATEMENTS:

Limited data is available on pregnancy outcomes in COVID-19 infection cases.

During the SARS epidemics an increased risk of miscarriage was reported during
the first trimester in seven proven infected cases (4/7 miscarriages). When
evaluating the data in detail, three of the four were as early as three to four weeks
of gestation.1, 2

Table 3-1. Summary of second and third trimester pregnancy outcomes in confirmed
COVID-19 positive patients

So far, for COVID-19, no first trimester cases have been published but further
research is needed. Second and third trimester outcomes were summarized in the
literature review3 (Table 3-1) of 31 singleton pregnancies at 25–39 weeks age of
gestation.4-7 One third of COVID-19 positive patients (10/31) presented with
PPROM and preterm labor and in 35.4% (11/32) fetal distress was reported.

It is unclear how much of this is directly related to COVID-19 infection. Therefore, in

proven cases of a new infection, alertness should be increased since maternal
hypoxemia can cause such complications. On the other hand, fever could also
explain the increased risk of PPROM and preterm labor. One case of intrauterine

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 fetal death is reported, in a case where the mother developed multi-organ failure
requiring intensive care hospitalization and extracorporeal membrane oxygenation
(ECMO). When reviewing the data, we noted a preterm birth rate of 53.6% (15/28).
In COVID-19 positive patients, a cesarean section rate of 96.4% was seen, possibly
indicating that iatrogenic reasons (obstetrician’s fear) can also be a factor
contributing to prematurity.

Intrauterine fetal growth restriction (IUGR) has so far not been reported in
association with COVID-19 infection. Although IUGR is a known consequence of
chronic maternal hypoxia, the effects of shorter and transient hypoxia in COVID-19
are unknown.8 During the SARS-epidemic, small for gestational age neonates were
reported in two women contracting the infection at 28 and 30 weeks of gestation
and delivering at 33 and 37 weeks respectively.1 In reported COVID-19 patients,
delivery generally occurred within one week of diagnosis, making it impossible to
assess the long-term effect of transient maternal hypoxemia on fetal growth.4-7
REFERENCES:
1. Wong, S.F.; Chow, K.M.; de Swiet, M. Severe acute respiratory syndrome and pregnancy. BJOG 2003, 110, 641–642.
2. Stockman, L.J.; Lowther, S.A.; Coy, K.; Saw, J.; Parashar, U.D. Sars during pregnancy, united states. Emerg. Infect. Dis.
2004, 10, 1689–1690.
3. Donders F, Lonnée-Hoffmann R, Tsiakalos A, Mendling W, Martinez de Oliveira J, Judlin P, Xue F, Donders GGG,
ISIDOG Covid-Guideline Workgroup. ISIDOG Recommendations Concerning COVID-19 and Pregnancy, Diagnostics
(Basel). 2020;10(4) Epub 2020 Apr 22.
4. Chen, H.; Guo, J.; Wang, C.; Luo, F.; Yu, X.; Zhang, W.; Li, J.; Zhao, D.; Xu, D.; Gong, Q.; et al. Clinical characteristics
and intrauterine vertical transmission potential of covid-19 infection in nine pregnant women: A retrospective review of
medical records. Lancet 2020, 395, 809–815.
5. Liu, Y.; Chen, H.; Tang, K.; Guo, Y. Clinical manifestations and outcome of sars-cov-2 infection during pregnancy. J.
Infect. 2020.
6. Wang, X.; Zhou, Z.; Zhang, J.; Zhu, F.; Tang, Y.; Shen, X. A case of 2019 novel coronavirus in a pregnant woman with
preterm delivery. Clin. Infect. Dis. 2020.
7. Zhu, H.; Wang, L.; Fang, C.; Peng, S.; Zhang, L.; Chang, G.; Xia, S.; Zhou, W. Clinical analysis of 10 neonates born to
mothers with 2019-ncov pneumonia. Transl. Pediatr. 2020, 9, 51–60.
8. Moore, L.G.; Charles, S.M.; Julian, C.G. Humans at high altitude: Hypoxia and fetal growth. Respir Physiol. Neurobiol.
2011, 178, 181–190.

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 CAN COVID-19 INFECT THE FETUS IN-UTERO?
STATEMENT:
It is still unclear whether there is vertical transmission from mother to fetus,
but limited cases have shown no evidence of vertical transmission in patients
with COVID-19 infection during the last trimester of pregnancy.
SUPPORTING STATEMENTS:

A vital question regarding COVID-19 in pregnancy is whether it could be transmitted

vertically from the mother to the neonate. A recent review by Schwartz assessed
38 pregnant women and their newborns in China, and no evidence of vertical
transmission was identified.1 Included in the said review was the study by Chen et
al, which enrolled nine pregnant women with COVID-19 in the late stage of
pregnancy.2 The researchers tested SARS-CoV-2 in amniotic fluid, cord blood,
neonatal throat swab, and breastmilk samples, and all results were negative.
However, the study failed to answer whether it was possible to get the infection
during vaginal delivery, because all the neonates were born by cesarean section.

Another study included five neonates who were born vaginally, and none of them
had evidence of COVID-19, which added clinical support for the safety of vaginal
delivery.3 However, another study investigated 19 neonates born to mothers with
COVID-19 in Wuhan, of which three were reported as SARS-CoV-2 positive.4
Because strict infection control and prevention procedures were implemented
during the delivery, and all infants with COVID-19 were confirmed early on the
second day of life, the authors concluded that potential vertical transmission still
cannot be ruled out. Moreover, it is important to note that evidence for no vertical
transmission to date is all based on the late stages of pregnancy; whether
intrauterine vertical transmission could happen during the first or second trimester
is still unclear.

Recently, vertical transmission of COVID-19: SARS-CoV-2 RNA on the fetal side of

the placenta in pregnancies with COVID-19 positive mothers and neonates at birth
was documented amongst a cohort of 22 pregnant women with COVID-19 infection
who delivered at Papa Giovanni XXIII Hospital in Bergam, Italy between March 5 –
April 21, 2020.5 Paraffin-embedded formalin-fixed (FFPE) placentas were stained
with H&E and anti-CD68 antibody to identify macrophages. SARS-CoV-2 was
identified in FFPE samples using RNA in-situ hybridization. Two of 22 neonates
tested positive by nasopharyngeal PCR swab. In the first one, the swab was positive
immediately at birth and again at one and seven days. In the second neonate, it was
negative at birth and turned positive on day 7 despite no maternal contact. Neither
infant had any symptoms. Both infants had SARS-CoV-2 detected in the placental
syncytiotrophoblast using in-situ hybridization. SARS-CoV-2 was not detected in
placentas from two control neonates without COVID-19. This is the first study
describing SARS-CoV-2 RNA on the fetal side of the placenta in two cases of

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 mothers infected with COVID-19 and with neonates also positive for the virus at
birth. These findings support the possibility of vertical transmission of SARS-CoV-2
from the mother to the baby in utero, though the authors recommended that further
studies are required to confirm their results.
REFERENCES:
1. Schwartz DA. An Analysis of 38 Pregnant Women with COVID-19, Their Newborn Infants, and Maternal-Fetal
Transmission of SARS-CoV-2: Maternal Coronavirus Infections and Pregnancy Outcomes. Arch Pathol Lab Med 2020;.
2. Chen H, Guo J, Wang C, Luo F, Yu X, Zhang W, et al. Clinical characteristics and intrauterine vertical transmission
potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records. Lancet (London,
England) 2020a;395(10226):809–15.
3. Xu Qianchenga, Shen Jianb, Pan Linglingc, Huang Leib, Jiang Xiaogana, Lu Weihuaa, Yang Gangd, Li Shirongd, Wang
Zhena, Xiong GuoPingb,, Zha Lei. Coronavirus disease 2019 in pregnancy. International Journal of Infectious Diseases
95 (2020) 376–383.
4. Zeng L, Xia S, Yuan W, Yan K, Xiao F, Shao J, et al. Neonatal Early-Onset Infection With SARS-CoV-2 in 33 Neonates
Born to Mothers With COVID-19 in Wuhan, China. JAMA pediatrics 2020
5. Patanè L, Morotti D, Giunta MR, Sigismondi C, Piccoli MG, Frigerio L, Mangili G, Arosio M, Cornolti G. Vertical
transmission of COVID-19: SARS-CoV-2 RNA on the fetal side of the placenta in pregnancies with COVID-19 positive
mothers and neonates at birth. AJOG, May 2020.

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 SHOULD CORTICOSTEROIDS BE GIVEN TO PREGNANT WOMEN IN
PRETERM LABOR WITH COVID-19 INFECTION?
STATEMENT:
Pregnant women at 24 to 33 6/7 weeks age of gestation, with suspected or
confirmed COVID-19 who are at risk of preterm labor within 7 days may benefit
from antenatal corticosteroids.
SUPPORTING STATEMENTS:
The American College of Obstetricians and Gynecologists (ACOG) recommends
offering antenatal corticosteroids to suspected or confirmed COVID-19 pregnant
women between 24 weeks and 33 6/7 weeks gestation who are at risk of preterm
birth within 7 days, as per guidelines for non-COVID patients. For pregnancies
between 34 and 36 6/7 weeks gestation at risk of preterm birth, antenatal
corticosteroids may not be offered since benefits for this group are less well-
established. However, this may be individualized based on clinical scenario.1
Likewise, the Royal College of Obstetricians and Gynecologists (RCOG), Society of
Obstetricians and Gynecologists of Canada (SOGC) and Queensland Health also
recommend that antenatal corticosteroids for fetal maturation be given as
indicated.2-4

The benefits of corticosteroids in promoting fetal lung maturity in preterm labor have
long been established in the field of obstetrics. Unfortunately, this practice is now
being challenged because corticosteroid use has been associated with increased
morbidity and mortality in COVID-19 positive patients. Studies by Guan and Shang
in China showed that outcomes were worse for COVID-19 patients who received
corticosteroids.5,6

The WHO did a systematic review of observational studies on corticosteroids

administered to patients with SARS-COV-2 which showed no survival benefit and
possible harms such as avascular necrosis, psychosis, diabetes, and delayed viral
clearance.7,8 Corticosteroid administration was found to potentially prolong viral
replication as observed by United States Centers for Disease Control and
Prevention (CDC) among coronavirus patients. 9,10 However, none of these patients
were pregnant and the glucocorticoid dosages used for obstetric indications were
different. McIntosh reported that the typical dose of betamethasone and
dexamethasone, in methylprednisolone equivalents, for obstetric use is 60mg.11
This dosage is similar to the studies used in China however, the duration of
treatment is longer (4–11 days) than the duration used for obstetric indications (1-2
days). 5,6 The typical corticosteroid use in pregnant women for fetal pulmonary
maturation is of lesser amount and shorter duration and hence, was found to have
minimal effects. Yu and colleagues reported five pregnant women who were treated
with steroids after caesarean section with good outcomes.12 The sample size is
small and more data on its effectiveness and safety are still needed. However, these

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 preliminary findings show that corticosteroids, if given in low doses and short
duration,11 may be beneficial and not as harmful as regimens with prolonged use or
large doses.
REFERENCES:
1. American College of Obstetricians and Gynecologists (ACOG) COVID-19 FAQs for Obstetrical care on ObG Project
COVID-19: Pregnancy Guidelines. and ACOG Guidelines on Uptodate at
https://www.uptodate.com/contents/coronavirus-disease-2019-covid-19-pregnancy-issues
2. RCOG Coronavirus (COVID-19) Infection in Pregnancy Information for healthcare professionals Version 8: Published
Friday 17 April 2020
3. SGOC 19 infection Guidance for Maternity Services. 2020.
4. Queensland Health Maternity care for mothers and babies during the COVID-19 pandemic. 2020.
5. Guan WJ, Ni ZY, Hu Y, et al; China Medical Treatment Expert GroupforCovid-
19.Clinicalcharacteristicsofcoronavirusdisease 2019 in China. N Engl J Med 2020
6. Shang J,LuQ, Wu, et al. The treatment and outcomes of patients with COVID-19 in Hubei, China: a multi-centered,
retrospective, observational study. Lancet 2020. Doi: 10.2139/ssrn.3546060
7. World Health Organization (WHO) Clinical management of severe acute respiratory infection when novel coronavirus
(nCoV) infection is suspected. Jan 28, 2020. https://www.who.int/publications-detail/clinical-management-ofsevereacute-
respiratory-infection-when-novel-coronavirus-(ncov)infection-issuspected (accessed March 6, 2020).
8. Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury.
Lancet 2020; 395: 473–75.
9. Centers for Disease Control and Prevention (CDC). Interim Considerations for Infection Prevention and Control of
Coronavirus Disease 2019 (COVID-19) in Inpatient Obstetric Healthcare Settings.
https://www.cdc.gov/coronavirus/2019-nCoV/hcp/infec tion-control.html. Accessed Feb 28, 2020.
10. Centers for Disease Control and Prevention (CDC) Considerations for Inpatient Obstetric Healthcare
Settingshttps://www.cdc.gov/coronavirus/2019-ncov/hcp/inpatient-obstetric-healthcare-guidance.html
11. McIntosh, J.J. Corticosteroid Guidance for Pregnancy during COVID-19 Pandemic, Am J Perinatol. 2020 Apr 9. doi:
10.1055/s-0040-1709684. [Epub ahead of print]
12. Yu N, Wei L, Kang Q, et al. Clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19
in Wuhan, China: a retrospective, single-centre, descriptive study. Lancet 2020;

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 WHEN IS THE BEST TIME TO DELIVER A PREGNANT PATIENT WITH COVID-
19 INFECTION?
STATEMENT:
COVID-19 infection alone is not an indication for pregnancy termination, and
decisions regarding delivery timing must be individualized. Ideally, if women
can be successfully treated, pregnancies should be allowed to continue until
term. Conversely, if a pregnant woman is critically ill, her clinical deterioration
may lead to intrauterine fetal demise or loss of both mother and infant. In such
circumstances, early delivery may be warranted. The indications for early
delivery depend upon: the mother's clinical status, gestational age, and fetal
well-being.
SUPPORTING STATEMENTS:
There is little data as to the best TIMING of DELIVERY amongst pregnant women
affected by COVID-19 infection making the decision for delivery in the setting of
severe COVID-19 infection more challenging. In the absence of strong data, it is
important to make decisions based on clinical judgment and with common sense,
hopefully, with the least adverse effects on the maternal and neonatal outcomes.

The increased oxygen consumption and reduced functional residual capacity of

pregnancy predispose to rapid deterioration of both maternal and fetal status when
combined with the pathologic changes associated with severe infection. The
decision for delivery should be based on the gestational age, maternal status, and
fetal status. Importantly, stabilizing the mother prior to emergent delivery for fetal
indications is imperative. Through stabilization of the mother, the fetus’ status will
likely improve.1

For most women with preterm COVID-19 and non-severe illness who have no
medical/obstetric indications for prompt delivery, delivery is not indicated and ideally
should occur sometime after a negative testing result is obtained or isolation status
is lifted, thereby minimizing the risk of postnatal transmission to the neonate.2

In women with severe illness, there are multiple issues to consider, and timing of
delivery needs to be individualized.2,3 Whether the mother's respiratory disease will
be improved by delivery, or the risk of postnatal transmission in the delivery room is
increased when maternal symptoms are acute are both unclear. It should also be
noted that maternal antibody production and in turn, passive newborn immunity may
not have had time to develop. On the other hand, increased oxygen consumption
and reduced functional residual capacity, which occur during pregnancy, may
facilitate maternal deterioration in patients with pneumonia.4 Excessive uterine
distention from multiple gestation or severe polyhydramnios in the third trimester
may further compromise pulmonary function.

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 Table 3-2. Indications for Delivery with Severe COVID-19 Infection
MATERNAL INDICATIONS FETAL INDICATIONS
§ Intrauterine infections § Fetal demise
§ Disseminated intravascular § Gestational age associated with
coagulation low neonatal morbidity or
§ Hepatic or renal failure mortality
§ Compromised cardiopulmonary
function due to uterine
overdistention or presence of
peritoneal fluid
§ Compartment syndrome
§ Severe ARDS
§ Cardiopulmonary arrest
Adapted from: General Guidelines in the Management of an Obstetrical Patient on the Labor
and Delivery Unit during COVID-19 Pandemic. (Stephens AJ, Barton JR, Bentum NA,
Blackwell Sc, Sibai BM, Am J Perinatol, Published online: 2020-04-28)

Clinical scenarios, for which delivery is likely indicated to maximize resuscitative

efforts in cases of severe COVID-19 complicated by sepsis and septic shock, are
presented in Table 3-2. Of note, uterine distention secondary to multifetal
gestations, macrosomia, and polyhydramnios among other conditions can result in
compromised cardiopulmonary function due to diaphragm displacement. In such
patients with compromised cardiopulmonary dysfunction that requires intubation,
delivery at 32 weeks should be considered and decision should be balanced with
the benefits of pregnancy continuation following consultation with neonatology.
Timing of Delivery for Preterm Prelabor Rupture of Membranes (32-34 weeks)

The potential benefits of additional in-utero time for preterm prelabor rupture of
membranes (PPROM) must be balanced in light of current COVID-19 pandemic
circumstances and known adverse outcomes in patients with PPROM such as
chorioamnionitis, placental abruption, cord prolapse, cord compression, or
uteroplacental insufficiency.5

Despite the recent randomized control trial of singletons between 34 0/7 and 36 6/7
weeks with PPROM by Morris et al demonstrating no increased risk of neonatal
sepsis or composite neonatal morbidity (sepsis, mechanical ventilation >24 hours,
stillbirth, or neonatal death), in the current setting, however, there are additional
risks associated with extended hospital stays to be considered for patients.
Additionally, this trial also demonstrated increased maternal morbidity, such as
hemorrhage and infection, associated with expectant management of PPROM after
34 weeks that would further increase exposure to different medical personnel,
movement between different hospital settings (i.e., labor, operating room, and
intensive care unit), and overall length of stay.6

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 The potential benefits of expectant management beyond 34 weeks may be
diminished by the development of associated adverse outcomes and continued
hospitalization during the COVID-19 pandemic.6-8

For the hospitalized patient with COVID-19 with pneumonia but not intubated, some
authorities9-11 have advocated consideration of delivery in pregnancies >32 to 34
weeks. The rationale is that delivery is performed before the pulmonary situation
worsens and ongoing maternal hypoxemia places the fetus at risk of compromise.
Most authorities do not advocate delivery prior to 32 weeks, even though the
maternal situation may worsen in the second week, given the known morbidity and
mortality of very preterm infants.12

Timing of delivery of the hospitalized pregnant woman who is intubated and critically
ill with COVID-19 is challenging. After 34 weeks, some have advocated delivery if
the patient is stable, but this could exacerbate the maternal condition. Between 32
to 34 weeks age of gestation, continuing maternal support with fetal monitoring is
usually suggested for perinatal benefit as long as the maternal situation remains
stable or improving. In some situations, maternal extracorporeal membrane
oxygenation (ECMO) may be necessary.13
REFERENCES:
1. Barton JR, Sibai BM. Severe sepsis and septic shock in pregnancy. Obstet Gynecol 2012;120(03):689–706.
2. Chen D, Yang H, Cao Y, Cheng W, Duan T, Fan C, Fan S, Feng L, Gao Y, He F, He J, Hu Y, Jiang Y, Li Y, Li J, Li X, Li
X, Lin K, Liu C, Liu J, Liu X, Pan X, Pang Q, Pu M, Qi H, Shi C, Sun Y, Sun J, Wang X, Wang Y, Wang Z, Wang Z, Wang
C, Wu S, Xin H, Yan J, Zhao Y, Zheng J, Zhou Y, Zou L, Zeng Y, Zhang Y, Guan X. Expert consensus for managing
pregnant women and neonates born to mothers with suspected or confirmed novel coronavirus (COVID-19) infection. Int
J Gynaecol Obstet. 2020;149(2):130. Epub 2020 Apr 1.
3. Donders F, Lonnée-Hoffmann R, Tsiakalos A, Mendling W, Martinez de Oliveira J, Judlin P, Xue F, Donders GGG,
ISIDOG Covid-Guideline Workgroup. ISIDOG Recommendations Concerning COVID-19 and Pregnancy, Diagnostics
(Basel). 2020;10(4) Epub 2020 Apr 22.
4. Stephens AJ, Barton JR, Bentum NA, Blackwell SC, Sibai BM. General Guidelines in the Management of an Obstetrical
Patient on the Labor and Delivery Unit during the COVID-19 Pandemic. Am J Perinatol, Published online: 2020-04-28.
5. Committee on Practice Bulletins-Obstetrics. ACOG practice bulletin no. 188: prelabor rupture of membranes. Obstet
Gynecol 2018;131(01): e1–e14.
6. Morris JM, Roberts CL, Bowen JR, et al; PPROMT Collaboration. Immediate delivery compared with expectant
management after preterm prelabor rupture of the membranes close to term (PPROMT trial): a randomised controlled
trial. Lancet 2016;387 (10017):444–452.
7. Mercer BM. Preterm premature rupture of the membranes. Obstet Gynecol 2003;101(01):178–193
8. Peaceman AM, Lai Y, Rouse DJ, et al; Eunice Kennedy Shriver National Institute of Child Health and Human
Development Maternal-Fetal Medicine Units Network. Length of latency with preterm premature rupture of membranes
before 32 weeks’ gestation. Am J Perinatol 2015;32(01):57–62
9. Rouse DJ, Hirtz DG, Thom E, et al; Eunice Kennedy Shriver NICHD Maternal-Fetal Medicine Units Network. A
randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med 2008;359(09):895–
905
10. Pasquier JC, Claris O, Rabilloud M, et al. Intentional early delivery versus expectant management for preterm premature
rupture of membranes at 28-32 weeks’ gestation: amulticentre randomized controlled trial (MICADO STUDY). Eur J
Obstet Gynecol Reprod Biol 2019;233:30–37
11. Cox SM, Leveno KJ. Intentional delivery versus expectant management with preterm ruptured membranes at 30-34
weeks’ gestation. Obstet Gynecol 1995;86(06):875–879
12. Berghella V. Coronavirus Disease 2019 Pregnancy Issues. UpToDate, May 14, 2020.
13. Webster CM, Smith KA, Manuck TA. Extracorporeal membrane oxygenation in pregnant and postpartum women: a ten-
year case series Am J Obstet Gynecol MFM. 2020.

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 SHOULD INDUCTION OF LABOR BE INSTITUTED FOR PREGNANT WOMEN
WITH COVID-19 INFECTION?
STATEMENT:
The decision to do induction of labor in patients with COVID-19 infection is
dependent on several factors which include patient’s clinical presentation,
presence of co-morbid illness/es, internal examination findings (Bishop’s
score) and hospital bed capacity. As exposure time between patients and
healthcare providers are increased with induction of labor, the risks and
benefits must be weighed and contemplated by the clinician when
considering this procedure.
SUPPORTING STATEMENTS:

COVID-19 is not an indication to alter the route of delivery and cesarean delivery is
still performed only for standard obstetric indication even in these patients.1
Induction of labor is an option which may be offered and considered in the
intrapartum care of asymptomatic COVID-19 positive women with medical or
obstetric indications.2 The indications for induction of labor are the same as those
for non-COVID pregnant women and includes induction at 39 weeks age of
gestation,4 post-term pregnancies, patients with co-morbidities (hypertensive
disorders or diabetes), oligohydramnios, severe fetal growth restriction, prelabor
rupture of membranes and those with favorable Bishop’s scores.5 On the other
hand, a poor Bishop’s score or a clinically unstable patient may be reasons not to
consider this procedure. Symptoms were observed to be more severe in the second
week of illness therefore planning delivery before this time is optimal.1,2 Appropriate
counselling should be given to these patients prior to induction since the situation
being considered among COVID-19 positive patients is that their condition may
worsen over time. Likewise, in extreme healthcare system burden, it may be
appropriate to consider postponing or re-scheduling induction of labor.2

The drawbacks of induction of labor, as elucidated in the study by Grobman and

colleagues entitled “A Randomized Trial of Induction Versus Expectant
Management” (ARRIVE), were the notable increase in the time of delivery and
length of stay in the hospital of patients undergoing this procedure.3 An extended
induction, even with successful vaginal delivery, increases exposure time between
patients and the healthcare delivery team. To address this concern, the Royal
College of Obstetricians and Gynecologists (RCOG) suggested that certain service
modifications may be done to decrease exposure and prevent viral transmission
between patients and their relatives and hospital staff. One of their proposals is to
reduce induction of labor in cases that are not medically-indicated.6 Another
proposal to limit in-hospital time of these patients, is by utilizing improved outpatient
protocols of induction of labor such as the use of cervical ripening agents like oral
misoprostol (25 mcg initially followed by 25 mcg every 2-4 hours or 50 mcg every 4-
6 hours) or, outpatient Foley bulb cervical ripening (i.e. 60 to 80 mL single balloon

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 Foley for 12 hours). These may be resorted to, in low-risk COVID-19 positive
women, to minimize contact.3,6
REFERENCES:
1. Berghella Vincenzo. Coronavirus disease 2019 (COVID-19): Pregnancy issues. Uptodate May 8, 2020.
2. Boelig R, Manuck T, Oliver E, Di Mascio D, Saccone G, Bellussi F, Berghella V. Labor and delivery guidance
for COVID-19. Am J Obstet Gynecol MFM [In press]. https://doi.org/10.1016/j.ajogmf.2020.10.
3. Grobman, WA, Rice MM, Reddy UM et al; Kennedy Shriver National Institute of Child Health and Human
Development Maternal-Fetal Medicine Units Network. Labor induction versus expectant management in
low-risk nulliparous women. N Engl J Med 2018; 379(06): 513-523.
4. Berghella, V. Induction for 39 weeks gestation: let’s call it what it is. AJOG MFM (in press).
5. Vrees, Roxanne A et al. Induction of Labor. Medscape Obstetrics & Gynecology. April 12, 2018.
6. Royal College of Obstetricians and Gynaecologists and Royal College of Midwives. Coronavirus (COVID-
19) in Pregnancy: Information for healthcare professionals. Version 9: updated May 13, 2020.

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 WHAT IS THE MODE OF DELIVERY FOR A PREGNANT WOMAN WITH COVID-
19 INFECTION?
STATEMENT:
The mode of delivery should be individualized based on standard obstetric
indications. COVID-19 is not an indication to change the route of delivery.
Vaginal deliveries can be attempted, and cesarean section is performed if
medically warranted.
SUPPORTING STATEMENTS:
According to WHO, the mode of delivery in a pregnant woman with COVID-19
infection should be individualized based on standard obstetric indications.1
Currently, there is no evidence to favor one mode of birth over another, therefore,
the manner of delivery should be discussed with the woman, taking into
consideration her preferences and the existing obstetric condition.2 Thus, for these
women, vaginal delivery can be attempted and cesarean section should only be
performed when medically warranted.1,2

The presence of COVID-19 infection in a pregnant woman is not an indication to

change the route of delivery.1,5,6 In fact, the mode of birth should not be influenced
by a positive SARS-CoV-2 result unless the woman’s respiratory condition demands
an urgent intervention.2,7,8 Furthermore, a positive SARS-CoV-2 result but stable
condition is not even an indication to expedite birth.8 As such, decisions for the
timing and mode of delivery should be individualized, mainly depending on the
severity of maternal condition, gestational age and fetal condition.1,9
Whenever possible, an operative vaginal delivery should be performed to avoid
maternal exhaustion and unnecessary surgical complications in a symptomatic
woman who is becoming hypoxic.2,10

In a systematic review of nineteen studies involving 79 women infected with

coronavirus (SARS, MERS and COVID-19), a diagnosis of pneumonia was made in
91.8% of cases. The most common symptoms were fever (82.6%), cough (57.1%),
and dyspnea (27.0%). Eighty four percent (84%) of the pregnant women were
delivered by cesarean birth. The study concluded that COVID-19 infection was
associated with a relatively higher rate of preterm birth, pre-eclampsia, cesarean
delivery, and perinatal death. There have been no published cases of clinical
evidence of vertical transmission.12 But according to Berghella, even if vertical
transmission is confirmed in more recent data, this would not be an indication for
cesarean delivery since it would only increase maternal risk and would unlikely
improve neonatal outcome. Reports of COVID-19 infection in the newborn have
been generally described as mild disease.6

When there is existing maternal and/or fetal compromise, an emergency delivery

must be performed. A prompt cesarean birth is advised for maternal indications,

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 such as septic shock, acute organ failure or any worsening condition of the mother
related to COVID-19, or fetal indications, such as non-reassuring fetal status.10,13 In
some cases, critical decisions are made whether to perform an emergency cesarean
delivery or to proceed with an induction of labor, as it is done in other maternal
emergencies such as severe pre-eclampsia.2

During COVID-19 infection, the threshold for cesarean delivery should be lower than
usual so that infection control procedures can be readily adhered to, in order to
minimize disease transmission.13 Donning of PPE is time consuming and may have
impact on the time of decision until delivery.2 Locally, there are settings where the
facility has no capacity for containing significant exposure on their health workers.
Expert opinion for these cases suggests that delivery should be expedited for
patients in active labor and have not delivered within two hours.
REFERENCES:
1. World Health Organization. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease
is suspected. Interim guidance 13 March 2020. https://www.who.int/publications-detail/clinical-management-of-severe-
acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected (Accessed on April 10, 2020).
2. Royal College of Obstetrics and Gynecology (RCOG) Coronavirus (COVID-19) Infection and Pregnancy: Information for
Healthcare Professionals Version 9 [Internet]. 2020 May 13. Available from: https://www.rcog.org.
3. CDC: Interim Clinical Guidance for Management of Patients with Confirmed 2019 Novel Coronavirus (2019-nCOV)
Infection.
4. CDC: Interim Considerations for Infection prevention and Control of Coronavirus Disease 2019 (COVID-19) in Inpatient
Obstetric Healthcare Settings.
5. https://www.acog.org/ (Accessed on March 25, 2020).
6. Berghella Vincenzo. Coronavirus disease 2019 (COVID-10): Pregnancy issues. Uptodate May 8, 2020.
7. The Royal Australian and New Zealand College of Obstetricians and Gynecologists. COVID-19 Statement. {Internet}.
2020 March 23 [cited 2020 April 23]. Available from: https://ranzcod.edu.au.
8. Government of Western Australia Department of Health. Management of COVID-19 infection in pregnant women
Statewide version 2. April 24, 2020, p.19>
9. ISUOG Interim Guidance on coronavirus disease 2019 (COVID-19) during pregnancy and puerperium: information for
healthcare professionals – an update doi: 10.1002/uog.22061
10. Lancet Infect Dis 2020. March 3, 2020. https//doi.org/10.1016/S1473-3099(20)30157-2.
11. Stephens AJ, Barton JR, Bentum, NA, Blackwell SC, Sibai BM, General Guidelines in the Management of an Obstetrical
Patient on the Labor and Delivery Unit during the COVID-19 Pandemic. Am J Perinatol. DOI: 10.1055/s-0040-1710308.
12. Di Mascio D, Khalil A, Saccone G, Rizzo G, Buca D, Liberati M, Vecchiet J, Nappi L, Scambia G, Berghella V, D’Antonio
F. Outcome of coronavirus spectrum infections (SARS, MERS, COVID-19) during pregnancy: a systematic review and
meta-analysis American Journal of Obstetrics and Gynecology. 25 March 2020.
https://doi.org/10.1016/j.ajogmf.2020.100107
13. Ashokka B, Loh MH, Tan CH, Su LL, Young BE, Lye DC, Biswas A, Illanes SE, Choolani M. Care of the pregnant woman
with coronavirus disease 2019 in labor and delivery: anesthesia, emergency cesarean delivery, differential
diagnosis in the acutely ill parturient, care of the newborn, and protection of the healthcare personnel. American Journal
of Obstetrics and Gynecology. 10 April 2020. https://doi.org/10.1016/j.ajog.2020.04.005

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 SHOULD ANESTHESIA BE GIVEN TO PREGNANT WOMEN WITH COVID-19
DURING DELIVERY?
STATEMENT:
Neuraxial anesthesia (epidural, spinal or caudal) is preferred. Inhalational or
general anesthesia should be avoided.
SUPPORTING STATEMENTS:

In patients with known or suspected COVID-19, neuraxial anesthetic (such as

spinal, caudal or epidural anesthesia) is not contraindicated and has several
advantages in laboring patients. It provides analgesia and reduces cardiopulmonary
stress from pain and anxiety which, in turn, decreases chance of viral dissemination.
Epidural anesthesia is recommended early in labor to women with suspected or
confirmed COVID-19 to minimize the need for general anesthesia if urgent delivery
is needed.1 It has been shown to be safer than general anesthesia (GA) even in
COVID-19 pregnant patients because GA poses a greater risk for atelectasis and
ICU admission due to decreased respiratory functional capacity. More importantly,
intubation and extubation during general anesthesia are considered aerosol-
generating procedures which may contribute to spread of the virus and should
therefore be avoided in COVID-19 pregnant patients.1,2

Literature review of confirmed COVID-19 pregnant patients who underwent

neuraxial anesthesia during labor showed that it is safe and no neurologic sequelae
nor adverse maternal neurologic events were reported in 77 cases.3 With epidural
anesthesia in place early during labor, it is readily available in case there is a need
to do emergency cesarean delivery, obviating the need for GA.4 However, some
authors advise against this routine practice of early epidural insertion during labor
for COVID-19 patients citing a 2.5 times increased risk of intrapartum pyrexia with
this procedure in general, which can complicate the clinical picture and subsequent
management of these patients.5 For this reason, the decision to do early insertion
should be individualized and not routinely done.

