NEW THIS WEEK: EPIDEMIOLOGY AND ELIMINATION OF MATERNAL AND NEONATAL TETANUS

Tuesday, 31st of December 2013

MATERNAL AND NEONATAL TETANUS

MNT elimination has missed several deadlines, and competing initiatives (polio, measles, rubella) have been more successful in attracting funds than MNTE. “Maternal and neonatal tetanus cases are clustered in poor, remote, and disenfranchised communities where unhygienic obstetric and postnatal practices prevail, and access to maternal tetanus toxoid immunisation is poor. Differences in neonatal tetanus incidence and mortality of at least an order of magnitude have been identified between regions and countries, and between urban and rural areas within countries.”

The W.H.O. position paper on tetanus vaccine is at http://www.who.int/wer/2006/wer8120.pdf

This review is best viewed at http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61261-6/fulltext

This review dates from 2007. There is a succinct 2012 update at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594855/

Maternal and neonatal tetanus

Martha H Roper MD a, Jos H Vandelaer MD b c , François L Gasse MD c

Summary

Maternal and neonatal tetanus are important causes of maternal and neonatal mortality, claiming about 180 000 lives worldwide every year, almost exclusively in developing countries. Although easily prevented by maternal immunisation with tetanus toxoid vaccine, and aseptic obstetric and postnatal umbilical-cord care practices, maternal and neonatal tetanus persist as public-health problems in 48 countries, mainly in Asia and Africa. Survival of tetanus patients has improved substantially for those treated in hospitals with modern intensive-care facilities; however, such facilities are often unavailable where the tetanus burden is highest. The Maternal and Neonatal Tetanus Elimination Initiative assists countries in which maternal and neonatal tetanus has not been eliminated to provide immunisation with tetanus toxoid to women of childbearing age. The ultimate goal of this initiative is the worldwide elimination of maternal and neonatal tetanus. Since tetanus spores cannot be removed from the environment, sustaining elimination will require improvements to presently inadequate immunisation and health-service infrastructures, and universal access to those services. The renewed worldwide commitment to the reduction of maternal and child mortality, if translated into effective action, could help to provide the systemic changes needed for long-term elimination of maternal and neonatal tetanus.

Tetanus in the first 28 days of life (neonatal tetanus) was long recognised by clinicians in resource-poor settings as an important cause of neonatal death. However, since babies affected by this disease usually are born at home and die there without registration of either event, the true burden was unknown. In the 1970s and 1980s, community-based surveys about neonatal tetanus from more than 40 countries showed that fewer than 10% of tetanus-related cases and deaths were routinely reported in most countries: in some regions, the reporting fraction was as low as 2—5%.1, 2 Estimates based on the results of these surveys, and tetanus data routinely reported to WHO suggested that, in the 1980s, more than 1 million deaths every year were attributable to tetanus, with an estimated 787 000 deaths in 1988 from neonatal tetanus alone.1, 3 In 1989, the worldwide public-health community made a commitment to the elimination of neonatal tetanus (defined as fewer than one case of neonatal tetanus per 1000 livebirths in all districts) by 1995.3, 4

Maternal tetanus is defined as tetanus during pregnancy, or within 6 weeks of the end of pregnancy (whether pregnancy ended with birth, miscarriage, or abortion), and has the same risk factors and means of prevention as neonatal tetanus. In the early 1990s it was estimated to account for about 5% of maternal mortality, or 15 000—30 000 deaths every year.5, 6 In 1999, the elimination of maternal tetanus was added to the goals of the elimination programme for neonatal tetanus, and the initiative was renamed the Maternal and Neonatal Tetanus Elimination Program.6

Good progress has been made in the 15 years since the neonatal tetanus elimination programme began (figure 1). Worldwide mortality from neonatal tetanus was estimated at 180 000 in 2002, which represents a 78% reduction since the late 1980s.13 This disease now accounts for 5—7% of worldwide neonatal mortality, compared with 14% in 1993.14, 15 Estimates of present incidence and mortality of maternal tetanus are unavailable; however, the number of deaths worldwide from this disease has probably undergone a commensurate reduction.

Figure 1 Full-size image (49K) Download to PowerPoint

Estimated deaths from neonatal tetanus and vaccine coverage with two doses of tetanus toxoid, 1980—20053,7—12

In developed countries, tetanus is now little more than a medical curiosity; maternal and neonatal tetanus are exceedingly rare.16, 17 However, tetanus as a whole continues to cause about 213 000—293 000 deaths worldwide each year,14, 18, 19 predominantly in low-income and middle-income countries. Deaths from maternal or neonatal tetanus are concentrated in 48 countries, mostly in Asia and Africa (figure 2).13

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Maternal and neonatal tetanus elimination status by country20

In this Seminar, we review general tetanus pathophysiology, clinical presentation, immunology, and the epidemiology, prevention, and control of maternal and neonatal tetanus, focusing on developing countries, where most cases and deaths take place.

Microbiology and pathophysiology

Tetanus is caused by a neurotoxin produced by Clostridium tetani, a gram-positive, obligate anaerobic rod-shaped bacterium that forms spores. C tetani spores occur worldwide as constituents of soil and in the gastrointestinal tracts of animals (including human beings), and can contaminate many surfaces and substances. The spores are extremely hardy; destruction requires autoclaving or prolonged exposure to iodine, hydrogen peroxide, formalin or gluteraldehyde.21, 22 Infection begins when tetanus spores are introduced into damaged tissue. Maternal and neonatal tetanus are caused by unhygienic methods of delivery, abortion, or umbilical-cord care. For germination and vegetative growth, the bacillus needs low tissue oxygen-reduction (redox) potential, such as that associated with necrosis; proliferation is enhanced by the presence of blood, foreign bodies, and chemicals such as lactic acid, calcium salts, and quinine.21, 23

Tetanus toxin, the endotoxin responsible for tetanus, is one of the most potent toxins ever identified, with a minimum lethal dose of less than 2·5 ng/kg in human beings.21, 24 This high potency is caused by the toxins absolute neurospecificity and enzymatic action.25 Tetanus toxin is synthesised as an inactive polypeptide chain during the bacterial growth phase. The genes for the neurotoxin and its transcriptional regulator, ToxR, which is needed for toxin production, are located in an intracellular plasmid. At autolysis, after death of the bacterium, the toxin molecule is released and transformed by bacterial or tissue proteases into its active form: a 100 kDa heavy chain and a 50 kDa light chain. The heavy chain is necessary for binding to and entry into the neuron. The light chain is responsible for the toxic properties.26—31

The complex mechanisms for binding of tetanus toxin to peripheral neurons and its absorption into these cells, transport to the CNS, and toxic activity has been reviewed in detail elsewhere.21,25,28,31—33 After its release, tetanus toxin diffuses to adjacent muscle tissue, where it binds to specific glycoproteins in lipid-raft microdomains of the plasma membrane of α motorneurons, and is absorbed by endocytosis. The lipid-raft constituents needed for the effective binding of tetanus toxin are not fully understood.28, 34 Free tetanus toxin also enters the lymphatic system and the bloodstream, disseminating widely before entering motor neurons at disparate sites. Inside motor neurons, tetanus toxin is transported to the CNS at 3—13 mm/h by a specific retrograde axonal transport system.25, 28, 35 At the spinal cord and brainstem, the toxin diffuses across synaptic spaces to enter glycinergic and gabinergic inhibitory interneurons.33, 35

Inside inhibitory interneurons, the disulphide bond connecting the heavy and light chains of the toxin is broken. The freed light chain is a zinc-endopeptidase that cleaves synaptobrevin proteins in synaptic vesicle membranes. Synaptobrevin is essential for the fusion of synaptic vesicles with the presynaptic nerve membrane; when this process is disrupted, synaptic vesicles accumulate at the nerve ending and are unable to release neurotransmitter into the adjacent synaptic space. The action of inhibitory neurons is thereby impeded, leaving α motorneuron excitation unopposed, and resulting in the muscle rigidity and longlasting painful spasms which are characteristic of tetanus.21,29—33 In addition to its action on the motor system, tetanus toxin can have profound and life-threatening effects on the autonomic nervous system by interrupting spinal inhibitory sympathetic reflexes, resulting in a hyperadrenergic state.21, 33 The action of tetanus toxin within neurons persists for several weeks; the mechanism of functional recovery remains unclear.21, 33

Clinical manifestations

Tetanus is characterised by muscle rigidity and painful muscle spasms caused by tetanus toxins blockade of inhibitory neurons that normally oppose and modulate the action of excitatory motor neurons. Maternal and neonatal tetanus are both forms of generalised tetanus (the most common manifestation of the disease), and have similar courses. The time from inoculation of tetanus spores into damaged tissue to the appearance of the first symptom, or incubation period, is usually 3—21 days36, 37 (median 8 days38, 39), although cases have been reported with incubation periods as short as 1 day, or longer than a month.32, 40 The average incubation period for neonatal tetanus (age at first symptom) is shorter than that of non-neonatal tetanus. About 90% of neonates with tetanus develop symptoms in the first 3—14 days of life, mostly on days 6—8, distinguishing neonatal tetanus from other causes of neonatal mortality which typically occur in the first two days of life.37, 41, 42

Tetanus muscle rigidity usually begins in the masseter muscles, resulting in trismus (lockjaw). Dysphagia and neck, shoulder, back, or abdominal muscle stiffness and pain are other common early symptoms. Risus sardonicus, a flat-lipped grimace resulting from tightened facial muscles is a pathognomonic finding, but can be subtle.33, 43 In neonatal tetanus, trismus and lip muscle rigidity interfere with normal sucking and feeding, which is the hallmark of disease onset.44 As disease severity increases, muscle rigidity extends throughout the body and muscle spasms begin, first in response to sensory stimuli but later progressing to spontaneous longlasting excruciating spasms of many muscle groups (figure 3). The onset period, or time from first symptom to first spasm, is typically 1—3 days, ranging from hours to 5 days.37—39 In severe tetanus, sudden generalised tonic contractions of all muscle groups, or tetanospasms, result in opisthotonos, adduction of the shoulders, flexion of the elbows and wrists, and extension of the legs, usually accompanied by temperature rises of several degrees.36 Consciousness is preserved, making tetanus a truly dreadful disease. Onset and disease progression are more rapid in neonatal tetanus than in non-neonatal tetanus, often taking hours instead of days, perhaps because axonal length, and thus the time for transport of toxin to the CNS, is shorter in young infants than in older children and adults.

