Abortion-related tetanus

Abortion-related tetanus is a specific problem, with a higher associated mortality compared with
tetanus arising from other portals of entry.4 Reliable data regarding the incidence of postabortion
tetanus are not available. Studies in Bangladesh in the late 1990s suggested that 55% of tetanus-
related deaths in women and girls aged 10–50 years were due to postabortion tetanus, and
national data showed that 35% of pregnancy-related tetanus deaths were due to
abortion.26 Fauveau and colleagues,23 in an analysis of 1101 cases of maternal tetanus in
developing countries, concluded that 27% of cases were secondary to abortion.
Traditional abortion methods commonly involve high-risk practices, such as the insertion of
sticks, herbs, or roots into the cervix, or the use of unsterile surgical instruments. An estimated
22 million unsafe abortions occurred in 2008.27 Women who use these methods are unlikely to
seek conventional health care and thus might miss pregnancy-linked vaccination services.
Adolescents might be too young to access maternal programmes. Although standard infant
immunisation is likely to confer protective antibodies to a sufficient level until antenatal boosters
are given, adolescents will be at risk of tetanus in areas where infant immunisation is deficient.
In one study done in the 1990s,28 serum concentrations of antitetanus IgG were undetectable in
27% of Nigerian adolescents who reported having had at least one abortion. WHO guidance on
standards for abortion, including sterilisation procedures designed to protect against tetanus,
provides no recommendations on concomitant immunisation strategies.29
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Pathophysiology
Tetanus is caused by the toxin produced by the Gram-positive bacillus C tetani, which is an
obligate anaerobe. Their spores, by contrast, are highly resistant and can tolerate air, extremes of
temperature, and common disinfectants. Spores of C tetani are mainly found in human and
animal faeces, soil, and manure, and have been isolated throughout the world. Environmental
factors, such as flooding and typhoons, can increase the number of C tetani spores in the soil,
potentially increasing the risk of tetanus infection after natural disasters.30 The spores enter the
body through contamination of both deep and superficial wounds, and can transform in anaerobic
conditions. The bacteria do not multiply in healthy tissue with normal oxygen tensions, but are
able to grow and multiply in the low-oxygen-tension environment in devitalised or necrotic
tissue.
Strains of C tetani can be differentiated by variations in flagellar antigens and their ability to
produce tetanus toxin. Genome sequencing has revealed the presence of multiple virulence
factors, including tetanolysin O, haemolysin, and fibronectin, as well as proteins involved in cell-
wall binding.31 Only bacteria capable of producing tetanus toxin are able to cause disease.
Tetanus toxin is encoded on plasmid pE88, which also encodes the gene for its direct
transcription regulator.32 The origin of this plasmid is unclear because much of its sequence is
unique to C tetani.31
Tetanus toxin is one of the most potent toxins identified, with a median human lethal dose of less
than 2·5 ng/kg.33 Similar to all clostridial toxins, it exerts its effect by very specific action on one
of the soluble N-ethylmaleimide-sensitive fusion attachment protein receptor proteins involved
in synaptic vesicle release.34 However, unlike most botulinum toxins, which mainly act at the
neuromuscular junction, tetanus toxin is transported into the CNS. This ability to travel
retrogradely inside neurons has led to recent interest in tetanus toxin as a means of mapping
neuronal connections or as a vehicle for transporting therapeutic agents into the CNS.35
The toxin is produced as a single-chain, 150-kDa protein, which is then cleaved to produce a
heavy and light chain of 100 and 50 kDa, respectively. The toxin is released during the stationary
phase of bacterial growth or after cell lysis. The two subchains remain linked by a disulphide
bond. The N-terminal domain of the heavy chain is involved in translocation of the light chain
into the cytosol from an endosome. The C terminus is further subdivided into two parts, with the
C-terminal subsection of the C-terminus being necessary for binding and internalisation into the
neuron.36,37
Tetanus toxin enters the nervous system at the neuromuscular junction after binding to
polysialogangliosides and other molecules in lipid rafts in the neuronal membrane.37,38 The toxin
is transported in the neuron along the same pathways as brain-derived neurotrophic factor, p75
neurotrophin receptor, and tropo-myosin-related kinase B.39 The toxin is then trancytosed to
preganglionic inhibitory interneurons via as yet unclear mechanisms.35 The N terminus of the
heavy chain triggers translocation of the light chain into the cytoplasm.40 The light chain has
zinc-dependent endopeptidase activity and cleaves vesicle-associated monophosphate 2
(synaptobrevin), preventing its action in synaptic vesicle docking and neurotransmitter
release.34 Tetanus toxin therefore inhibits presynaptic inhibitory interneurons, resulting in
disinhibition of motor neuron discharge.
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Clinical features
The clinical signs and symptoms of tetanus result from disinhibition of motor neuron discharge,
causing hypertonus and spasm of skeletal muscle. In severe forms, additional autonomic nervous
system dysfunction can occur. Distinct stages of disease progression are noted and correlate with
toxin uptake and action. The incubation period is defined as the time between wound
contamination and the first symptom, and is the period during which toxin release and transport
occurs. The period of onset is the time during which generalised muscle spasms subsequently
develop.