The Society of Obstetric Anesthesia and Perinatology suggests suspending the use
of nitrous oxide for labor analgesia because of insufficient data about cleaning,
filtering and potential aerosolization of nitrous oxide system.6 Limiting the use of
intravenous, patient-controlled analgesia is also advised because of the risk of
respiratory depression in COVID-19 patients.4 Unplanned conversion from regional
to general anesthesia (GA) should be avoided if at all possible but should GA be
really warranted in these patients, Level 4 PPE must be worn by all involved
healthcare providers during such cesarean delivery.4,7

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 REFERENCES:
1 Royal College of Obstetrics and Gynecology (RCOG) Coronavirus (COVID-19) Infection in Pregnancy: information for
Healthcare Professionals Version 8 [Internet]. 2020 April 17 available from https://www.rcog.org.
2 Government of Western Australia Department of Health. Manangement of COVID-19 infection in pregnant women
Statewide version 2. April 24,2020,p.19.
3 Bauer et al. Neuraxial Procedures for Pregnant COVID-19 Patients in Labor (OBG Projects). Anaesthesia and Analgesia,
2020.
4 Berghella, Vincenzo et al. Coronavirus 2019 (COVID-19): Pregnancy Issues on UptoDate. May 8,2020 on
www.uptodate.com.
5 Mullington et al. Review article on Anesthesia and Analgesia. 2020
6 Considerations For Obstetric Anesthesia Care Related To Covid-19 https://soap.org/education/provider-
education/expert-summaries/interim-considerations-for-obstetric-anesthesia-care-related-to-covid-19/.
7 PGH-HICU Risk-Based PPE Levels “What to Wear”. (April 24,2020).

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 CAN ESSENTIAL INTRAPARTUM AND NEWBORN CARE (EINC) BE
INSTITUTED IN DELIVERIES WITH COVID-19 INFECTION?
STATEMENT:
The decision whether or not to perform the four time-bound interventions of
EINC should be done on a case to case basis. EINC remains to be the most
effective way to protect the newborn. The mother should be advised to strictly
follow proper hand hygiene, cough etiquette, wearing of medical mask and
disinfection of often-touched surfaces as infection prevention and control
measures.
SUPPORTING STATEMENTS:

Essential Intrapartum and Newborn care (EINC) is a package of evidence-based

practices recommended by the Department of Health, PhilHealth, and the WHO as
the standard of care in all births by skilled attendants in all government and private
settings.

EINC practices for newborn care constitute a series of time-bound, chronologically-

ordered standard procedures that a baby receives at birth. At the heart of the
protocol are four time-bound interventions: immediate drying, skin-to-skin contact
followed by clamping of the cord after 1-3 minutes, non-separation of the baby from
the mother, and breastfeeding initiation.

The United Nations Children’s Fund (UNICEF), the World Health Organization
(WHO), the United Nations Population Fund (UNFPA), and World Food Programme
(WFP) called on those involved in the response to the COVID-19 pandemic in the
Philippines to emphasize that the most effective way to save newborn lives is still
through the practice of Essential Intrapartum and Newborn Care (EINC, or “Unang
Yakap”) and the promotion and protection of breastfeeding while strictly following
precautions for infection prevention and control (IPC). The agencies further added
that “as with all confirmed or suspected COVID-19 cases, symptomatic mothers who
are breastfeeding or practicing skin-to-skin contact or kangaroo mother care should
observe hand hygiene and basic IPC measures”. When performing skin-to-skin
contact, breastfeeding, and any activities involving touching or being close to the
baby, infected mothers must use a medical mask, wash their hands properly before
and after contact with the child, and routinely clean and disinfect surfaces which the
mother has touched.

ACOG has stated that delayed umbilical cord clamping is highly unlikely to increase
the risk of transmitting pathogens from an infected mother to the fetus; however,
many institutions have chosen to prohibit this practice in term infants, in whom the
benefits are modest, to minimize newborn exposure to any virus in the immediate
environment and reduce the chances that the newborn will require phototherapy for
jaundice.1 Many institutions also prohibit skin-to-skin contact in these cases,2

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 although the World Health Organization has not advised against this.3 One expert
group suggested leaving the vernix caseosa in place for 24 hours after birth since it
contains antimicrobial peptides,4 whereas the American Academy of Pediatrics
advised bathing newborns as soon as reasonably possible after birth to remove
virus potentially present on skin surfaces.5

It cannot be denied that during emergency situations, the rates of disease and death
among babies and children are higher than for any other age group. The younger
the child, the higher the risk, leaving babies under six months most vulnerable.
Babies who drink formula from an unsterile bottle or teat, or made with unclean
water, can become very sick with diarrhea and die within a few hours. Mortality is
particularly high, when there is a prevalence of communicable diseases and
diarrhea, combined with high rates of undernutrition.
REFERENCES:
1. American College of Obstetricians and Gynecologists. Coronavirus (COVID-19), Pregnancy and Breastfeeding.
https://www.acog.org/ (Accessed on March 25, 2020).
2. Ashokka B, Loh MH, Tan CH, et al. Care of the Pregnant Woman with COVID-19 in Labor and Delivery: Anesthesia,
Emergency cesarean delivery, Differential diagnosis in the acutely ill parturient, Care of the newborn, and Protection of
the healthcare personnel. Am J Obstet Gynecol 2020.
3. World Health Organziation. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease
is suspected. Interim guidance 13 March 2020. https://www.who.int/publications-detail/clinical-management-of-severe-
acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected (Accessed on April 10, 2020).
4. Favre G, Pomar L, Qi X, et al. Guidelines for pregnant women with suspected SARS CoV-2 infection. Lancet Infect Dis
2020.
5. Puopolo KM, Hudak ML, Kimberline DW, Cummings J. INITIAL GUIDANCE: Management of Infants Born to Mothers
with COVID-19.

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 CAN MOTHERS WITH COVID-19 INFECTION BREASTFEED THEIR INFANTS?
STATEMENT:
The health care professional should inform the patient and her family on the
risk of viral transmission to the infant during breastfeeding, vis-à-vis the
numerous benefits of breastfeeding to the baby. The decision whether or not
to breastfeed ultimately depends on the patient and her family.
SUPPORTING STATEMENTS:

Much is still unknown about the risk of transmission of SARS-COV-2 virus to the
infant through breastfeeding. The virus has not been detected in breastmilk however
a mother could infect her newborn through droplet transmission during
breastfeeding.

The WHO recommends that mothers who are suspected or confirmed to have
COVID-19 infection should be allowed to have skin-to-skin contact and to breastfeed
their infants. The CDC advises that the decision whether to practice skin-to-skin
contact and to breastfeed should be decided on a case-to-case basis, using shared
decision-making between the mother and the clinical team.

If the parents and family choose to breastfeed, they should understand that the
mother can infect her infant during breastfeeding. The risk of infecting the baby while
breastfeeding can be lowered if:
1) The mother is separated from her baby except when breastfeeding. She
should be at least 2 meters away from the baby with a curtain between them.
2) The mother wears a well-fitting medical mask at all times when near her baby
or other household members.
3) She practices handwashing with soap and water prior to touching her baby
and breastfeeding, and she practices regular body hygiene (e.g. takes daily
showers).
4) She follows cough etiquette.
5) Her baby is not exposed to the sick mother’s respiratory and stool secretions.

On the other hand, breastfeeding confers numerous benefits to the mother and the
infant, specifically immunological protection to the baby. Breast milk is a passive
source of antibodies and anti-infective factors. Breastfeeding also reduces the risk
of sudden infant death syndrome (SIDS), pneumonia, gastroenteritis, otitis media
and other life-threatening diseases.

If the parents and family decide not to breastfeed, or if the mother is too ill to
breastfeed, in order to reduce COVID-19 transmission to the infant:
1) The infant is separated from the mother until the mother is no longer
infectious (at least 2 meters apart, with a curtain separating them).

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 2) If the mother will not breastfeed, infant feeding options include mother’s own
expressed breastmilk, pasteurized donor human milk, infant milk formula, or
re-lactation (once the mother is no longer infectious).
3) The mother can pump her breasts regularly in a hygienic manner and a
healthy caregiver can feed the milk to the baby.
4) The mother should wash her hands and breasts with soap and water prior to
pumping.
5) The pump and parts should be sterilized by a healthy caregiver before each
pumping session.
6) The mother should wear a well-fitting mask during pumping.
7) The caregiver who will take care of the baby should be healthy and should
not be a symptomatic or asymptomatic carrier of the SARS-CoV-2 virus.
8) Ideally, there should be a dedicated pump solely for the mother’s use.
9) All the pump parts that have been in contact with the mother’s milk and skin
should be washed with soap and water after pumping. This should ideally be
done by a healthy person.
10) The doctor should explain to the parents that even if the mother does not
touch her baby, the baby might still get infected if another caregiver is infected
with COVID-19 (symptomatic or asymptomatic infection).
REFERENCES:
1. Academy of Breastfeeding Medicine. Academy of Breastfeeding Medicine Statement on Coronavirus 2019 (COVID-19).
March 10, 2020.
2. Centers for Disease Control. Pregnancy, breastfeeding and caring for young children.
3. Chen H, Guo J, Wang C, Luo F, Yu X, Zhang W et al. Clinical characteristics and intrauterine vertical transmission
potential of COVID-19 infection in nine pregnant women: A retrospective review of medical records. Lancet 2020;
395:809-15.
4. De Rose, Piersigilli,et al. The Study Group of Neonatal Infectious Diseases of the Italian Society of Neonatology. Novel
Coronavirus disease (COVID-19) in newborns and infants: what we know so far. Italian J of Pediatrics 46,Article number
56 (2020).

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 WHO AMONG THE PREGNANT WOMEN WITH COVID-19 INFECTION NEED
ADMISSION?
STATEMENT:
Not all pregnant women with COVID-19 warrant admission. Those who are
asymptomatic or with mild disease and/or stable co-morbid illness can be
sent home for isolation with proper instructions and counselling. Only those
with severe disease and are critically ill should be admitted.
SUPPORTING STATEMENTS:

The rationale for admission of COVID-19 pregnant women is the same with the
general population and this is based on the patient’s vital signs, clinical
manifestation and severity of symptoms. Patients presenting with fever, cough,
dyspnea and/or shortness of breath should be assessed and categorized according
to the gravity of symptoms. If found to be positive for pneumonia, the management
recommendation of the Philippine Clinical Practice Guidelines for Community-
Acquired Pneumonia is followed.1 The table below (Table 3-3) summarizes the
classification of pregnant women with COVID-19 infection based on disease severity
and provides the recommended laboratory examination and appropriate
management for each category.2,4

Table 3-3: Disease Severity Classification of Pregnant Women with COVID-19

Disease Severity Recommended Management

Pregnant patients with • No diagnostic tests are needed for this group
MILD SYMPTOMS AND NO CO- except for RT PCR for SARS-CoV-2.
MORBID ILLNESS • Patient may opt to undergo home quarantine
for 14 days with strict instructions, or may
• Have no co-morbid illness stay in a community health facility.
• Present with mild non-specific • Give symptomatic treatment and supportive
symptoms (fever, cough, sore care.
throat, nasal congestion, • Most cases will not require antibiotics.
headache, muscle pain or
malaise)

Pregnant patients with • Perform RT-PCR for SARS-CoV-2, Chest X-

STABLE CO-MORBID ILLNESS ray with abdominal shield, complete blood
AND MILD PNEUMONIA count, AST, ALT and creatinine.
• Patient may be managed at home or
• Have clinical signs of mild admitted in a COVID-19 designated unit and
pneumonia (fever, respiratory managed as CAP-Low Risk based on the
rate <30 breaths per minute, 2016 Updated Philippine Community
heart rate <125 beats per minute Acquired Pneumonia Guidelines (Appendix
and SpO2 >92%). B1).

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 Disease Severity Recommended Management

Pregnant patients with • Perform the following recommended

SEVERE ACUTE RESPIRATORY diagnostic tests:
INFECTION (SARI) * - RT-PCR for SARS-CoV-2
- Complete blood count
• Present with fever, respiratory - Comprehensive metabolic panel
rate >30 breaths/minute, with - Ferritin
severe respiratory distress or - Lactate dehydrogenase (LDH), Lactate
SpO2 <92% - Procalcitonin
- C-reactive Protein (CRP)
- INR/PT
- D-dimer
- Chest X-ray with abdominal shield or
CT imaging without contrast
- Sputum GS/CS
- Blood culture
- Arterial blood gas (ABG)
• Patient must be admitted and managed as a
case of CAP-Moderate Risk. (Appendix B2)

Pregnant patients with • Perform the following recommended

SEPSIS OR SEPTIC SHOCK * diagnostic tests:
- RT-PCR for SARS-CoV-2
• Present with life-threatening - Complete blood count
organ dysfunction, which is - Comprehensive metabolic panel
characterized by - Ferritin
- Altered mental status - Lactate dehydrogenase (LDH), Lactate
- Difficult or fast breathing - Procalcitonin
- Low oxygen saturation - C-reactive Protein (CRP)
- Reduced urine output - INR/PT
- Fast heart rate - D-dimer
- Weak pulse - Chest X-ray with abdominal shield or
- Low blood pressure CT imaging without contrast
- Cold extremities or skin - Sputum GS/CS
mottling - Blood culture
• OR laboratory evidence of - Arterial blood gas (ABG)
coagulopathy, • Patient must be admitted and managed as a
thrombocytopenia, acidosis and case of CAP-High Risk. (Appendix B3)
high lactate or hyperbilirubinemia

**Patients with septic shock present

with persistent hypotension despite
volume resuscitation, requiring
vasopressors to maintain MAP more
than or equal to 65 mmHg and serum
lactate level > 2mmol/L.

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 Disease Severity Recommended Management

Pregnant patients with ACUTE • Perform the following recommended

RESPIRATORY DISTRESS diagnostic tests:
SYNDROME (ARDS) * - RT-PCR for SARS-CoV-2
- Complete blood count
• Present with new or worsening - Comprehensive metabolic panel
respiratory symptoms within - Ferritin
one week of known clinical insult - Lactate dehydrogenase (LDH), Lactate
• Physical exam findings include - Procalcitonin
respiratory rate > 30 breath per - C-reactive Protein (CRP)
minute and SpO2 of < 90%, with - INR/PT
or without progressing infiltrates - D-dimer
on CXR - Repeat Chest X-ray with abdominal
shield or CT imaging without contrast
- Endotracheal tube aspirate GS/CS
- Blood culture
- ABG
• Management is based on the classification
of ARDS (Appendices C1-C4)

Adapted from: PSMID Interim Guidelines on the Clinical Management of Adult Patients with Suspected or
Confirmed COVID-19 Infection

REFERENCES:
1. Joint Statement of Philippine Society for Microbiology and Infectious Diseases, Philippine College of Chest Physicians,
Philippine Academy of Family Physicians, Inc. and Philippine College of Radiology. Philippine Clinical Practice
Guidelines. Diagnosis, Empiric Management and Prevention of Community-Acquired Pneumonia in Immunocompetent
Adults 2016 Update Treatment.
2. Joseph T, Moslehi MA et al. International Pulmonologists’ Consensus on Covid-19. March 2020.
3. National Institutes of Health, National Heart, Lung and Blood Institute Acute Respiratory Distress Syndrome Clinical
Network Mechanical Ventilation Summary. July 2008. www.ardsnet.org
4. PSMID Interim Guidelines on the Clinical Management of Adult Patients with Suspected or Confirmed COVID-19
Infection

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 HOW ARE SEVERE OR CRITICALLY ILL COVID-19 PREGNANT WOMEN
MEDICALLY MANAGED?
STATEMENT:
COVID-19 pregnant patients with severe acute respiratory infection, sepsis,
septic shock and ARDS should be admitted and managed in an Intensive Care
Unit (ICU) setting. A multi-disciplinary team approach composed of an
obstetrician, intensivist, pulmonologist, infectious disease specialist and
obstetric anesthetist is recommended. In these cases, the use of anti-viral and
investigational drugs for COVID-19 may be considered.
SUPPORTING STATEMENTS:

Severe respiratory symptoms from COVID-19 pneumonia are associated with a high
maternal and perinatal mortality, therefore aggressive treatment is required
including supportive measures with hydration and oxygen therapy. The patient
should ideally be managed in a negative pressure isolation room in the ICU with the
support of a multi-disciplinary team composed of obstetrician, intensivist,
pulmonologist, infectious disease specialist and obstetric anesthetist.1

COVID-19 should be distinguished from other respiratory distress infections such

as bacterial pneumonia, other viral pneumonias and non-infectious lung diseases.
Appropriate broad-spectrum antibiotic should be started when there is suspected or
confirmed secondary bacterial infection.2

Critically ill patients without shock should be treated with conservative fluid
management measures.3 Oxygen should be provided immediately to prevent
hypoxemia, reduce the work of breathing and preclude respiratory failure or arrest.
Oxygen saturation equal to or greater than 95% should be maintained in these
patients.4 They should be made to lie in a left lateral decubitus position for optimal
uteroplacental oxygenation. Hemodialysis may be required if severe sepsis will lead
to renal failure and if electrolyte imbalances become life-threatening.

Antiretroviral agents and other novel drugs for COVID-19 may be introduced in
consultation with the whole multi-disciplinary team to reduce the number of deaths
associated with SARS-CoV-2 infection. The healthcare team should consider the
most up to date recommendations on the use of these investigational agents as their
efficacy on the treatment of this emerging viral infection is yet to be proven.2
REFERENCES:
1. Poon, Liona et al Global Interim Guidance on Coronavirus disease 2019 (COVID-19) during pregnancy and puerperium
from FIGO and allied partners: Information for healthcare professional. Int J of Gynaecol and Obstet. Vol 149 Issue 3.
2. Chen, D. et al. Expert Consensus for managing pregnant women and neonate born to mothers with suspected or
confirmed novel coronavirus (COVID-19) infection. Int J. Gynaecol Obstet. Vol 149 Issue 2. April 6, 2020
3. Plante, L. A. etal SMFM Consult Series #47: Sepsis during pregnancy and the puerperium. AJOG 2019; 220: B2-10
4. Bhatia, P.K et al. Acute Respiratory Failure and Mechanical Ventilation in Pregnant Patients: A narrative review of
literature. J Anaesthesia Clin Pharmacol 2016;32: 431-439.

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 INVESTIGATIONAL DRUGS USED IN COVID-19
Analyn F. Fallarme, MD, MHA
Katherine A. Angelo-Dela Cruz, MD / Sybil Lizanne R. Bravo, RPh, MD, MSc
Mary Judith C. Clemente, MD / Lorina Q. Esteban, MD / Jhorose R. Gementiza, MD
Helen V. Madamba MD, MPH-TM / Josefa Dawn V. Martin MD / Mariles H. Nazal, MD
Rojannah T. Sahagun, MD / Florida F. Taladtad, MD / Cheryl T. Tiuseco, MD

WHAT ARE THE TREATMENT OPTIONS FOR PREGNANT AND LACTATING

WOMEN INFECTED WITH COVID-19?
STATEMENT:
In general, there are no specific drugs for COVID-19. The management options
for pregnant patients with COVID-19 are the same as with non-pregnant
individuals, except for some considerations on the therapeutics. All of the
pharmacologic treatment options being used at present are based on
previous experience in treating SARS, MERS and other new influenza viruses.
The drugs included in this section may be helpful in the treatment of COVID-
19, but their efficacy is still under investigation and further studies are
needed.

Table 4.1 Summary of Investigational Drugs Used for COVID-19 Infection

SAFE FOR
US FDA
NAME MECHANISM PREGNANCY &
EFFICACY SAFETY PREGNANCY DOSAGE
OF DRUG OF ACTION BREAST-
CATEGORY
FEEDING

Azithromycin Bacteriostatic Conflicting Good safety B Yes 500mg OD on

results profile day 1, then
Immuno- 250 mg OD PO
modulatory or Always in Precautions for x 4 days
anti-inflammatory combination with those with
effects in some in Chloroquine or cardiac, liver,
vitro and animal Hydroxy- and renal
research chloroquine disease, and
myasthenia
gravis

Oseltamivir Neuraminidase No exact Well-tolerated C Yes Cr Cl 30-60

inhibitor evidence of its mL/min:
efficacy for Needs renal dose 30 mg BID x 5
COVID-19 adjustment to10 days

May be effective CrCl <30

if given as soon mL/min:
as possible after 30 mg PO OD
illness onset x 5-10 days

Hemodialysis
patients:
30 mg after
dialysis x 5
days

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 SAFE FOR
US FDA
NAME MECHANISM PREGNANCY &
EFFICACY SAFETY PREGNANCY DOSAGE
OF DRUG OF ACTION BREAST-
CATEGORY
FEEDING

Remdesivir RNA chain Unknown No reported Unclassified Unknown 200mg IV on

terminator adverse events day 1, then
except for 100mg IV OD x
transient GI 10 days,
symptoms and infused over
AST elevation 30-60 minutes
(included in
the solidarity
trial)

Lopinavir/ Protease inhibitor No significant Option for C Yes 200mg/50mg

Ritonavir difference patients with tab, 2 tabs BID
(LPV/RTV) compared to prolonged QT PO x 14 days
standard interval,
treatment arrythmias,
decompensated
heart disease,
elevated AST &
ALT, G6PD
deficiency or
hypersensitivity
to CQ & HCQ

Favipirarir RNA polymerase Limited data Well tolerated X No 2400-3000 mg

inhibitor but adverse every 12 hours
events are for 2 doses,
observed in then 1200-
higher doses 1800 mg BID
PO x 5 to 7
No renal dose days
adjustment

Tocilizumab Humanized Could be an Use of 6 months Unclassified Unknown 4-8 mg/kg IV

monoclonal efficient or more with
antibody treatment increases risk of recommended
infections and dose of 400
infestations mg diluted
with NSS to
100 ml, given
as 2-hour
infusion

Ribavirin Inosine Unknown Excessive X No 1.2-2.4 grams

monophosphate hematologic PO every 8
dehydrogenase toxicity hours
inhibitor

RNA polymerase
inhibitor

Interferon Biologic response With potential Fever, headache C Unknown 5 million units
modifier/ cytokine role especially at and fatigue are BID given in
the late stage of common at initial 2ml of sterile
the disease injection water
administered
Used together Neuropsychiatric by nebulization
with LPV/RTV side effects can
be most
troublesome

Corticosteroids Anti-inflammatory Inconclusive or Causes delayed Prednisolone Yes Hydro-

and possible harm viral clearance D cortisone
immunomodulation 50 mg IV every
Maybe of use in Dexa/Beta- 6 hours OR
septic shock methasone 100 mg IV
C bolus followed
by infusion at
10mg/hour x 7
days

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 SAFE FOR
US FDA
NAME MECHANISM PREGNANCY &
EFFICACY SAFETY PREGNANCY DOSAGE
OF DRUG OF ACTION BREAST-
CATEGORY
FEEDING

Immuno- Blocking of Not Most reactions C Yes 0.3-0.5

globulin macrophage Fc recommended are mild and g/kg/day x 5
receptors reversible consecutive
days
Adjust in renal
and cardiac
patients

Ascorbic Acid Biosynthetic and At high doses, Good safety A Yes 50 mg/kg
antioxidant may reduce the profile every 6 hours x
length of ICU 4 days
stay
Must be given
with
Hydrocortisone
50 mg IV every
6 hours x 7
days

Melatonin Anti-inflammatory Have potential Safe for short- A Yes 36-72 mg/day
for improving term use (for short-term (for short-term in 4 divided
clinical outcomes use) use) doses
High dose may
increase
production of
pro-inflammatory
cytokines

Zinc Mineral/essential Zinc may have an Zinc as a C Yes 50 mg once a

micronutrient; effect on COVID- micronutrient is day
inhibition of pro- 19 related found in various
symptoms like multivitamin
inflammatory
diarrhea and lower
cytokines preparations. It is
respiratory tract
infection and can proven to be safe
be used as an if taken in usual
adjunct to doses.
monotherapy or as
combination
therapy with
lopinavir-ritonavir,
interferon, ribavirin
and remdesivir.
Theoretically,
inhibition of pro-
inflammatory
cytokines through
the use of zinc
may have a
beneficial effect in
reducing cytokine
storm seen in
patients with
COVID-19.

Chloroquine Immuno- Has potential for Latest evidence C Yes Both of these
(CQ) modulatory being both point out to drugs were
& prophylactic and increased deleted from
Hydroxy- therapeutic morbidity and the WHO
chloroquine mortality Solidarity Trial
(HCQ) Significant lower associated with
viral carriage these anti-
malarial drugs

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Below are the detailed information (i.e. mechanism of action, efficacy, safety,
pregnancy category, breastfeeding safety and dosage) on the various investigational
drugs used for COVID-19.

I. AZITHROMYCIN

Azithromycin belongs to the macrolide antibiotic class. It has a broad spectrum of

action against various Gram-positive and Gram-negative bacteria. The activity
extends to Legionella species, Bordetella pertussis, Mycoplasma pneumonia,
Chlamydia, Treponema pallidum, and Mycobacterium avium complex.1 This
antimicrobial agent is bacteriostatic as it exhibits reversible binding to bacterial
ribosome thus inhibiting protein synthesis.2 Azithromycin possesses a rather long
half-life because of uptake in lung tissue, tonsil, and in men, in the prostate glands.
The oral bioavailability is 35 to 42% among healthy people. Average concentrations
in the tissues are 10 to 100-fold higher than in serum and may persist for many
days.1 This antibiotic is usually given by oral route though a parenteral form is also
in use for those who cannot tolerate per orem intake. The duration of intake varies
depending on the disease condition and the severity of illness and as such,
guidelines are instituted which have been based on years of research.3

Compared with clarithromycin, azithromycin does not interact with cytochrome P450
3A4 enzyme system. Azithromycin is also stable in acid conditions, and so it can be
given with food. General indications include treatment of Chlamydial cervicitis, pelvic
inflammatory disease (PID), trachoma infection, upper and lower respiratory tract
infections, and as prophylaxis against opportunistic Mycobacterium avium complex
infection among those with human immunodeficiency virus (HIV) disease. It is also
effective in the therapy of chancroid, granuloma inguinale, bacterial enteritis
secondary to Campylobacter and Salmonella species, and cholera.4

Some in vitro and animal research has demonstrated immunomodulatory or anti-

inflammatory effects of azithromycin. Previous data have shown efficacy in therapy
of diffuse bronchiolitis wherein macrolides have been shown to improve lung
function and prognosis. Macrolides were also beneficial in the management of
cystic fibrosis. In particular, azithromycin has been effective in improving lung
function at seven months in patients who had lung transplant for bronchiolitis
obliterans.5,6 Because of these reports, azithromycin and other macrolides have
been suggested as therapy for sepsis and epidemic viral infections involving the
respiratory tract to prevent cytokine storm. Its use for cytokine storm, however, is
controversial especially concerning antimicrobial resistance and limited clinical
evidence.1

Drug Interactions: Azithromycin interacts with nelfinavir (increased azithromycin),

and warfarin (potentiation of warfarin anticoagulant effects). Significant potentiation

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 occurs with concomitant intake of the following drugs, and as such, concurrent
administration is avoided:7 Cisapride, Dihydroergotamine, Dronedarone,
Methyleronovine, Piperaquine, Saquinavir, Terfenadine, Thioridazine, Ziprasidone.

Pregnancy Category: B

EFFICACY OF AZITHROMYCIN IN THE TREATMENT OF COVID-19 INFECTION

The use of azithromycin in combination of HCQ may be considered in clinical

conditions when the healthcare provider assesses that there would be more
benefit than harm.

Azithromycin has always been used in combination with hydroxychloroquine (HCQ)

in the treatment of SARS-CoV-2 or Covid-19 infection. At current time, there have
been opposing conclusions from the French studies with regard to viral clearance
and clinical utility.8 In a study by Molina et al., use of HCQ plus azithromycin did not
show a significant antiviral effect of this drug combination. HCQ (at 600mg per day
for 10 days) was given with azithromycin (at 500mg on day 1, 250mg on days 2-5)
to eleven patients with mean age of 58.7 years. Most of the patients had comorbid
conditions (8 out of 11), and they had poor outcomes. Both drugs were stopped in
a patient for prolonged QT interval. PCR tests for the virus remained positive in 80%
of patients after 5-6 days of therapy.9

In another study in France included azithromycin in the regimen together with

hydroxychloroquine, among twenty patients against a control group of sixteen
patients who got standard of care. The patients received HCQ at 200mg 3x a day
who showed nasopharyngeal viral clearance on 6th day. Six patients were excluded
due to incomplete data and 4 out of these excluded patients had either ICU
admission or death. Azithromycin was also added to 6 patients for possible bacterial
superinfection at 500 mg on day 1 then followed by 250 mg daily for 4 days. There
was 100% viral clearance among those given azithromycin though this warrants
further analysis since these patients who received combination HCQ + azithromycin
were the ones who had lower viral loads.10 The same French doctors went through
with their study of combining HCQ and azithromycin among 80 patients. Sixty-five
of these patients met the criteria of having a favorable outcome. While the results
of this particular study seem promising, there were many flaws because the study
had no control group, and the results did not differentiate between asymptomatic
carriers and patients having high or low viral load.