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Photograph of newborn child with neonatal tetanus

Tetanus symptoms typically progress after the patient presents for medical care, despite aggressive treatment, because tetanus toxin being transported inside neurons is shielded from neutralising antibodies. In moderate and severe tetanus, respiratory compromise develops because of chest wall muscle rigidity and spasm, diaphragmatic dysfunction, airway obstruction from laryngeal or glottal spasm, or aspiration pneumonia.45, 46 Episodes of cyanosis and apnoea are common in uncontrolled severe disease. Before mechanical ventilation and effective agents to control muscle spasm were available, tetanus mortality was mainly caused by respiratory failure.33, 47

Autonomic dysfunction leading to severe sustained or labile hypertension, hypotension, tachycardia, bradycardia, and arrhythmias can result in life-threatening haemodynamic instability and cardiac arrest. This sympathetic overactivity and catecholamine excess develops later in the disease course and has become an important cause of death in patients whose muscle spasms and respiratory function have been stabilised.38,47—49

In newborn babies, sepsis can accompany tetanus, exacerbating the severity of illness.50—52 The hospital course of tetanus patients who survive is often protracted and complicated by pneumonia or other nosocomial infections. Other complications such as pulmonary embolism, decubitus ulcers, and contractures can result from the lengthy debilitation and catabolic state that accompanies the disease.

Historically, survivors of neonatal tetanus have been few, and little attention has been paid to the long-term consequences of the disease. Although several studies assessing long-term sequelae of neonatal tetanus did not detect any abnormalities,42, 53, 54 other studies identified neurological damage, ranging from cerebral palsy and severe psychomotor retardation to subtle intellectual and behavioural abnormalities.55—60 These findings are plausible in view of the repeated hypoxic insults sustained during tetanus, especially in settings where drugs and equipment to control spasms and ventilation are scarce. The available case series and small studies describe neurological abnormalities or cognitive impairment in 4—50% of patients; severe disabilities are identified in 10—20%. The frequency of such complications might vary substantially in relation to availability and quality of medical facilities.

The prognosis of generalised tetanus is strongly predicted by the incubation and onset periods. Short incubation and onset periods correlate with increased disease severity and higher mortality.33, 37, 38, 40, 42 Autonomic dysfunction also predicts high mortality, especially if it manifests early in the disease course.38, 61 The risk of death is highest for very young and very old patients. Neonatal tetanus mortality approached 100% in community-based surveys in the 1980s,2, 37 but is now 10—60% with hospital care.62—64 Low birthweight might compound the risk of death.65 Several classification systems,32, 33, 66 based on incubation and onset, portal of entry of infection, disease severity at presentation, and other factors, predict prognosis in non-neonatal tetanus better than any one factor, and have been used for therapeutic decisionmaking.32, 33, 66 Their true clinical utility is unclear; however, they provide a valuable objective approach to grouping patients participating in clinical tetanus research.

Overall case fatality rates for patients admitted to hospital with non-neonatal tetanus in developing countries are 8—50%; mortality increases with age.38,39,67—72 Maternal tetanus has been associated with higher mortality in some series than has adult tetanus associated with other types of wounds.37, 39, 71 Women with tetanus after abortion seem to have especially high mortality, perhaps because they might delay seeking medical care until later in their disease.5 A history of previous tetanus immunisation, even if distant or incomplete, is associated with longer incubation periods, milder disease and decreased mortality than with no previous immunisation.16, 64, 73

The diagnosis of tetanus is made strictly on clinical grounds. Cultures of tetanus patients wounds frequently fail to detect growth of C tetani; moreover, the organism occasionally grows in cultures from patients without tetanus. Negligible serum tetanus antibody concentrations can support but cannot prove the diagnosis. The minimum tetanus antibody concentration conferring protection against disease or death in human beings has not been convincingly established.74 Tetanus antibody concentrations in the conventionally accepted protective range (greater than 0·01 IU/mL by in vivo neutralisation assay or 0·10—0·16 IU/mL by ELISA) do not exclude the diagnosis; many tetanus cases, some fatal, have been reported in patients whose tetanus antibody levels were well above the protective threshold.75—79 The differential diagnosis of tetanus includes other causes of trismus such as dental infections, tonsillitis, parotitis, temporomandibular joint disease, strychnine poisoning, phenothiazine toxicity, stiff man syndrome, hypocalcaemia, CNS infections, and psychogenic tetanus. In neonates, tetanus must be differentiated from neonatal seizures, meningitis, and metabolic disorders such as hypoglycaemia and hypocalcaemia.

Treatment

The mortality and morbidity of tetanus patients admitted to hospital decreased substantially in the 1960s and 1970s, with the advent of mechanical ventilation and the introduction of benzodiazepines, with their high efficacy and wide therapeutic index. Mortality rates of less than 20% are increasingly common for both neonatal and non-neonatal tetanus if patients have the benefits of care in a modern intensive-care unit.38, 39, 47, 49, 62, 72 Even in settings with limited resources, if basic medication, experienced medical supervision, and high-quality nursing can be provided, mortality can be reduced to less than 50%.42, 63, 80 The greatest impediment to improved survival of tetanus patients in developing countries is the lack of access to appropriate medical care.

The specific objectives of tetanus treatment are to stop the production of toxin at the site of infection, with appropriate wound care and antibiotic use; to neutralise circulating toxin with antitetanus immunoglobulin; and to provide effective management of muscle spasm, respiratory failure, autonomic dysfunction, and complications that arise during the course of illness. Therapeutic approaches depend on the resources available in the facility to which the patient presents. Comprehensive reviews of tetanus management should be referred to for details of specific drug use.32, 33, 81, 82

Immunology

Although some researchers have suggested that natural immunity against tetanus toxin can be induced by gut carriage of C tetani,83—85 the serological and epidemiological evidence in support of this hypothesis is unconvincing.22, 74 The only reliable immunity against tetanus is that induced by vaccination with tetanus toxoid. Tetanus toxoid vaccine is one of the most effective, safe, stable, and inexpensive vaccines ever developed, and can be given safely during pregnancy and to immunocompromised individuals.22, 74 It is available as single-antigen vaccine and in many multiple-antigen preparations. When handled and given properly, it provides highly protective, longlasting immunity against tetanus. Although mild local and systemic reactions to tetanus toxoid are common, serious adverse reactions are quite rare.

The duration of protection provided by tetanus toxoid immunisation depends on the total number of doses and the age at which they were received; the potency of the vaccine; and the underlying immune competency of the recipient. Antibody response to the first dose of tetanus toxoid develops slowly, and consists of non-neutralising IgM and small amounts of IgG antibodies: this response is insufficient to provide protection. After a second dose, about 90% of people develop protective antibody concentrations; however, a year after vaccination, the proportion of protected individuals drops to 80% or fewer. A third dose results in protection of at least 98% of recipients; the proportion of individuals protected remains high for several years. Subsequent boosters, even when given many years after a three-dose primary series, result in high quantities of effective antibody (figure 4).22, 74 The length of long-term protection after five or six doses is uncertain, but seems to be at least 20—25 years in populations receiving primary doses in infancy, and boosters in childhood and adolescence.86—88 Recommended vaccination schedules vary by country. WHO recommends that at least five doses of tetanus toxoid vaccine be given over 12—15 years, starting in infancy; a sixth dose given in early adulthood is encouraged, to ensure longlasting protection.13

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Antibody response to tetanus toxoid74

Newborn babies and young infants born to mothers with antitetanus antibodies are protected against tetanus by acquired maternal antibody. Maternal IgG is actively transported by the placenta into the fetal circulation, in a process mediated by IgG Fc-specific receptors on syncytiotrophoblast cells. Antibody transfer increases with gestational age, reaching maximum efficiency in the third trimester.89, 90 Two doses of tetanus toxoid are needed to ensure protection in previously unimmunised pregnant women and their newborn babies.91—93 The longer the interval between doses, the greater the antibody response to the second dose; an interval of at least 6 weeks is recommended when feasible.94 Maternal tetanus antibody transfer peaks at 60 or more days after the second dose, which should be given several weeks before delivery to ensure protective antibody concentrations in newborn babies.94—96 The attainment of optimum timing of vaccine doses during pregnancy can be difficult in developing countries, where women often do not seek antenatal care until late in their pregnancies.74, 94 In recognition of practical constraints, WHOs five-dose tetanus toxoid schedule for previously unimmunised pregnant women and women of childbearing age provides recommendations for the minimum dosing intervals resulting in acceptable antibody levels (table).13, 97 A modified schedule, taking into account doses of tetanus toxoid received in infancy or childhood, has also been developed.13, 74

TableTable image

Tetanus toxoid vaccination schedule for pregnant women and women of childbearing age who have not received previous immunisation against tetanus

Concerns have been raised that maternal malaria could affect neonatal protection by reduction of maternal response to immunisation or placental antibody transfer. In some studies, malaria infection has been seen to decrease the antibody response to tetanus toxoid in children, although malaria chemoprophylaxis seems to preserve the response.89, 100 A study comparing pregnant women with and without malaria parasitaemia noted no difference in the antibody response to tetanus toxoid; however, all participants received chloroquine prophylaxis.101 Studies investigating the effects of placental malaria on transplacental tetanus antibody transfer have had conflicting results: one showed reduced tetanus antibody concentrations in newborn babies of mothers with severe placental malaria,102 yet two others detected no such effect.103, 104

Most studies of the immune response to tetanus toxoid in HIV-infected patients have been done in children and non-pregnant adults. Infants and adults infected with HIV generally do mount a protective response to tetanus toxoid, but their antibody levels tend to be lower than those of uninfected controls, especially in those whose CD4 lymphocyte counts are less than 300 cells per μL. With disease progression, immune response and serum tetanus antibody concentrations decrease.105—110 This blunted response suggests that HIV-infected individuals might need more frequent booster doses.106, 107 Placental transfer of tetanus IgG was significantly lower in HIV-infected Brazilian mothers than in uninfected controls,111 a finding that was not replicated in a subsequent study in Malawi.103 In both studies, all neonates had protective tetanus antibody concentrations.