In neonatal tetanus, infection occurs via the umbilical cord, which can become contaminated
during cutting with unsterile instruments at birth or because of substances being applied to the
cord (eg, animal faeces), meaning that the incubation period is equal to the age at which
symptoms develop. The median incubation period is 5–7 days (range 3–24) after
birth.3,4 Neonates present with refusal to feed, with difficulty in opening the mouth due to
trismus.41 Sucking then stops and facial muscle spasm can produce risus sardonicus. The hands
often become clenched, along with dorsiflexion of the feet and increased muscle tone,
progressing to rigidity and opisthotonus (spasm of spinal extensors). Spasms of the limbs
develop early, initially provoked by physical, auditory, or visual stimuli, but eventually occurring
spontaneously.
In most cases, maternal tetanus presents as a generalised form, affecting all muscle groups.
Incubation periods in older children and adults are usually longer than in neonates, with means of
7–10 days (range 2–38).42–44 The period of onset is typically 24–72 h. Both periods of time are
shorter the more severe the disease.4,42,44 Maternal tetanus arising from internal entry sites
(postpartum, postabortional, or intramuscular injection) are associated with higher mortality than
tetanus arising from other entry sites.4,45,46
Proximal muscle groups are usually affected first in maternal tetanus and, similar to neonatal
tetanus, initial symptoms invariably include trismus,43 with risus sardonicus often evident.
Pharyngeal and laryngeal muscle involvement results in airway compromise at an early stage.
Respiration is further compromised by tension and spasm in respiratory muscles. Opisthotonus
also occurs and can result in spinal fractures.47,48
Autonomic nervous system dysfunction occurs in severe tetanus, usually becoming apparent
during the second week of illness. Cardiovascular manifestations are the most common and
include labile blood pressure, tachycardia, bradycardia, and arrhythmias. Circulating
concentrations of noradrenaline and adrenaline, as indicated by urinary excretion, are higher in
tetanus compared with those measured in other critical illnesses, and normal cardiovascular
regulation is impaired.49,50 Direct catecholamine-related necrosis has been shown at autopsy and
tumour necrosis factor α-associated dysfunction has also been implicated in the
pathophysiology.51 Electrocardiograms of 33 patients in Dakar (Senegal) showed more than one
abnormality in 93% of patients, despite normal echocardiography.52
Localised forms of tetanus can occur, which are generally milder with a better prognosis,
although localised cephalic tetanus is associated with increased airway and respiratory
complications.
Mortality from maternal and neonatal tetanus is high. Adult mortality rates up to 52% are
reported in Asia and Africa.42,43,53–56 Neonatal mortality is even higher, ranging from 3% to 88% in
these regions.57–61 Most tetanus occurs in rural areas. Mortality is highest in patients not admitted
to hospital, and delayed admission to hospital is associated with worse outcomes in neonatal
tetanus.62–64 Facilities for ventilation and intensive care are associated with improved outcome in
both neonatal and non-neonatal tetanus.45,65,66 However, with improved respiratory support,
cardiovascular and other respiratory complications then become apparent.45,65,67,68
Low birthweight (especially <2·5 kg), young age at presentation, fever, generalised rigidity, and
risus sardonicus are associated with worse outcome in neonatal tetanus.58 A meta-analysis of
4535 cases69 of neonatal tetanus (from studies published between 1974 and 2011) concluded that
low birthweight and age at onset were the most important prognostic factors (low birthweight:
odds ratio [OR] 2·09, 95% CI 1·29–3·37), with the combination of a low birthweight of less than
2·5 kg and an age at onset of younger than 6 days most significant (OR 6·8, 95% CI 2·42–
19·11). In maternal tetanus, rapid progression (short incubation and period of onset), an internal
entry site, and underlying disease are all significant indicators of worse prognosis.42–44
Tetanus can take 6–8 weeks to resolve completely, with spasms often lasting 2–3 weeks.70–72 Both
adults and neonates can need ventilation for several weeks (median 23 days, range 17–60) and
intensive care for longer.65,70 Data for long-term sequelae are scarce. In patients in a hospital in
northwestern Tanzania, Chalya and colleagues42 reported that 8·6% of survivors were discharged
with permanent disability, such as a persistent vegetative state, limb amputations, and gait
abnormality. Neurological impairments of persistent rigidity and memory loss were described in
a study of Bangledeshi patients, with a total of three of 75 patients discharged with permanent
disability.43 Muscle rigidity was reported in all 45 surviving patients at discharge in a study in
Thailand.67
Few studies have examined sequelae of neonatal tetanus, but complication rates are likely to be
even higher. The authors of one Kenyan study found that 20–40% of survivors of neonatal
tetanus had evidence of brain damage, manifesting as microcephaly and mild neurological,
developmental, or behavioural problems.73 Complications of cerebral palsy, cognitive delay, and
deafness were described in 20% of survivors in one Nigerian case series.62 These complications
might be caused by the hypoxia and hypoglycaemia commonly detected during the clinical
course.
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Diagnosis
The diagnosis of tetanus is clinical, and criteria for neonatal tetanus diagnosis are described in
the previous section. The differential diagnosis of neonatal tetanus includes birth asphyxia,
hypoglycaemia, hypocalcaemic tetany, and seizures. Few conditions truly mimic generalised
maternal tetanus.
C tetani can be cultured from entry sites with oxygen-reduced blood agar or meat broth,74 but
facilities are often not available and interventions should not be delayed. Bedside inoculation of
media has been reported to improve detection rates. A serum antitetanus IgG concentration
higher than >0·1 IU/mL (taken before antitoxin is given) is accepted as sufficient protection
against tetanus infection and would make the clinical diagnosis less likely.75,76 Bioassay or PCR
detection of tetanus toxin in plasma or wound exudates can also be used, although these are
rarely available in most settings.74,77