An ongoing trial named The Recovery Trial (Randomized Evaluation of COVID-19

Therapy) is being done in the United Kingdom presently. HCQ and azithromycin are
being tested separately initially, and then if there is any effect among subjects given

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 alone, compared to those without drugs, they can be combined later. Results from
this large trial are still pending.12

The COVID-19 Treatment Guidelines Panel of the National Institutes of Health (NIH)
“recommends against the use of HCQ plus azithromycin for the treatment of COVID-
19, except in the context of a clinical trial.”13 From the Clinical Practice Guidelines
(CPG) for COVID-19 formulated by the Philippine Society for Microbiology and
Infectious Diseases (PSMID), it is stated that “the known toxicities of both
medications (HCQ and azithromycin) should be weighed against the potential
benefit of eliminating viral load, decreasing infectivity, and improving clinical
outcomes in patients who are otherwise have no way of combating the pandemic.
With the view that the combination may save lives (HCQ and azithromycin), hence
relieving the healthcare system temporarily, the medication should be offered to
patients and decision-making shared between them and their healthcare
professional…critical monitoring of hospital course and expected adverse events is
warranted.”14 Based on these statements the PSMID recommends use of
azithromycin in combination of HCQ in clinical conditions when the healthcare
provider assesses that there would be more benefit than harm and advises
monitoring of side effects. The group also concluded that more studies with bigger
sample sizes are needed.

SAFETY ISSUES ON THE USE OF AZITHROMYCIN

There are various side effects related to azithromycin. Precautions should be

observed in all clinical cases.

The National Institutes of Health COVID-19 Treatment Guidelines state that the
combination of HCQ and azithromycin was associated with QT prolongation in
patients with COVID-19.13 Likewise, the PSMID CPG states the same.14 In year
2012, a research looked into the cardiovascular adverse effects of azithromycin. A
Tennessee study demonstrated that azithromycin was associated with increased
risk of death compared with amoxicillin (odds ratio 2.49, 95% CI 1.38-4.50).15 A year
later, a study published in New England Journal of Medicine (NEJM), found no
increased risk of cardiac death among patients who took azithromycin relative to
penicillin (rate ratio 0.93, 95% CI 0.56-1.55).16 The 2012 Tennessee study
demonstrated prolongation of QT interval, which is a major risk factor for torsades
de pointes. The latter is a lethal arrhythmia that is associated with macrolides in
general, and terfenadine, cisapride, astemizole, and grepafloxacin. Compared with
other macrolides, the occurrence of torsades de pointes is very rare, and this
complication is more common among patients with other risk factors.17

A meta-analysis of 6 trials in which azithromycin was compared with placebo was

conducted among 14,000 patients with known coronary disease demonstrated that

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 azithromycin was associated with a trend toward decreased mortality (OR 0.91, 95%
CI 0.77-1.09).18 A more recent observational analysis with more than 70,000 adult
patients with pneumonia found a lower mortality and no increase in arrhythmia in 90
days.19 From these studies, it was shown that there are conflicting reports about
the cardiovascular profile of this antibiotic. Some have concluded that the
association with mortality most likely represents the effects of the infectious
condition and not the side effects of azithromycin. The reported adverse cardiac
complications are higher among patients with known and existing cardiovascular
morbidity. But caution is observed when giving this drug to patients with preexisting
QT abnormalities or with risk factors for it, especially those with hypokalemia,
hypomagnesemia, and concomitant intake of other medicines, which could also
cause QT prolongation.20

Adverse reactions include gastrointestinal effects such as diarrhea, nausea, and

vomiting, which occur in about >10% of patients given this drug. Dermatologic
effects are diaphoresis, eczema, fungal dermatitis, pruritus, and vesiculobullous
dermatitis, especially among children (1-2%). Among adult, dermatologic
manifestations (<1%) are skin photosensitivity, rash, and urticaria. Endocrine and
metabolic side effects are decreased serum glucose, increased gamma-glutamyl
transferase, increased lactate dehydrogenase, increased serum glucose, and
increased potassium (1-3%). Genitourinary effects include candidiasis and vaginitis
among adults (1-3%). Hematologic effects (1%) are anemia, eosinophilia, increased
neutrophil count, leukopenia, lymphocytopenia, lymphocytosis, thrombocythemia,
and monocytosis. Hypersensitivity reactions are rare (<1%) and may manifest as
angioedema and true hypersensitivity reaction. Nervous system effects (<1%)
include agitation, dizziness, fatigue, headache, insomnia, malaise, and vertigo.
Nephrotoxic effects (1-3%) may be increased BUN levels, increased serum
creatinine, and nephritis. Contraindications are known hypersensitivity to
azithromycin, erythromycin, and other macrolides or to any of the components of
the formulation. It is also not given to those with history of cholestatic jaundice, or
hepatic disease experienced with a previous use of this antibiotic.21

Warnings and precautions include those related to the above-mentioned adverse

effects especially cardiac effects, disease-related concerns such as when it is used
to treat syphilis or gonorrhea because the drug may delay symptoms of incubating
gonorrhea or syphilis. Concerns also include hepatic dysfunction in particular among
those with preexisting liver conditions, and also among those inflicted with
myasthenia gravis due to possible exacerbation. Precautions should also be
observed among patients with renal disease especially those with filtration rate
<10ml/minute.22

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 SAFETY OF AZITHROMYCIN IN PREGNANCY

Azithromycin is relatively safe for use among pregnant women.

Azithromycin is classified under US FDA Class B. In a study about 123 pregnancy

outcomes after exposure to azithromycin in 2006, 3 groups of women were enrolled:
women who took the drug, women exposed to non-teratogenic antibiotics for the
same conditions, and women exposed to non-teratogenic agents. Results showed
that there were no significant differences in the 3 groups regarding the rate of
congenital defects. The authors concluded that gestational exposure to this
antibiotic is not associated with congenital malformation above the 1-3% rate in the
general population. They concluded that azithromycin is safe for use in pregnancy.23

In a retrospective study published in 2013 by the American Society for Microbiology

(ASM) entitled Fetal Safety of Macrolides, the authors investigated the occurrence
of minor and major birth defects among pregnant women who used macrolides such
as erythromycin, clarithromycin, azithromycin, and roxithromycin during the first
trimester or the third trimester of pregnancy. They excluded chromosomal diseases
and included about 105,492 births and 1,112 pregnancy terminations for 10 years
between 1999 to 2009. Of these, about 1,033 fetuses were exposed to any of the
antibiotics mentioned. Results showed that about 1,033 women were exposed to
macrolides in the 1st trimester and there was no associated major or specific
congenital abnormality accounting for maternal age, parity, ethnic origin, diabetes
mellitus, and year of exposure (OR 1.08, 95% CI 0.84 to 1.38). And during the 3rd
trimester about 959 women had use of macrolides. There was also no relationship
between macrolide use and perinatal mortality, low birth weight, low APGAR score,
or preterm birth. There was also no relation with pyloric stenosis or intussusception.
The authors reported that macrolide use, including azithromycin intake, in the 1st
trimester is not linked with increased incidence of major congenital defects.
Likewise, use of this group of antibiotics is not also related to neonatal pyloric
stenosis, or intussusception.24

SAFETY OF AZITHROMYCIN IN BREASTFEEDING

Azithromycin can be given to lactating mothers with minimal to no risk for the
neonate.

This drug is excreted in breast milk. After intake of 2 grams of azithromycin as a

single dose to twenty women undergoing labor, the drug was present for up to 28
days in breast milk. There were no associated adverse effects on the breastfed
babies.25

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 In another study, a lactating woman was given oral azithromycin for cellulitis, at 1 g
loading dose followed by oral azithromycin at 500 mg for next 3 days. The
concentration of azithromycin increased over time in her breast milk that reached a
peak at 30th hour after the last dose.26 Another study showed the mean half-life in
breastmilk was about 15.6 hours but that the breast milk concentration was very
low.27

In 2009, a prospective, controlled observational study on safety of macrolides during

lactation was conducted among 55 infants exposed to macrolide antibiotics
compared to 36 infants exposed to amoxicillin by breast feeding. The study
revealed that the rates and types of minor adverse reactions among both groups of
infants were comparable. They concluded that macrolide use by lactating women
was not associated with pyloric stenosis, but the authors recommended to conduct
further larger studies to confirm their observation.28 From the manufacturer’s stand,
they recommend to consider risk of infant exposure when using macrolides to
breastfeeding mothers.

From the US Centers for Disease Control and Prevention of Sexually Transmitted
Diseases Treatment Guidelines, the authors state that azithromycin is one of
recommended agents for the therapy of granuloma inguinale among lactating
women. Additionally, this antibiotic is also considered an alternate agent among
breastfeeding women suffering from lymphogranuloma venereum.29

DOSAGE OF AZITHROMYCIN FOR THE TREATMENT OF COVID-19

Azithromycin is given as 500 mg on day 1, followed by 250 mg once a day for

the next 4 days.

Azithromycin is always given together with hydroxychloroquine (HCQ). One case

series used azithromycin at 500mg at day 1 followed by 250 mg daily for the next 4
days. A prospective study in France also used the same dosage. As was mentioned
in the studies cited above, there are conflicting results of combination HCQ plus
azithromycin. Until further studies or research will prove the utility of azithromycin in
the therapy of coronavirus infection, there are no definite recommendations unless
this drug is given in circumstances wherein the physician believes there would be
more benefits than harm to the patient.

REFERENCES:
1. Parnham MJ, Erakovic Haber V, Giamarellos-Bourboulis EJ, Perletti G, Verleden GM, Vos R. Azithromycin:
mechanisms of action and their relevance for clinical applications. Pharmacol Ther. 2014 Aug; 143(2):225-45.
2. Zuckerman JM, Qamar F, Bono BR. Macrolides, ketolides, and glycylcyclines: azithromycin, clarithromycin,
telithromycin, tigecycline. Infect Dis Clin North Am. 2009 Dec; 23(4):997-1026, ix-x.
3. Antibiotic Expert Groups. Therapeutic guidelines: antibiotic. Version 15. Melbourne: Therapeutic Guidelines Limited;
2014.
4. Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty Ltd; 2015.
5. Southern KW, Barker PM, Solis-Moya A, Patel L Macrolide antibiotics for cystic fibrosis. Cochrane Database Syst Rev.
2012 Nov 14; 11():CD002203.

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 6. Kingah PL, Muma G, Soubani A. Azithromycin improves lung function in patients with post-lung transplant bronchiolitis
obliterans syndrome: a meta-analysis. Clin Transplant. 2014 Aug; 28(8):906-10.
7. Drugs and Supplements. Azithromycin. 1998-2020 Mayo Foundation for Medical Education and Research (MFMER)
8. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a
treatment of COVID-19: results of an open-label non-randomized clinical trial International Journal of Antimicrobial
Agents (2020) (prepublication).
9. Molina JM, Delaugerre C, Goff JL, Mela-Lima B, Ponscarme D, Goldwirt L, et al. No Evidence of Rapid Antiviral
Clearance or Clinical Benefit with the Combination of Hydroxychloroquine and Azithromycin in Patients with Severe
COVID-19 Infection. Med Mal Infect. 2020 Mar 30.
10. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a
treatment of COVID-19: results of an open-label non-randomized clinical trial International Journal of Antimicrobial
Agents (2020) (prepublication).
11. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb, Sevestre J, et al. Hydroxychloroquine-Azithromycin and COVID-
19. Available at https://www.mediterranee-infection.com/wp content/uploads/2020/03/COVID-IHU-2-1.pdf. 2020 Mar
30;
12. 12. Recovery Trial (Randomised Evaluation of CIVD-19 Therapy). Gant from UK Research and Innovatino/National
Institute for Health research (NIHR) The RECOVERY Trial is registered at ISRCTN50189673
EU Clinical Trials Register: EudraCT 2020-001113-21
13. NIH COVID-19 Treatment Guidelines: Potential Antiviral Drugs Under Evaluation for the Treatment of COVID-19
(Updated on April 21, 2020)
14. CPG for COVID-19 (version 2.1 as of March 31, 2020). Philippine Society for Microbiology and Infectious Diseases
(PSMID).
15. Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med.
2012 May 17; 366(20):1881-90.
16. Svanström H, Pasternak B, Hviid A. Use of azithromycin and death from cardiovascular causes. N Engl J Med. 2013
May 2; 368(18):1704-12.
17. Albert RK, Schuller JL. Macrolide antibiotics and the risk of cardiac arrhythmias. COPD Clinical Research Network. Am
J Respir Crit Care Med. 2014 May 15; 189(10):1173-80.
18. Baker WL, Couch KA Azithromycin for the secondary prevention of coronary artery disease: a meta-analysis. Am J
Health Syst Pharm. 2007 Apr 15; 64(8):830-6.
19. Mortensen EM, Halm EA, Pugh MJ, Copeland LA, Metersky M, Fine MJ, Johnson CS, Alvarez CA, Frei CR, Good C,
Restrepo MI, Downs JR, Anzueto A. Association of azithromycin with mortality and cardiovascular events among older
patients hospitalized with pneumonia. JAMA. 2014 Jun 4; 311(21):2199-208.
20. Juurlink DN. The cardiovascular safety of azithromycin. CMAJ. 2014;186(15):1127–1128. doi:10.1503/cmaj.140572
21. Rao GA, Mann JR, Shoaibi A, et al. Azithromycin and levofloxacin use and increased risk of cardiac arrhythmia and
death. Ann Fam Med. 2014;12(2):121-127. doi: 10.1370/afm.1601.
22. Lockwood AM, Cole S, and Rabinovich M, "Azithromycin-Induced Liver Injury," Am J Health Syst Pharm, 2010,
67(10):810-4
23. Sarkar M, Woodland C, Koren G, Einarson AR. Pregnancy outcome following gestational exposure to
azithromycin. BMC Pregnancy Childbirth. 2006;6:18. Published 2006 May 30. doi:10.1186/1471-2393-6-18
24. Dinur, Anat, et al. Fetal Safety of Macrolides. Antimicrobial Agents and Chemotherapy. May 2013
25. Salman, S. et al. Pharmacokinetics of transfer of azithromycin into the breast milk of African mothers. Antimicrob Agents
Chemother. 2015 Dec 28
26. Kelsey JJ, Moser LR, Jennings JC, Munger MA. Presence of azithromycin breast milk concentrations: a case report. Am
J Obstet Gynecol. 1994;170(5 Pt 1):1375–1376. doi:10.1016/s0002-9378(94)70161-x
27. Sutton AL, Acosta EP, Larson KB, Kerstner-Wood CD, Tita AT, Biggio JR. Perinatal pharmacokinetics of azithromycin
for cesarean prophylaxis. Am J ObstetGynecol.2015;212(6):812.e1–812.e8126.
28. Goldstein LH, Berlin M, Tsur L, Bortnik O, Binyamini L, Berkovitch M. The safety of macrolides during
lactation. Breastfeed Med. 2009;4(4):197–200. doi:10.1089/bfm.2008.0135
29. US Centers for Disease Control and Prevention Sexually Treatment Guidelines 2015

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 II. OSELTAMIVIR

Oseltamivir was originally used for the treatment of acute, uncomplicated influenza
A or B illness. It is an antiviral neuraminidase inhibitor with potent and selective
competitive inhibition of the influenza virus neuraminidase, an enzyme necessary
for viral replication. Oseltamivir phosphate is an inactive prodrug that exerts
pharmacologic activity when hydrolyzed in vivo to the active form. It interferes with
the release of progeny influenza virus from infected host cells and stops spread of
infection to new host cells. Oseltamivir reduces the duration of shedding and lowers
the viral titers and can shorten the length of symptoms by 0.5 to 3 days.1 Oseltamivir
is a prodrug that is hydrolyzed by the liver to its active metabolite, oseltamivir
carboxylate, with an elimination half-life of about 6–10 hours.2 A study by Tanaka et
al using an ex vivo human placenta model showed that oseltamivir was extensively
metabolized by the placenta however, transplacental transfer of the metabolite was
incomplete with minimal accumulation on the fetal side.2

Drug interactions: Entecavir, methotrexate, probenecid and warfarin.

Pregnancy Category: C

EFFICACY OF OSELTAMIVIR IN THE TREATMENT OF COVID-19

Neuraminidase inhibitors are indicated in the management of influenza.

Oseltamivir was also used in the management of SARS-CoV-2 cases reported
in China, however definitive evidence of efficacy is inconclusive because of
lack of suitable control group in the studies. Empirical antiviral therapy could be
initiated to cover for possible co-infecting organisms, which may be responsible for
the severe acute respiratory infection.5 It should be emphasized, however, that
empirical antiviral therapy should be discontinued once PCR tests yield more
specific results.6

1. Seasonal viruses and influenza viruses were the most common pathogens
identified in patients who were suspected to have MERS-CoV. Influenza
viruses were found in 35% of the microbiologically documented patients, which
is consistent with other results showing prevalence ranging from 13% to 64%
for patients with suspected MERS-CoV infection. Results in the study by
Bleibtreu et al suggest that empirical oseltamivir therapy should be initiated in
patients admitted to the isolation ward for suspected MERS-CoV infection and
should be discontinued when PCR results turn out negative for influenza.5

2. A possibility of the presence of more than one viral etiologic agent in

respiratory infection should be considered by clinicians since co-infection
with various viral pathogens has been confirmed in a substantial number of

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 patients with a respiratory tract disease. A rapid and proper diagnostics of
wide spectrum of viral respiratory pathogens shows an accurate picture of
the disease which is essential for appropriate therapeutic management and
infection control.

In the study of Stefanska et al, they reported five cases of multiple respiratory
infection in hospitalized immunosuppressed patients, with the following
results: two double infections with influenza virus (IV) type A/respiratory
syncytial virus (RSV) type A and IV type A/coronavirus (CoV) OC43, one
infection with four viruses – IV type A/RSV type A and B/CoV OC43, and two
cases of mixed infections caused by five viral agents – IV type A and B/RSV
type A and B/ parainfluenza type 3 or CoV OC43. Each patient is noted to be
immunocompromised, with an underlying chronic disease receiving
immunosuppressive treatment. Despite a low number of tested specimens,
their study shows that the inclusions of multiplex PCR methods for
diagnostics of respiratory tract infections and the extension of diagnostic
strategies to detect viruses other than influenza could help in identifying the
true rate of co-infections and their correlation with the clinical symptoms and
severity of disease.7

3. The increasing use of molecular assays has led to an increase in the detection
of viral pathogens among critically ill adult patients with respiratory illness.
Various studies have reported prevalence between 17% and 53% of patients.
The most common viruses that can cause severe respiratory viral infections
(RVIs) are influenza A and B viruses, picornaviruses, human coronaviruses,
respiratory syncytial virus, parainfluenza virus and adenovirus. Novel
pathogens including zoonotic coronaviruses like the agents causing Severe
Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome
(MERS) and the SARS-CoV-2 are still being identified.8

With the cases of SARS-CoV-2 pneumonia emerging during the influenza

season, patients were immediately given empirical treatment with antibiotics
(given orally and intravenously) and Oseltamivir (given orally 75 mg twice
daily); however, there is still no exact evidence that Oseltamivir is an effective
treatment for SARS-CoV-2. Early initiation of NAI treatment is associated with
lower duration of symptoms and reduced mortality.

1. Neuraminidase inhibitors (NAIs) such as oral oseltamivir are recommended as

antiviral treatment for influenza. It has been widely used for 2019-nCoV or
suspected cases in China Hospitals. The mainstay is to initiate antiviral
medication as soon as possible after illness onset. It has shown that
neuraminidase inhibitors are effective as empirical treatment in MERS-CoV

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 infection, however, there is no exact evidence that oseltamivir is effective in
the treatment of SARS-CoV-2.13

2. Oseltamivir reduces the duration of influenza symptoms and the risk of

hospitalization, however, in can lead to an increased risk of nausea and
vomiting. A meta-analysis by Sangsang et al of 12 studies including 107, 712
patients showed that Oseltamivir effectively alleviate the symptoms of
influenza and reduce hospitalization, antibiotic usage and the risk of otitis
media without significantly increasing the rate of adverse drug reactions.14

3. Oral oseltamivir is the most widely available agent among the neuraminidase
inhibitors. The individual participant data meta-analysis of NAI treatment
(almost exclusively oseltamivir) done by Santesso et al showed that NAI use
is associated with a reduction in mortality compared with no treatment,
including the subgroup of ICU patients. Early treatment (within 2 days of
symptom onset) was associated with a reduction in mortality compared with
later treatment.15

4. Observational data also indicate reduction in influenza A(H5N1)-associated

mortality with timely oseltamivir treatment before the onset of respiratory
failure. The importance of timing of oseltamivir treatment has been
demonstrated in an observational study of 1950 patients admitted to ICUs with
influenza A(H1N1), which showed better survival rates for those treated
earliest.8

5. The study by Santesso et al also suggests that oseltamivir may reduce

mortality in high-risk populations, such as hospitalized patients, compared with
no antiviral treatment, but this effect is less pronounced especially when data
from unadjusted studies are pooled. Their meta-analyses indicate that
oseltamivir may also reduce both hospitalization in outpatients as well as
duration of symptoms. Oseltamivir may also reduce complications such as
pneumonia, otitis media, or any recurrent cardiovascular outcome.15

SUPPORTING STUDIES:
1) Cohort of 41 admitted patients with • 38 or 93% were given Oseltamivir in addition to a
laboratory-confirmed SARS-CoV-2 combination of antibiotics.
infection in Wuhan, China • In the ICU setting, 12 or 92% were given Oseltamivir,
while 26 or 93% were given in the non-ICU setting, with
a total of 6 deaths.9

2) Cohort of 138 patients hospitalized in • 90% of patients received Oseltamivir, in combination with
Wuhan, China antibiotics such as Ceftriaxone, Moxifloxacin and
Azithromycin.
• 85 patients (61.6%) were still admitted, 47 patients (34%)
were discharged and 6 patients (4.3%) died.
• 9.4% required additional vasopressors and 1.44%
required renal replacement therapy.

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 • The severity of disease was an important determinant of
antiviral and corticosteroid therapy. However, no effective
outcomes were observed.10

3) Cohort of 99 patients of 2019 novel • All patients were treated in isolation.

coronavirus pneumonia in Wuhan, • Antiviral therapy was given to 76% (75 patients) in the
China form of either oral oseltamivir or IV ganciclovir and
lopinavir/ritonavir tablets.
• The duration of antiviral therapy ranged from 3 to 14
days. 70 patients received antibiotic treatment for 3-14
days, and 19 patients (19%) were also treated with
additional corticosteroids for a duration of 3-15 days.
• Out of the 99 patients, 31 patients (31%) were
discharged, and 11 (11%) died.11

4) Case report of 2 patients with SARS- • Both patients were treated with IV corticosteroids, human
CooV-2 pneumonia in Wuhan, China gammaglobulin, antibiotics (Moxifloxacin) and antiviral
(Oseltamivir and Abidol hydrochloride) and Chinese
herbal medicine (Tanreqing IV gtt). Both patients
recovered.12

SAFETY ISSUES ON THE USE OF OSELTAMIVIR

Oseltamivir is generally well tolerated but there are associated mild to

moderate adverse events.

The most common side effects of Oseltamivir are nausea (10%), vomiting (2-15%),
abdominal pain, diarrhea, headache, insomnia, vertigo. The meta-analyses by
Santesso et al shows that in clinical trials of oseltamivir, adverse events (AEs) in
adults and children were generally mild or moderate, the most common being
nausea and vomiting during the first 1 to 2 days of treatment. As with many other
medications, however, further data on adverse effects have been generated from
post-marketing reports. Rare adverse effects reported include serious skin
hypersensitivity reactions, cardiac arrhythmias, and neuropsychiatric
episodes. Previous analyses of healthcare claim databases have, however,
suggested that the risks of these events were no more than the risk in the general
population.15 The study by Blumental and Song noted that there was no increase
in CNS-related and neuropsychiatric events among adults, children, or adolescents
with influenza who were prescribed oseltamivir.16

Known allergies or hypersensitivities are a contraindication to oseltamivir use. It

should be used cautiously in patients with hereditary fructose intolerance.3

SAFETY OF OSELTAMIVIR IN PREGNANCY

Designated as Pregnancy Class C, Oseltamivir may be used during

pregnancy.

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 Oseltamivir is used to treat influenza and to provide post-exposure prophylaxis.
There are no controlled data in human pregnancy but post-marketing reports and
observational studies showed no malformations nor fetal/ neonatal toxicity by this
drug.1

In the study by Ehrenstein et al including 946, 176 pregnancies, there was no

evidence of an association between prenatal exposure to oseltamivir and any of the
birth outcomes assessed (congenital malformations, fetal death, preterm birth, fetal
growth, and low 5-min Apgar score). Of these, 449 had first-trimester exposure and
1449 had second/third-trimester exposure to oseltamivir. Adjusted ORs following
first-trimester exposure were 0.94 (95% CI 0.49 to 1.83) for any major congenital
malformation and 1.75 (95% CI 0.51 to 5.98) for congenital heart defects, based on
7 exposed cases.17 These were noted to be no more than what is observed in the
general population.

SAFETY OF OSELTAMIVIR IN BREASTFEEDING

Oseltamivir is safe for breastfeeding mothers. It is excreted in low levels into

human milk and is not expected to cause harmful effects in the nursing infants.1

In a case report of a lactating woman who received oseltamivir (75 mg twice daily
for 5 days), the reported maximum milk concentrations of oseltamivir and its active
metabolite were 38.2 ng/mL and 39.5 ng/mL (equivalent to 43.4 ng/mL of
oseltamivir), respectively. The authors estimated that the infant would have been
exposed to milk containing a maximum of 81.6 ng/mL oseltamivir–equivalents,
which corresponds to 0.012 mg/kg per day which is way smaller than the pediatric
doses (2–4 mg/kg per day).2

DOSAGE OF OSELTAMIVIR FOR THE TREATMENT OF COVID-19

Oseltamivir is taken at 75 mg taken twice daily for 5 days, starting within 48

hours of the initial symptoms. Duration of intake may be extended to 10 days
for severely ill patients with ARDS or pneumonia or those who are
immunocompromised.

The therapeutic oral dosage for influenza, including novel H1N1 influenza, for adults
is 75 mg taken twice daily for 5 days, starting within 48 hours of the initial symptoms
to capture the early phase of viral replication.2 The same daily dosing of 75mg twice
daily was used for hospitalized 2019-nCoV pneumonia patients in Wuhan, China,
as well as for pregnant and lactating mothers.11 However, once PCR results prove
negative for influenza, Oseltamivir should be discontinued. For chemoprophylaxis,
the recommended dosage is 75 mg taken once daily for 10 days after exposure.2

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 The Clinical Practice Guideline by the Infectious Diseases Society of America
(IDSA) recommends Oseltamivir for all hospitalized patients with influenza,
regardless of illness duration prior to hospitalization. Higher doses of Oseltamivir
found no advantage with respect to virologic and clinical endpoints. Duration of
treatment is traditionally 5 days, but treatment duration is often extended to 10 days
for severely ill patients with ARDS or pneumonia or those who are
immunocompromised.18 This approach is supported by data showing slow influenza
viral clearance from the lower respiratory tract in critically ill patients with influenza
A(H1N1). The study by Arabi et al have documented emergence of Oseltamivir
resistance in 23% of 22 critically ill A(H1N1) patients. This emerging resistance is
noted to be associated with persistent virus detection and much higher mortality.8

For patients with kidney impairment, the treatment dosing adjustments for creatinine
clearance is as follows:1
CrCl = 30-60 mL/min 30mg twice daily
CrCl less than 30 mL/min 30mg daily
Hemodialysis patients 30mg after dialysis x 5 days

REFERENCES:
1. Sur, Moushumi and Baker, Mari. Oseltamivir. (Updated 2019 October 10). In: StatPearls (Internet). Treasure Island
(FL): StatPearls Publishing 2020 Jan.)
2. Tanaka T, Nakajima K, Murashima A, Garcia-Bournissen F, Koren G, Ito S. Safety of neuraminidase inhibitors against
novel influenza A (H1N1) in pregnant and breastfeeding women. CMAJ. 2009 Jul 7; 181(1-2): 55–58. Published
online 2009 Jun 15. doi: 10.1503/cmaj.090866.)
3. TGA. Therapeutic Goods Administration. Australian Drug Evaluation Committee. Prescribing medicines in
pregnancy: an Australian categorization of risk of drug use in pregnancy. Available from URL:
http://www.tga.gov.au/docs/pdf/medpreg.pdf.(1999).
4. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 6th ed. Philadelphia, PA: LippincottWilliams
and Wilkins.)
5. Sarma P, Prajapat M, Avti P, Kaur H, Kumar S and Medhi B. Therapeutic options for the treatment of 2019-novel
coronavirus: an evidence-based approach. Indian J Pharmacol. 2020 Jan-Feb; 52(1):1-5. Published online 2020 Mar
11. Doi:10.4103/ijp.IJP_119_20.
6. Bleibtreu et al. Clinical management of respiratory syndrome in patients hospitalized for suspected Middle East
respiratory syndrome coronavirus infection in the Paris area from 2013 to 2018. BMJ Infect Dis. 2018; 18:331.
Published online 2018 Jul 16. doi: 10.1186/s12879-018-3223-5.
7. Stefanska I., Romanowska M., Donevski S., Gawryluk D., Brydak L.B. (2013) Co-Infections with Influenza and
Other Respiratory Viruses. In: Pokorski M. (eds) Respiratory Regulation - The Molecular Approach. Advances
in Experimental Medicine and Biology, vol 756. Springer, Dordrecht. 2012 June. https://doi.org/10.1007/978-
94-007-4549-0_3
8. Arabi Y, Fowler R, Hayden F. Critical care management if adults with community-acquired severe respiratory viral
infection. Intensive Care Medicine. 2020; 46(2): 315-328. Published online 2020 Feb 10. Doi: 10.1007/s00134-020-
05943-5
9. Huang C, Wang Y, Li X et al. Clinical features of patients infected with 2019 Novel Coronavirus in Wuhan, China.
Lancet. 2020; 395(10223):497-506.doi:10.1016/S0140-6736(20)30183-5.
10. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel
coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020.
https://jamanetworkcom/journals/jama/fullarticle/2761044.
11. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y et al. Epidemiological and clinical characteristics of 99 cases of 2019
novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet. 2020;395:507-13.(PubMed).
12. Zhang Z, Li X, Zhang W. Shi ZL, Zheng Z, Wang T. Clinical features and treatment of 2019-nCoV pneumonia patients
in Wuhan: Report of a couple cases. Virol Sin. 2020 doi: 101007/s12250-020-00203-8. (PubMed)

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 13. Lu Hongzhou. Drug treatment options for 2019-new coronavirus (2019-nCoV).
https://doi.org/10.5582/bst.2020.01020.
14. Sangsang Qiu et al. Effectiveness and safety of Oseltamivir for treating influenza: An Updated Meta-analysis of
clinical trials. Infect Dis (Lond). 2015 (PubMed)
15. Santesso N, Hsu J, Mustafa R et al. Antivirals for influenza: a summary of systematic review and meta-analysis of
observational studies. Influenza Other Respir Viruses. 2013 Sep; 7(Suppl 2): 76–81. Published online 2013 Aug
27. doi: 10.1111/irv.12085
16. Blumentals William and Song Xue. The Safety of Oseltamivir in Patients with Influenza: Analysis of Healthcare Claims
Data from Six Influenza Seasons. MedGenMed. 2007; 9(4): 23. Published online 2007 Oct 30
17. Ehrenstein V, Kristensen N, Monz B, Clinch B, Kenwright A, Sorensen H. Oseltamivir in pregnancy and birth
outcomes. BMC Infect Dis. 2018; 18: 519. Published online 2018 Oct 16. doi: 10.1186/s12879-018-3423-z
18. Infectious Diseases Society of America. Clinical Practice Guidelines: 2018 Update on Diagnosis, Treatment,
Chemoprophylaxis and Institutional Outbreak Management of Seasonal Influenza. Clinical Infectious Diseases,
Volume 68, Issue 6, 15 March 2019. https//idsociety.org/ https://doi.org/10.1093/cid/ciy866.