Other factors affect transplacental maternal tetanus antibody transfer. Prematurity, severe maternal hypergammaglobulinaemia, and high maternal antitetanus IgG concentrations have been associated with reduced cord-maternal ratios of tetanus antibody, compared with controls,90, 111, 112 although these findings have not been consistent.103, 104, 111 Malaria, HIV, hypergammaglobulinaemia, and prematurity are factors that coexist in countries with a high burden of neonatal tetanus. Although the studies discussed above suggest that maternal tetanus antibody concentrations or placental transfer, or both, can be reduced in these conditions, in all but two studies102, 112 the relative reductions in tetanus antibody did not result in subprotective antibody concentrations in neonates. Thus, it seems that tetanus toxoid vaccine is usually sufficiently immunogenic to afford protection against maternal or neonatal tetanus, even in the presence of disorders affecting maternal and neonatal tetanus antibodies.

Distribution and risk

Maternal and neonatal tetanus cases are clustered in poor, remote, and disenfranchised communities where unhygienic obstetric and postnatal practices prevail, and access to maternal tetanus toxoid immunisation is poor. Differences in neonatal tetanus incidence and mortality of at least an order of magnitude have been identified between regions and countries, and between urban and rural areas within countries.1, 2, 41, 113 In industrialised countries, neonatal tetanus ceased to be a substantial problem by the mid-20th century: once tetanus toxoid vaccination became widespread, neonatal tetanus disappeared.17, 22 By contrast, mortality rates as high as 67—110 per 1000 livebirths were identified in rural populations in developing countries in the 1960s and 1970s,41, 92, 114, 115 with neonatal tetanus accounting for 50% or more of all neonatal deaths and 25% of infant mortality in some countries.1, 2, 116 Although this situation has improved in the past 20 years, neonatal tetanus mortality rates of 23 and 82 per 1000 livebirths were detected in remote communities in the late 1990s.117, 118 49 countries continue to have neonatal tetanus rates of more than 1 per 1000 livebirths in some districts.13

Information about the incidence and distribution of maternal tetanus is based on more limited data than that available for neonatal tetanus. Both tetanus and maternal mortality are under-reported. Induced abortion is illegal in many countries, so resulting tetanus cases and deaths are even less likely to be reported than those resulting from childbirth. In studies from several Asian countries from the 1950s and 1960s, maternal tetanus accounted for 3—22% of all tetanus cases, with an overall average of 7%.113 In a 1993 review of studies addressing maternal tetanus, tetanus-associated maternal mortality rates established in community-based studies ranged from 4—56 per 100 000 livebirths.5 Tetanus was the cause of 0·2—10% of all maternal deaths, with an overall average of about 5%. Of reported cases of maternal tetanus, 27% took place after induced abortion.5 In a subsequent community-based study from Bangladesh, where efforts to eliminate neonatal tetanus were underway, 1% of deaths in women aged 10—50 years were due to maternal tetanus, of which 35% were associated with abortion. In a related hospital record review, of women aged 10—50 years who died of tetanus, 55% developed tetanus after induced abortion and 5% after childbirth.119

Panel 1 summarises specific risk factors associated with maternal and neonatal tetanus. Many factors often coexist, compounding risk of those diseases. Home deliveries assisted by untrained birth attendants are the norm in many developing countries, especially in rural areas, and bring together many factors that confer a high risk of tetanus to both mother and child.1,41,117,120—123,126 Postnatal cord treatment with contaminated traditional substances in the first few days of life has been identified with multivariate analysis as a particular hazard in case-control studies;121, 125, 126, 130, 132 the use of such materials has been noted to negate the benefits of hospital deliveries.140—142 Poverty, lack of maternal and paternal education, rural residence, young maternal age, and cultural restrictions on womens access to health services are all associated with unhygienic practices, low antenatal care attendance, and inadequate vaccination with tetanus toxoid.1, 41, 117, 123, 124, 131, 137, 138 Lack of access to effective contraception and safe abortions are additional risk factors associated with tetanus from abortions.5, 119, 127, 143 Adolescents face special abortion-related risks because they frequently are not targeted for contraceptive services and tetanus toxoid vaccination, and might have increased difficulty in obtaining safe abortions because of societal prohibitions and cultural taboos.143, 144

Panel 1

Risk factors associated with neonatal and maternal tetanus

Factors associated with unsafe procedures

Deliveries or medical procedures done outside health-care facilities*5,120—122 †,123, 124

Birth attendants without medical training*5, 120 †,122 †,123, 125 †,126 †,127

Unclean hands* and instruments*120 †,123,127—131 †

Dirt,* straw,* or other unclean materials as delivery surface117 †,120 †,129 †

Animals kept inside or adjacent to home (for home deliveries)117 †,123

Animal dung used for fuel126 †,129

Traditional substances used during labour, delivery, or abortion (ie, cow ghee* and other animal or vegetable oils,* juices or herbs)121 †,124, 127, 128 †,129 †,132 †

Traditional substances used for umbilical cord care (ie, cow dung,* rat faeces, cow ghee, other oils or juices, herbs, ash,* surma,* soil, sand)121 †,122 †,124, 126 †,130 †,133 †,134

Neonates swaddled in animal dung* or soil129 †,135

Traditional neonatal surgeries (ie, circumcision, ritual scarification, ear piercing, uvulectomy)124, 136 †

Immunisation-related factors

Absent or incomplete immunisation with tetanus toxoid120 †,123, 130 †,131 †

Factors associated with unsafe procedures or incomplete immunisation, or both

Poverty*117 †,123, 137 †

Absent or poor maternal* or paternal education,* or both117 †,121 †,123, 131 †,137 †

Poor antenatal-care attendance*123, 124, 131 †,137 †

Young maternal age or first pregnancy,* or both120 †,123, 137 †

Cultural constraints to womens movements and contacts124, 138

Other factors

Death of a previous child in a family from neonatal tetanus (predictive of subsequent cases)*122 †,125 †,126 †,128 †

Male sex (increased risk of neonatal tetanus)‡2

Specific factors can be related to unsafe delivery, abortion, or cord-care practices, or to inadequate immunisation with tetanus toxoid, or both.

* Identified as independent risk factors for neonatal tetanus by multivariate analysis.

† References for studies using multivariate analysis to identify independent risk factors.

‡ Inconsistent findings in community-based and hospital-based studies; unclear if related to differential cord care, maternal recall, or medical-care seeking for males,1, 22, 136 or because of a biological difference between boys and girls.113, 139

Prevention

Maternal and neonatal tetanus prevention relies on avoidance of unsafe delivery, abortion, and umbilical cord care practices, and promotion of maternal tetanus immunisation. The powerful effect that puerperal and umbilical stump hygiene have on prevention of neonatal tetanus is evident from the history of developed countries before the availability of tetanus toxoid. In the first half of the 20th century, neonatal tetanus in Denmark and the USA steadily decreased to 0·05 and 0·02 cases per 1000 livebirths, respectively, as health facility deliveries and hygienic obstetric and cord-care practices became widespread.145, 146 Even in rural regions of the developing world where home deliveries are common, concerted efforts to educate health workers and pregnant women about safe deliveries and care of neonates can result in substantial reductions in neonatal tetanus.115, 147, 148

A notable example is a controlled trial in Maasai villages in Kenya and Tanzania where a reduction in annual neonatal tetanus incidence from 80 to 0·75 per 1000 livebirths was achieved with the introduction of a programme promoting clean delivery practices, and the replacement of cow dung for postnatal umbilical-cord care by clean water or milk, both culturally acceptable and safer alternatives. The incidence of neonatal tetanus remained below 1·0 per 1000 per year in the intervention villages throughout a decade of observation, while remaining unchanged in control villages.118 An analysis of interventions aimed at the improvement of neonatal survival estimated that 75—85% of deaths from neonatal tetanus could be prevented through the effective implementation of a family-based package of interventions that included clean home deliveries and hygienic cord care.149

The use of topical antimicrobials to replace traditional substances applied for cord care could have an important effect on neonatal tetanus in communities where high-risk cord carre practices persist. Case-control studies in rural Pakistan documented reduced risk of neonatal tetanus in association with topical antibiotic use for cord and circumcision wound care.125, 130, 136 Additional indirect suport comes from a randomised trial in Nepal that showed significant reductions in omphalitis and neonatal mortality with the use of chlorhexidine for postnatal cord care.150 By contrast, clinical trials investigating the role of topical antimicrobials for cord care on neonatal illness and death have not shown any benefit in developed countries where aseptic obstetric and surgical practices prevail.151, 152

Hygienic deliveries and cord care clearly reduce neonatal tetanus, and have the additional benefit of reducing maternal and neonatal sepsis caused by other bacterial pathogens. As important as these measures are for the improvement of maternal and neonatal survival, progress in developing the necessary infrastructure and behavioural changes needed to ensure safe deliveries and neonatal care has proven difficult to achieve, especially in the areas with the greatest burden of maternal and neonatal tetanus. Vaccination with tetanus toxoid to induce immunity against tetanus in both mother and newborn child is the most reliable way to prevent this disease.

The efficacy of tetanus toxoid for the prevention of neonatal tetanus was initially shown by two clinical trials undertaken in the early 1960s, in places with an annual neonatal tetanus incidence of about 80 cases per 1000 livebirths. In the first trial, three doses of fluid tetanus toxoid (without adjuvant; equivalent to about two doses of aluminium-adsorbed tetanus toxoid) had an efficacy of 94% for the prevention of deaths from neonatal tetanus;114 in the second trial, no deaths from neonatal tetanus were seen in neonates born to mothers who had received two or three doses of aluminium-adsorbed tetanus toxoid within the previous 5 years.92 Subsequent observational and case-control studies assessing the effect of tetanus toxoid on neonatal tetanus frequency or mortality have consistently noted vaccine effectiveness to be 80% or better,74, 115, 131, 153, 154 except when subpotent tetanus toxoid vaccine was inadvertently used.128 Although no studies designed to measure the effect of tetanus toxoid on maternal tetanus are available, a hospital-based study in Vietnam, where the vaccination of women has been vigorously promoted, showed a 90% reduction in tetanus in women aged 20—40 years.39

Control: the Maternal and Neonatal Tetanus Elimination Initiative

Tetanus toxoid vaccination of pregnant women to prevent neonatal tetanus was included in WHOs Expanded Program on Immunization a few years after its inception in 1974. By contrast with the notable gains in child immunisation achieved in the 1980s, only 27% of pregnant women were receiving at least two doses of tetanus toxoid by 1989 (figure 1).155 In recognition of the substantial burden of neonatal tetanus in developing countries, the 1989 World Health Assembly (WHA) adopted a resolution to eliminate neonatal tetanus by 1995, through the increased availability of tetanus toxoid and clean deliveries, and improved surveillance.4, 156 The elimination of neonatal tetanus was defined as fewer than 1 case per 1000 livebirths in every district.3 This definition also has been adopted as a proxy for the elimination of maternal tetanus.6

When WHA called for global elimination of neonatal tetanus, 90 countries had mortality rates above the elimination threshold. In areas with reasonably well-developed health services, improvements in tetanus toxoid vaccination coverage were fairly easy to achieve, leading to a 25% reduction in worldwide deaths from neonatal tetanus by 1992.155 However, elimination activities continued to miss communities with a high burden of neonatal tetanus and poor access to routine health services. The high-risk approach was introduced to address this shortcoming (panel 2, Figure 5, Figure 6).16, 157 Women of childbearing age living in areas where the risk of neonatal tetanus is high are immunised against tetanus in campaigns, which are accompanied by community education programmes and followed by strengthening of routine services for pregnant women.6

Panel 2

The high-risk approach

Since its inception in 1990 the neonatal tetanus elimination initiative has stressed focus on communities traditionally missed by routine immunisation and maternal and child health services, because of geographical and sociocultural barriers to health-service access. These high-risk communities typically have a disproportionately high neonatal tetanus burden, and high infant and maternal mortality in general. As the programme matured, guidelines were developed for systematically identifying high-risk districts or areas with the algorithm in figure 5.6, 158

Core indicators for identification of high-risk areas include data from tetanus surveillance, clean delivery coverage, and the proportion of women who received at least two doses of tetanus toxoid in their last pregnancy, or the proportion of women whose last child was protected at birth on the basis of their mothers vaccination history. Since the reliability of core indicator data varies, surrogate indicators such as the proportion of deliveries that take place in health-care facilities, availability of trained delivery attendants, antenatal care attendance, and infant coverage with three doses of diphtheria-tetanus-pertussis vaccine are also used to help classify and prioritise districts needing intensive efforts.6, 158

After high-risk areas have been selected, supplemental immunisation activities are organised, targeting all women of childbearing age (usually 15—45 years) with three doses of tetanus toxoid. Additionally, educational programmes and materials stressing the importance of immunisation against tetanus, and hygienic delivery and cord-care practices, are developed specifically for the targeted communities. After these campaigns, efforts are made to systematically strengthen routine immunisation and perinatal services.6, 158

When done successfully, such campaigns result in a rapid reduction in neonatal tetanus cases and deaths. Because efforts are focused on a relatively small number of communities with high burden of neonatal tetanus, the reductions in the disease are often more striking than improvements in national tetanus toxoid coverage rates.6, 158 Figure 6 shows the effect of the high-risk approach in Egypt.6, 159

Figure 5 Full-size image (40K) Download to PowerPoint

Algorithm for identification of districts at high risk of maternal or neonatal tetanus6

*Based on zero reporting, completeness of reporting, adequate number and distribution of reporting sites, and annual record reviews or active surveillance. †Delivery by a physician, nurse, or midwife, or as defined by national policy.

Figure 6 Full-size image (65K) Download to PowerPoint

Effect of high-risk approach in Egypt

Adapted from reference 9.

The high-risk approach is an economical method for the reduction of neonatal tetanus, despite the higher costs typically associated with mass vaccination campaigns. The cost of provision of three doses of tetanus toxoid to each woman, including supplies, operational costs, and education about safe delivery, is about US$1·20.14 A study in Pakistan showed the cost-effectiveness of these campaigns in an area with a high incidence of neonatal tetanus (23 cases per 1000 livebirths per year). The cost of three rounds of tetanus toxoid vaccination was $117 per averted death and $3·61 per disability-adjusted life year (DALY) averted.160 By contrast, the cost of scaling up to provide complete tetanus toxoid vaccination to unimmunised women of childbearing age on a widespread basis in south Asia and sub-Saharan Africa is $3·28—4·06 per woman, with an overall incremental cost per death averted of $271—394 ($14 per DALY averted).161, 162

As cost effective as tetanus toxoid campaigns are, in the absence of external funding to support the supplemental activities, the implementation of the high-risk approach was weak in the countries most in need. As a result, the 1995 target date for global elimination of neonatal tetanus was not met. In 2000, WHO, UNICEF, and UNFPA formed a partnership to relaunch efforts towards this goal, adding the elimination of maternal tetanus as a programme objective, and setting a new target date of 2005. Worldwide deaths caused by neonatal tetanus had decreased by 75% to 200 000 every year (figure 1), with 90% of these deaths occurring in 27 countries, mainly in south Asia and sub-Saharan Africa. The focus of the renewed programme for elimination of maternal and neonatal tetanus was to assist the 57 countries (now 58, since East Timor has been established as an independent country) where maternal and neonatal tetanus persisted as a public-health problem.6, 14

By February 2007, 40 countries had implemented tetanus campaigns in high-risk areas, targeting more than 94 million women, and protecting more than 70 million with at least two doses of tetanus toxoid. Ten of the 58 priority countries showed elimination of maternal and neonatal tetanus, as did seven Indian states.12 Many countries still striving to achieve elimination have improved tetanus toxoid coverage in most districts and are close to meeting elimination criteria (figure 2). With available and pledged funding, the elimination of maternal and neonatal tetanus is expected in all but 11 countries by 2009.

Efforts are underway to estimate the present burden of neonatal tetanus, taking into account the progress in tetanus toxoid immunisation of women of childbearing age made through the many campaigns of the past few years. Despite increased awareness of neonatal tetanus, surveillance has not improved much, and reporting is still below 10% in countries in which this disease continues to be a substantial public-health problem.6, 163 Systematic community-based surveys of neonatal tetanus, like those undertaken in the 1970s and 1980s, have not been repeated since the initiation of neonatal tetanus elimination programme. Thus, estimates of the burden of neonatal tetanus and progress in its elimination, derive from mathematical models that compute the yearly incidence and mortality for each country using the baseline rate of neonatal tetanus before introduction of tetanus toxoid and promotion of clean deliveries, with adjustment for the estimated proportion of women immunised with tetanus toxoid and deliveries assisted by trained personnel.2, 3 Modelled estimates of neonatal tetanus burden probably provide reasonable approximations of continuing worldwide burden and the effect of activities to eliminate maternal and neonatal tetanus. However, variations in assumptions and data sources used in the modelling process have led to large differences in estimates, with broad uncertainty intervals that highlight the limitations of the available data.2, 164 Improved surveillance of maternal and neonatal tetanus, and systematic community-based surveys, are clearly needed to validate assumptions used in the models, and to improve the accuracy of present estimates of burden.

Sustaining elimination

Sustaining elimination of maternal and neonatal tetanus will be a challenge, especially in places where the high-risk approach is needed. Worldwide, 62% of deliveries are attended by trained personnel, with skilled attendant coverage of only 32% in the least developed countries. Antenatal care attendance (at least one visit) is far below 50% in many countries in which neonatal tetanus has yet to be eliminated.165 Routine immunisation with tetanus toxoid has been stagnant over the past decade, with only 50—54% of pregnant women worldwide receiving adequate immunisation, a situation largely unchanged since the late 1980s (figure 2).166 Although data for vaccine coverage underestimate the true proportion of protected women because of unregistered doses of tetanus toxoid, and the increasing number of women who received a primary series of tetanus toxoid-containing vaccine in infancy,167 the continued need to increase the routine vaccination of women of childbearing age is indisputable.