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 III. REMDESIVIR

Remdesivir, or GS-5734, is a monophosphoramidate prodrug of an adenosine

analog. This investigational drug was developed by Gilead Sciences, Inc. intended
to treat Ebola virus. In its active form, this nucleotide analog can block nucleotide
synthesis and stop viral replication. The mechanism of action of remdesivir is thru
binding to the RNA-dependent RNA polymerase and acts as an RNA chain
terminator.1

Remdesivir has broad spectrum antiviral and was found to be effective against
human and pre-epidemic zoonotic coronaviruses (CoVs) and can inhibit replication
of SARS-CoV and MERS-CoV in vitro. 2 Animal experiments showed that remdesivir
can effectively reduce the viral load in lung tissue of mice infected with MERS- CoV,
improve lung function, and alleviate pathological damage to lung tissue. 3 Similarly,
remdesivir potently blocks SARS-CoV-2 infection at low micromolar concentrations
and has a high selectivity index. 3,4,5

Drug Interactions: Clarithromycin, Rifampin, Phenytoin, Phenobarbital, St. John’s

Wort

Pregnancy Category: Unclassified

EFFICACY OF REMDESIVIR IN TREATMENT OF COVID-19

More studies are needed to prove the efficacy of remdesivir.

Remdesivir has completed the phase III clinical trial for treatment of Ebola virus
infection. However, the efficacy and safety of remdesivir in patients with 2019-nCoV
infection still need to be further confirmed by clinical research.6 There are currently,
6 clinical trials (in the US, China and France) on remdesivir and its use for COVID-
19.

The first reported case of remdesivir-treated COVID-19 patient was reported in the
US last January 2020. The patient was a 35 year old male from Washington who
presented with symptoms and had a travel history to Wuhan, China. He was given
remdesivir on his 7th hospital day (day 11 of illness) due to developing pneumonia
and persistent fever. The patient noted improvement of symptoms and clinical
findings. There was no reported adverse event in the case.1,8

SAFETY ISSUES ON THE USE OF REMDESIVIR

There are reported transient gastrointestinal side effects and

aminotransferase elevation with remdesivir use.

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 “Among the first 12 patients confirmed by the CDC to have COVID-19 in the United
States, 3 were treated with remdesivir via compassionate use protocol. All patients
reported transient gastrointestinal symptoms and aminotransferase elevation. All
patients are reportedly recovering, but the authors were unable to assess the
efficacy or safety of remdesivir based on the lack of comparator and confounding
treatments, including concomitant use in steroids in one patient.” There were no
adverse events to remdesivir reported for the COVID-19 patient treated in the US
last January 2020.1

Remdesivir has been used for compassionate use in 2015 for a case of late relapse
with CNS involvement in a patient who was previously treated for severe Ebola virus
infection. The patient was a 39-year old female nurse from Scotland, who acquired
the Ebola infection after a humanitarian mission in Sierra Leone. She was treated
with remdesivir for her relapse, as studies have shown that the antiviral drug can
cross the blood-brain barrier. The patient had improvement of symptoms and there
were no reported adverse events in the case, apart from a minimal rise in the
patient’s serum amylase levels. 9

SAFETY OF REMDESIVIR USE IN PREGNANCY

There is currently no data available on the use of remdesivir among pregnant

patients.

In preclinical trials, studies showed remdesivir is considered non-genotoxic. In the

reproductive and development toxicity studies, the only notable finding was a
decrease in corpora lutea, a consequent decrease in implantation sites and viable
embryos, and lower ovary and uterus/cervix/oviduct weights in the rat fertility study;
these changes were observed at a systemically toxic dose. There were no
remarkable findings in male rats in the fertility study, no adverse findings in the
developmental toxicity studies in rats and rabbits, and no adverse changes in the
pre- and postnatal study in rats.10

SAFETY OF REMDESIVIR USE IN BREASTFEEDING

There is currently no data available on the use of remdesivir among lactating

women.

DOSAGE OF REMDESIVIR FOR TREATMENT OF COVID-19 INFECTION

Remdesivir is given at 200 mg IV on day 1, followed by 100 mg IV daily up to

10 days and is infused over 30-60 minutes.1,3

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 REFERENCES:
1. McCreary EK, J M Pogue JM, COVID-19 Treatment: A Review of Early and Emerging Options. Open Forum Infectious
Diseases: http://doi.org/10.1093/ofid/ofaa105
2. Pruijssers AJ, Denison MR. Nucleoside analogues for the treatment of coronavirus infections. Current Opinion in
Virology 2019, 35: 57-62. https://doi.org/10.1016/j.coviro.2019.04.002
3. Dong L, Hu S, Gao L. Discovering drugs to treat coronavirus disease 2019 (COVID-19). Drug Discoveries &
Therapeutics. 2020; 14(1): 58-60. DOI: 10.5582/ddt.2020.01012
4. Wang, M., Cao, R., Zhang, L. et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel
coronavirus (2019-nCoV) in vitro. Cell Res 30, 269–271 (2020). https://doi.org/10.1038/s41422-020-0282-0
5. T. P. Sheahan, A. C. Sims, R. L. Graham, V. D. Menachery, L. E. Gralinski, J. B. Case, S. R. Leist, K. Pyrc, J. Y. Feng,
I. Trantcheva, R. Bannister, Y. Park, D. Babusis, M. O. Clarke, R. L. Mackman, J. E. Spahn, C. A. Palmiotti, D. Siegel,
A. S. Ray, T. Cihlar, R. Jordan, M. R. Denison, R. S. Baric, Broad-spectrum antiviral GS-5734 inhibits both epidemic
and zoonotic coronaviruses. Sci. Transl. Med. 9, eaal3653 (2017).
6. Lu, H. Drug treatment options for the 2019-new-coronavirus (2019-nCoV). BioScience Trends. 2020; 14(1): 69-71. DOI:
10.5582/bst.2020.01020
7. https://www.gilead.com/purpose/advancing-global-health/covid-19/remdesivir-clinical-trials
8. Holshue, ML et al. First case of the 2019 noverl coronavirus in the United States. N Engl J Med 2020;382:929-36. DOI:
10.1056/NEJMoa2001191
9. Jacobs M, et al. Late Ebola virys relapse causing menigoencephalitis: a case report. The Lancet. Published Online:
May18,2016. http://dx.doi.org/10.1016/ S0140-6736(16)30386-5
10. WHO R&D Blueprint – Ad-hoc Expert Consultation on clinical trials for Ebola Therapeutics. Available online:
https://www.who.int/ebola/drc-2018/treatments-approved-for-compassionate-use-update/en/

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 IV. LOPINAVIR / RITONAVIR

Lopinavir is a protease inhibitor used to treat HIV infection, with ritonavir as a

booster. It has been widely used in treating patients with human immunodeficiency
virus. The standard dose in pregnant women is LPV/r 400 mg/100 mg twice daily.

HIV protease is a 99-amino-acid, aspartic acid protein which is responsible for

maturation of virus particles late in the viral life cycle. HIV protease systematically
cleaves individual proteins into functional subunits for viral capsid formation during
or shortly after viral budding from an infected cell. HIV protease inhibitors function
as competitive inhibitors that directly bind to HIV protease and prevent subsequent
cleavage of polypeptides They exhibit activity against clinical isolates of both HIV-1
and HIV-2.1

Drug-drug interaction: Lopinavir/ritonavir is anticipated to have varying degrees of

interaction with other medications that are also CYP3A and/or P-gp substrates.2
Some products that may interact with this drug include: cobicistat, certain HIV
medications (fosamprenavir, tipranavir), orlistat, boceprevir, rifampin, alpha
blockers (alfuzosin, tamsulosin), fluticasone, salmeterol, cisapride, sildenafil,
tadalafil, ergot drugs (ergotamine, dihydroergotamine), pimozide, rivaroxaban,
simeprevir, certain sedatives (midazolam, triazolam) and statins (lovastatin,
simvastatin).

Pregnancy Category: C

EFFICACY OF LOPINAVIR/RITONAVIR IN THE TREATMENT OF COVID-19

More studies are needed to prove the efficacy of Lopinavir-Ritonavir in the

therapy of COVID-19 and other related viral illnesses.

Lopinavir/ritonavir was used as treatment for Severe Acute Respiratory Distress

Syndrome (SARS) caused by a coronavirus in 2003. In the study by Chu et.al.
involving 152 patients with SARS found that compared with ribavirin alone, patients
treated with lopinavir/ritonavir and ribavirin had lower risk of acute respiratory
distress syndrome (ARDS) or death.3 Sheahan et.al. compared the efficacy of
lopinavir, ritonavir and interferon alpha versus remdesivir against the Middle East
Respiratory Syndrome (MERS)-CoV, another coronavirus. Remdesivir was effective
in reducing the virus titer of mice infected and improving the lung tissue damage.
Its effect is better than that of the Lopinavir/Ritonavir combined with interferon-β
treatment group.4

The First Affiliated Hospital, Zhejiang University School of Medicine (FAHZU) used
lopinavir/ritonavir (2 capsules, po q12h) combined with arbidol (200 mg po q12h) as

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 the basic regimen against SARS-COV2. In their treatment experience on 49
patients, the average time to achieve negative viral nucleic acid test for the first time
was 12 days (95% CI: 8-15 days). The duration of negative nucleic acid test result
(negative for more than 2 times consecutively with interval ≥ 24h) was 13.5 days
(95% CI: 9.5 - 17.5 days). In their protocol, when the basic regimen is not effective,
chloroquine phosphate was used on adults between 18-65 years old (weight ≥ 50
kg: 500 mg bid; weight ≤50 kg: 500 mg bid for first two days, 500 mg qid for following
five days).The incidence of abnormal liver function test was 51.9% in COVID-19
patients who received lopinavir/ritonavir combined arbidol antiviral treatment.5

A randomized, controlled, open-label trial of hospitalized adults (n=199) with

confirmed SARS-CoV-2 infection, enrolled patients who had oxygen saturation of
94% or less on ambient air or PaO2 of less than 300 mm Hg. These patients were
randomized to receive lopinavir/ritonavir 400 mg/100 mg PO BID for 14 days added
to standard care (n=99) or standard care alone (n=100). Standard care involved, as
necessary, giving of supplemental oxygen, noninvasive and invasive ventilation,
antibiotic agents, vasopressor support, renal-replacement therapy, and
extracorporeal membrane oxygenation (ECMO). Results showed that time to clinical
improvement did not differ between the two groups (16 vs. 16 days, HR 1.31, 95%
CI 0.95-1.85, p=0.09). The mortality rate at 28 days was numerically lower for
lopinavir/ritonavir compared with standard care (19.2% vs 25%) but did not reach
statistical significance. Lopinavir-ritonavir was associated with a statistically shorter
time to clinical improvement when started early within 12 days after the onset of
symptoms (HR 1.25, 95% CI 1.77 to 2.05, median not reported). They concluded
that in hospitalized adult patients with severe Covid-19, no benefit was observed
with lopinavir–ritonavir treatment beyond standard care. Fourteen percent of
patients in the intervention group could not complete their 14-day course mainly due
to gastrointestinal side effects.6

LPV/r is an option for COVID 19 cases with prolonged QT interval, arrhythmias,

elevated AST or ALT >5x, G6PD deficiency, hypersensitivity to CQ or HCQ and
decompensated heart failure.

SAFETY ISSUES ON THE USE OF LOPINAVIR/RITONAVIR

The main adverse reactions were diarrhea, nausea, vomiting, increase in

serum aminotransferase, jaundice, dyslipidemia and increase of lactic acid in
the 49 COVID 19 patients who were given LPV/r.5

Precautions: History of liver disease, patients with chronic Hepatitis B or C,

redistribution accumulation or loss of body fat may occur.8

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 The French Perinatal Cohort found no association between birth defects and LPV
or RTV use with 85% power to detect a 1.5-fold increase.9 The Pediatric HIV/AIDS
Cohort Study found no association between LPV and congenital anomalies.10 In a
10-year surveillance data from the United Kingdom and Ireland, among LPV-
exposed pregnancies, the overall congenital abnormality rate was 2.9% (134 infants
out 4,609 LPV-exposed pregnancies). This rate is comparable to rates of congenital
abnormalities observed in populations without HIV.11 Among cases of first-trimester
exposure to LPV/r reported to the Antiretroviral Pregnancy Registry, the prevalence
of birth defects was 2.1% compared with a prevalence of either 2.7% when using
data from the Metropolitan Atlanta Congenital Defects Program (MACDP) or 4.2%
when using data from the Texas Birth Defects Registry (TBDR).12

SAFETY OF LOPINAVIR/RITONAVIR IN PREGNANCY

Among HIV pregnant women given this drug combination, there have been
reports of increased risk of preterm delivery. More studies are needed to
prove the safety and efficacy of LPV/r for COVID-19 treatment among pregnant
women.

LPV/r has been widely used in the treatment of HIV in pregnant women. A study in
China found that women who received PI-based regimens had higher rates of
preterm birth than those who received non-nucleoside reverse transcriptase
inhibitor (NNRTI)-based regimens.13 A similar finding was noted in the United
Kingdom/Ireland National Study of HIV in Pregnancy and Childhood. In this study,
38.9% of women (2,368 out of 6,073) who took LPV/r during their pregnancies
carried a greater risk of preterm delivery than the use of NNRTI-based regimens.14

SAFETY OF LOINAVIR/RITONAVIR IN BREASTFEEDING

Amounts of LPV/r in breastmilk are not clinically significant.

In a study of 51 mother-infant pairs in Uganda where the mother received LPV/r

during pregnancy and breastfeeding, transfer during breastfeeding was not
observed, and no infant had detectable plasma LPV levels at 12 weeks. LPV
concentrations in human breast milk are very low to undetectable and LPV
concentrations in breastfeeding infants whose mothers received LPV are not
clinically significant.15-18

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 DOSAGE OF LOPINAVIR/RITONAVIR FOR THE TREATMENT OF COVID-19
INFECTION

The dose is 200mg/50mg tablet 2 tablets BID po x 14 days.

There are 16 on going trials with use of LPV/r in the management of SARS-CoV-2.7

REFERENCES:
1. HIV protease inhibitors. Flexner C. N Engl J Med. 1998. 338: 1281-1293.
2. Zhang L, Zhang Y, Huang SM (19 October 2009). "Scientific and regulatory perspectives on metabolizing enzyme-
transporter interplay and its role in drug interactions: challenges in predicting drug interactions". Molecular
Pharmaceutics. 6 (6): 1766–74.
3. Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH, Chan KS, Kao RY, Poon LL, Wong CL, Guan Y, Peiris JS, Yuen
KY; HKU/UCH SARS Study Group. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical
findings. Thorax. 2004; 59:252256.
4. Sheahan TP, Sims AC, Leist SR, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir,
ritonavir, and interferon beta against MERSCoV. Nat Commun. 2020 ; 11:222.
5. Liang Tingbo, CAI Hongliu, CHEN Yu, CHEN Zuobing, FANG Qiang, HAN Weili, HU Shaohua, LI Jianping, LI Tong,
LU Xiaoyang, QU Tingting, SHEN Yihong, SHENG Jifang, WANG Huafen, WEI Guoqing, XU Kaijin, ZHAO Xuehong,
ZHONG Zifeng, ZHOU Jianying. Handbook of Covid-19 Prevention and Treatment 2020, page 24.
6. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe
Covid-19. N Engl J Med. 2020 Mar 18.
7. Philippine Society for Microbiology and Infectious Diseases (PSMID) Interim Guideline on the management of patients
suspected and confirmed COVI-1. Version 2, 26 March 2020.
8. MIMS Drug Reference Philippines. Issue 2, page 456.
9. Sibiude J, Mandelbrot L, Blanche S, et al. Association between prenatal exposure to antiretroviral therapy and birth
defects: an analysis of the French perinatal cohort study (ANRS CO1/CO11). PLoS Med. 2014;11(4):e1001635.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/24781315
10. Williams PL, Crain M, Yildirim C, et al. Congenital anomalies and in utero antiretroviral exposure in human
immunodeficiency virus-exposed uninfected infants. JAMA Pediatr. 2015;169(1):45-55. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/25383770.
11. Tookey PA, Thorne C, van Wyk J, Norton M. Maternal and foetal outcomes among 4118 women with HIV infection
treated with lopinavir/ritonavir during pregnancy: analysis of population-based surveillance data from the national study
of HIV in pregnancy and childhood in the United Kingdom and Ireland. BMC Infect Dis. 2016;16:65. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26847625.
12. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry international interim report for
1 January 1989–31 January 2019. Wilmington, NC: Registry Coordinating Center. 2019. Available at: http://www.
apregistry.com/.
13. Wang L, Zhao H, Tao J, et al. Risk factors associated with preterm and low birth weight among infants born to HIV-
infected mothers in five tertiary hospitals in China, 2009-2014. Presented at: AIDS. 2016. Durban, South Africa.
14. Favarato G, Townsend CL, Bailey H, et al. Protease inhibitors and preterm delivery: another piece in the puzzle. AIDS.
2018;32(2):243-252. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29135577.
15. Gandhi M, Mwesigwa J, Aweeka F, et al. Hair and plasma data show that lopinavir, ritonavir, and efavirenz all transfer
from mother to infant in utero, but only efavirenz transfers via breastfeeding. J Acquir Immune Defic Syndr.
2013;63(5):578-584. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24135775.
16. Shapiro RL, Rossi S, Ogwu A, et al. Therapeutic levels of lopinavir in late pregnancy and abacavir passage into breast
milk in the Mma Bana Study, Botswana. Antivir Ther. 2013;18(4):585-590. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23183881.
17. Corbett AH, Kayira D, White NR, et al. Antiretroviral pharmacokinetics in mothers and breastfeeding infants from 6 to
24 weeks post-partum: results of the BAN Study. Antivir Ther. 2014;19(6):587-595. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/24464632.
18. Oumar AA, Bagayoko-Maiga K, Bahachimi A, et al. Efavirenz and lopinavir levels in HIV-infected women and their
nursing infants, in Mali. J Pharmacol Exp Ther. 2018;366(3):479-484. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29986950

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 V. FAVIPIRAVIR

Favipiravir is previously known as T-705, is a prodrug of a purine nucleotide,

favipiravirribofuranosyl-5′-triphosphate. This drug works by inhibiting the RNA
polymerase, halting viral replication. Most of favipiravir’s preclinical data are derived
from its influenza and Ebola activity; however, it also demonstrated broad activity
against other RNA viruses.1 This drug is currently available in Japan for the
treatment of influenza since 2014.

Drug Interactions: CYP2C8 and aldehyde oxidase inhibitor

Pregnancy Category: X

EFFICACY OF FAVIPIRAVIR IN THE TREATMENT OF COVID-19

More studies are needed to prove the efficacy of Favipiravir in the

management of COVID-19.

There is currently limited data supporting the use of Favipiravir as treatment for
COVID-19. In a prospective, randomized, multicenter study, favipiravir (n = 120) was
compared with Arbidol (n = 120) for the treatment of moderate and severe COVID-
19 infections. Differences in clinical recovery at day 7 were observed in patients with
moderate infections (71.4% favipiravir and 55.9% Arbidol, P = .019). No significant
differences were observed in the severe or severe and moderate (combined) arms.2

Favipiravir was also successfully used for the post-exposure prophylaxis and
treatment of patients with Ebola virus infection3,4 and Influenza.5 During the 2014
epidemic of Ebola virus infection in West Africa, two studies were done. The control
group were patients who were treated without favipiravir in the period before
favipiravir treatment became available; and the treatment group were those who
received favipiravir. The first is an Ebola study conducted in Guinea included 126
patients, and 111 were analyzed and compared with 540 patients as a historical
control group. Favipiravir treatment reduced the mortality rate in the low viral load
group to 33% compared with the historical control group that was not treated with
favipiravir, but this reduction in the mortality rate was not statistically significant.6
The second Ebola study was conducted in Sierra Leone included 39 favipiravir-
treated patients and 85 historical control patients. The overall survival rate in the
favipiravir treatment group was higher than the control group (56.4% [22/39] vs
35.3% [30/85]; P = .027).3

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 SAFETY ISSUES ON THE USE OF FAVIPIRAVIR

Favipiravir has minimal side effects. This drug has mild adverse effect profile and
is overall well-tolerated, although the adverse event profile for higher-dose regimens
is limited.7,8 Most commonly observed side effects are hyperuricemia, diarrhea,
elevated transaminases, and reduction in neutrophil count.

SAFETY OF FAVIPIRAVIR FOR PREGNANT WOMEN AND BREASTFEEDING

Favipiravir is contraindicated among pregnant and lactating women.

This drug is contraindicated in pregnant patients since it has been shown to cause
congenital anomalies in animals. Its metabolite is excreted in breastmilk.9

DOSAGE OF FAVIPIRAVIR FOR THE TREATMENF OF COVID-19

Favipiravir is given with loading of 2400 mg to 3000 mg every 12 hours for 2

doses, followed by a maintenance dose of 1200 mg to 1800 mg every 12 hours.

It comes in 200 mg/tablet and can be given crushed or mixed with liquid. Its
bioavailability is >95%. No renal adjustment is needed.9

REFERENCES:
1. Furuta Y, Komeno T, Nakamura T. Favipiravir (T-705), a broad-spectrum inhibitor of viral RNA polymerase. Proc Jpn
Acad Ser B Phys Biol Sci. 2017; 93(7):449-463. doi:10.2183/pjab.93.027
2. Chen C, Huang J, Cheng Z, et al. Favipiravir versus Arbidol for COVID-19: a randomized clinical trial. medRxiv. Preprint
posted March 27, 2020. doi: 10.1101/2020.03.17.20037432
3. C.Q. Bai, J.S. Mu, D. Kargbo, Y.B. Song, W.K. Niu, W.M. Nie, ..., J.F. Jiang Clinical and Virological characteristics of
Ebola virus disease patients treated with Favipiravir (T-705)-Sierra Leone, 2014 Clinical Infectious Diseases, 63 (2016),
pp. 1288-1294
4. M. Jacobs, E. Aarons, S. Bhagani, R. Buchanan, I. Cropley, S. Hopkins, ..., A. Rodger. Post-exposure prophylaxis
against Ebola virus disease with experimental antiviral agents: A case-series of health-care workers. The Lancet
Infectious Diseases, 15 (2015), pp. 1300-1304
5. B. Cao. A Pharmacokinetics Study of Favipiravir in Patients With Severe Influenza. NCT03394209.
https://clinicaltrials.gov/ct2/show/NCT03394209 (2018).
6. D. Sissoko, C. Laouenan, E. Folkesson, A.B. M’Lebing, A.H. Beavogui, S. Baize, ..., J.S. Group Experimental treatment
with Favipiravir for Ebola virus disease (the JIKI trial): A historically controlled, single-arm proof-of-concept trial in
Guinea PLoS Medicine, 13 (2016), Article e1001967
7. Dong L, Hu S, Gao J. Discovering drugs to treat coronavirus disease 2019 (COVID-19). Drug Discov Ther.
2020;14(1):58-60. doi:10.5582/ddt.2020.01012
8. Sissoko D, Laouenan C, Folkesson E, et al; JIKI Study Group. Experimental treatment with favipiravir for Ebola virus
disease (the JIKI Trial): a historically controlled, single-arm proof-of-concept trial in Guinea [published correction
appears in PLoS Med. 2016;13(4): e1002009]. PLoS Med. 2016;13(3):e1001967. doi: 10.1371/journal.pmed.1001967
9. JM Sanders, ML Monogue, TZ Jodlowski, JB Cutrell. Pharmacologic Treatment for Coronavirus Disease 2019 (COVID-
19): A review. JAMA April 13, 2020. Doi:10.1001/jama.2020.6019

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 VI. TOCILIZUMAB

Tocilizumab is a humanized monoclonal antibody targeting the interleukin-6

receptor approved for the treatment of rheumatoid arthritis and juvenile idiopathic
arthritis.3 Tocilizumab has been shown to be effective against cytokine release
syndrome resulting from CAR-T cell infusion against B cell acute lymphoblastic
leukemia.2 US FDA pregnancy category for tocilizumab is not assigned due to
limited data, so it should be used during pregnancy only if the benefit outweighs the
risk.8

EFFICACY OF TOCILIZUMAB IN THE TREATMENT OF COVID-19

Tocilizumab is a promising antiviral drug in the management of COVID-19.

More research is needed to prove the efficacy of this drug in treating patients
with coronavirus infection.

A case series of 14 COVID-19 cases showed that T cells are reduced significantly
in COVID-19 patients, and the surviving T cells appear functionally exhausted. T
cell numbers are negatively correlated to serum IL-6, IL-10 and TNF-α
concentration.2

In the pathogenesis of SARS, a cytokine storm occurred, involving a considerable

release of proinflammatory cytokine including interleukin (IL)-6, tumor necrosis
factor α (TNF-α) and IL-2. Similar to the changes in SARS and MERS-CoV, in
COVID-19, higher plasma levels of cytokines including IL-6, IL-2, IL-7, IL-10,
granulocyte-colony stimulating factor (G-CSF) interferon-γ-inducible protein (IP10),
monocyte chemoattractant protein (MCP1), macrophage inflammatory protein 1
alpha (MIP1A) and TNF-α were found in ICU patients, which implied a cytokine
storm occurred.9

Interleukin-6 (IL-6) plays a central role in cytokine storm. The classical IL-6 signal
is limited to the cells that express IL-6R and plays a leading role in the low level of
IL-6. The binding of tocilizumab with cell-related IL-6R and soluble IL-6R can inhibit
classical and trans signal. Therefore, tocilizumab can inhibit cytokine release
syndrome.10

In a study of 21 patients who were treated with tocilizumab 400 mg once through an
intravenous drip, added on top of standard care showed that patients improved
immediately after the treatment. Clinical symptoms of all patients improved
remarkably with good prognosis after the treatment. This suggests that tocilizumab
could be an efficient therapeutic for the treatment of COVID-19, by blocking of IL-6-
associated febrile and inflammatory storm response.9

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 SAFETY ISSUES ON THE USE OF TOCILIZUMAB

More studies are needed to elucidate the adverse events associated with use
of Tocilizumab.

Among patients with rheumatoid arthritis who received tocilizumab over a period of
at least 6 months, the most common adverse events include infections and
infestations.5 Other common adverse events by system organ classes include
abnormal laboratory findings (investigations), musculoskeletal and connective
tissue disorders, gastrointestinal disorders, skin and subcutaneous tissue disorders
and blood and lymphatic system disorders.3 Tocilizumab can cause hypertension,
diabetes and other cardiovascular disease.10 Long term studies are essential to
determine safety of tocilizumab over time.

SAFETY OF TOCILIZUMAB DURING PREGNANCY

Few initial studies demonstrated no increase in abortion or incidence of

congenital anomalies among women and fetuses exposed to this drug during
pregnancy. More studies are needed to prove the safety of use in pregnancy.

Women found to have been exposed to tocilizumab shortly before or during

pregnancy under the Roche Global Safety Database4 and the Chugai’s tocilizumab
safety database6 indicated no increased rates of spontaneous abortion or congenital
abnormalities. No increased risk for adverse pregnancy outcomes were observed
after paternal exposure in pregnancies with known outcome.4 Considering the
limitations of global safety databases, the data do not yet prove safety. Further
study is necessary to confirm the benefit-risk profile of tocilizumab treatment during
pregnancy.5

SAFETY OF TOCILIZUMAB DURING BREASTFEEDING

More studies are needed to prove the safety of use of Tocilizumab among
lactating women.

A study measured tocilizumab concentrations in the breast milk of two nursing

mothers with rheumatoid arthritis and evaluated the safety of their breastfed infants.
Tocilizumab concentrations in breast milk were measured frequently after injections,
reaching a peak 3 days after each injection and decreasing gradually thereafter.
The maximum tocilizumab concentrations in breast milk as 148.2 ng/ml after 3 days.
Breast milk levels of tocilizumab ranged from 1/500 to 1/1000 of those in serum.
Infants exclusively breastfed experienced no serious infections that required
hospitalization and no developmental delays.7 Further studies are needed to show
impact of tocilizumab exposure on breastfeeding infant.

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 DOSAGE OF TOCILIZUMAB FOR THE TREATMENT OF COVID-19

Tocilizumab is administered at an initial dose of 4-8 mg/kg, prepared as 400

mg diluted with 0.9% normal saline to 100 mL, given as a 2-hour infusion. A
single extra dose may be given after 12 hours if the initial medication is not
effective.

Tocilizumab can be given to patients in severe conditions with extensive lung

lesions and increased level of IL-6 in laboratory testing.

REFERENCES:
1. (2020). Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7) . National Health
Commission & State Administration of Traditional Chinese Medicine.
2. Diao B, W. C. (2020). Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019
(COVID-19). medRxiv.
3. Haraoui B, C. G. (2019). Tocilizumab Patterns of Use, Effectiveness, and Safety in Patients with Rheumatoid Arthritis:
Final Results from a Set of Multi-National Non-Interventional Studies. RHeumatol Ther, 6, 231-243.
4. Hoeltzenbein M, B. E. (2016). Tocilizumab use in pregnancy: Analysis of a Global Safety Database including data
from clinical trials and post-marketing data. Reproductive Technology, 60, 172-187.
5. Jones G, P. E. (2018). New insights and long term safety of tocilizumab in rheumatoid arthritis. Therapeutic Advances
in Muskuloskeletal Disease, 10(10), 195-199.
6. Nakajima K, W. O. (2016). Pregnancy outcomes after exposure to tocilizumab: A retrospective analysis of 61 patients
in Japan. Modern Rheumatology, 26(5), 667-671.
7. Saito J, Y. N. (2018). Tocilizumab concentrations in maternal serum and breast milk during breastfeeding and a
safety assessment in infants: a case study. Rheumatology, 1499-1501.
8. Tocilizumab Pregnancy and Breastfeeding Warnings. (2019, July 9). Retrieved from Drugs.com:
https://www.drugs.com/pregnancy/tocilizumab.html
9. Xu X, H. M. (2020). Effective Treatment of Severe COIVD-19 Patients with Tocilizumab. ChinaXiv:202003.00026v1.
10. Zhang C, W. Z. (2020). The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R)
antagonist Tocilizumab may be the key to reduce the mortality. International Journal of Antimicrobial Agents.