The rejuvenated worldwide commitment to improvement of maternal and child health, and special attention to the importance of neonatal survival, catalysed by the child and maternal mortality Millennium Development Goals (MDG4 and MDG5), is heartening.168 Many initiatives and partnerships have been developed to ensure that effective and affordable interventions are successfully applied, in an integrated continuum-of-care framework that recognises the important inter-relationships between maternal, neonatal, and child health.169—171 The proposed packages of interventions include improved antenatal care, tetanus toxoid immunisation of mothers, and promotion of hygienic delivery and postpartum cord-care, all of which will directly contribute to prevention of maternal and neonatal tetanus.149, 172 Similarly, the Global Immunization Vision and Strategy, launched by WHO and UNICEF in 2005, includes strategies to increase routine tetanus toxoid coverage in hard-to-reach, previously underserved populations that will contribute to the expansion and maintenance of maternal and neonatal tetanus elimination strategies.173 If the WHO recommendations for booster doses of tetanus toxoid in childhood and adolescence can be widely implemented, the need for repeated doses during pregnancy will be reduced, increasing the likelihood that elimination can be sustained.13 Since C tetani cannot be removed from the environment, continued worldwide elimination of maternal and neonatal tetanus will depend on universal access to immunisation and health services.

Search strategy and selection criteria

We searched PubMed without date or language restrictions for the terms: “tetanus”, “Clostridium tetani”, “tetanus toxin”, and “tetanus toxoid”, alone and in combination with relevant secondary terms (“physiopathology”, “therapy”, “diagnosis”, “complications”, “mortality”, “immunology”, “neonatal” “maternal”, “epidemiology”, and “prevention and control”). Additional references were identified from citations in articles retrieved in the initial search. We searched the Cochrane database for “tetanus”. We also searched WHOs website and electronic library for the terms “tetanus” and “neonatal tetanus”. Articles were selected for their importance and relevance to the understanding of maternal and neonatal tetanus. Preference was given to articles published in the past 10 years.

Conflict of interest statement

MR worked as a consultant for WHO on this subject and other work related to tetanus and neonatal tetanus. JV is a staff member of UNICEF seconded to WHO. FG is a staff member of UNICEF. WHO and UNICEF are major partners in the Maternal and Neonatal Tetanus Initiative. No external funding was used to support this work. The authors alone are responsible for the views expressed in this publication; they do not necessarily represent the decisions, policy or views of WHO or UNICEF.

Acknowledgments

We thank Kristin Brown for assistance in obtaining articles for review, Susan Byrne for producing maps and graphs, and Steve Wassilak and Margaret Cortese for review of early drafts of the manuscript.

References

1 Stanfield JP, Galazka A. Neonatal tetanus in the world today. Bull World Health Organ 1984; 62: 647-669. PubMed

2 Galazka A, Birmingham M, Kurian M, Gasse F. Tetanus. In: Murray CJL, Lopez AD, Mathers CD, eds. The Global Epidemiology of Infectious Diseases. Geneva: World Health Organization, 2004: 151-199. http://whqlibdoc.who.int/publications/2004/9241592303.pdf. (accessed Dec 19, 2005).

3 WHO. Expanded programme on immunization. The global elimination of neonatal tetanus: progress to date. Wkly Epidemiol Rec 1993; 68: 277-282. PubMed

4 WHO. WHA 42.32 Expanded Programme on Immunization. World Health Assembly Resolutions and Decisions. Geneva: World Health Assembly, 1989.

5 Fauveau V, Mamdani M, Steinglass R, Koblinsky M. Maternal tetanus: magnitude, epidemiology and potential control measures. Int J Gynaecol Obstet 1993; 40: 3-12. CrossRef | PubMed

6 WHO, UNICEF, UNFPA. Maternal and neonatal tetanus elimination by 2005. Strategies for achieving and maintaining elimination. WHO/V&B/02.09. Geneva: World Health Organization, United Nations Childrens Fund, and United Nations Population Fund, 2000.

7 WHO. Expanded programme on immunization. Progress towards the global elimination of neonatal tetanus, 1989—1993. Wkly Epidemiol Rec 1995; 70: 81-85. PubMed

8 WHO. Expanded programme on immunization. Global advisory group part II. Wkly Epidemiol Rec 1994; 69: 29-35. PubMed

9 WHO. Expanded programme on immunization. The “high risk” approach: the WHO-recommended strategy to accelerate elimination of neonatal tetanus. Wkly Epidemiol Rec 1996; 71: 33-36. PubMed

10 WHO. Expanded programme on immunization. Progress towards the global elimination of neonatal tetanus, 1990—1998. Wkly Epidemiol Rec 1999; 74: 73-80. PubMed

11 WHO, UNICEF, World Bank. State of the worlds vaccines and immunization. Geneva: World Health Organization, 2003.

12 WHO. Validation of neonatal tetanus elimination in Andhra Pradesh, India. Wkly Epidemiol Rec 2004; 79: 292-297. PubMed

13 WHO. Tetanus Vaccine: WHO position paper. Wkly Epidemiol Rec 2006; 81: 198-208. PubMed

14 Vandelaer J, Birmingham M, Gasse F, Kurian M, Shaw C, Garnier S. Tetanus in developing countries: an update on the Maternal and Neonatal Tetanus Elimination Initiative. Vaccine 2003; 21: 3442-3445. CrossRef | PubMed

15 Lawn JE, Cousens S, Darmstadt GL, Paul V, Martines J. Why are 4 million newborn babies dying every year?. Lancet 2004; 364: 2020. Full Text | PDF(106KB) | CrossRef | PubMed

16 Pascual FB, McGinley EL, Zanardi LR, Cortese MM, Murphy TV. Tetanus surveillance—United States, 1998—2000. MMWR Surveill Summ 2003; 52: 1-8. PubMed

17 Rushdy AA, White JM, Ramsay ME, Crowcroft NS. Tetanus in England and Wales, 1984—2000. Epidemiol Infect 2003; 130: 71-77. CrossRef | PubMed

18 WHO. The World health report 2003: Shaping the future. In: Annex Table 2. Geneva: World Health Organization, 2003: 193. http://whqlibdoc.who.int/whr/2003/9241562439.pdf.

19 Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJL. Global Burden of Disease and Risk Factors. Table 3B.9. New York: The World Bank & Oxford University Press, 2006.

20 WHO. Immunization surveillance, assessment and monitoring. Maternal and neonatal tetanus (MNT) elimination. http://www.who.int/immunization_monitoring/diseases/MNTE_initiative/en/index5.html. (accessed July 11, 2007).

21 Feingold SM. Tetanus. In: Collier L, Balows A, Sussman M, eds. Topley & Wilsons Microbiology and Microbial Infections. New York: Oxford University Press, 1998: 694-722.

22 Wassilak SGF, Roper MH, Murphy TV, Orenstein WA. Tetanus Toxoid. In: Plotkin SA, Orenstein WA, eds. Vaccines. Philadelphia: WB Saunders, 2004: 745-781.

23 Yen LM, Dao LM, Day NP, et al. Role of quinine in the high mortality of intramuscular injection tetanus. Lancet 1994; 344: 786-787. Summary | CrossRef | PubMed

24 Gill DM. Bacterial toxins: a table of lethal amounts. Microbiol Rev 1982; 46: 86-94. PubMed

25 Schiavo G, Matteoli M, Montecucco C. Neurotoxins affecting neuroexocytosis. Physiol Rev 2000; 80: 717-766. PubMed

26 Laird WJ, Aaronson W, Silver RP, Habig WH, Hardegree MC. Plasmid-associated toxigenicity in Clostridium tetani. J Infect Dis 1980; 142: 623. CrossRef | PubMed

27 Marvaud JC, Eisel U, Binz T, Niemann H, Popoff MR. TetR is a positive regulator of the tetanus toxin gene in Clostridium tetani and is homologous to botR. Infect Immun 1998; 66: 5698-5702. PubMed

28 Lalli G, Bohnert S, Deinhardt K, Verastegui C, Schiavo G. The journey of tetanus and botulinum neurotoxins in neurons. Trends Microbiol 2003; 11: 431-437. CrossRef | PubMed

29 Schiavo G, Benfenati F, Poulain B, et al. Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin. Nature 1992; 359: 832-835. CrossRef | PubMed

30 Link E, Edelmann L, Chou JH, et al. Tetanus toxin action: inhibition of neurotransmitter release linked to synaptobrevin proteolysis. Biochem Biophys Res Commun 1992; 189: 1017-1023. CrossRef | PubMed

31 Pellizzari R, Rossetto O, Schiavo G, Montecucco C. Tetanus and botulinum neurotoxins: mechanism of action and therapeutic uses. Philos Trans R Soc Lond B Biol Sci 1999; 354: 259-268. CrossRef | PubMed

32 Farrar JJ, Yen LM, Cook T, et al. Tetanus. J Neurol Neurosurg Psychiatry 2000; 69: 292-301. CrossRef | PubMed

33 Bleck TP, Brauner JS. Tetanus. In: Scheld WM, Whitley RJ, Marra CM, eds. Infections of the Central Nervous System. Philadelphia: Lippincott, Williams & Wilkins, 2004: 625-648.

34 Herreros J, Schiavo G. Lipid microdomains are involved in neurospecific binding and internalisation of clostridial neurotoxins. Int J Med Microbiol 2002; 291: 447-453. CrossRef | PubMed

35 Lalli G, Schiavo G. Analysis of retrograde transport in motor neurons reveals common endocytic carriers for tetanus toxin and neurotrophin receptor p75NTR. J Cell Biol 2002; 156: 233-239. CrossRef | PubMed

36 Weinstein L. Tetanus. N Engl J Med 1973; 289: 1293-1296. CrossRef | PubMed

37 Patel JC, Mehta BC. Tetanus: study of 8697 cases. Indian J Med Sci 1999; 53: 393-401. PubMed

38 Brauner JS, Vieira SR, Bleck TP. Changes in severe accidental tetanus mortality in the ICU during two decades in Brazil. Intensive Care Med 2002; 28: 930-935. CrossRef | PubMed

39 Thwaites CL, Yen LM, Nga NT, et al. Impact of improved vaccination programme and intensive care facilities on incidence and outcome of tetanus in southern Vietnam, 1993—2002. Trans R Soc Trop Med Hyg 2004; 98: 671-677. CrossRef | PubMed

40 Bruce D. Tetanus: Analysis of one thousand cases Presidential Address. Transactions of the Royal Society of Tropical Medicine and Hygiene 1917; 11: 1-53. CrossRef | PubMed

41 WHO. Expanded programme on immunization. Prevention of neonatal tetanus. Wkly Epidemiol Rec 1982; 57: 137-144. PubMed

42 Salimpour R. Tetanus of the newborn in Tehran. A ten year study of 880 cases. J Trop Pediatr Environ Child Health 1978; 24: 140-142. PubMed

43 Dunn ER. The altered whistle in tetanus. Med J Aust 2002; 177: 687. PubMed

44 Galazka A, Stroh G. Guidelines on the community-based survey on neonatal tetanus mortality. Geneva: World Health Organization, 1986. WHO/EPI/GEN/86/8

45 Panda NB, Yaddanapudi S, Bharadwaj N, Das C, Chari P. Phrenic nerve palsy in severe tetanus. Anaesth Intensive Care 2004; 32: 271-274. PubMed

46 Bunch TJ, Thalji MK, Pellikka PA, Aksamit TR. Respiratory failure in tetanus: case report and review of a 25-year experience. Chest 2002; 122: 1488-1492. CrossRef | PubMed

47 Trujillo MH, Castillo A, Espana J, Manzo A, Zerpa R. Impact of intensive care management on the prognosis of tetanus. Analysis of 641 cases. Chest 1987; 92: 63-65. CrossRef | PubMed

48 Kerr JH, Corbett JL, Prys-Roberts C, Smith AC, Spalding JM. Involvement of the sympathetic nervous system in tetanus. Studies on 82 cases. Lancet 1968; 2: 236-241. CrossRef | PubMed

49 Udwadia FE, Lall A, Udwadia ZF, Sekhar M, Vora A. Tetanus and its complications: intensive care and management experience in 150 Indian patients. Epidemiol Infect 1987; 99: 675-684. CrossRef | PubMed

50 Oyelami OA, Owa JA, Olusanya IO. Septicaemia associated with neonatal tetanus. Cent Afr J Med 1995; 41: 171-173. PubMed

51 Antia-Obong OE, Ekanem EE, Udo JJ, Utsalo SJ. Septicaemia among neonates with tetanus. J Trop Pediatr 1992; 38: 173-175. CrossRef | PubMed

52 Ogunlesi TA, Oyelami OA. Fresh plasma transfusion in the management of neonatal tetanus. Ann Trop Paediatr 2004; 24: 367. CrossRef | PubMed

53 Marshall FN. Tetanus of the newborn. With special reference to experiences in Haiti, W.I. Adv Pediatr 1968; 15: 65-110. PubMed

54 Sharma A, Dhatt PS, Lall JC, Singh H, Gupta HL, Sallan RN. Neonatal tetanus: a developmental follow-up study. Indian Pediatr 1976; 13: 51-54. PubMed

55 Teknetzi P, Manios S, Katsouyanopoulos V. Neonatal tetanus—long-term residual handicaps. Arch Dis Child 1983; 58: 68-69. CrossRef | PubMed

56 Khanna SS, Bharucha B, Bhatia AK, Dastur FD. Neonatal tetanus: psychomotor development in survivors. Indian Pediatr 1985; 22: 125-130. PubMed

57 Anlar B, Yalaz K, Dizmen R. Long-term prognosis after neonatal tetanus. Dev Med Child Neurol 1989; 31: 76-80. CrossRef | PubMed

58 Tutuncuoglu S, Demir E, Koprubasi F, Selcuki D. The evaluation of late sequelae of tetanus infection. Indian J Pediatr 1994; 61: 263-267. CrossRef | PubMed

59 Okan M, Hacimustafaoglu M, Ildirim I, Donmez O, Eralp O, Ozer ET. Long-term neurologic and psychomotor sequelae after neonatal tetanus. J Child Neurol 1997; 12: 270-272. CrossRef | PubMed

60 Barlow JL, MungAla-Odera V, Gona J, Newton CR. Brain damage after neonatal tetanus in a rural Kenyan hospital. Trop Med Int Health 2001; 6: 305-308. CrossRef | PubMed

61 Wasay M, Khealani BA, Talati N, Shamsi R, Syed NA, Salahuddin N. Autonomic nervous system dysfunction predicts poor prognosis in patients with mild to moderate tetanus. BMC Neurol 2005; 5: 2. CrossRef | PubMed

62 Saltigeral Simental P, Macias Parra M, Mejia Valdez J, Sosa Vazquez M, Castilla Serna L, Gonzalez Saldana N. Neonatal tetanus experience at the National Institute of Pediatrics in Mexico City. Pediatr Infect Dis J 1993; 12: 722-725. CrossRef | PubMed

63 Ertem M, Cakmak A, Saka G, Ceylan A. Neonatal tetanus in the South-Eastern region of Turkey: changes in prognostic aspects by better health care. J Trop Pediatr 2004; 50: 297-300. CrossRef | PubMed

64 Omoigberale AI, Abiodun PO. Upsurge in neonatal tetanus in Benin City, Nigeria. East Afr Med J 2005; 82: 98-102. PubMed

65 Davies-Adetugbo AA, Torimiro SE, Ako-Nai KA. Prognostic factors in neonatal tetanus. Trop Med Int Health 1998; 3: 9-13. CrossRef | PubMed

66 Thwaites CL, Yen LM, Glover C, et al. Predicting the clinical outcome of tetanus: the tetanus severity score. Trop Med Int Health 2006; 11: 279-287. CrossRef | PubMed

67 Seydi M, Soumare M, Sow PS, et al. Tetanus: epidemiological aspects at the Infectious Disease Clinics at the Fann University Hospital Center in Dakar. Dakar Med 2000; 45: 5-7. PubMed

68 Seydi M, Soumare M, Gbangba-ngai E, et al. Current aspects of pediatric and adult tetanus in Dakar. Med Mal Infect 2005; 35: 28-32. CrossRef | PubMed

69 Soumare M, Seydi M, Ndour CT, Ndour JD, Diop BM. Epidemiology, clinical features and prognosis of juvenile tetanus in Dakar, Senegal. Bull Soc Pathol Exot 2005; 98: 371-373. PubMed

70 Hesse IF, Mensah A, Asante DK, Lartey M, Neequaye A. Adult tetanus in Accra, why the high mortality? An audit of clinical management of tetanus. West Afr J Med 2005; 24: 157-161. PubMed

71 Saltoglu N, Tasova Y, Midikli D, Burgut R, Dundar IH. Prognostic factors affecting deaths from adult tetanus. Clin Microbiol Infect 2004; 10: 229-233. CrossRef | PubMed

72 Kanchanapongkul J. Tetanus in adults: a review of 85 cases at Chon Buri Hospital. J Med Assoc Thai 2001; 84: 494-499. PubMed

73 Humbert G, Fillastre JP, Dordain M, Leroy J, Robert M, Delaunay P. 100 cases of tetanus. Scand J Infect Dis 1972; 4: 129-131. PubMed

74 Balmer P, Borrow R, Roper MH. The immunological basis for immunization series, module 3: tetanus. 2007 Update. Geneva: World Health Organization, 2007.

75 Maselle SY, Matre R, Mbise R, Hofstad T. Neonatal tetanus despite protective serum antitoxin concentration. FEMS Microbiol Immunol 1991; 3: 171-175. PubMed

76 de Moraes-Pinto MI, Oruamabo RS, Igbagiri FP, et al. Neonatal tetanus despite immunization and protective antitoxin antibody. J Infect Dis 1995; 171: 1076-1077. CrossRef | PubMed

77 Crone NE, Reder AT. Severe tetanus in immunized patients with high anti-tetanus titers. Neurology 1992; 42: 761-764. CrossRef | PubMed

78 Pryor T, Onarecker C, Coniglione T. Elevated antitoxin titers in a man with generalized tetanus. J Fam Pract 1997; 44: 299-303. PubMed

79 Abrahamian FM, Pollack CV, LoVecchio F, Nanda R, Carlson RW. Fatal tetanus in a drug abuser with “protective” antitetanus antibodies. J Emerg Med 2000; 18: 189-193. CrossRef | PubMed

80 Moore RM, Singleton AO. Tetanus at the John Sealy Hospital. Observations upon the distribution of tetanus throughout the United States. Surg Gynecol Obstet 1939; 69: 146-154. PubMed

81 Attygalle D, Rodrigo N. New trends in the management of tetanus. Expert Rev Anti Infect Ther 2004; 2: 73-84. CrossRef | PubMed

82 Bassin SL. Tetanus. Curr Treat Options Neurol 2004; 6: 25-34. PubMed

83 Veronesi R, Cecin H, Correa A, Tavares J, Moraes C, Bertoldo OJ. New concepts on tetanus immunization: naturally acquired immunity. J Hyg Epidemiol Microbiol Immunol 1975; 19: 126-134. PubMed

84 Dastur FD, Awatramani VP, Dixit SK, DSa JA, Cooverji ND, Anand MP. Response to single dose of tetanus vaccine in subjects with naturally acquired tetanus antitoxin. Lancet 1981; 2: 219-222. CrossRef | PubMed

85 Matzkin H, Regev S. Naturally acquired immunity to tetanus toxin in an isolated community. Infect Immun 1985; 48: 267-268. PubMed