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 VII. RIBAVIRIN

Ribavirin is a unique guanosine analogue with broad-spectrum activity against many

RNA and DNA viruses. It is a 1-ribosyltriazole that is the 1-ribofuranosyl derivative
of 1,2,4-triazole-3-carboxamide. As a nucleoside analogue, it can mimic the
structure of a natural nucleoside such that it is recognized by cellular or viral
enzymes, however due to modifications to their structure, leads to disruption and/or
termination of replication or other biological processes.1

The following are the mechanisms of action of Ribavirin:

1. Inhibition of inosine monophosphate dehydrogenase (IMPDH) resulting in
intracellular guanosine triphosphate (GTP) depletion occurs at lower ribavirin
concentrations (10μM ribavirin). Reduced intracellular GTP secondarily may
result in inhibition of mRNA capping and impact on host cell gene expression,
inflammation and immunomodulation.
2. Inhibition of viral RNA dependent RNA polymerase
3. Enhancement of viral mutagenesis, which occurs at higher ribavirin
concentrations in vitro (≥100μM), by means of the incorrect substitution of
ribavirin triphosphate for GTP.2

Drug Interaction
1. In vitro and in vivo antiviral activity of ribavirin against some viruses (eg,
influenza virus) may be enhanced by other antiviral agents (eg, amantadine,
rimantadine).3
2. Ribavirin may antagonize the in vitro antiviral activity of stavudine and
zidovudine against HIV; concomitant use of ribavirin with either of these
drugs should be avoided.3
3. The co-administration of didanosine with oral ribavirin is not recommended.
There were cases of fatal hepatic failure, peripheral neuropathy, pancreatitis,
and symptomatic hyperlactatemia/lactic acidosis have been reported in
clinical trials. Ribavirin appears to potentiate the antiretroviral effects of
didanosine by promoting formation of didanosine-S'-triphosphate, the
metabolically active metabolite of didanosine with antiviral activity.3
4. Results of in vitro tests in various cell cultures and peripheral blood
lymphocytes indicate that ribavirin may potentiate the antiretroviral activity of
didanosine against human immunodeficiency virus (HIV; formerly HTLV-
III/LAV) and Moloney murine sarcoma virus.3
5. Conversely, results of in vitro tests indicate that ribavirin antagonizes the
antiviral activity of zidovudine and zalcitabine against HIV. The mechanism
by which ribavirin antagonizes the antiretroviral effects of zidovudine or
zalcitabine has not been elucidated to date but it has been suggested that
ribavirin may interfere with phosphorylation steps that convert the drugs to

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 their active triphosphate metabolites, deoxythymidine triphosphate or
dideoxycytidine-S'-triphosphate, respectively.3

Pregnancy Category: X

EFFICACY OF RIBAVIRIN IN THE TREATMENT OF COVID-19

Ribavirin is currently not considered a viable drug in the therapy of SARS-

CoV-2 infection due to lack of efficacy and associated side effects with the
high doses needed to be given to patients afflicted with the condition.

Ribavirin was evaluated against SARS- CoV-1 in 2003 and used clinically in
combination with corticosteroids and/or interferon in the absence of other treatment
options; however, outcomes were either poor or ill-defined. The doses required for
antiviral activity against SARS range from 1.2 gm to 2.4 gm by mouth every 8 hours,
which are associated with excessive toxicity to patients. Wang and colleagues
evaluated the in vitro activity of ribavirin against SARS-CoV-2 and found an EC50
of 109.5μM, which was over 100 times less potent than remdesivir. The risk of
hematologic toxicity at high doses likely outweighs potential clinical benefit, and
therefore ribavirin was not considered a viable candidate for further investigation by
the World Health Organization research and development plan for SARS-CoV-2
given lack of in vitro efficacy, toxicity profile, and poor outcomes.4

SAFETY ISSUES ON THE USE OF RIBAVIRIN

Ribavirin is contraindicated during pregnancy and breastfeeding due to its

potential teratogenicity demonstrated in all animal models studied. Avoidance of
pregnancy for 4 months after ribavirin exposure for treated women and for 7 months
for female partners of treated men is therefore recommended, although preliminary
analysis of the Ribavirin Pregnancy Registry established in 2003 has not been able
to demonstrate any clear evidence for human teratogenicity for ribavirin.

Rivabirin and PEG-Interferon Alfa-2A dual therapy is associated with flu-like

symptoms, depression, suicide, insomnia, irritability, relapse of drug
abuse/overdose, hepatic decompensation in 2% of HIV co-infected patients and
bacterial infections each occurring at a frequency of less than 1%. Ribavirin-induced
anemia is a dose-dependent adverse effect where reduced hemoglobin levels can
be seen within the first 1-2 weeks in therapy. The mechanism of ribavirin-induced
anemia has been shown to involve reductions in reticulocyte counts and erythrocyte
Na-K pump activity, and increases in K-Cl co-transport.2,3

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 SAFETY OF RIBAVIRIN IN PREGNANCY

Ribavirin is contraindicated in pregnancy.

Avoidance of pregnancy for 4 months after ribavirin exposure for treated women
and for 7 months for female partners of treated men is recommended.

SAFETY OF RIBAVIRIN IN BREASTFEEDING

Ribavirin is contraindicated in breastfeeding women.

DOSAGE OF RIBAVIRIN IN THE TREATMENT OF COVID-19

Ribavirin is given at 1.2 to 2.4 grams per orem every 8 hours.

REFERENCES:
1. Seley-Radtke KL, Yates MK. The evolution of nucleoside analogue antivirals: A review for chemists and non-chemists.
Part 1: Early structural modifications to the nucleoside scaffold. Antiviral Res. 2018 Jun;154:66-86. doi:
10.1016/j.antiviral.2018.04.004. Epub 2018 Apr 10. PMID: 29649496; PMCID: PMC6396324.
2. Nystrom K, Waldenstrom, J et al. Ribavirin: pharmacology, multiple modes of action and possible future perspectives
FutureVirology (2019)14(3),153–160
3. National Center for Biotechnology Information. PubChem Database. Ribavirin, CID=37542,
https://pubchem.ncbi.nlm.nih.gov/compound/Ribavirin (accessed on Apr. 2, 2020)
4. Erin K McCreary, PharmD, BCPS, BCIDP, Jason M Pogue, PharmD, BCPS, BCIDP, on behalf of the Society of Infectious
Diseases Pharmacists, COVID-19 Treatment: A Review of Early and Emerging Options, Open Forum Infectious
Diseases, , ofaa105, https://doi.org/10.1093/ofid/ofaa105

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 VIII. INTERFERON

Interferon is a biologic response modifier/cytokine. There are three types of

interferons (IFN), alpha, beta and gamma. IFN has antiviral activity and also various
kinds of biological activities including cell growth inhibition, immunosuppressive
effects, enhancement of macrophage, natural killer (NK) cell, killer (K) cell and
neutrophil function , and cell differentiation-inducing activity. 1Interferons (IFNs)
were the first therapeutic agents that permitted successful antiviral therapy with
acceptable side effects in patients with chronic hepatitis B, D, and C.2

Although interferon (IFN) has been used as a treatment for chronic hepatitis B virus
(HBV) infection for 40 years, its exact mechanisms of action are still unclear.
Interferon is thought to induce specific genes that interfere with several steps in the
HBV lifecycle, including virus entry; uncoating of the virion; transcription of viral DNA
into RNA; translation of viral RNA into proteins; and assembly of nucleoplasmids. It
may also augment cell-mediated immunity, thereby promoting clearance of HBV-
infected hepatocytes.3

It is assumed that increased expression of antiviral genes induced by type 1 IFNs is

an important factor in the elimination of hepatitis viruses. These antiviral genes are
only partially understood with respect to function.4

Control of hepatitis B is only rarely achieved in patients with an incompetent immune

system, the immunostimulatory properties of type 1 IFNs are probably required to
eliminate the hepatitis B virus.4

Drug Interactions: Barbiturates (e.g. phenobarbital), Colchicine, Chemotherapeutic

drugs (e.g. aldesleukin, cyclosporine), Hydroxyurea, Telbivudine, Theophyllines
(e.g. aminophylline) 5,6

Pregnancy Category: C

EFFICACY OF INTERFERON IN THE TREATMENT OF COVID-19

Further studies are needed to prove the efficacy of interferon in the therapy
of COVID-19 and other viral illnesses.

Interferons have shown to possess a crucial role in the defense against coronavirus
diseases. The virus can impede the interferon induction in humans. Moreover,
STAT1, a key protein in the interferon mediated immune response, is antagonized
by the virus. This could explain the increased response threshold of immune cells
to IFNs during CoV infections.7

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 Patients with SARS-CoV at the late stages of the disease suffer from many
abnormalities, which are the result of immune system imbalance and malfunction
and lack of effective IFN-specific immune responses that can lead to pro-
inflammatory reactions and immunopathological conditions, presented by lethal
inflammations in the lungs and vascular leakage.8

The key for success in reducing the disease fatality might be the stimulation of the
innate immune responses to trigger IFN production at the very early stages of the
disease, which might be done through administration of agents that are able to
augment IFNs production.8

SAFETY ISSUES ON THE USE OF INTERFERON

Various systemic side effects are associated with the use of interferon.

The lack of data on safety of interferon use for treatment of COVID-19 infection,
warrants further investigation. However, a wide array of adverse effects of alpha
interferon treatment have been described in Chronic Hepatitis C patients. Several
side effects such as fever, headache, fatigue, arthralgias, and myalgias are common
specially with initial injections, as interferon treatment for chronic hepatitis C
infection is administered by subcutaneous or intramuscular injection.9

Neuropsychiatric side effects such as depression and irritability can be most

troublesome, their mechanisms are not well understood. IFN treatment can induce
autoimmune thyroiditis with either hypothyroidism or hyperthyroidism.9

SAFETY OF INTERFERON IN PREGNANCY

Few data show no associated increase in rate of congenital anomaly

formation with use of interferon during pregnancy. More studies are needed
to prove its safety in pregnancy.

Currently, limited data are available on pregnancy outcomes in patients exposed to

interferon-beta (IFN-beta) before or during pregnancy. However, recent European
IFN-beta Pregnancy Registry released a cumulative pregnancy exposure data and
prevalence of pregnancy and infant outcomes in IFN-beta-exposed pregnant
women between years 2009 to 2017.10 The data gathered from these cases suggest
no evidence that IFN-beta exposure before conception and/or during pregnancy
adversely increases the rate of congenital anomalies or spontaneous abortions.10

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 SAFETY OF INTERFERON IN BREASTFEEDING

Further studies are needed to prove the safety of interferon among lactating
women.

A decision should be made to discontinue breastfeeding or discontinue interferon,

taking into account the importance of the drug to the mother. Excretion of interferon
into human milk is unknown.11

DOSAGE INTERFERON IN THE TREATMENT OF COVID-19

Interferon has been administered as 5 million units of interferon-α or its

equivalent as twice daily, given in 2 mL of sterile water by nebulization.

Despite the evidences for the efficacy of IFNs in treating CoV-induced infections,
the proper dosing and ideal timing for such interventions needs to be verified in
clinical trials. Moreover, adding IFN-γ to an IFN-I as a combination therapy is
strongly suggested.8

Based on COVID-19 clinical experience released by American Society of Health-

System Pharmacists (ASHP), there are data accumulating on lopinavir/ritonavir
(LPV/RTV) used with or without interferon in patients with COVID-19 outside of
clinical trials wherein they used 5 million units of interferon-α or equivalent twice
daily given in 2mL of sterile water by nebulization.12

REFERENCES:
1. Imanishi, J. Interferon – alpha, beta, gamma. Gan to kagaku ryoho, 1994. 21(16), 28538. PMID 7993128
2. Di Bisceglie AM, et al. Therapy of chronic hepatitis B with recombinant human alpha and gamma interferon. Hepatology.
1990;11(2):266.
3. Konerman MA, Lok AS, Interferon Treatment for Hepatitis B. Clin Liver Dis. 2016;20(4):645. PMID 27742005
4. Peters M, Mechanism of action of interferons. Semin Liver Dis. 1989;9 (4):235. PMID 2481341
5. Jonkman, JH et al., Effects of alpha-interferon on theophylline pharmacokinetics and metabolism. Br J Clin Pharamcol.
1989 Jun; 27(6): 795-802. PMID 2757895
6. Siu-Fun Wong, James G Jakowatz, Reza Taheri. Potential Drug-Drug Interaction Between Interferon alfa-2b and
Gemfibrozil in a Patient With Malignant Melanoma. Clin Ther, 27 (12), 2005. PMID: 16507380
7. Nezhad, F et al., Therapeutic approaches for COVID-19 based on the dynamics of interferon-mediated immune
responses. March 2020. Doi:10.20944/preprints202003.0206.v1
8. Channappanavar R, Fehr AR, Vijay R, Mack M, Zhao J, Meyerholz DK, et al. Dysregulated Type I Interferon and
Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice. Cell Host
Microbe. 2016;19(2):181–93
9. Dusheiko, G. Side effects of Alpha Interferon in Chronic hepatitis C. US National Library of Medicine. Hepatology, 26
(3 Suppl 1), 112S-121S. sep 1997
10. Hellwig, K et al., pregnancy outcomes in interferon-beta-exposed patients with multiple sclerosis: Results from the
European interferon-beta pregnancy registry. J Neurol. 2020. PMID: 32100126
11. United states National Library of Medicine”Toxnet. Toxicology Data Network. Available from: URL:
http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT.” ([cited 2013]
12. ASHP Assessment of Evidence for COVID-19-Related treatments: Mar 27, 2020

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 IX. CORTICOSTEROIDS

Many of the clinical use of corticosteroids has been associated to their potent anti-
inflammatory and immune-modulating properties.1 The corticosteroids are steroid
hormones produced by the adrenal cortex, consisting of 2 major physiologic and
pharmacologic groups: (1) glucocorticoids, which have important effects on
carbohydrate metabolism, catabolism, immune responses, and inflammation; and
(2) mineralocorticoids, on the other hand has pronounced effects on fluid and
electrolyte balance.2 Corticosteroids encompasses a spectrum of exclusively
glucocorticoid effects to exclusively mineralocorticoid effects, thus steroid
compounds are selected based on their appropriateness for a given treatment.1

The anti-inflammatory property is mainly attributed to their inhibitory effects on the

action of enzyme essential to the production of inflammatory compounds, the
phospholipase A2. Its physiologic effects are the result of several biochemical
pathways. One of these pathways is through their production of proteins called
lipocortins. This inhibits the production of multiple inflammatory cells (macrophages,
monocytes, endothelial cells, basophils, fibroblasts and lymphocytes) that are
crucial in generating an inflammatory response. Thus, it effectively halts the
inflammatory cascade. Furthermore, they are also recognized for its
immunosuppressive property. This may be associated to the suppression of
lymphocyte function and multiplication, altering the immune response.1,2

Drug Interactions: Corticosteroids can interact with drugs that affect the levels of
potassium in the blood (e.g. diuretics, certain laxatives); drugs that have known side
effects when potassium levels drop in the blood stream (e.g. digitalis); drugs
resulting in decreased cortisone in the blood (e.g. rifampicin, carbamazepine,
phenobarbital, phenytoin, primidone) or decrease the gastrointestinal absorption of
cortisone (e.g. gastric dressing); and lithium (corticosteroids decrease blood levels
of lithium). Moreover, corticosteroids can increase blood sugar level and blood
pressure.

Pregnancy Category: Prednisolone - D

Dexamethasone and Betamethasone – C

EFFICACY OF CORTICOSTEROIDS IN THE TREATMENT OF COVID-19

There is insufficient evidence to support corticosteroid use in the treatment

of viral pneumonia, unless warranted for other medical indications. Results of
existing studies showed either inconclusive or possible harm with
corticosteroid use.

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 WHO Interim Guidance (March 13, 2020): Does not support routine use of systemic
corticosteroids for treatment of viral pneumonia outside clinical trials.3

(1) Given the lack of effectiveness and possible harm, routine corticosteroids should
be avoided unless they are indicated for another reason. Other reasons may include
exacerbation of asthma or COPD, septic shock, and risk/benefit analysis needs to
be conducted for individual patients.

(2) Clinicians considering corticosteroids for a patient with COVID-19 and sepsis
must balance the potential small reduction in mortality with the potential downside
of prolonged shedding of coronavirus in the respiratory tract, as has been observed
in patients with MERS.

STUDY
SOURCE DRUGS/DOSE CONCLUSION
POPULATION
Stockman L.J. et al.4 29 studies 13 Articles: 25 Studies:
Systematic Review of involving steroid INCONCLUSIVE INCONCLUSIVE
Published Literature on use High-dose
ribavirin, corticosteroids, methylprednisolone (0.5–1 4 Studies:
lopinavir and ritonavir mg/kg prednisolone on day 3 POSSIBLE HARM
(LPV/r), type I interferon of illness, followed by
(IFN), intravenous hydrocortisone 100 mg every
immunoglobulin (IVIG), 8 h, and pulse-doses of
and SARS convalescent methylprednisolone 0.5 g IV
plasma from both in for 3 days) after the first
vitro studies and in week of illness recovered
SARS patients. (2002- from progressive lung
2005) disease

2 Articles:
EVIDENCE OF POSSIBLE
HARM
(1) Early hydrocortisone use
(200-400mg/day) and SARS-
CoV plasma viral
load clearance: higher
subsequent viral load -
DELAYED VIRAL
CLEARANCE 5

(2) Higher cumulative doses

or prolonged duration of
corticosteroid use is
associated with
PSYCHOSIS.6

14 Chinese Literatures:
12 Studies:

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 INCONCLUSIVE
2 Studies:
POSSIBLE HARM
(1) 1 study: DIABETES
associated with
methylprednisolone7

(2) 1 Study: AVASCULAR

NECROSIS and
OSTEOPOROSIS
associated with
Corticosteroid
methylprednisolone use
(4949 +/- 2959) mg, and the
average course of treatment
(16 to 30 days)8
Rodrigo C et.al,9 19 Doses of corticosteroids INCONCLUSIVE
Cochrane Database observational used were high (mostly >40
Systematic Review, studies mg methylprednisolone [or There is insufficient
Corticosteroids as equivalent] per day), and evidence that
adjunctive therapy in indications for their use were corticosteroids are
the treatment of not well reported. effective for the
influenza. (2016) treatment of
On meta-analysis, influenza. There is
corticosteroid therapy was limited number of
associated with increased laboratory-confirmed
mortality (odds ratio (OR) influenza in the
3.90, 95% confidence treatment and
interval (CI) 2.31 to 6.60; I2 = placebo arms to
68%; 15 studies). draw conclusions for
corticosteroids
effectiveness.
Delaney JW et.al10 Observational The most commonly POSSIBLE HARM
Observational Study, cohort study administered corticosteroids
The Influence of (51 Canadian were prednisone, CAUTION should be
Corticosteroid ICU’s- 607 methylprednisolone, and observed in using
Treatment on the patients) hydrocortisone. corticosteroids
Outcome of Influenza among Adult patients
A(H1N1pdm09)-related Median dose of 227mg of with Influenza-
Critical Illness (2016) hydrocortisone equivalents. associated ARDS.

Median duration of steroid Early corticosteroid

use is 7 days. treatment and higher
dosing was
Corticosteroids were started associated with a
a median of 0 (0, 3) days significantly
from the onset of critical INCREASED
illness and 1 (0, 3) day from HOSPITAL
the initiation of mechanical MORTALITY.
ventilation.

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 Arabi YM et al., 11 Observational Hydrocortisone: median of POSSIBLE HARM
Corticosteroid Therapy study maximum daily equivalent
for Critically ill patients (14 Saudi dose was 300mg (200- There was NO
with Middle East Arabian 400mg) or its SIGNIFICANT
Respiratory Syndrome Centers, 309 equivalent doses DIFFERENCE IN
(2017) patients, Sept (methylprednisolone 1:5, MORTALITY with
2012 to October dexamethasone 1:25, Corticosteroid
2015) prednisolone 1:4) therapy with MERS
after adjustment for
time-varying
confounders but was
associated with
DELAYED MERS
coronavirus RNA
CLEARANCE

(3) For PREGNANT women at risk for preterm birth (24 to 34 weeks) with mild
COVID-19, WHO recommends antenatal corticosteroid when there is no clinical
evidence of maternal infection, and adequate childbirth and newborn care is
available. The clinical benefits of antenatal corticosteroid might outweigh the risks
of potential harm to the mother. The balance of benefits and harms for the woman
and the preterm newborn should be discussed with the woman to ensure an
informed decision, as this assessment may vary depending on the woman’s clinical
condition, her wishes and that of her family, and available health care resources.

(4) WHO has prioritized the evaluation of corticosteroids in clinical trials to assess
safety and efficacy.

CDC: Corticosteroids should be avoided, because of the potential for prolonging

viral replication as observed in MERS-CoV patients, unless indicated for other
reasons. For example, for a chronic obstructive pulmonary disease exacerbation or
for septic shock per Surviving Sepsis guidelines for adults and children.12

STUDY
SOURCE DRUGS/DOSE CONCLUSION
POPULATION
Zumla A et al.,13 Based on 2 Retrospective Observational POSSIBLE HARM
Middle East respiratory studies: Study: 5 cases
syndrome, 2015 Systemic
Observational Case 1: methylprednisolone corticosteroids
study (14 40 mg IV every 8 h for 1 day, showed
centers, 309 then twice daily for 1 day, REDUCTION IN
patient)11 then daily for 2 days. IMMUNE-
PATHOLOGICAL
Retrospective Case 2: HOST
Observational methylprednisolone 60 mg IV RESPONSES, NO
study (5 cases) every 6 h for 6 days, then SIGNIFICANT

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 every 8 h for 1 day, then 40 DIFFERENCE IN
mg every 12 h for 1 day, MORTALITY RATE
followed by a prednisolone and its use was
tapered dose for another 10 associated with
days. WORSENED
CLINICAL
Case 3: OUTCOME in
prednisone 40 mg PO daily, patients infected
tapered to 10 mg PO daily with SARS-Cov in
for 10 days 2002-2003.4

Case 4:
methylprednisolone 40 mg IV
every 8 h for 4 days, then 40
mg IV twice daily for 2 days,
then 40 mg daily for 2 days

Case 5:
methylprednisolone 40 mg IV
every 8 h for 4 days, then 40
mg IV twice daily for 2 days,
and then 40 mg daily for 2
days.

ASHP: Supports the CDC and WHO and Expert consensus statement from Chinese
Thoracic Society regarding use of corticosteroids for in COVID-19 following basic
principles in the use of steroids:

(1) benefits and risks should be carefully weighed before using corticosteroids
(2) corticosteroids should be used prudently in critically ill patients with 2019-nCoV
pneumonia
(3) for patients with hypoxemia due to underlying diseases or who regularly use
corticosteroids for chronic diseases, further use of corticosteroids should be
cautious
(4) dosage should be low to moderate (≤ 0.5–1 mg/ kg daily of methylprednisolone
or equivalent) and duration should be short (≤7 days).14

PSMID, PIDSP: Do not routinely give systemic corticosteroids for treatment of viral
pneumonia or ARDS outside of clinical trials unless they are indicated for another
reason.

There is insufficient evidence to support the use of steroids in the management of

patients with confirmed or suspected 2019-nCoV infection with acute lung injury and
ARDS. Use of steroids may provide little benefit but may cause more harm among
these patients.15

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 In the study by Russel et al., they found that there is limited evidence to support the
advantage in the use of corticosteroids in patients with 2019-nCoV infection as more
harm rather than benefit was observed. Hence, corticosteroid treatment should not
be used for the treatment of 2019-nCoV-induced lung injury or shock outside of a
clinical trial.16

SAFETY ISSUES ON THE USE OF CORTICOSTEROIDS

Corticosteroids are known to have various side effects. Benefits and risks
should always be weighed.

The following harmful side-effects of corticosteroids is mostly associated with the

pattern of linear increase of dose and duration of therapy.

1. DELAYED VIRAL CLEARANCE: This may be associated with the alterations in

the immune system primarily by the T-cell mediated responses by the
corticosteroids leading to the immunosuppression.11

2. PSYCHOSIS: Adverse effects occur up to 90% of patients taking even at a low

glucocorticoid dose (≤7.5mg/dL) with a duration of >60 days. This may be related to
the disturbance of the cortisol pathway by the synthetic steroids stimulating the
glucocorticoid receptors, which has synthetic steroid preference, suppressing the
adrenals cortisol production, promoting an imbalance of glucocorticoid versus
mineralocorticoid receptor stimulation, leading to cognitive-emotional disturbances.
However, prognosis is favorable once the medication is reduced or discontinued.11

3. DIABETES: Glucocorticoids decrease the liver’s sensitivity to insulin, thereby the

output of hepatic glucose is increased. Screening guidelines such as fasting glucose
≥126 mg/dL or HbA1c ≥6.5% should be done to diagnose steroid-induced diabetes
and repeated for confirmation as recommended by American Diabetes Association
guidelines. Management is similar to that of type 2 diabetes mellitus. Patients with
preexisting diabetes, blood sugars should be measured more often than in patients
without preexisting diabetes, and medications should be adjusted to maintain
adequate control.18

4. OSTEOPOROSIS: Bone mineralization is altered with glucocorticoid use through

inhibiting gastrointestinal calcium absorption and shifting signaling-molecule
production to favor bone resorption. It is also associated with the reduction of the
replication, differentiation and function of osteoblasts4 and increasing the rate of
mature cells apoptosis, thereby depleting the osteoblastic cell population and
inhibiting the function of mature cells. Prevention of osteopenia by calcium with
vitamin D when using glucocorticoid doses ≥5 mg/d and starting bisphosphonates
is indicated after densitometry evaluation.19

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 5. AVASCULAR NECROSIS/ OSTEONECROSIS: A combined effect of High dose-
duration-response relationship of corticosteroids, underlying disease and host
susceptibility causes corticosteroid-induced avascular necrosis. This condition
could be secondary to increased osteocyte apoptotic rate due to glucocorticoids
resulting in diminution of bone hydraulic support and disruption of normal bone
vascularity. A high corticosteroid dose of >2g/day corticosteroid (prednisone
equivalent), each 10mg/day increase was associated with 3.6% increase in
osteonecrosis rate especially in the first 3 months are at a higher risk of developing
osteonecrosis.19

6. SECONDARY FUNGAL INFECTION: SARS infection experience induced mild

immunosuppression and further immunosuppression could be aggravated following
a high-dose and prolonged corticosteroid use. Hence, use of corticosteroid in the
treatment of SARS is discouraged.20

SAFETY OF CORTICOSTEROIDS IN PREGNANCY

There is limited data to support the use corticosteroids for the treatment of
COVID-19 infection in pregnant women. However, corticosteroid use can be
considered with prudence in conditions where its clinical benefits outweigh
its risks for both the mother and the fetus.

Physiological adaptive changes during pregnancy particularly the pregnancy-

induced immunological changes leaves women to a state of immunosuppression,
predisposing these women to infections including COVID-19 infection over the
general population.

Corticosteroids, known for promoting immunosuppression through reduction of

lymphocyte proliferation and function, thereby suppressing mainly the cell mediated
immunity and of lesser degree the humoral immunity11 especially to pregnant
women. Together with the limited studies available concerning the use of
corticosteroid for Covid-19 pregnant women, data suggests that there is inadequate
evidence to recommend the use of corticosteroids for pregnant COVID-19
patients.21

Corticosteroids is rated C under FDA category, translated as animal studies

revealed adverse effects on the fetus and there are no controlled studies in women
and animals available. Thus, this drug should be given with discretion if potential
benefits outweighs potential risk to the fetus.22

In a systematic review investigating adverse pregnancy and birth outcomes

following corticosteroid exposure, results showed that there may be a small

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 increased risk of cleft lip with or without cleft palate with use of corticosteroid at first
trimester of pregnancy by 3/1000 births. However, there is insufficient evidence to
support an increased risk of preterm birth, low birth weight or preeclampsia after
corticoid use in pregnancy. They also suggested that use of prednisone dose at less
than 20mg/day in pregnancy is generally safe, however higher doses are considered
in cases of more advanced disease. Inflammation from uncontrolled autoimmune
activity (Rheumatoid arthritis, systemic lupus erythematosus and inflammatory
bowel disease) is potentially more harmful to maternal and fetal health than high-
dose steroids.23

However, WHO recommends use of antenatal corticosteroid only in situations where

no clinical evidence of maternal infection is observed, and adequate childbirth and
newborn care is accessible. The clinical benefits of its use must outweigh the risks
of potential harm to the mother and the preterm newborn, hence thorough
discussion with the woman regarding its risks and benefits is highly encouraged.3

The most commonly used corticosteroid in pregnancy are prednisolone/prednisone,

dexamethasone and betamethasone. Betamethasone and Dexamethasone are
synthetic corticosteroids which has the ability to cross the placental barrier. These
are recommended treatment for anticipated preterm birth. Betamethasone is
administered 12mg intramuscularly daily x 2 doses and Dexamethasone 6mg
intramuscularly every 12 hours x 4 doses. But among these three, prednisolone is
the most commonly used in medical conditions, predominantly for purposes of
immunosuppression and autoimmune treatments other than anticipated preterm
labor in pregnancy.24

SAFETY OF CORTICOSTEROIDS IN BREASTFEEDING

Available data suggests that maternal corticosteroid (prednisone,

prednisolone, betamethasone) use during lactation has no documented
adverse effect on breastfed infants.

Generally, the amount of prednisone measured in breastmilk are very low. No

adverse effects were reported in breastfed infants with maternal use of any
corticosteroid during breastfeeding. Those requiring high maternal doses (especially
with use of prednisolone instead of prednisone) warrants avoidance of
breastfeeding for 4 hours. High doses might occasionally cause temporary loss of
milk supply.28

DOSAGE OF CORTICOSTEROIDS IN THE TREATMENT OF COVID-19

The recommended dose is 50 mg IV every 6 hours, or 100 mg IV bolus followed

by an infusion of 10 mg/hour for seven days.29

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 Low dose hydrocortisone should be added to the treatment regimen for patients with
septic shock that is unresponsive to IV fluids and vasopressor therapy.

REFERENCES:
1. Ericson-Neilsen W, Kaye AD. Steroids: pharmacology, complications, and practice delivery issues. Ochsner J.
2014;14(2):203–207.
2. Goodman & Gilman’s he Pharmacological Basis of Therapeutics 9th Ed, Chapter 59, 1996
3. WHO, Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected,
Interim guidance, March 13, 2020
4. Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med. 2006;3(9):e343. Epub
2006/09/14. doi: 10.1371/journal.pmed.0030343. PubMed PMID: 16968120; PMCID: PMC1564166.

5. Lee N, Allen Chan KC, Hui DS, Ng EK, Wu A, et al. Effects of early corticosteroid treatment on plasma SARS-
associated coronavirus RNA concentrations in adult patients. J Clin Virol. 2004;31:304–309
6. Lee DTS, Wing YK, Leung HCM, Sung JJY, Ng YK, et al. Factors associated with psychosis among patients with
severe acute respiratory syndrome
7. Xiao JZ, Ma L, Gao J, Yang ZJ, Xing XY, et al. (2004) [Glucocorticoid-induced diabetes in severe acute respiratory
syndrome: The impact of high dosage and duration of methylprednisolone therapy]. Zhonghua Nei Ke Za Zhi 43: 179–
182
8. Li YM, Wang SX, Gao HS, Wang JG, Wei CS, et al. (2004) [Factors of avascular necrosis of femoral head and
osteoporosis in SARS patients' convalescence]. Zhonghua Yi Xue Za Zhi 84: 1348–1353.
9. Rodrigo C, Leonardi-Bee J, Nguyen-Van-Tam J, Lim WS. Corticosteroids as adjunctive therapy in the treatment of
influenza. Cochrane Database Syst Rev. 2016
10. Delaney JW, Pinto R, Long J, Lamontagne F, Adhikari NK, Kumar A et al. The influence of corticosteroid treatment on
the outcome of influenza A(H1N1pdm09)-related critical illness. Crit Care. 2016;20:75. Epub 2016/04/03. doi:
10.1186/s13054-016-1230-8. PubMed PMID: 27036638; PMCID: PMC4818504
11. Arabi YM, Mandourah Y, Al-Hameed F, Sindi AA, Almekhlafi GA, Hussein MA et al. Corticosteroid therapy for critically
ill patients with Middle East respiratory syndrome. Am J Respir Crit Care Med. 2018;197(6):757-767. doi:
10.1164/rccm.201706-1172OC. PMID: 29161116.