86 Simonsen O, Bentzon MW, Kjeldsen K, Venborg HA, Heron I. Evaluation of vaccination requirements to secure continuous antitoxin immunity to tetanus. Vaccine 1987; 5: 115-122. CrossRef | PubMed

87 de Melker HE, van den Hof S, Berbers GA, Nagelkerke NJ, Rumke HC, Conyn-van Spaendonck MA. A population-based study on tetanus antitoxin levels in The Netherlands. Vaccine 1999; 18: 100-108. CrossRef | PubMed

88 Matouskova I, Matlerova S, Janoutova G, Janout V. Persistence of antibodies against tetanus upon revaccination. Cent Eur J Public Health 2005; 13: 99-102. PubMed

89 Dietz V, Galazka A, van Loon F, Cochi S. Factors affecting the immunogenicity and potency of tetanus toxoid: implications for the elimination of neonatal and non-neonatal tetanus as public health problems. Bull World Health Organ 1997; 75: 81-93. PubMed

90 Okoko JB, Wesumperuma HL, Hart CA. The influence of prematurity and low birthweight on transplacental antibody transfer in a rural West African population. Trop Med Int Health 2001; 6: 529-534. CrossRef | PubMed

91 MacLennan R, Schofield FD, Pittman M, Hardegree MC, Barile MF. Immunization against neonatal tetanus in New Guinea. Antitoxin response of pregnant women to adjuvant and plain toxoids. Bull World Health Organ 1965; 32: 683-697. PubMed

92 Newell KW, Duenas Lehmann A, LeBlanc DR, Garces Osorio N. The use of toxoid for the prevention of tetanus neonatorum. Final report of a double-blind controlled field trial. Bull World Health Organ 1966; 35: 863-871. PubMed

93 Relyveld E, Bengounia A, Huet M, Kreeftenberg JG. Antibody response of pregnant women to two different absorbed tetanus toxoids. Vaccine 1991; 9: 369-372. CrossRef | PubMed

94 Jones TS. The use of tetanus toxoid for the prevention of neonatal tetanus in developing countries. In: Recent Advances in Immunization, a Bibliographic Review. Washington, DC: Pan American Health Organization, 1983: 52-64.

95 Chen ST, Edsall G, Peel MM, Sinnathuray TA. Timing of antenatal tetanus immunization for effective protection of the neonate. Bull World Health Organ 1983; 61: 159-165. PubMed

96 Stanfield JP, Gall D, Bracken PM. Single-dose antenatal tetanus immunisation. Lancet 1973; 1: 215-219. PubMed

97 WHO. Tetanus Toxoid Vaccine. Expanded Programme on Immunization. In: Core information for the development of immunization policy, 2002 update. WHO/V&B/02.28. Geneva: World Health Organization, 2002: 129-132.

98 CDC. Diphtheria, tetanus and pertussis: Guidelines for vaccine prophylaxis and other preventive measures. Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR Recomm Rep 1991; 40: 1-28. PubMed

99 United Kingdom Department of Health. Immunization against infectious disease—The Green Book. Tetanus: London: Department of Health, 2005. www.dh.gov.uk/assetRoot/04/12/33/50/04123350.pdf. Chapter 31: (accessed 15 August 2006).

100 Rosen JB, Breman JG, Manclark CR, et al. Malaria chemoprophylaxis and the serologic response to measles and diphtheria-tetanus-whole-cell pertussis vaccines. Malar J 2005; 4: 53. CrossRef | PubMed

101 Brabin BJ, Nagel J, Hagenaars AM, Ruitenberg E, van Tilborgh AM. The influence of malaria and gestation on the immune response to one and two doses of adsorbed tetanus toxoid in pregnancy. Bull World Health Organ 1984; 62: 919-930. PubMed

102 Brair ME, Brabin BJ, Milligan P, Maxwell S, Hart CA. Reduced transfer of tetanus antibodies with placental malaria. Lancet 1994; 343: 208-209. Summary | CrossRef | PubMed

103 de Moraes-Pinto MI, Verhoeff F, Chimsuku L, et al. Placental antibody transfer: influence of maternal HIV infection and placental malaria. Arch Dis Child Fetal Neonatal Ed 1998; 79: 202-205. PubMed

104 Okoko BJ, Wesuperuma LH, Ota MO, et al. Influence of placental malaria infection and maternal hypergammaglobulinaemia on materno-foetal transfer of measles and tetanus antibodies in a rural west African population. J Health Popul Nutr 2001; 19: 59-65. PubMed

105 Dieye TN, Sow PS, Simonart T, et al. Immunologic and virologic response after tetanus toxoid booster among HIV-1- and HIV-2-infected Senegalese individuals. Vaccine 2002; 20: 905-913. CrossRef | PubMed

106 Moss WJ, Clements CJ, Halsey NA. Immunization of children at risk of infection with human immunodeficiency virus. Bull World Health Organ 2003; 81: 61-70. PubMed

107 Rosenblatt HM, Song LY, Nachman SA, et al. Tetanus immunity after diphtheria, tetanus toxoids, and acellular pertussis vaccination in children with clinically stable HIV infection. J Allergy Clin Immunol 2005; 116: 698-703. CrossRef | PubMed

108 Lederman HM, Williams PL, Wu JW, et al. Incomplete immune reconstitution after initiation of highly active antiretroviral therapy in human immunodeficiency virus-infected patients with severe CD4+ cell depletion. J Infect Dis 2003; 188: 1794-1803. CrossRef | PubMed

109 Talesnik E, Vial PA, Labarca J, Mendez C, Soza X. Time course of antibody response to tetanus toxoid and pneumococcal capsular polysaccharides in patients infected with HIV. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 19: 471-477. CrossRef | PubMed

110 Bonetti TC, Succi RC, Weckx LY, Tavares-Lopes L, de Moraes-Pinto MI. Tetanus and diphtheria antibodies and response to a booster dose in Brazilian HIV-1-infected women. Vaccine 2004; 22: 3707-3712. CrossRef | PubMed

111 de Moraes-Pinto MI, Almeida AC, Kenj G, et al. Placental transfer and maternally acquired neonatal IgG immunity in human immunodeficiency virus infection. J Infect Dis 1996; 173: 1077-1084. CrossRef | PubMed

112 Gendrel D, Richard-Lenoble D, Massamba MB, Picaud A, Francoual C, Blot P. Placental transfer of tetanus antibodies and protection of the newborn. J Trop Pediatr 1990; 36: 279-282. CrossRef | PubMed

113 Bytchenko B. Geographical distribution of tetanus in the world, 1951—60. A review of the problem. Bull World Health Organ 1966; 34: 71-104. PubMed

114 Schofield FD, Tucker VM, Westbrook GR. Neonatal tetanus in New Guinea. Effect of active immunization in pregnancy. BMJ 1961; 5255: 785-789. PubMed

115 Berggren WL. Administration and evaluation of rural health services. I. A tetanus control program in Haiti. Am J Trop Med Hyg 1974; 23: 936-949. PubMed

116 WHO. Neonatal Tetanus Elimination. WHO, Expanded Program on Immuniation, Global Advisory Group. WHO/EPI/GAG/89/WP.9. Tokyo: World Health Organization, 1989.

117 Quddus A, Luby S, Rahbar M, Pervaiz Y. Neonatal tetanus: mortality rate and risk factors in Loralai District, Pakistan. Int J Epidemiol 2002; 31: 648-653. CrossRef | PubMed

118 Meegan ME, Conroy RM, Lengeny SO, Renhault K, Nyangole J. Effect on neonatal tetanus mortality after a culturally-based health promotion programme. Lancet 2001; 358: 640-641. Summary | Full Text | PDF(59KB) | CrossRef | PubMed

119 Rochat R, Akhter HH. Tetanus and pregnancy-related mortality in Bangladesh. Lancet 1999; 354: 565. Summary | Full Text | PDF(23KB) | CrossRef | PubMed

120 Gitta SN, Wabwire-Mangen F, Kitimbo D, Pariyo G. Risk factors for neonatal tetanus—Busoga region, Uganda, 2002—2003. MMWR Morb Mortal Wkly Rep 2006; 55 (suppl 1): 25-30. PubMed

121 Raza SA, Akhtar S, Avan BI, Hamza H, Rahbar MH. A matched case-control study of risk factors for neonatal tetanus in Karachi, Pakistan. J Postgrad Med 2004; 50: 247-252. PubMed

122 Chai F, Prevots DR, Wang X, Birmingham M, Zhang R. Neonatal tetanus incidence in China, 1996—2001, and risk factors for neonatal tetanus, Guangxi Province, China. Int J Epidemiol 2004; 33: 551-557. CrossRef | PubMed

123 Asekun-Olarinmoye EO, Lawoyin TO, Onadeko MO. Risk factors for neonatal tetanus in Ibadan, Nigeria. Eur J Pediatr 2003; 162: 526-527. CrossRef | PubMed

124 Eregie CO. Epidemiological factors associated with neonatal tetanus mortality: observations from a cluster survey in Nigeria. East Afr Med J 1993; 70: 434-437. PubMed

125 Traverso HP, Kamil S, Rahim H, Samadi AR, Boring JR, Bennett JV. A reassessment of risk factors for neonatal tetanus. Bull World Health Organ 1991; 69: 573-579. PubMed

126 Bennett J, Azhar N, Rahim F, et al. Further observations on ghee as a risk factor for neonatal tetanus. Int J Epidemiol 1995; 24: 643-647. PubMed

127 Thapa PJ, Thapa S, Shrestha N. A hospital-based study of abortion in Nepal. Stud Fam Plann 1992; 23: 311-318. CrossRef | PubMed

128 Hlady WG, Bennett JV, Samadi AR, et al. Neonatal tetanus in rural Bangladesh: risk factors and toxoid efficacy. Am J Public Health 1992; 82: 1365-1369. CrossRef | PubMed