12. CDC, https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html#foot31
13. Zumla A, Hui DS, Perlman S. Middle East respiratory syndrome. Lancet. 2015 Sep 5;386(9997):995-1007. doi:
10.1016/S0140-6736(15)60454-8. Epub 2015 Jun 3. Review.
14. ASHP, https://www.ashp.org/-/media/assets/pharmacy-practice/resource-centers/Coronavirus/docs/ASHP-COVID-19-
EvidenceTable.ashx?la=en&hash=B414CC64FD64E1AE8CA47AD753BA744EDF4FFB8C
15. PSMD,PIDSP, Interim guideline on the management of patients with suspected and confirmed 2019-nCoV ARD
Version 1.0, as of 12 February 2020
16. Russel, C. et.al., Clinical evidence does not support corticosteroid treatment for 2019-nCov Lung Injury, Feb 7, 2020.
https://www.thelancet.com/journals/lancet/article/fulltext https://doi.org/10.1016/S0140-6736(20)30317-2
17. International Pulmonologist’s Concensus on COVID-19: https://www.unah.edu.hn/dmsdocument/9674-consenso-
internacional-de-neumologos-sobre-covid-19-version-ingles
18. Lansang MC, Hustak LK. Glucocorticoid-induced diabetes and adrenal suppression: how to detect and manage
them. Cleve Clin J Med. 2011 Nov;78(11):748–756.
19. Mont MA, Pivec R, Banerjee S, Issa K, Elmallah RK, Jones LC. High-dose corticosteroid use and risk of hip
osteonecrosis: Meta-analysis and systematic literature review. J Arthroplasty. 2015;30:1506–12.e5. doi:
10.1016/j.arth.2015.03.036.
20. Wang H, Ding Y, Li X, Yang L, Zhang W, et al. (2003) Fatal aspergillosis in a patient with SARS who was treated with
corticosteroids. N Engl J Med 349: 507–508.
21. Luo, Y., Yin, K. Management of Pregnant Women Infected with Covid -19. Lancet 2020 March 24;
https://doi.org/10.1016/S1473-3099(20)30191-2).
22. Smyth A, Radovic M, Garovic VD. Women, kidney disease, and pregnancy. Adv Chronic Kidney Dis.
2013;20(5):402–410. doi:10.1053/j.ackd.2013.06.004
23. Bandoli G, Palmsten K, Forbess Smith CJ, Chambers CD. A Review of Systemic Corticosteroid Use in Pregnancy and
the Risk of Select Pregnancy and Birth Outcomes. Rheum Dis Clin North Am. 2017;43(3):489–502.
doi:10.1016/j.rdc.2017.04.013
24. M.W. Kemp, J.P. Newnham, J.G. Challis, A.H. Jobe, S.J. Stock, The clinical use of corticosteroids in
pregnancy, Human Reproduction Update, Volume 22, Issue 2, March/April 2016, Pages 240–
259, https://doi.org/10.1093/humupd/dmv047
25. Karkhanis, J. et al. Steroid use in acute liver failure. Hepatology 59, 612–621 (2014)
26. R. Moenne-Loccoz, F. Severac, T.F. Baumert, F. Habersetzer, Usefulness of corticosteroids as first-line therapy in
patients with acute severe autoimmune hepatitis J Hepatol, 65 (2016), pp. 444-446
27. Henderson JJ, Hartmann PE, Newnham JP, Simmer K. Effect of preterm birth and antenatal corticosteroid treatment
on lactogenesis II in women. Pediatrics. 2008;121(1):e92–e100. doi:10.1542/peds.2007-1107
28. Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006-.
Prednisone. [Updated 2018 Oct 31]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK501077/
29. Update in Surviving Sepsis Campaign 2019

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 X. INTRAVENOUS IMMMUNOGLOBULIN

It was in 1952 that immune globulin products were used in the therapy of primary
immune deficiency states.1 Intravenous immunoglobulin, or IVIG preparations
contain pooled immunoglobulin G (IgG) from the plasma of about a thousand blood
donors. These intravenous preparations contain >95% unmodified IgG with trace
quantities of immunoglobulin A (IgA), or immunoglobulin M (IgM). Sorbitol-based
formulae are now utilized for intravenous (IV) administration as compared to
previous sucrose-based preparations, which are given intramuscularly, the IV route
decreasing adverse reactions.2

The primary mode of action is blocking of macrophage Fc receptors among patients

with idiopathic thrombocytopenic purpura (ITP) and other autoantibody-related
cytopenias. Among those with Kawasaki condition, and dermatomyositis, IVIG
inhibits production of membrane attack complexes and complement-mediated
tissue damage by binding activated components and so preventing deposition on
certain tissues.3 Some studies also have shown that IVIG results in a kinetic
depression of complement (C3) uptake and modifies process of complement
fragment deposition on erythrocytes. Aside from this, IVIG also has natural
antibodies. IgG, IgM, and IgA antibodies are important components of IVIG
preparations that are immunoregulatory. These natural antibodies bind to
pathogens, may remove senescent molecules, cells, and tumors, may induce
remyelination, and inhibit growth of autoreactive B-cell clones.4

Clinical utility of IVIG preparations is in the therapy of many autoimmune, infectious,

and idiopathic conditions. They are approved for treatment of motor neuropathy,
chronic lymphocytic lymphoma, demyelinating polyneuropathy, Kawasaki disease,
and ITP. A wide range of inflammatory and autoimmune diseases have benefited
from intravenous administration of IVIG, and these conditions range from skin
disorders to transplant rejection, and neurologic conditions. They also have been
used in treating persons afflicted with Guillain-Barre syndrome (GBS), multiple
myeloma, myasthenia gravis, factor VII syndrome, autoimmune neutropenia, post-
transfusion purpura, and polymyositis/dermatomyositis.5

US Food and Drug Administration has approved indications for IVIG:

a. Chronic lymphocytic leukemia
b. Common variable immunodeficiency
c. Chronic inflammatory demyelinating polyneuropathy
d. Primary immunodeficiency disorders with defects in humoral immunity
e. Immune-mediated thrombocytopenia
f. Kawasaki disease
g. Chronic B-cell lymphocytic leukemia
h. Pediatric HIV type I infection

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 i. Multifocal motor neuropathy

Additional data on the uses of IVIG include the following:

a. In obstetrics – may be helpful in treating recurrent pregnancy loss
b.
Monoclonal gammopathy-associated systemic capillary-leak syndrome
(Clarkon disease) – possible survival benefit if IVIG is used for prevention6
c.
Miller Fisher syndrome – no effect on treatment7
d.
Pyoderma gangrenosum – effective as sole immunomodulatory agent for
cases unresponsive to steroids8
e. Peripheral polyneuropathy in Churg-Strauss syndrome – may have benefit9

Drug Interactions: IVIG preparations may interact with

a. Selected live viral vaccines such as measles, mumps, and rubella-containing
vaccines, yellow fever vaccine – may decrease efficacy of live vaccines (may
delay giving the IVIG if a live vaccine is administered the previous month, or
may repeat the dose of the live vaccine after completing IVIG therapy)10
b. Estrogens – when given concomitantly, there may be increased risk of
thromboembolic episodes11
c. Nephrotoxic agents – when given together may increase risk of renal failure12

Pregnancy Category: US FDA Category C

Whole immune globulins have been known to cross the placenta increasingly after
the 30th week age of gestation. But clinical experience does not show ill effects
during pregnancy and on the unborn fetus. If given before delivery among gravidas
with ITP, the platelet response and clinical effects were the same in the mother and
the baby. From this knowledge, there may be potential benefits, which may warrant
use of this drug during pregnancy after weighing risks and benefits.13

EFFICACY OF IMMUNOGLOBULIN IN THE TREATMENT OF COVID-19

Few data are associated with the efficacy of use of IVIG in the therapy of
COVID-19. More studies are needed.

The Immunology and Allergy Clinical Reference Group of the NHS England, does
not recommend use of IVIG in treating patients with coronavirus infection. The
literature, currently, does not provide much rationale for use of this drug in the
therapy of COVID-19 infection. IVIG does not contain the appropriate antibodies
against SARS-CoV-2.14

On one hand, a study was published recently regarding use of IVIG for deteriorating
patients with COVID-19 infection in China. In this practice, IVIG was used in three
critical patients diagnosed with SARS CoV-2 infection. The drug is infused at a high

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 dose regimen of 0.3-0.5 g/kg/day or about 25g/day x 5 days to the 3 patients who
were all diagnosed with severe COVID-19 infection. In this review, all the patients
improved significantly after administration. The authors based the utility of this drug
on experience with therapy of neuromuscular disorders, thrombocytopenic purpura
and other immune diseases, as an immune modulator. There were no reported side
effects among these patients. All 3 had return to normal body temperature in one to
two days, and were relieved of respiratory depression in 3-5 days of therapy. The
authors concluded that high dose IVIG therapy might be a promising treatment
option for early stage of clinical deterioration among patients suffering from this
condition.15

An on-going entitled “A Randomized, Open-label, Controlled, Single-center Study to

Evaluate the Efficacy of Intravenous Immunoglobulin Therapy in Patients With
Severe 2019-nCoV Pneumonia” includes 80 patients who are randomized to
standard of care or to IVIG for severe coronavirus pneumonia. Patients are
randomized to IVIG therapy at 0.5g/kg/day for 5 days plus standard of care and to
placebo which is standard of care only. Outcome measures include clinical
improvement, decrease in lung injury, 28-day mortality, duration of mechanical
ventilation, duration of hospitalization, proportion of patients with negative RT-PCR
results, and occurrence of adverse events. The study started last February 10, 2020
and will finish by June 30, 2020. Results with regard to safety and efficacy of IVIG
in the therapy of severe COVID-19 pneumonia are still pending.16

From the Clinical Practice Guidelines (CPG) for COVID-19 formulated by the
Philippine Society for Microbiology and Infectious Diseases (PSMID), there was no
mention of IVIG as an investigational drug.

SAFETY ISSUES IN THE USE OF IMMUNOGLOBULIN

Side effects have been known to occur in 5-15% of patients receiving IVIG
therapy.

Most reactions to IVIG therapy are mild and reversible. After an intravenous
infusion, patients may have flushing, headache, chills, myalgia, tachycardia,
wheezing, back pain, nausea, and hypotension. If any of these occurs during the
infusion, the rate should be slowed or discontinued. Pre-medication may be done
with antihistamines, or hydrocortisone.

The following are potential adverse effects of IVIG:

a. In IgA deficiency states, serious anaphylactoid reactions may occur and this
can be prevented by using IgA-depleted IVIG17
b. Eczematous reactions

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 c. Acute renal failure which occurs with sucrose-formulations (not with sorbitol-
stabilized preparations)
d. Rarely, thrombosis, and transient neutropenia
e.
Acute myocardial infarction19
f. Aseptic meningitis
g. Post-infusion hyperproteinemia

SAFETY OF IMMUNOGLOBULIN IN PREGNANCY

IVIG can be given to pregnant women if there would be more benefits than
risks for both the mother and the fetus.

IVIG is US FDA Pregnancy Category C. It has been used for many years during
pregnancy for various immune disorders such as autoimmune thrombocytopenia,
immune deficiency disorders, fetal-neonatal alloimmune thrombocytopenia,
antiphospholipid syndrome (APAS), and recurrent pregnancy loss. A review done
in 2001 revealed that IVIG is effective in the therapy of fetal-neonatal alloimmune
thrombocytopenia. It is also promising in managing severe fetal-neonatal
alloimmune hemolysis secondary to anti-erythrocyte antibodies. However, the same
authors concluded that in the management of recurrent pregnancy loss, IVIG is not
effective and warrants further studies.19

The Korean Society for Reproductive Immunology in 2017 recommends IVIG

treatment among women with reproductive failure, including recurrent pregnancy
loss and/or repeated implantation failure, who have cellular immune factors such as
abnormal natural killer cell levels, natural killer cell cytotoxicity, and/or type 1 T-
helper immunity.20

SAFETY OF IMMUNOGLOBULIN IN BREASTFEEDING

IVIG can be offered to lactating women if there would be more benefits than
risks to the breastfeeding infant.

Immune globulin (IgG) is naturally present in breast milk. Some data indicate that
IgG concentrations in milk are normal or even higher and IgM titers in milk are
normal or lower during IVIG therapy.21 There is a consensus that IVIG is a therapy
of choice for lactating mothers afflicted with multiple sclerosis.22

A retrospective study done among 108 women suffering from multiple sclerosis, 69
received the drug postpartum. There were no serious adverse effects among
breastfed infants whose mothers were given IVIG.23 Another study was conducted
among 24 postpartum women given IVIG for relapsing-remitting multiple sclerosis
and was breastfeeding. There were no adverse effects seen among their infants.24

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 DOSAGE OF IMMUNOGLOBULIN FOR THE TREATMENT OF COVID-19

According to limited experience with use of this drug for the management of severe
patients with COVID-19 pneumonia, and with the recommendation by the Philippine
Society of Allergy, Asthma and Immunology, Inc. (PSAAI), IVIG has been noted to
decrease levels of IL-1 receptor antagonists by about 1000x resulting to inhibition of
tumor necrosis factor – alpha (TNF-α)-mediated cytotoxicity. And so IVIG may have
clinical utility in the control of the initial phase of the cytokine storm in patients with
severe COVID-19 infection, as adjunct to anti-inflammatory corticosteroid
administration. It is best given between 7 to 14 days in the acute critical pneumonia
stage in the following dosage regimens:25

a. As an adjunctive therapy at the 1st sign of respiratory depression with:

1. Dyspnea, or
2. ii. RR > 30 cycles per minute, or
3. iii. SpO2 < 93%, or
4. iv. PaO2/FiO2 <300, or
5. v. Progression of lung infiltrates > 50% within 24-48 hours

b. Suggested dose: 0.3-0.5 g/kg/day x 5 consecutive days

1. Start at 30ml/hr (0.5 ml/kg/hr), doubling the rate every 15 minutes
up to maximum of 100ml/hr
2. Consider adjustments per renal and cardiac status of the patient

The PSAAI concluded that IVIG may have clinical advantage when started during
the early course of the disease, though further trials are much needed to prove its
efficacy and safety in this condition. The decision to utilize this preparation should
take into consideration benefits and risks to the patient with severe disease, and to
consider cost of therapy.25

REFERENCES:
1. Purpura in childhood. Lancet. 1981 Jun 6. 1(8232):1228-31.
2. Dantal J. Intravenous immunoglobulins: in-depth review of excipients and acute kidney injury risk. Am J Nephrol. 2013.
38(4):275-84.
3. Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune
globulin. N Engl J Med. 2001 Sep 6. 345(10):747-55.
4. Yuki N, Watanabe H, Nakajima T, Späth PJ. IVIG blocks complement deposition mediated by anti-GM1 antibodies in
multifocal motor neuropathy. J Neurol Neurosurg Psychiatry. 2010 Jul 28.
5. Perez EE, Orange JS, Bonilla F, Chinen J, Chinn IK, Dorsey M, et al. Update on the use of immunoglobulin in human
disease: A review of evidence. J Allergy Clin Immunol. 2017 Mar. 139 (3S):S1-S46.
6. de Chambrun MP, Gousseff M, Mauhin W, et al. Intravenous immunoglobulins improve survival in monoclonal
gammopathy-associated systemic capillary-leak syndrome. Am J Med. 2017 Jun 8.
7. Mori M, Kuwabara S, Fukutake T, Hattori T. Intravenous immunoglobulin therapy for Miller Fisher syndrome. Neurology.
2007 Apr 3. 68(14):1144-6.
8. Suchak R, Macedo C, Glover M, Lawlor F. Intravenous immunoglobulin is effective as a sole immunomodulatory agent
in pyoderma gangrenosum unresponsive to systemic corticosteroids. Clin Exp Dermatol. 2007 Mar. 32(2):205-7.
9. Asashima H, Inokuma S, Yamada H. Step by Step Improvement of Peripheral Polyneuropathy Associated with Churg-
Strauss Syndrome by Six Courses of High-Dose Intravenous Immunoglobulin Therapy. Allergol Int. 2012 Jun 25.

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 10. Centers for Disease Control and Prevention. General Recommendations on Immunization. Recommendations of the
Advisory Committee on Immunization Practices (ACIP). MMWR. Available at:
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6002a1.htm January 28, 2011; 60
11. US Food and Drug Administration. FDA Safety Communication: New boxed warning for thrombosis related to human
immune globulin products. Available at: http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm375096.htm
November 14, 2013.
12. US Food and Drug Administration. MMWR Weekly: Renal Insufficiency and Failure Associated with Immune Globulin
Intravenous Therapy – United States, 1985-1998. Available at:
https://www.cdc.gov/mmwr/preview/mmwrhtml/mm4824a3.htm June 25, 1999
13. "Product Information. Gammagard S/D (immune globulin intravenous)." Baxter Healthcare Corporation, Deerfield, IL
14. Clinical guide for the management of patients requiring immunoglobulin treatment during the coronavirus pandemic and
management of supply. NHS England and NHS Improvement. 27 March 2020 Version 1
15. Wei Cao, Xiaosheng Liu, Tao Bai, Hongwei Fan, Ke Hong, Hui Song, Yang Han, Ling Lin, Lianguo Ruan, Taisheng Li,
High-Dose Intravenous Immunoglobulin as a Therapeutic Option for Deteriorating Patients With Coronavirus Disease
2019, Open Forum Infectious Diseases, Volume 7, Issue 3, March 2020, ofaa102, https://doi.org/10.1093/ofid/ofaa102
16. “A Randomized, Open-label, Controlled, Single-center Study to Evaluate the Efficacy of Intravenous Immunoglobulin
Therapy in Patients With Severe 2019- nCoV Pneumonia”, ClinicalTrials.gov. U.S. National Library of Medicine April
2020
17. Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune
globulin. N Engl J Med. 2001 Sep 6. 345(10):747-55.
18. Nakano Y, Hayashi T, Deguchi K, Sato K, Hishikawa N, Yamashita T, et al. Two young stroke patients associated with
regular intravenous immunoglobulin (IVIg) therapy. J Neurol Sci. 2016 Feb 15. 361:9-12.
19. Branch DW, Porter TF, Paidas MJ, Belfort MA, Gonik B. Obstetric uses of intravenous immunoglobulin: successes,
failures, and promises. J Allergy Clin Immunol. 2001;108(4 Suppl):S133–S138. doi:10.1067/mai.2001.117821
20. Sung N, Han AR, Park CW, et al. Intravenous immunoglobulin G in women with reproductive failure: The Korean Society
for Reproductive Immunology practice guidelines. Clin Exp Reprod Med. 2017;44(1):1–7.
doi:10.5653/cerm.2017.44.1.1
21. Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006-. Immune
Globulin. [Updated 2020 Feb 17]. Available from: https://www.st-va.ncbi.nlm.nih.gov/books/NBK501437/
22. Gotestam Skorpen C, Hoeltzenbein M, Tincani A, et al. The EULAR points to consider for use of antirheumatic drugs
before pregnancy, and during pregnancy and lactation. Ann Rheum Dis. 2016;75:795–810
23. Palmeira P, Costa-Carvalho BT, Arslanian C, et al. Transfer of antibodies across the placenta and in breast milk from
mothers on intravenous immunoglobulin. Pediatr Allergy Immunol. 2009;20:528–35.
24. Winkelmann A, Benecke R, Zettl U. Effect of intravenous immunoglobulin treatment on pregnancy and postpartum-
related relapses in multiple sclerosis: A prospective, rater-blinded analysis. Neurology 2012;78 (1 Suppl):P06.185.
25. A review of Immunomodulators as Therapeutic Interventions for Moderate to Severe COVID-19 Infections (April 20,
2020). Philippine Society of Allergy, Asthma, and Immunology, Inc., (PSAAI)

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 XI. ASCORBIC ACID

Also known as L-ascorbic acid or L-ascorbate is a water-soluble vitamin that is found

in a variety of foods and commonly sold as a dietary supplement. Vitamin C is
required for the biosynthesis of collagen, L-carnitine. Collagen is an essential
component of connective tissue, which plays a vital role in wound healing.1 Aside
from its biosynthetic and antioxidant functions, vitamin C plays a crucial role in
immune function and improves the absorption of non-heme iron,2 the form of iron
present in plant-based foods. Insufficient vitamin C intake for prolonged periods
causes scurvy, which is characterized by fatigue, widespread connective tissue
weakness, and capillary fragility. In general, the daily recommended dietary
allowances (RDAs) are: 90 mg for men, 75 mg for women, Pregnancy and Lactation
115 mg.1,2

Drug interactions: Barbiturates, Aluminum, Estrogens, Chemotherapies, Protease

Inhibitors, Statins, Niacin, Warfarin.

Pregnancy Category: A

EFFICACY OF ASCORBIC ACID IN THE TREATMENT OF COVID-19

There are few evidences that show the efficacy of high dose ascorbic acid in
the therapy of COVID-19. Further studies are needed.

Vitamin C has been proposed for treating respiratory infections when it was isolated
several decades ago. It became particularly popular when Linus Pauling concluded
from previous placebo-controlled trials that vitamin C can prevent and alleviate the
common cold.

Based on a 2013 Cochrane review, regular supplementation of vitamin C has no

effect on common cold incidence in the general population. This indicates that
routine high dose intake is not rationally justified for community use. However,
evidence show that in participants exposed to short periods of extreme physical
stress and or cold environments, vitamin C reduced the risk of the common cold by
50%.3

Although varying amounts and duration of vitamin C supplementation were included

in the review, the minimum amount was 200mg of vitamin C. The review also found
that vitamin C supplements taken during a cold consistently reduces the duration of
the illness by 8% in adults and 14% in children. It translates to shortening the
duration by approximately 1 day.3

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 Among patients with sepsis and ARDS, high dose vitamin C infusion did not
significantly reduce organ failure and biomarkers of inflammation and vascular injury
compared with placebo. However, secondary outcomes show that the vitamin C
group have a significant reduction in mortality at 28 days compared with the placebo
group.4 Re-evaluating the high dose infusion of vitamin C may be a timely choice
for COVID-19 related ARDS.5

In a meta-analysis by Hemila, et al. vitamin C administered orally in doses of 1-

3g/day reduced the length of ICU stay by 8.6% in 12 trials with 1, 766 patients.
Vitamin C also shortened the duration of mechanical ventilation by 18.2% among
patients needing mechanical ventilation for over 24 hours.6

As the COVID-19 situation is an evolving pandemic, a summary of therapeutic

options is being proposed which includes vitamin C in the armamentarium.7
Because of this, rescue therapy with high dose vitamin C may also be considered.8

SAFETY ISSUES IN THE USE OF ASCORBIC ACID

As a water-soluble vitamin, vitamin C poses little risk in regular amounts.

Ascorbic acid tablet dissolves completely once ingested, and any excess is excreted
in the urine. In high doses, exceeding a daily level of 2000 mg, vitamin C has the
potential to cause adverse reactions such as nausea, diarrhea and abdominal pain.9
Also, at very high doses, it can cause calcium oxalate nephrolithiasis.9, 10

SAFETY OF ASCORBIC ACID IN PREGNANCY AND BREASTFEEDING

Vitamin C is safe for use during pregnancy and breastfeeding.

Vitamin C is classified as a US FDA Category A drug. However, current evidence

does not support the routine use of vitamin C supplementation during pregnancy,
as it does not improve outcomes (such as stillbirth, preterm birth, preeclampsia or
low birthweight) for women and their pregnancy.11

A Cochrane review done in 2015 proved that routine supplementation with vitamin
C during pregnancy does not improve outcomes for women and their babies. The
author concluded that there was no convincing evidence that Vitamin C
supplementation alone or in combination with other supplements results in other
important benefits or harms11.

Until such time that high dose vitamin C be proven beneficial, it is prudent to follow
the RDA for pregnant and lactating women at 85-120mg/day and not exceed the
upper limit of 2 grams/day.8

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 DOSAGE OF ASCORBIC ACID FOR THE TREATMENT ON COVID-19

The proposed dosage from previous treatment regimens for high-dose

intravenous vitamin C for COVID-19 is 50 mg/kg BW every 6 hours for 4 days
with glucose restriction.

Several researches are looking into what benefit vitamin C may have among
COVID-19 patients. Clinical trials are on-going as scientists in Wuhan, China and in
New York, USA have been giving ultra-high doses of vitamin C, given intravenously,
among COVID-19 patients. Results of these studies have yet to be published.

Concomitant hydrocortisone 50 mg IV every 6 hours for 7 days must be given to

fight against therapy-induced inflammation.5 Vitamin C is unlikely to prevent or cure
a COVID-19 infection based on current evidence but studies seem to suggest that
it may be a useful adjunct to fight off this viral infection.

REFERENCES:
1. Jacob RA, Sotoudeh G. Vitamin C function and status in chronic disease. Nutr Clin Care 2002;5:66-74.
2. Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and
Carotenoids external link disclaimer. Washington, DC: National Academy Press, 2000.
3. Hemilä H, Chalker E. Vitamin C for preventing and treating the common cold. Cochrane Database Syst
Rev.2013;(3):CD000980.
4. Fowler AA, Truwit JD, Hite RD, et al. 2019. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation
and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical
Trial. JAMA 322(13):1261-1270.
5. Erol, Adnan. High-dose intravenous vitamin C treatment for COVID-19 (A mechanistic approach).
https://www.researchgate.net. Feb 2020.
6. Hemila, Harri; Chalker, Elizabeth. 2019. Vitamin C can shorten the Length of Stay in the ICU: A Meta-Analysis. Nutrients
2019, 11(4),708
7. Lei Zhang; Yunhui Lui. Potential Interventions for Novel Coronavirus in China: A Systematic Review. Jour of Medical
Virol. Feb 2020, 92(5).
8. Matthay MA, Aldrich JM, Gotts JE 2020. Treatment for severe acute respiratory distress syndrome from COVID-19.
Lancet Respir Med doi: 10.1016/S2213-2600(20)30127-2
9. Urivetzky M1, Kessaris D, Smith AD. 1993. Ascorbic acid overdosing: a risk factor for calcium oxalate nephrolithiasis. J
Urol. 1992 May;147(5):1215-8.
10. Taylor EN, Stampfer MJ, Curhan GC. Dietary factors and the risk of incident kidney stones in men: new insights after 14
years of follow-up. J Am Soc Nephrol 2004;15:3225-32.
11. Rumbold A, Ota E, Nagata C, Shahrook S, Crowther CA. Vitamin C supplementation in pregnancy. Cochrane Database
Syst Rev. 2015;(9):CD004072.

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 XII. ZINC

Zinc is a mineral and an essential micronutrient. Zinc is a cofactor for polymerases

and proteases involved in many cellular functions such as wound repair and
intestinal epithelial cell regeneration. It has antioxidant properties and may protect
against oxidative stress.1 Zinc influences the immune system through enhancing
innate and adaptive immunity. It increases chemotaxis and phagocytosis of
polymorphonuclear cells and macrophages as initial response to infections. It also
causes a decrease in the production of proinflammatory cytokines such as IL-1, IL-
6 and tumor necrosis factor (TNF). It also enhances the formation of premature and
immature B cells to facilitate antibody production.2

Drug Interaction: Decrease absorption of antibiotics such as quinolones and

tetracycline

Pregnancy Category: C

EFFICACY OF ZINC IN THE TREATMENT OF COVID-19

Further studies are needed to prove the efficacy of zinc in the therapy of
COVID-19 and other related viral illnesses.

Majority of the studies are in the pediatric age group. Zinc reduces the severity and
duration of acute and chronic diarrhea in children from developing countries.1 Its
supplementation was significantly associated with reducing the incidence and
prevalence of pneumonia among children.3 Zinc has shown antiviral activity in
various infections like influenza and the common cold5,6. It was shown to impair
replication of a variety of RNA viruses. At low concentrations and in combination
with pyrithione, inhibition of SARS-CoV replication has been observed.4 Zinc may
also have an effect on COVID-19 related symptoms like diarrhea and lower
respiratory tract infection and can be used as an adjunct to monotherapy or as
combination therapy with lopinavir-ritonavir, interferon, ribavirin and remdesivir4,5.
Theoretically, inhibition of pro-inflammatory cytokines through the use of zinc may
have a beneficial effect in reducing cytokine storm seen in patients with COVID-19.7

SAFETY ISSUES ON THE USE OF ZINC

Common adverse effects are gastrointestinal distress and irritation.

Nausea and vomiting can occur in high doses. When taken in high dosage, zinc can
cause decreased copper absorption resulting to anemia.

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 SAFETY OF ZINC IN PREGNANCY

Zinc can be given to pregnant women when the benefits outweigh the risks.

Zinc is assigned to pregnancy Category C drug. Although there appears to be no

harmful effects of zinc supplementation, the overall public health benefit of zinc
supplementation in pregnancy currently appears limited8.

SAFETY OF ZINC IN BREASTFEEDING

Zinc can be given to lactating women when the benefits outweigh the risks.

Among mothers who are lactating, in view of the possible benefits of zinc
supplementation for reducing the risk of premature delivery, the possible positive
impact of zinc supplementation on infant birthweight among undernourished
women, and the lack of reported adverse effects, zinc should be included in
maternal supplements given during pregnancy in populations at risk for zinc
deficiency9.

DOSAGE OF ZINC IN THE TREATMENT OF COVID-19

Zinc is given as 50 mg per orem daily.

In a paper written by Derward et al. regarding zinc supplemetation to enhance the

efficacy of CQ/HCQ in the therapy of COVID-19, the authors stated that
comprehensive zinc dose findings studies may currently not be feasible but as
sufficient clinical safety needs to be ensured. They recommended administering
zinc in the range of the upper limit of dosing based on recommended dietary
allowances10.

REFERENCES:
1. Saper R and Rash R. Zinc: An Essential Micronutrient. Am Fam Physician. 2009;79(9):768-772.
2. Nour ZG and Lothar R. Zinc in Infection and Inflammation. Nutrients 2017, 9, 624
3. Lassi ZS, Moin A and Bhutta ZA. Zinc supplementation for the prevention of pneumonia in children aged 2 months to
59 months. Cochrane Database of systematic Reviews 2016. Issue 12.
4. Zhang K and Liu Y. Potential interventions for coronavirus in China: A Systematic Review. J Med Virol. 2020;92:479-
490
5. Zumla A, Hui D Azhar E et al. Reducing mortality from 2019-nCoV: host directed therapies should be an option. The
Lancet. 2020 Vol 395
6. Ghaffari H et al. Inhibition of H1N1 influenza virus infection by zinc oxide nanoparticles: another emerging application
of nanomedicine. Journal of Biomedical Science. 2019 26(70)
7. Sarma P, Prajapat M, Avti P et al. Therapeutic options for the treatment of 2019-novel coronavirus: An evidence based
approach. Indian J Pharmacol 2020; 52: 1-5.
8. Chaffee BW, King JC. Effect of zinc supplementation on pregnancy and infant outcomes: a systematic
review. Paediatric and Perinatal Epidemiology. 2012, 26 (Suppl. 1):118–137.p _1289
9. Hess SY, King JC. Effects of maternal zinc supplementation on pregnancy and lactation outcomes. Food Nutr Bull.
2009;30(1 Suppl):S60‐S78.
10. Derwand R, et al Does zinc supplementation enhance the clinical efficacy of chloroquine/hydroxychloroquine to win
today’s battle against COVID-19? Elsevier. May 5, 2020.

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 XIII. MELATONIN

Melatonin is a hormone that regulates the sleep-wake cycle. It is primarily released

by the pineal gland1, but is currently marketed as supplement, used for the short-
term treatment of sleep disorders such as from jet lag or shift work.2 Melatonin is
also used to treat delirium, atherosclerosis, respiratory disease and viral infections.3

Melatonin will have supportive adjuvant utility in treating COVID-19 induced

pneumonia, acute lung injury (ALI) and acute respiratory Distress Syndrome
(ARDS) through the following mechanisms of actions:

1. Anti-inflammatory effects through several pathways

a. Proper regulation of Sirtuin-1 (SIRT1) which inhibits high mobility group
boxechromosomal protein 1 (HMGB1) leading to down-regulation of the
polarization of macrophages towards the proinflammatory type.4 This
attenuates lung injury and inflammation.5
b. Suppression of Nuclear factor kappa-B (NF-κB) activation in T cells and
lung tissue, hence preventing ARDS 6,7
c. Up-regulation of NF-E2-related factor 2 (Nrf2) which protects lung, liver
and heart from injury.8
d. Reduction in the pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-6,
and IL-8, and an elevation in the level of anti-inflammatory cytokine IL-10.9
e. Up-regulation of anti-oxidative enzymes (e.g. superoxide dismutase),
down-regulation of pro-oxidative enzymes (e.g. nitric oxide synthase) and
may interact directly with free radicals, functioning as free radical
scavenger.10,11
f. Enhancement of the immune response by improving proliferation and
maturation of natural killing cells, T and B lymphocytes, granulocytes and
monocytes in both bone marrow and other tissues.12 Antigen presentation
is also augmented in macrophages, where the up-regulation of
complement receptor 3, MHC Class I and class II, and CD4 antigens were
detected.13
g. Suppression of NOD-like receptor 3 (NLRP3) inflammasome at the peak
of infection protects the lungs from ALI/ARDS.14
h. Mediates the suppression of VEGF in vascular endothelial cells, hence
maintaining integrity of the vascular endothelial barrier, preventing edema
and extravasation of the immune cells from blood vessels.15

2. Published studies also showed the following additional benefits of melatonin:

a. Ameliorate septic shock via the NLRP3 pathway,16 hence preventing
sepsis-induced renal injury, septic cardiomyopathy and liver injury.17
b. Have benefits in patients with myocardial infarction, hypertensive heart
diseases, cardiomyopathy, and pulmonary hypertension.18

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 c. Neurological protection by reducing the cerebral inflammatory response,
cerebral edema and brain-blood barrier permeability.19
d. In ICU patients, melatonin reduces the need for using drugs that causes
deep sedation. It also decreases frequency of pain, agitation and anxiety20
and improves sleep quality.21

Drug Interactions: Other sedatives, Aspirin, OCPs, insulin and other OHAs,
narcotic pain killers, antacids (lansoprazole, omeprazole), ondansetron, ADHD
medications, cardiac and anti-hypertensive medications.

Pregnancy Category: Unknown

EFFICACY OF MELATONIN IN THE TREATMENT OF COVID-19

Limited evidence shows promising results for use of melatonin in therapy of

COVID-19 disease. More studies are needed.

The rationale for the use of melatonin in COVID-19 patients not only focuses on the
attenuation of the infection-induced respiratory disorders, but also an overall
improvement and prevention of patients’ wellbeing and potential complications.22.
On literature review, majority of the studies done on melatonin are in-vitro or animal
studies. Very few studies were done on humans. In a randomized controlled trial of
Gitto et al. in 2005 involving 110 newborns with ARDS, 55 were treated with
melatonin and 55 with placebo. All were mechanically ventilated. IL-6, IL-8 and
TNF-alpha were measured in tracheobronchial aspirate and the clinical outcome
was evaluated. The study concluded that melatonin treatment reduced the pro-
inflammatory cytokines and improved the clinical outcome.25

SAFETY ISSUES IN THE USE OF MELATONIN

When used in very high doses or under suppressed immune conditions,

melatonin may induce increase production of pro-inflammatory cytokines.23

SAFETY OF MELATONIN IN PREGNANCY AND BREASTFEEDING

Due to lack of human studies, pregnant and breastfeeding women should not
take exogenous melatonin at this moment.24

In a Cochrane study done in 2016, it was concluded that there was a lack of any
completed randomised controlled trials, which assessed that melatonin given to the
mother during pregnancy, can help protect the baby's brain. The authors concluded
that further studies are needed.26

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 DOSAGE OF MELATONIN IN THE TREATMENT OF COVID-19

Melatonin is given at high dose at 36-72 mg/day in four divided doses.

In clinical trials, doses of 3 mg, 6 mg and 10 mg of melatonin oral intake by patients

in ICU showed satisfactory safety when compared to placebo. Also, even when
melatonin was given to humans at dose of 1 g/d for a month, there were no adverse
reports of the treatment. 23

REFERENCES:
1. Auld F, Maschauer EL, Morrison I, Skene DJ, Riha RL (August 2017). "Evidence for the efficacy of melatonin in the
treatment of primary adult sleep disorders" (PDF). Sleep Medicine Reviews. 34: 10–22.
doi:10.1016/j.smrv.2016.06.005. PMID 28648359.
2. Matheson E, Hainer BL (July 2017). "Insomnia: Pharmacologic Therapy". American Family Physician. 96 (1): 29–35.
PMID 28671376.
3. R.J. Reiter, Q. Ma, R. Sharma, Treatment of Ebola and other infectious diseases: melatonin “goes viral”, Melatonin Res
3 (2020) 43–57, https://doi.org/10.32794/ mr11250047.
4. R. Hardeland, Melatonin and inflammation-story of a double-edged blade, J. Pineal Res. 65 (2018) e12525,
https://doi.org/10.1111/jpi.12525.
5. Q.-L. Wang, L. Yang, Y. Peng, M. Gao, M.-S. Yang, W. Xing, X.-Z. Xiao, Ginsenoside Rg1 regulates SIRT1 to
ameliorate sepsis-induced lung inflammation and injury via inhibiting endoplasmic reticulum stress and inflammation,
Mediat. Inflamm. 2019 (2019) 6453296, https://doi.org/10.1155/2019/6453296.
6. C.-K. Sun, F.-Y. Lee, Y.-H. Kao, H.-J. Chiang, P.-H. Sung, T.-H. Tsai, Y.-C. Lin, S. Leu, Y.-C. Wu, H.-I. Lu, Y.-L. Chen,
S.-Y. Chung, H.-L. Su, H.-K. Yip, Systemic combined melatonin-mitochondria treatment improves acute respiratory
distress syndrome in the rat, J. Pineal Res. 58 (2015) 137–150, https://doi.org/10.1111/jpi.12199.
7. A.M. da C. Pedrosa, R. Weinlich, G.P. Mognol, B.K. Robbs, J.P. de B. Viola, A. Campa, G.P. Amarante-Mendes,
Melatonin protects CD4+ T cells from activation-induced cell death by blocking NFAT-mediated CD95 ligand
upregulation, J. Immunol (Baltimore, Md.: 1950) 184 (2010) 3487–3494, https://doi.org/10.4049/ jimmunol.0902961.
8. Z. Ahmadi, M. Ashrafizadeh, Melatonin as a potential modulator of Nrf2, Fund.Clin. Pharmacol. 34 (2020) 11–19,
https://doi.org/10.1111/fcp.12498.
9. S. Habtemariam, M. Daglia, A. Sureda, Z. Selamoglu, M.F. Gulhan, S.M. Nabavi, Melatonin and respiratory diseases:
a review, Curr. Top. Med. Chem. 17 (2017) 467–488, https://doi.org/10.2174/1568026616666160824120338.
10. R.J. Reiter, Q. Ma, R. Sharma, Treatment of Ebola and other infectious diseases:
melatonin “goes viral”, Melatonin Res 3 (2020) 43–57, https://doi.org/10.32794/ mr11250047.
11. X. Wu, H. Ji, Y. Wang, C. Gu, W. Gu, L. Hu, L. Zhu, Melatonin alleviates radiationinduced lung injury via regulation of
miR-30e/NLRP3 axis, Oxidative Med. Cell. Longev. 2019 (2019) 4087298, https://doi.org/10.1155/2019/4087298.
12. S.C. Miller, S.R. Pandi-Perumal, A.I. Esquifino, D.P. Cardinali, G.J.M. Maestroni, The role of melatonin in immuno-
enhancement: potential application in cancer, Int. J. Exp. Pathol. 87 (2006) 81–87, https://doi.org/10.1111/j.0959-
9673.2006. 00474.x.
13. C. Kaur, E.A. Ling, Effects of melatonin on macrophages/microglia in postnatal rat brain, J. Pineal Res. 26 (1999) 158–
168, https://doi.org/10.1111/j.1600-079x. 1999.tb00578.x.
14. M.D. Tate, J.D.H. Ong, J.K. Dowling, J.L. McAuley, A.B. Robertson, E. Latz, G.R. Drummond, M.A. Cooper, P.J.
Hertzog, A. Mansell, Reassessing the role of the NLRP3 inflammasome during pathogenic influenza a virus infection
via temporal inhibition, Sci. Rep. 6 (2016) 27912, https://doi.org/10.1038/srep27912.
15. J. Cheng, H.-L. Yang, C.-J. Gu, Y.-K. Liu, J. Shao, R. Zhu, Y.-Y. He, X.-Y. Zhu, M. Q. Li, Melatonin restricts the viability
and angiogenesis of vascular endothelial cells by suppressing HIF-1alpha/ROS/VEGF, Int. J. Mol. Med. 43 (2019) 945–
955, https://doi.org/10.3892/ijmm.2018.4021.
16. H. Volt, J.A. Garcia, C. Doerrier, M.E. Diaz-Casado, A. Guerra-Librero, L.C. Lopez, G. Escames, J.A. Tresguerres, D.
Acuna-Castroviejo, Same molecule but different expression: aging and sepsis trigger NLRP3 inflammasome activation,
a target of melatonin, J. Pineal Res. 60 (2016) 193–205, https://doi.org/10.1111/jpi.12303.
17. J. Chen, H. Xia, L. Zhang, H. Zhang, D. Wang, X. Tao, Protective effects of melatonin on sepsis-induced liver injury
and dysregulation of gluconeogenesis in rats through activating SIRT1/STAT3 pathway, Biomed. Pharmacother. 117
(2019) 109150, https://doi.org/10.1016/j.biopha.2019.109150.
18. F. Nduhirabandi, K. Lamont, Z. Albertyn, L.H. Opie, S. Lecour, Role of toll-like receptor 4 in melatonin-induced
cardioprotection, J. Pineal Res. 60 (2016) 39–47, https://doi.org/10.1111/jpi.12286.
19. S. Tordjman, S. Chokron, R. Delorme, A. Charrier, E. Bellissant, N. Jaafari,C. Fougerou, Melatonin: pharmacology,
functions and therapeutic benefits, Curr. Neuropharmacol. 15 (2017) 434–443, https://doi.org/10.2174/
1570159X14666161228122115.
20. K. Lewandowska, M.A. Malkiewicz, M. Sieminski, W.J. Cubala, P.J. Winklewski, W.A. Medrzycka-Dabrowska, The role
of melatonin and melatonin receptor agonist in the prevention of sleep disturbances and delirium in intensive care unit
- a clinical review, Sleep Med. 69 (2020) 127–134, https://doi.org/10.1016/j.sleep. 2020.01.019.

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 21. S.R. Lewis, M.W. Pritchard, O.J. Schofield-Robinson, P. Alderson, A.F. Smith, Melatonin for the promotion of sleep in
adults in the intensive care unit, The Cochrane Database of Syst. Rev. 5 (2018) CD012455, https://doi.org/10.1002/
14651858.CD012455.pub2.
22. L. Carrascal, P. Nunez-Abades, A. Ayala, M. Cano, Role of melatonin in the inflammatory process and its therapeutic
potential, Curr. Pharm. Design. 24 (2018) 1563–1588, https://doi.org/10.2174/1381612824666180426112832.
23. R Zhang, X Wang, L Ni, X Di, B Ma, S Niu, C Liu, RJ Reiter. COVID-19: melatonin as a potential adjuvant treatment.
Life Sciences 250 (2020). https://doi.org/10.1016/j.lfs.2020.117583.
24. LPH Andersen, I Gogenur, J Rosenberg, RJ Reiter. The Safety of Melatonin in Humans. Clinical Drug Investigation 36,
169-175 (2016).
25. Gitto E, et al, 2005, Correlation among cytokines, bronchopulmonary dysplasia and modality of ventilation in preterm
newborns: improvement with melatonin treatment. Journal of Pineal Research/Vol 39, Issue 3. https://doi.org/10.1111/j.
1600-079X.2005.00251.x
26. Wilkinson D, Shepherd E, Wallace EM. Melatonin for women in pregnancy for neuroprotection of the fetus. Cochrane
Database of Systematic Reviews 2016, Issue 3. Art. No.: CD010527. DOI: 10.1002/14651858.CD010527.pub2

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 XIV. CHLOROQUINE AND HYDROCHLOROQUINE

Chloroquine and hydroxychloroquine were among the first drugs used in the
treatment of COVID-19 infection. These drugs, particularly hydroxychloroquine,
were initially found to have seeming benefit in small observational studies. These
studies purported benefit based on viral clearance and clinical resolution. More
recent data however suggests that greater harm was seen in patients being given
HCQ. The Lancet on May 22, 2020 published a multinational registry analysis
composed of 671 hospitals in six continents. The analysis included a total of 96,032
in-patients with COVID-19 infection. After controlling for multiple confounding
factors, the use of HCQ or CQ with or without a macrolide was associated with an
increased risk of in-hospital mortality and an increased frequency of ventricular
arrhythmias. In light of these findings and the findings of other smaller studies, the
World Health Organization has decided to withdraw HCQ from the SOLIDARITY
Trial involving 3,500 patients in 17 countries on May 25, 2020.1

REFERENCES:
1. Mehra, M, Desai S, Ruschitzka F, Patel A. Hydroxychloroquine or chloroquine with or without a macrolide for treatment
of COVID-19: a multination registry analysis. The Lancet. May 22, 2020. DOI: https://doi.org/10.1016/S0140-
6736(20)31180-6.

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 Recommended PPE Use for Healthcare Workers
Caring for Suspected and Confirmed
COVID-19 Pregnant Women
Valiant L. See, MD
Sybil Lizanne R. Bravo, RPh, MD, MSc / Jennifer T. Co, MD
Catherine Jane R. Costa, MD, MHA / Christine D. Dizon, MD
Shareza B. Nadal, MD / Mary Jane B. Noble, MD, MBAH

WHAT IS PERSONAL PROTECTIVE EQUIPMENT?

Personal protective equipment, commonly referred to as PPE, is an equipment worn
to minimize exposure and to stop the spread of COVID-19. It is one crucial way of
keeping the frontliners safe.
WHAT CAN BE DONE TO ENSURE PROPER USE OF PERSONAL
PROTECTIVE EQUIPMENT?
All personal protective equipment should be safely designed and made in a reliable
fashion. It should fit comfortably, encouraging worker usage. If the personal
protective equipment does not fit properly, it can make the difference between being
safely covered or dangerously exposed. The things to consider when using PPEs
are:
• What kind is necessary
• How to properly put it on, adjust, wear and take it off
• The limitations of the equipment
• Proper care, maintenance, useful life, and disposal of the equipment
WHAT ARE THE COMPONENTS OF PPE?
The components of PPE used when caring for suspected or confirmed COVID-19
pregnant patients will vary according to the setting and activity. Obstetrician-
Gynecologists involved in the direct care of patients should use the following PPE:
1. Disposable cap – acts as a barrier to prevent microorganisms that may
emerge from the hair and cause infection or contamination
2. Eye goggles or Face shield – prevents contamination to the eyes from
splashing of secretions (including respiratory secretions), blood, body fluids
or excretions
3. Face mask – prevents contamination from inhalation of respiratory
secretions especially during an aerosol-generating procedure (Appendix E1
and E2)

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 a. Surgical mask / medical mask – filters out large particles in the air,
protect through reducing exposure to the saliva and respiratory
secretions
b. N95 mask – a type of respirator that offers more protection and can
filter out both large and small particles. It is designed to block 95% of
very small particles
c. FFP (Filtering Face Piece) mask – a half-face mask that protects
the chin, nose and mouth; serves to protect against particulates such
as dust particles and viruses
• FFP1 – has the least filtering capacity
• FFP2 – protection from powdered chemicals; can also serve as
protection against several viruses and bacteria, similar to
the N95 mask
• FFP3 – has the most filtering capacity among the FFP masks;
can protect against very fine particles
d. Elastomeric respirators – widely used by workers for industrial,
mining, and military purposes, but they are not currently used widely
in health care
e. Powered air-purifying respirator (PAPR) – used for protection
during healthcare procedures in which there is a greater risk of
aerosolized pathogens causing acute respiratory infections, its
assigned protection factor exceed the APF of 10 for N95 FFR or
elastomeric half face piece respirators
4. Scrub suit – sanitary clothing worn by the healthcare worker in the sterile
environment
5. Isolation or Disposable gown – protects the clothes from contamination
when providing direct patient care
6. Coveralls / Disposable apron – protective body wear that is fluid resistant
to prevent the possibility of infected body fluids penetrating and
contaminating the underlying clothes or skin with possible subsequent
unrecognized transmission via the hands to the mucous membranes of the
eyes, nose or mouth
7. Disposable Gloves – worn when providing direct patient care and to
protect from exposure to blood and/or other body fluids.
8. Footwear / Shoe covers – helps maintain a sterile environment and
eliminates the risk of contamination to the wearer
REFERENCES:
1. Recommendations from WHO Article on “Interim Guidelines on Rational Use of Personal Protective Equipment for
Coronavirus Disease 2019 (COVID-19). 27 February 2020.

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 WHAT ARE THE LEVELS OF PPE FOR HEALTHCARE WORKERS PROVIDING
SERVICES TO PATIENTS?
STATEMENT:
There are recommended PPEs to minimize risk of cross-transmission of
infection to self and others when providing patient care. The level of PPE that
must be used by a healthcare worker is based on the identified or suspected
infectious agent, severity of illness, route of transmission of infectious agent,
area of care and anticipated exposure to blood or body fluids in the
procedures undertaken.
SUPPORTING STATEMENTS:
Currently, an international and a local recommendation for PPE level use may be
utilized. The Health Protection Scotland PPE has based their PPE level
recommendation on the suspected or identified infectious agent being handled and
the clinical scenario of anticipated risk which depends on route of microbial
transmission, i.e. contact, droplet or airborne (Table 5-1). The local recommendation
was devised by the Philippine General Hospital-Hospital Infection Control Unit
(PGH-HICU) as part of its preparation for the establishment of PGH as a COVID
center in the National Capital Region (NCR). Its recommendation is based on
anticipated exposure risks from different areas in the hospital (Table 5-2, Appendix
F). The PGH recommendation appears to be more apt for use in our local setting.
However, clinicians should observe caution, possess good judgment and make
sound decisions on what level of PPE to utilize based on anticipated risks in their
geographic healthcare settings.

Table 5-1. Levels of Personal Protective Equipment according to Health Protection

Scotland *
CLINICAL SCENARIO /
LEVEL RECOMMENDED PPE
INFECTIOUS AGENT

LEVEL 1 STANDARD INFECTION • No suspected or known

SICPs CONTROL PRECAUTIONS infectious agent
(SICPs)
• Disposable apron • Anticipated exposure to
• Disposable gloves blood and/or other body
fluids
If with risk of spraying or splashing,
use eye and face protection (i.e.
fluid-resistant Type IIR surgical
face mask & full face visor or
goggles)

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 LEVEL 2 DIRECT / INDIRECT • Suspected or confirmed
CONTACT CONTACT PRECAUTIONS infectious agent spread by
• Disposable apron; consider direct/indirect contact:
fluid-resistant disposable
gown if apron provides Examples: C. difficile, Hepatitis C,
MRSA, Salmonella
inadequate cover for the
procedure/task being • Anticipated exposure to
performed blood and/or other body
• Disposable gloves fluids
If with risk of spraying or splashing,
use eye and face protection (i.e.
fluid-resistant Type IIR surgical
face mask & full face visor or
goggles)

LEVEL 2 DROPLET (RESPIRATORY) Suspected or confirmed

DROPLET PRECAUTIONS infectious agent spread by the
• Disposable apron; consider droplet route
fluid-resistant disposable
Examples: SARS-CoV-2, whooping
gown if apron provides
cough, influenza
inadequate cover for the
procedure/task being
performed
• Disposable gloves
• Fluid-resistant Type IIR
surgical face mask &
goggles or fluid-resistant
Type IIR surgical face mask
& full face visor

LEVEL 2 AIRBORNE (RESPIRATORY) Suspected or confirmed

AIRBORNE PRECAUTIONS infectious agent spread by the
• Disposable apron; consider airborne route
fluid-resistant disposable
Examples: Chickenpox, PTB,
gown if apron provides
measles, SARS-CoV-2 (in
inadequate cover for the aerosolizing procedures)
procedure/task being
performed
• Disposable gloves
• Filtering face piece 3 (FFP3)
respirator and eye protection
or a powered hood
respirator

FOR ALL AEROSOL-GENERATING PROCEDURES: FFP3 respirator (and eye

protection) or a powered hood respirator

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 CLINICAL SCENARIO /
LEVEL RECOMMENDED PPE
INFECTIOUS AGENT

LEVEL 3 ENHANCED PRECAUTIONS For suspected or confirmed

ENHANCED • Reinforced fluid-resistant Infectious Diseases of High
long-sleeved surgical gown Consequence (IDHC)
• Disposable fluid-resistant
hood (if wearing a gown w/o • Spread by
an attached hood) DIRECT/INDIRECT
• Full length disposable plastic CONTACT
apron
Examples: Ebola virus, Lassa
• FFP3 respirator or powered virus
hood respirator
• Disposable full face visor • Spread by AIRBORNE
• 2 sets of long or extended ROUTE
cuff non-sterile, non-latex
disposable gloves Examples: SARS, MERS-CoV,
Avian Influenza, SARS-CoV-2
• Surgical wellington boots or (aerosolizing procedures)
closed shoes
• Disposable boot covers

* Adapted from Public Health England & NHS Sheffield (Feb 2019)1

Table 5-2. PGH-HICU Risk-Based Personal Protective Equipment Levels *

AREA
PPE LEVEL PPE COMPONENTS
(Based on PGH set-up)

LEVEL 1 • Surgical mask AT ALL Non-COVID-19

TIMES Lowest Risk Areas
• Alcohol plus hand hygiene

LEVEL 2 • Surgical mask AT ALL Non-COVID-19

TIMES Low Risk Areas
• Goggles/Face shield
• Alcohol plus hand hygiene

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 • N95, KN95, FPP2 mask (fit- COVID-19
tested) Moderate Risk Areas
• Goggles/Face shield
• Surgical cap • In COVID areas where stay
• Double gloves is < 4hrs
LEVEL 3 • Surgical gown • During brief interaction with
• Scrub suits patients
• Shoe covers • To perform NPS/OPS swab
• For all safety officers in the
doffing areas

• COVID-19 Triage Area

• Areas with suspect COVID-
19 cases

LEVEL 4 • N95 mask (fit-tested) COVID-19

• Goggles/Face shield (covers High Risk Areas
front and sides of face with
no areas left uncovered) • In COVID areas where stay
• Surgical cap is > 4 hours
• Double gloves • When performing close
• Coveralls contact with patients
• Scrub suits (intubation, doing CPR,
• Dedicated shoes suctioning ET, inserting
• Shoe covers NGT, changing
linens/diaper)
• In the OR theater during
procedures or surgery
• At the ER to evaluate or
stabilize new patients with
unknown status

In case of doubt if Level 3

or 4, opt for Level 4 PPE

* Adapted from PGH HICU Risk-based PPE Levels “What to Wear” (April 24, 2020)

REFERENCES:
1. Aide Memoire for Levels of Personal Protective Equipment (PPE) – NIPCM. Appendix 16.
http://www.nipcm.hps.scot.nhs.uk/appendices/appendix-16-best-practice-aide-memoire-for-levels-of-personal-protective-
equipment-ppe-for-healthcare-workers-when-providing-patient-care/. V1.0 February 20
2. Recommendations from PGH HICU PPE LEVELS infographic on “What to Wear”. March 29,2020.
3. Recommendations from PGH HICU PPE LEVELS Infographic on “What to Wear”. April 24,2020.

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 WHAT ARE THE RECOMMENDED LEVELS OF PPE AS TO HEALTHCARE
TASK AND AREAS OF EXPOSURE IN THE HOSPITAL?
STATEMENT:
The PPE is essential in protecting healthcare workers from infectious agents
transmitted through contact, droplet or by airborne route.1 To streamline this
process, the recommended level of PPE is classified according to healthcare
personnel task and area of exposure in the hospital (Table 5.3).2,3

Table 5-3. Levels of PPE According to Task and Area of Exposure

AREA 1: PATIENT IN SCREENING ZONE

HEALTH RECOMMENDED
TASK PPE
PERSONNEL LEVEL OF PPE

Doctors and Triage stable • Disposable gloves LEVEL 2

nurses suspect case of • Apron (disposable (Contact)
COVID-19 and water repellant)

Consider fluid-resistant
disposable gown if apron is
inadequate to provide
protection for the
procedure/task being
performed

Doctors and Initial evaluation • Disposable gloves LEVEL 2

nurses of unstable • Apron (disposable (Contact, Droplet)
suspect case of and water repellant)
COVID-19 at • Surgical face mask
triage area and goggles OR
surgical face mask
and full-face visor

AREA 2: PATIENT IN TRANSIT TO TREATMENT ZONE, DELIVERY ROOM OR

OPERATING ROOM COMPLEX (AMBULANCE OR STRETCHER-BORNE)

HEALTH RECOMMENDED
TASK PPE
PERSONNEL LEVEL OF PPE

Paramedics Transport and • Disposable gloves LEVEL 2

Ambulance carry suspect, • Apron, disposable (Contact, Droplet)
Driver probable or and water repellant
Utility Worker confirmed • Surgical face mask
COVID-19 and goggles OR
pregnant patients surgical face mask
and full-face visor

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 AREA 2: PATIENT IN TRANSIT TO TREATMENT ZONE, DELIVERY ROOM OR
OPERATING ROOM COMPLEX (AMBULANCE OR STRETCHER-BORNE)

Utility Worker Disinfection of the • N95 Mask LEVEL 3

Janitorial ambulance • Goggles/Face
shield
• Surgical cap
• Double gloves
• Scrub suit
• Disposable gown
• Shoe covers

AREA 3: PATIENT IN TREATMENT ZONE

HEALTH RECOMMENDED
TASK PPE
PERSONNEL LEVEL OF PPE

ICU/NICU (HIGH RISK)

Doctors and Management of • 2 sets of disposable LEVEL 3

nurses suspect, probable gloves, long or (Enhanced)
or confirmed extended cuff, non-
COVID-19 sterile, non-latex
pregnant patient • Apron, full length
disposable and
water repellant
• Surgical gown, long
sleeved and fluid
resistant
• Filtering facepiece 3
(FFP3) respirator or
a powered hood
respirator
• Disposable fluid
resistant hood (if
wearing a gown
without an attached
hood)
• Disposable full
visor/face shield
• Surgical wellington
boots/closed shoes
• Disposable boot
covers

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 AREA 3: PATIENT IN TREATMENT ZONE

HEALTH RECOMMENDED
TASK PPE
PERSONNEL LEVEL OF PPE

WARD

Doctors and Management of • N95 Mask LEVEL 3

nurses suspect, • Goggles/Face
probable or shield
confirmed • Surgical cap
COVID-19 • Double gloves
postpartum • Disposable gown or
patients impermeable
coveralls
• Shoe covers

Performing CPR • N95 Mask LEVEL 4

• Goggles/Face
shield
• Surgical cap
• Double gloves
• Scrub suit
• Coveralls
• Dedicated shoes
• Shoe covers

LABOR ROOM / DELIVERY ROOM / OPERATING ROOM

Doctors and Labor and • N95 Mask LEVEL 4

nurses delivery of • Goggles/Face
suspect, probable shield
or confirmed • Surgical cap
COVID-19 • Double gloves
pregnant patient • Scrub suit
• Coveralls
• Dedicated shoes
• Shoe covers

Utility Workers Labor and • N95 Mask LEVEL 3

Cleaners delivery of • Goggles/Face
suspect, probable shield
or confirmed • Surgical cap
COVID-19 • Double gloves
pregnant patient • Scrub suit
• Disposable gown
• Shoe covers

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 AREA 3: PATIENT IN TREATMENT ZONE

HEALTH RECOMMENDED
TASK PPE
PERSONNEL LEVEL OF PPE

OUTPATIENT CLINIC AND ULTRASOUND UNIT

Physicians Consultation • N95 Mask LEVEL 3

Sonologist room • Goggles/Face
Nurses shield
Utility Workers Ultrasound room • Surgical cap
Cleaners • Double gloves
Performing • Disposable gown or
diagnostic tests impermeable
coveralls
• Shoe covers

AREA 4: NON-TREATMENT HOSPITAL ZONES / AREAS

HEALTH RECOMMENDED
TASK PPE
PERSONNEL LEVEL OF PPE

Accounting Receive cash or • Disposable gloves LEVEL 1

Billing paper money • Apron, disposable
Cashier payments and water repellant
• Surgical face mask
and goggles OR
surgical face mask
and full-face visor

HR / IT / Heavy handlers • Surgical facemask LEVEL 1

Medical records of papers or AT ALL TIMES
surfaces • Alcohol/Hand
hygiene

Kitchen Food handlers in • Surgical facemask LEVEL 1

Mess Hall direct contact AT ALL TIMES
with exposed • Alcohol/Hand
personnel hygiene

Pharmacy Issue medicines • Surgical facemask LEVEL 1

and supplies AT ALL TIMES
• Alcohol/Hand
hygiene

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 AREA 4: NON-TREATMENT HOSPITAL ZONES / AREAS

HEALTH RECOMMENDED
TASK PPE
PERSONNEL LEVEL OF PPE

Executive Indirect contact • Surgical facemask LEVEL 1

offices with suspect, AT ALL TIMES
probable and • Alcohol/Hand
confirmed hygiene
COVID-19 patient

Hospital support Clean patient’s • N95 Mask LEVEL 3

group and bathrooms • Goggles/Face shield
Janitorial • Surgical cap
services Disinfect rooms • Double gloves
of probable, • Scrub suit
suspect or • Disposable gown
confirmed • Shoe covers
COVID-19 patient

REFERENCES:
1. Aide Memoire for Levels of Personal Protective Equipment (PPE) – NIPCM. Appendix 16.
http://www.nipcm.hps.scot.nhs.uk/appendices/appendix-16-best-practice-aide-memoire-for-levels-of-personal-protective-
equipment-ppe-for-healthcare-workers-when-providing-patient-care/. V1.0 February 20
2. Recommendations from PSMID Article on “Interim Guidelines on the Infection Prevention and Control (IPC) for COVID-19:
Suggested PPEs According to Tasks (Table 2)” V 2.0. pp 9-10. February 26, 2020.
3. Recommendations from PGH HICU PPE LEVELS infographic on “What to Wear”. March 29,2020.
4. Recommendations from PGH HICU PPE LEVELS Infographic on “What to Wear”. April 24,2020.