129 Bennett J, Schooley M, Traverso H, Agha SB, Boring J. Bundling, a newly identified risk factor for neonatal tetanus: implications for global control. Int J Epidemiol 1996; 25: 879-884. CrossRef | PubMed

130 Parashar UD, Bennett JV, Boring JR, Hlady WG. Topical antimicrobials applied to the umbilical cord stump: a new intervention against neonatal tetanus. Int J Epidemiol 1998; 27: 904-908. CrossRef | PubMed

131 Gupta SD, Keyl PM. Effectiveness of prenatal tetanus toxoid immunization against neonatal tetanus in a rural area in India. Pediatr Infect Dis J 1998; 17: 316-321. CrossRef | PubMed

132 Bennett J, Ma C, Traverso H, Agha SB, Boring J. Neonatal tetanus associated with topical umbilical ghee: covert role of cow dung. Int J Epidemiol 1999; 28: 1172-1175. CrossRef | PubMed

133 Bennett J, Macia J, Traverso H, Banoagha S, Malooly C, Boring J. Protective effects of topical antimicrobials against neonatal tetanus. Int J Epidemiol 1997; 26: 897-903. CrossRef | PubMed

134 Idema CD, Harris BN, Ogunbanjo GA, Durrheim DN. Neonatal tetanus elimination in Mpumalanga Province, South Africa. Trop Med Int Health 2002; 7: 622-624. CrossRef | PubMed

135 Gultekin A, Akarca MY, Oguz A, Gokalp A, Kanra G. Double-blind trial of intramuscular and intramuscular plus intrathecal human tetanus immunoglobulin and intramuscular equine tetanus antitoxin in the treatment of tetanus neonatorum. Turk J Pediatr 1988; 30: 9-15. PubMed

136 Bennett J, Breen C, Traverso H, Agha SB, Macia J, Boring J. Circumcision and neonatal tetanus: disclosure of risk and its reduction by topical antibiotics. Int J Epidemiol 1999; 28: 263-266. CrossRef | PubMed

137 Thind A. Determinants of tetanus toxoid immunization in pregnancy in rural Bihar. Trop Doct 2005; 35: 75-77. CrossRef | PubMed

138 Afridi NK, Hatcher J, Mahmud S, Nanan D. Coverage and factors associated with tetanus toxoid vaccination status among females of reproductive age in Peshawar. J Coll Physicians Surg Pak 2005; 15: 391-395. PubMed

139 Oudesluys-Murphy AM. Umbilical cord care and neonatal tetanus. Lancet 1989; 1: 843. PubMed

140 Okuonghae HO, Airede AI. Neonatal tetanus: incidence and improved outcome with diazepam. Dev Med Child Neurol 1992; 34: 448-453. CrossRef | PubMed

141 CDC. Neonatal tetanus—Montana, 1998. MMWR Morb Mortal Wkly Rep 1998; 47: 928-930. PubMed

142 Owa JA, Osinaike AI. Neonatal morbidity and mortality in Nigeria. Indian J Pediatr 1998; 65: 441-449. CrossRef | PubMed

143 Brabin L, Kemp J, Maxwell SM, Ikimalo J, Obunge OK, Briggs ND. Protecting adolescent girls against tetanus. BMJ 1995; 311: 73-74. CrossRef | PubMed

144 Brabin L, Kemp J, Obunge OK, et al. Reproductive tract infections and abortion among adolescent girls in rural Nigeria. Lancet 1995; 345: 300-304. Summary | CrossRef | PubMed

145 Simonsen O, Bloch AV, Heron I. Epidemiology of tetanus in Denmark 1920—1982. Scand J Infect Dis 1987; 19: 437-444. CrossRef | PubMed

146 Heath CW, Zusman J, Sherman IL. Tetanus in the United States, 19501960. Am J Public Health Nations Health 1964; 54: 769-779. PubMed

147 WHO. Maternal and child health. Control of neonatal tetanus. Wkly Epidemiol Rec 1985; 60: 5-6. PubMed

148 Rahman S. The effect of traditional birth attendants and tetanus toxoid in reduction of neo-natal mortality. J Trop Pediatr 1982; 28: 163-165. CrossRef | PubMed

149 Darmstadt GL, Bhutta ZA, Cousens S, Adam T, Walker N, de Bernis L. Evidence-based, cost-effective interventions: how many newborn babies can we save?. Lancet 2005; 365: 977-988. Summary | Full Text | PDF(147KB) | CrossRef | PubMed

150 Mullany LC, Darmstadt GL, Khatry SK, et al. Topical applications of chlorhexidine to the umbilical cord for prevention of omphalitis and neonatal mortality in southern Nepal: a community-based, cluster-randomised trial. Lancet 2006; 367: 910-918. Summary | Full Text | PDF(123KB) | CrossRef | PubMed

151 Mullany LC, Darmstadt GL, Tielsch JM. Role of antimicrobial applications to the umbilical cord in neonates to prevent bacterial colonization and infection: a review of the evidence. Pediatr Infect Dis J 2003; 22: 996-1002. CrossRef | PubMed

152 Zupan J, Garner P, Omari AA. Topical umbilical cord care at birth. Cochrane Database Syst Rev 2004; 3. CD001057.

153 Yusuf B, Solter S, Bertsch D, Arnold RB. Impact of a tetanus toxoid immunization mass campaign on neonatal tetanus mortality in Aceh Province, Indonesia. Southeast Asian J Trop Med Public Health 1991; 22: 351-356. PubMed

154 Arnold RB, Soewarso TI, Karyadi A. Mortality from neonatal tetanus in Indonesia: results of two surveys. Bull World Health Organ 1986; 64: 259-262. PubMed

155 WHO. Expanded programme on immunization. Global Advisory Group—Part II. Achieving the major disease control goals. Wkly Epidemiol Rec 1994; 69: 29-35. PubMed

156 WHO. Expanded programme on immunization. Global Advisory Group. Part I. Wkly Epidemiol Rec 1990; 65: 5-11. PubMed

157 da Silveira CM, de Quadros CA. Neonatal tetanus: countdown to 1995. World Health Forum 1991; 12: 289-296. PubMed

158 WHO. Field manual for neonatal tetanus elimination. WHO/V&B/99.14. Geneva: World Health Organization, 1999.

159 Mansour E, Aylward RB, Cummings F. Integrated disease control initiatives: polio eradication and neonatal tetanus elimination in Egypt. J Infect Dis 1997; 175 (suppl 1): S277-S280. CrossRef | PubMed

160 Griffiths UK, Wolfson LJ, Quddus A, Younus M, Hafiz RA. Incremental cost-effectiveness of supplementary immunization activities to prevent neonatal tetanus in Pakistan. Bull World Health Organ 2004; 82: 643-651. PubMed

161 Brenzel L, Wolfson LJ, Fox-Rushby J, Halsey NA. Vaccine-Preventable Disease. In: Jamison DT, Breman JG, Measham JR, et al, eds. Disease control priorities in developing countries. New York: Oxford University Press, 2006: 389-411.

162 Laxminarayan R, Mills AJ, Breman JG, et al. Advancement of global health: key messages from the Disease Control Priorities Project. Lancet 2006; 367: 1193-1208. Summary | Full Text | PDF(175KB) | CrossRef | PubMed

163 Singh J, Datta KK, Foster SO. Sensitivity of neonatal tetanus surveillance system in India. Indian Pediatr 1997; 34: 398-401. PubMed

164 Lawn JE, Wilczynska-Ketende K, Cousens SN. Estimating the causes of 4 million neonatal deaths in the year 2000. Int J Epidemiol 2006; 35: 706-718. CrossRef | PubMed

165 UNICEF. The state of the worlds children 2005. New York: United Nations Childrens Fund, 2004.

166 WHO. Immunization surveillance, assessment and monitoring. 2004 Global Immunization Data. Geneva: World Health Organization, 2005. http://www.who.int/immunization_monitoring/data/GlobalImmunizationData.pdf. (accessed March 2, 2006).

167 Deming MS, Roungou JB, Kristiansen M, et al. Tetanus toxoid coverage as an indicator of serological protection against neonatal tetanus. Bull World Health Organ 2002; 80: 696-703. PubMed

168 The Lancets neonatal survival series. http://www.thelancet.com/collections/neonatal_survival.

169 Tinker A, Hoope-Bender P, Azfar S, Bustreo F, Bell R. A continuum of care to save newborn lives. Lancet 2005; 365: 822-825. Full Text | PDF(160KB) | CrossRef | PubMed

170 Lawn JE, Cousens SN, Darmstadt GL, et al. 1 year after The Lancet Neonatal Survival Series—was the call for action heard?. Lancet 2006; 367: 1541-1547. Full Text | PDF(1967KB) | CrossRef | PubMed

171 Horton R. The coming decade for global action on child health. Lancet 2006; 367: 3-5. Full Text | PDF(45KB) | CrossRef | PubMed

172 Knippenberg R, Lawn JE, Darmstadt GL, et al. Systematic scaling up of neonatal care in countries. Lancet 2005; 365: 1087-1098. Summary | Full Text | PDF(302KB) | CrossRef | PubMed

173 WHO/UNICEF. GIVS: Global Immunization Vision and Strategy, 2006—2015. Geneva: World Health Organization, 2005. http://www.who.int/vaccines/GIVS/english/english.htm. (accessed May 12, 2006).

a Weybridge, VT, USA

b WHO Expanded Programme on Immunization, Department of Immunization, Vaccines, and Biologicals, Geneva, Switzerland

c UNICEF, Health Section, Programme Division, New York, NY, USA

Correspondence to: Jos H Vandelaer, c/o WHO, Department of Immunization, Vaccines, and Biologicals, 20 Ave Appia, Geneva 27, Switzerland