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 WHAT IS THE RECOMMENDED PPE LEVEL TO BE USED DURING OBSTETRIC
AND GYNECOLOGIC PROCEDURES?
STATEMENT:
For COVID-19 suspect and confirmed pregnant patients, healthcare providers
should use the level 3 personal protective equipment (PPE) for all minor
procedures and in performance of moderate-risk activities, and level 4 PPE
for major procedures.
SUPPORTING STATEMENTS:

A level 3 PPE is enhanced precaution and consists of the following: cap, goggles or
face shield, N95 mask, double gloves, scrub suits, surgical gown and shoe covers
(Appendix G-1 and G-2).

A level 4 PPE is level 3 (i.e. cap, goggles or face shield, N95 mask, double gloves,
scrub suits and shoe covers), with the addition of the following components for
added protection: surgical cap, coveralls, sterile surgical gown, sterile gloves,
apron/raincoat (optional) and dedicated shoes (Appendix H-1 to H3).

Table 5-4. Areas and activities involved where level 3 and level 4 PPEs are used
PPE Level AREAS AND ACTIVITIES INVOLVED

1. At the COVID-designated areas staying < 4 hours

2. Doing history-taking, physical examination (doing pelvic or
internal examination)
3. Performing chest x-ray, blood extraction, making daily rounds
LEVEL 3
4. Performing transvaginal / abdominal ultrasound
5. Performing nasopharyngeal and oropharyngeal specimen
collection (NPS/OPS swabbing)
6. At the Doffing area - for safety officers

1. At the COVID-designated areas staying > 4 hours

2. Transferring the patient
3. Performing change of bed linens with the patient on the bed
4. Changing diapers and doing personal hygiene on the patient
5. Suctioning procedures
6. Doing oral or endotracheal care, insertion of nasogastric tube
LEVEL 4 (NGT - use additional apron or raincoat)
7. Performing intubation and cardiopulmonary resuscitation
(CPR - use additional apron or raincoat)
8. At the operation room theatre (OR), in the performance of any
obstetrics and gynecologic surgery – don sterile surgical gown
and sterile gloves
9. Stabilizing patients at the Emergency Room (ER)

REFERENCES:
1. Recommendations from PSMID Article on “Interim Guidelines on the Infection Prevention and Control (IPC) for COVID-
19: Suggested PPEs According to Tasks (Table 2)” V 2.0. pp 9-10. February 26, 2020.2
2. Recommendations from PGH Article on “What Personnel Protective Equipment to Wear”. March 29, 2020.

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 WHAT IS THE PROPER SEQUENCE OF DONNING AND DOFFING PPE IN
OBSTETRIC AND GYNECOLOGIC PROCEDURES?
STATEMENT:
The type of PPE used will vary based on the level of precautions required. The
procedure for donning and doffing of PPE should be tailored to the specific
type of PPE.
SUPPORTING STATEMENTS:
The World Health Organization (WHO) and the Centers for Disease Control and
Prevention (CDC) have guidelines on the proper donning and doffing of PPEs. More
than one donning and doffing method may be acceptable. Training and
demonstrated competency in donning and doffing PPE ensure proficiency in the use
of the equipment.

DONNING METHOD USING LEVEL 3 PPE

1. Remove all personal items (ex. jewelry, watches, cellphones, etc.).

2. Put on scrub suit.
3. Identify and gather the proper PPE to don.
- Make sure choice of gown size is correct (based on training)
- Undertake the procedure of putting on PPE under the guidance and
supervision of trained observer.
4. Perform hand hygiene.
5. Put on shoe covers.
6. Put on isolation gown.
- Tie all of the ties on the gown.
- Assistance may be needed by other healthcare personnel.
7. Put on NIOSH-approved N95 filtering facepiece respirator or higher (use
facemask if respirator is not available).
- If the respirator has a nosepiece, it should be fitted to the nose with
both hands, not bent or tented. Do not pinch the nosepiece with one
hand.
- Respirator / facemask should be extended under the chin. Both your
mouth and nose should be protected. Do not wear respirator /
facemask under your chin or store in scrubs pocket between patients.
- Respirator: Respirator straps should be placed on crown of head (top
strap) and base of neck (bottom strap). Perform a user seal check
each time you put on the respirator.
- Facemask: mask ties should be secured on crown of head (top tie)
and base of the neck (bottom tie). If mask has loops, hook them
appropriately around your ears.
8. Put on the face shield or goggles.
- Face shields provide full face coverage.

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 - Goggles also provide excellent protection for the eyes, but fogging is
common.
9. Put on head cover or surgical cap.
10. Perform hand hygiene.
11. Put on pair of gloves.
- Gloves should cover the cuff (wrist) of the gown.

DONNING METHOD USING LEVEL 4 PPE

1. Remove all personal items (ex. jewelry, watches, cellphone, pens, etc.)
2. Put on scrub suit and dedicated shoes/rubber boots and put on shoe cover.
- If rubber boots are not available, make sure you have closed and
fluid resistant shoes.
3. Identify and gather the proper PPE to don.
- By visual inspection, ensure that all sizes of the PPE are correct, and
the quality is appropriate.
- Undertake the procedure of putting on the PPE under the guidance
and supervision of a trained observer.
4. Perform hand hygiene.
5. Put on first pair of gloves.
6. Put on coverall.
- Do not use adhesive tape to attach the gloves.
- If the gloves or the coverall sleeves are not long enough, make a
thumb (or middle finger) hole in the coverall sleeve to ensure that
your forearm is not exposed when making wide movements.
- Some coverall models have finger loops attached to sleeves.
7. Put on NIOSH-approved N95 filtering facepiece respirator or higher
- Use facemask if respirator is not available
- Perform a user seal check each time you put on the respirator
8. Put on face shields or goggles
9. Put on head and neck covering (surgical bonnet/cap, covering neck and
sides of the head or hood).
10. Put on disposable waterproof apron (optional)
- Apron that covers the torso and extends to mid-calf may be worn for
additional protection in case a patient has diarrhea or is vomiting
11. Put on second pair of gloves (preferably long cuff) over the cuff.
- Do not use adhesive tape to attach the gloves.
12. Put on sterile gown and sterile gloves without contamination if a sterile
obstetric or gynecologic surgery is to be performed after doing hand
hygiene.

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 DOFFING METHOD USING LEVEL 3 PPE

1. Always remove PPE under the guidance and supervision of a trained

observer.
- Ensure that infectious waste containers are available in the doffing
area for safe disposal of PPE.
- Separate containers should be available for reusable items
2. Perform hand hygiene on gloved hands.
3. Remove shoe covers by one gloved hand
4. Remove pair of gloves.
- Ensure glove removal does not cause additional contamination of the
hands. Gloves can be removed using more than one technique (e.g.,
glove-in-glove or bird beak)
5. Remove gown.
- Untie all ties (or unsnap all buttons). Some gown ties can be broken
rather than untied. Do so in gentle manner, avoiding forceful
movement.
- Reach up to the shoulders and carefully pull gown down and away
from the body. Rolling the gown down is an acceptable approach.
- Dispose in trash receptacle.
- Facilities implementing the reuse or extended use of PPE will need
to adjust their donning and doffing procedures to accommodate
those practices
6. Perform hand hygiene.
7. Remove head cover or surgical cap.
8. Remove face shield or goggles.
- Carefully remove face shield or goggles by grabbing the strap and
pulling upwards and away from the head.
- Do not touch the front of face shield or goggles.
9. Remove and discard respirator (or facemask if used instead of respirator).
- Do not touch the front of the respirator or facemask.
- Facilities implementing the reuse or extended use of PPE will need
to adjust their donning and doffing procedures to accommodate
those practices.
- Respirator: Remove the bottom of the strap by touching only the
strap and bring it carefully over the head, and then pull the respirator
away from the face without touching the front of the respirator.
- Facemask: Carefully untie (or unhook from the ears) and pull away
from the face without touching the front.
10. Perform hand hygiene after removing the respirator/facemask and before
putting it on again if your workplace is practicing reuse.

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 - Facilities implementing the reuse or extended use of PPE will need
to adjust their donning and doffing procedures to accommodate
those practices

DOFFING METHOD USING LEVEL 4 PPE

1. Always remove PPE under the guidance and supervision of a trained

observer (colleague).
- Ensure that infectious waste containers are available in the doffing
area for safe disposal of PPE.
- Separate containers should be available for reusable items.
2. Perform hand hygiene on gloved hands.
3. Remove apron (if worn) by leaning forward and taking care to avoid
contaminating your hands.
- When removing disposable apron, tear it off at the neck and roll it.
Down without touching the front area. Then untie the back and roll
the apron forward.
4. Remove shoe covers (if worn).
5. Perform hand hygiene on gloved hands.
6. Remove head and neck covering taking care to avoid contaminating your
face by starting from the bottom of the hood in the back and rolling from the
back to front and from the inside to outside, and then dispose of it safely.
7. Perform hand hygiene on gloved hands.
8. Remove coverall and outer pair of gloves.
- Ideally this step should be done in front of a mirror.
- Tilt head back to reach zipper, unzip completely without touching any
skin or scrubs, and start removing coverall from top to bottom. After
freeing shoulders, remove the outer gloves.
- This procedure requires properly fitted gloves. When outer gloves
are too tight or inner gloves are too loose and/or hands are sweaty,
the outer gloves may need to be removed separately, after removing
the apron while pulling the arms out of the sleeves. With inner gloves
roll the coverall, from the waist down and from the inside of the
coverall, down to the top of the boots. Use one boot and vice versa,
then step away from the coverall and dispose of it safely.
9. Perform hand hygiene on gloved hands.
10. Remove eye protection (face shield and goggles) by pulling the string from
behind the head and dispose of it safely.
11. Perform hand hygiene on gloved hands.
12. Remove the mask from behind the head by first untying the bottom string
above the head and leaving it hanging in front; and then the top string next
from behind head and dispose of it safely.
13. Perform hand hygiene on gloved hands.

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 - Remove the rubber boots without touching them
- If the same boots are to be used outside of the high-risk zone, keep
them on but clean and decontaminate appropriately before leaving
the doffing area.
14. Perform hand hygiene on gloved hands.
15. Remove gloves carefully with appropriate technique and dispose of them
safely.
16. Perform hand hygiene.
REFERENCES:
1. Using Personal Protective Equipment. Accessed thru: https://www.cdc.gov
2. Steps to put on/take off personal protective equipment including coverall. Accessed thru: https://www.who.int

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 WHAT ARE THE ADVANTAGES AND DISADVANTAGES OF PPE GOWNS AND
COVERALLS BASED ON TYPE OF MATERIAL USED?
STATEMENT:
Materials used for coverall and isolation gown for PPEs can be woven or non-
woven fabric. Each has its advantages and disadvantages.

Table 5-5. Types of Material Used for Coveralls and Isolation Gowns
TYPE OF GOWN MATERIAL ADVANTAGES DISADVANTAGES

Medical-grade GSM fabric • Bacterial barrier • High

coverall or gown material (non- • Water repellant susceptibility to
woven) • Washable UV degradation
• 90 days life • Poorly-resistant
span to chlorinated
solvents and
aromatics1

Improvised Taffeta cloth with • Washable • Porous

coverall or gown 70 Denier Heat • Waterproof • Non-
Sealable / Taslan • Reusable biodegradable
(woven nylon or • Lightweight • May cause
polyester) • Heat-resistant allergic reaction
to resin
component
• Cannot be used
if in direct
contact with
skin; body heat
interacts with
polyester
component that
release toxic
chemicals and
may be
absorbed by the
skin1

REFERENCES:
1. Antimicrobial Characteristics of Pulsed Laser Deposited Metal Oxides on Polypropylene Hydroentangled Nonwovens for
Medical Textiles.
https://www.researchgate.net/publication/316958768_Antimicrobial_Characteristics_of_Pulsed_Laser_Deposited_Metal_O
xides_on_Polypropylene_Hydroentangled_Nonwovens_for_Medical_Textiles

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 WHAT ARE THE NON-WOVEN FABRIC MATERIALS USED IN PPEs?
STATEMENT:
Non-woven fabric materials are textiles made thru a process other than
weaving. They are extruded or blown fibers, usually polyethylene and
polypropylene, that are bound into fabric using heat, and finished to achieve
repellence, absorbance and anti-static properties. The basic method of
producing this material is by “spun-bonding”. Other methods result in a
different type of finished fabric (Table 5.5).1

Table 5-6. Non-Woven Fabric Materials Used for Standard Coverall and Improvised
PPEs
TYPE OF FIBER NO. OF
TYPE OF FABRIC DESCRIPTION
USED LAYERS

Flashspun Dense structure of fine 100% 1

Polyethylene continuous polyethylene polyethylene
(FSPE) fibers fiber

Microporous Film Microporous layer features Outer layer: 2

Laminate interlinked cavities forming polyethylene
(MPFL) “wormholes” through the film fiber

Inner layer:
polypropylene
fiber

Spun bond-Melt Spunbond layer provides 3 layers of 3

blown-Spun bond strength propylene fibers
(SMS)
Meltblown layer provides
filtration

REFERENCES:
1. Coverall [email protected].

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 IS THERE A STANDARD TESTING FOR FABRICS IN PROTECTING AGAINST
INFECTIOUS AGENTS AND BIOLOGICAL HAZARDS?
STATEMENT:
Yes. The EN 14126 is the standard protective clothing against infectious
agents and biological hazards. It defines no requirements for garment
construction, but undergoes four different tests which measure a fabric’s
ability to resist penetration by liquids that may be contaminated by bacteria
or other infectious agents.1

Table 5-7. Fabric Testing for EN 14126 Infectious Agent Protection2

COMPARISON OF FLASHSPUN POLYETHYLENE (FSPE)
AND MICROPOROUS FILM LAMINATE (MPFL)
TEST DESCRIPTION TEST # CLASSES FPSE MPFL
Resistance to ISO 1 TO 3 1 3
Penetration by Biological 22611 (3=highest)
Contaminated Aerosols
Resistance to ISO 1 TO 6 unclassified 6
Penetration by Blood- 16604 (6=highest)
borne Pathogens
Resistance to EN ISO 1 TO 6 1 6
Penetration by 22610 (6=highest)
Contaminated Liquids
Resistance to ISO 1 TO 3 1 3
Contamination by Solid 22612 (3=highest)
Particles
*SMS fabric is not tested because it is not recommended for this type of protection.2

REFERENCES:
1. Coverall [email protected].
2. Lill, Martin. “Type 6 Disposable Safety Clothing: Which Coveralls Offer Best Liquid Protection?”. Lakeland Europe Blog.
August 30, 2019.

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 HOW ARE PPEs DISINFECTED FOR REUSE?
STATEMENT:
PPEs are intended to be disposed after a single use. However, the abrupt
large-scale increase in demand during this pandemic has depleted the current
global stockpile and manufacturers are unable to keep up with the worldwide
request for supplies. For this reason, WHO released interim guidelines on the
extended use and reprocessing of PPEs. The CDC also released strategies
for effective decontamination which aim to sterilize the PPEs for reuse while
maintaining their protective functions to the user.1,2,3,

Table 5-7. Sterilization and Disinfection Techniques for PPEs

PPE METHOD OF DISINFECTION

FFP3 / N95 masks Preserve the integrity of the mask by decontamination

through use of:
1) vaporous hydrogen peroxide,
2) 6% liquid hydrogen peroxide submersion for 30
minutes,
3) UV germicidal irradiation or
4) moist heat at 60⁰C and 85% RH (relative humidity)

Avoid using isopropyl alcohol, soap, bleach, autoclave, dry

heat and microwave for disinfection as they cause significant
filter degradation and disruption of particle penetration level.1

Limit number of reuses to no more than 5 times to ensure

adequate safety margin.2

Goggles / Face shields Clean with soap and water followed by disinfection using
and hoods either sodium hypochlorite 0.1% (1:1000) or 70% alcohol
wipes. Then rinse off with water. Contact time when using
sodium hypochlorite disinfectant must be at least 10 minutes
for optimum sterilization.3

Isolation gown / Cotton Machine-wash with warm water (60-90°C) and laundry
gowns detergent.

If machine-washing is not possible, linen can be soaked in

hot water and soap in a large drum, using a stick to stir, taking
care to avoid splashing. Then soak linen in 0.05% chlorine
for approximately 30 minutes. Rinse with clean water and let
dry fully in the sunlight.3

REFERENCES:
1. CDC website on Coronavirus 2019: “Decontamination and Reuse of Filtering Facepiece Respirators”. April 29, 2020.
2. CDC website on The National Institute for Occupational Safety and Health (NIOSH) Pandemic Planning: “Recommended
Guidance for Extended Use and Limited Reuse of N95 Filtering Facepiece Respirators in Healthcare Settings”. March
27,2020.
3. WHO Interim Guidance: “Rational use of PPE for coronavirus disease (COVID-19) and considerations during severe
shortage”. April 6, 2020.

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 WHAT ARE SOME OF THE INNOVATIONS CREATED TO PROTECT
HEALTHCARE WORKERS DURING THIS COVID-19 PANDEMIC?
STATEMENT:
With the increasing incidence of healthcare workers getting infected with the
COVID-19 while handling their patients here in our country, a number of novel
improvised barriers were invented by colleagues in the medical field to
address this concern. The main objective of which is to protect healthcare
workers by minimizing their exposure to patients when necessary procedures
or diagnostics need to be undertaken.

Table 5-7. Improvised Barrier Protection Against SARS-CoV-2 in Different Healthcare

Settings
IMPROVISED HARM OR
USES BENEFIT
BARRIER LIMITATION

Acrylic aerosol Endotracheal Minimizes exposure Poor organ

box intubation to droplets while exposure due to
performing intubation limitation of mobility

Consultation Minimizes exposure Limited protection

barrier to droplets during
history-taking Limited access to
patient for doing
physical
examination

Plastic-covered Labor/Delivery Minimizes exposure Prolonged use can

isolation to droplets/aerosols lead to suffocation
compartment during second stage
of labor and during
delivery

Ultrasound Minimizes exposure Poor disinfection

procedures to droplet for both between patients
sonologist and may lead to
machine enhancement of
transmission

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Table 5-9. Miscellaneous Agents Used Against SARS-CoV-2 for Protection of
Healthcare Workers and/or their Environment
HARM
AGENT USES BENEFIT
OR LIMITATION

Ultraviolet Inactivates Destroys airborne Can cause eye

Germicidal microorganisms by organisms and damage (cataract
Irradiation destruction of their inactivates formation, macular
(UVGI) nucleic acid through microorganisms on degeneration) and
strand breakage and surfaces2 surface burns on
formation of photo- unshielded skin, eyes
induced byproducts Suitable for and other organs1
such as thymine viruses because of
dimer. Damaged their higher Kills microorganisms
nucleic acid cannot be susceptibility to UVGI depending on UV
used for cell than bacteria. Viruses intensity and time of
reproduction.1 are also difficult to exposure.1
filter because of their
size.1 Germicidal
effectiveness and use
is influenced by
organic matter,
temperature,
wavelength and type
of microorganism2

High Efficiency Captures a portion of Effective at removing Molds and bacteria

Particulate Air airborne virus-sized bacteria, fungus, can grow on filters.
(HEPA) Filter particles by diffusion. some viruses and Spores from molds
Trapped viruses large particulate can get released
cannot multiply on allergens like pollen, back into the air while
their own2 dander, and dust endotoxins from
mites3 degraded bacteria
Newer models provide can get dispersed
efficiency down to 0.1 into the airstream.3
micron particle size at
a removal efficiency of Filters should be
99.97%1 replaced regularly
every 6 months for
commercial use and
up to 1-2 years for
residential use.3

REFERENCES:
1. Schentagg, JJ et. al. . SARS: Clearing the Air. Washington DC: National Academics Press (USA). 2004.
2. www.cdc.gov/coronavirus/2019-ncov/hcp/guidance-prevent-spread
3. “Pros and Cons of HEPA Filter Air Purifiers, Dissected” at https://molekule.science/pros

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APPENDIX A: Algorithm on Screening Pregnant Patients for SARS-CoV-2

DISCLAIMER: This algorithm was formulated to guide clinicians on the benefit

of SARS-CoV-2 testing in this population. This recommendation can be
adopted and modified based on geographical risk, available resources and
testing capacity of each institution or facility.

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APPENDIX B-1: Empiric Antimicrobial Therapy for Low-Risk Community
Acquired Pneumonia with usual recommended dosages in 50-60kg adults with
normal liver and renal functions

Risk Stratification Potential Pathogens Empiric Therapy

Low-risk CAP Streptococcus Without co-morbid

Stable VS: pneumoniae illness
RR <30/min Haemophilus influenzae Amoxicillin 1 gm TID
PR <125/min Chlamydophilia OR
SBP > 90 mmHg pneumoniae Extended Macrolides
DBP >60 mmHg Mycoplasma pneumoniae Azithromycin 500mg OD
Temp >36 °C or <40 °C Moraxella catarrhalis OR
Enteric Gram-negative Clarithromycin 500mg
• No altered mental state bacilli (among those with BID
of acute onset co-morbid illness)
• No suspected aspiration With stable co-morbid
• No or stable co-morbid illness
conditions ß-lactam/ß-lactamase
• Chest X-ray inhibitor combination
- Localized infiltrates (BLIC) OR 2nd Gen oral
- No evidence of Cephalosporin +/-
pleural effusion extended macrolides
Co-amoxyclav 1 gm BID
OR
Sultamicillin 750 mg BID
OR Cefuroxime axetil 500
mg BID
+/-
Azithromycin 500mg OD
OR
Clarithromycin 500mg
BID

SOURCE: Joint Statement of the Philippine Society for Microbiology and Infectious Diseases, Philippine College of Chest
Physicians, Philippine Academy of Family Physicians, Inc. and Philippine College of Radiology. Philippine Clinical Practice
Guidelines. Diagnosis, Empiric Management and Prevention of Community-Acquired Pneumonia in Immunocompetent Adults
2016 Update Treatment.

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APPENDIX B-2:
Empiric Antimicrobial Therapy for Moderate-Risk
Community Acquired Pneumonia with usual recommended dosages in 50-
60kg adults with normal liver and renal functions

Risk Stratification Potential Pathogens Empiric Therapy

Moderate-risk CAP Streptococcus pneumoniae IV non-antipseudomonal

Unstable VS: Haemophilus influenzae ß-lactam
RR ≥30/min Chlamydophilia pneumoniae (BLIC, cephalosporin) +
PR ≥125/min Mycoplasma pneumoniae extended macrolides or
SBP < 90 mmHg Moraxella catarrhalis respiratory fluoroquinolones
DBP <60 mmHg Enteric Gram-negative bacilli (PO)
Temp ≤36 °C or ≥40 °C Legionella pneumophilia Ampicillin-Sulbactam 1.5gm
Anaerobes (among those with q6h IV
• Altered mental state of acute risk of aspiration) OR
onset Cefuroxime 1.5gm q8h IV OR
• Suspected aspiration Ceftriaxone 2gm OD
• Unstable/Decompensated co- +
morbid condition Azithromycin 500mg OD PO
- uncontrolled DM OR
- active malignancies Clarithromycin 500mg BID PO
- neurologic disease in OR
evolution Levofloxacin 500mg OD PO
- congestive heart failure OR
(CHF) Class II-IV Moxifloxacin400mg OD PO
- unstable coronary artery
disease
- renal failure on dialysis
- uncompensated COPD
- decompensated liver
disease

Moderate-risk CAP Streptococcus pneumoniae If aspiration pneumonia is

Unstable VS: Haemophilus influenzae suspected and, a regimen
RR ≥30/min Chlamydophilia pneumoniae containing
PR ≥125/min Mycoplasma pneumoniae Ampicillin-Sulbactam and/or
SBP < 90 mmHg Moraxella catarrhalis Moxifloxacin is used, there is
DBP <60 mmHg Enteric Gram-negative bacilli no need to add another
Temp ≤36 °C or ≥40 °C Legionella pneumophilia antibiotic for additional
Anaerobes (among those with anaerobic coverage.
• Altered mental state of acute risk of aspiration) If another combination is used,
onset may add Clindamycin to the
• Suspected aspiration regimen to cover
• Unstable/Decompensated co- microaerophilic streptococci
morbid condition Clindamycin 600mg q8h IV
- uncontrolled DM OR
- active malignancies Ampicillin-Sulbactam 3gm q6h
- neurologic disease in IV
evolution OR
- congestive heart failure Moxifloxacin 400mg OD PO
(CHF) Class II-IV
- unstable coronary artery
disease
- renal failure on dialysis
- uncompensated COPD
- decompensated liver
disease

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APPENDIX B-3: Empiric Antimicrobial Therapy for High-Risk Community
Acquired Pneumonia with usual recommended dosages in 50-60kg adults with
normal liver and renal functions1

Risk Stratification Potential Pathogens Empiric Therapy

High-risk CAP Streptococcus pneumoniae No risk for P. Aeruginosa
Haemophilus influenzae IV non-antipseudomonal
Any of the clinical feature of Chlamydophilia pneumoniae ß-lactam
Moderate-risk CAP plus any Mycoplasma pneumoniae + IV extended macrolides or
of the following: Moraxella catarrhalis respiratory fluoroquinolones
Enteric Gram-negative bacilli Ceftriaxone 2 gm OD OR
Severe Sepsis and Septic Legionella pneumophilia Ertapenem 1 gm OD
Shock OR Anaerobes (among those with +
Need for Mechanical risk of aspiration) Azithromycin dihydrate 500mg
Ventilation Staphylococcus aureus OD IV OR
Pseudomonas aeruginosa Levofloxacin 500mg OD IV
OR
Moxifloxacin 400mg OD IV

High-risk CAP Streptococcus pneumoniae Risk for P. Aeruginosa

Haemophilus influenzae IV antipneumococcal
Any of the clinical feature of Chlamydophilia pneumoniae antipseudomonal
Moderate-risk CAP plus any Mycoplasma pneumoniae ß-lactam (BLIC,cephalosporin
of the following: Moraxella catarrhalis or carbapenem)
Enteric Gram-negative bacilli + IV extended macrolides +
Severe Sepsis and Septic Legionella pneumophilia aminoglycoside
Shock OR Anaerobes (among those with Piperacillin-Tazobactam 4.5
Need for Mechanical risk of aspiration) gm q6h OR
Ventilation Staphylococcus aureus Cefepime 2 gm q8-12h OR
Pseudomonas aeruginosa Meropenem 1 gm q8h
+
Azithromycin dihydrate 500mg
OD IV
+
Gentamicin 3mg/kg OD OR
Amikacin 15mg/kg OD
OR

IV antipneumococcal
antipseudomonal
ß-lactam (BLIC,cephalosporin
or carbapenem)
+ IV Ciprofloxacin/
high dose Levofloxacin
Piperacillin-Tazobactam 4.5
gm q6h OR
Cefepime 2 gm q8-12h OR
Meropenem 1 gm q8h
+
Levofloxacin 750mg OD IV
OR
Ciprofloxacin 400mg q8-12h IV

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 Risk Stratification Potential Pathogens Empiric Therapy

High-risk CAP Streptococcus pneumoniae If MRSA pneumonia is

Haemophilus influenzae suspected, add
Any of the clinical feature of Chlamydophilia pneumoniae Vancomycin 15mg/kg q8-12h
Moderate-risk CAP plus any Mycoplasma pneumoniae OR
of the following: Moraxella catarrhalis Linezolid 600mg q12h IV
Enteric Gram-negative bacilli OR
Severe Sepsis and Septic Legionella pneumophilia Clindamycin 600mg q8h IV
Shock OR Anaerobes (among those with
Need for Mechanical risk of aspiration)
Ventilation Staphylococcus aureus
Pseudomonas aeruginosa

SOURCE: Joint Statement of the Philippine Society for Microbiology and Infectious Diseases, Philippine College of Chest
Physicians, Philippine Academy of Family Physicians, Inc. and Philippine College of Radiology. Philippine Clinical Practice
Guidelines. Diagnosis, Empiric Management and Prevention of Community-Acquired Pneumonia in Immunocompetent Adults
2016 Update Treatment.

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APPENDIX C-1: NIH NHLBI ARDS Clinical Network Mechanical Ventilation
Protocol Summary (Source: www.ards.net.org)

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APPENDIX C-2: NIH NHLBI ARDS Clinical Network Mechanical Ventilation
Protocol Summary (Source: www.ards.net.org)

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APPENDIX C-3: NIH NHLBI ARDS Clinical Network Mechanical Ventilation
Protocol Summary (Source: www.ards.net.org)

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APPENDIX C-4: NIH NHLBI ARDS Clinical Network Mechanical Ventilation
Protocol Summary (Source: www.ards.net.org)

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APPENDIX D: Algorithm on the Clinical Approach to the Management of
COVID-19 in Pregnancy and the Newborn

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APPENDIX E-1: Different Kinds of Face Mask

MASK TYPE STANDARDS FILTRATION EFFECTIVENESS

Image downloaded from: https://smartairfilters.com/en/blog/comparison-mask-standards-rating-effectiveness/

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APPENDIX E-2: Different Kinds of N95 Face Mask

Source: Surgical N95 vs. Standard N95 – Which to Consider? 3M Technical Bulletin, March 2020, Revision 2
https://multimedia.3m.com/mws/media/1794572O/surgical-n95-vs-standard-n95-which-to-consider.pdf

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APPENDIX F: PGH-HICU Risk-Based Personal Protective Equipment
(PPE) Levels Infographic*

*Posted with permission from the Philippine General Hospital-Hospital Infection Control Unit

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APPENDIX G-1: Components of Level 3 PPE for OB-Gyn Procedures

Face shield

Goggles
N95 mask

Gloves

Scrub suit
worn inside
with
impermeable
gown on top

Shoe cover

Image showing the complete components of level 3 PPE

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APPENDIX G-2: Level 3 PPE for OB-Gyn Procedures

An obstetrician wearing level 3 PPE while examining a pregnant patient

An obstetrician wearing level 3 PPE while performing ultrasound

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 APPENDIX H-1 Components of Level 4 PPE for OB-Gyn Procedures

Face shield

Goggles
N95 mask

Gloves
Hazmat suit
or coveralls

Plastic apron
worn over the
Hazmat suit or
coveralls

Shoe cover

Image taken shows the components of level 4 PPE prior to donning of

sterile OR gown and gloves. The physician on the left is wearing a plastic
apron over her overalls as an additional protective layer.

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 APPENDIX H-2 Components of Level 4 PPE for OB-Gyn Procedures

Face shield

Goggles
N95 mask

Gloves Hazmat suit or

coveralls (white)
worn under the
sterile OR gown
(violet)

Shoe cover

Image taken shows the components of level 4 PPE, with the

addition of sterile OR gown worn over the coveralls and
additional layer of sterile gloves.

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APPENDIX H-3 Components of Level 4 PPE for OB-Gyn Procedures

Prior to donning sterile OR gown After donning sterile OR gown

Image on the left illustrates the components of level 4 PPE prior to donning the sterile OR
gown, namely: goggles, N95 mask, hair cap, coverall, scrub suit (worn underneath the
coveralls), gloves, and shoe cover.

Image on the right illustrates the components of level 4 PPE, with the addition of sterile OR
gown worn over the coveralls and another layer of sterile gloves.

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