Use of tetanus toxoid for the prevention of neonatal tetanus. 1. Reduction of neonatal mortality by immunization of non-pregnant and pregnant women in rural Bangladesh.

Bulletin of the World Health Organization, 60 (2): 261 - 267 (1982) Use of tetanus toxoid for the prevention of neonatal tetanus. 1. Reduction of neonatal mortality by immunization of non-pregnant and pregnant women in rural Bangladesh MAKHLISUR RAHMAN,l LINCOLN C. CHEN,2 J. CHAKRABORTY,3 MD. YUNUS,4 A. I. CHOWDHURY, A. M. SARDER, SHUSHUM BHATIA, & GEORGE T. CURLIN * An analysis ofthe live births between September 1978 andDecember1979 in a rural epi- demiological surveillance area of Bangladesh showed that for infants whose mother had received two tetanus injections 48- 64 months prior to delivery, the neonatal mortality rate was 63.8 per 1000 live births compared with 78.3 per 1000for infants whose mother did not receive tetanus immunization. Immunization of women with two tetanus injections during pregnancy reduced neonatal mortality rates to 42.8 per 1000, a reduction of35.5 per 1000. Mortality on days 4-14 was reduced even more- by about 70%. One injection during pregnancy did not appear to provide protection against tetanus neonatorum. Tetanus neonatorum is one of the leading causes of infant death throughout the world, accounting for up to one-third of all neonatal deaths in some developing countries (1, 2). One approach to the prevention of this problem is through improving the quality of pre- natal, obstetric, and postnatal maternal and child health services. Another complementary approach is the active immunization of women before or during pregnancy with tetanus toxoid. Any programme that aims to protect all neonates by means of active immunization of mothers, con- fronts two strategic choices. The first is the immuniz- ation of women during pregnancy with two injections of an aluminium-adsorbed tetanus toxoid. This immunization procedure is highly efficacious (2- 6), but its implementation depends upon the capacity to identify in a timely manner all eligible women, to maintain a "cold-chain" for vaccine preservation, transport, and delivery, and to ensure continuous Assistant Scientist, International Centre for Diarrhoeal Disease Research (ICDDR,B), GPO Box No. 128, Dacca-2, Bangladesh. 2 Formerly: Head, Scientific Programme, ICDDR,B. Present address: Department of Population Sciences, Harvard University, School of Public Health, Boston, MA 02115, USA. 3 Field Research Officer, Grade 1, ICDDR,B. 4 Acting Head, Matlab Field Station, ICDDR,B. 5 Statistical Officer, ICDDR,B. 6 Formerly: Research Physician, ICDDR,B. Present address: Senior Research Scientist, Department of Population Dynamics, The John Hopkins University, School of Hygiene and Public Health, Baltimore, MD 21205, USA. 7 Formerly: Head, Epidemiology Division, ICDDR,B. Present address: Regional Office for Asia, USAID, Washington DC, USA. provision of health services. In many developing countries such an advanced health infrastructure has not yet been developed, and in these countries mass immunization of women, both pregnant as well as non-pregnant, is an alternative strategy. However, mass immunization campaigns may disrupt rather than strengthen the village-based basic health service infrastructure, organization, and development. The constraints to this approach also include logistic diffi- culties in delivering two immunizations to the eligible population and in providing booster immunizations at appropriate intervals (7, 8). Work in progress at the Matlab field station of the International Centre for Diarrhoeal Disease Re- search, Bangladesh (ICDDR,B) provided a unique opportunity to study the effectiveness of certain aspects of these two strategies. In 1974, during a field trial of cholera toxoid vaccine, two injections of an aluminium phosphate tetanus - diphtheria toxoid were provided as a control to a randomly assigned group of non-pregnant women. Beginning in June 1978, a programme of immunizing women during pregnancy with aluminium phosphate-adsorbed tetanus toxoid was initiated in conjunction with the implementation of a village-based maternal and child health and family planning programme in half of the same Matlab surveillance area. Throughout the period of these two programmes, the ICDDR,B main- tained an independent, longitudinal, vital registration system, identifying all births and deaths in the study area. As a consequence, precise data are available on 4172 -261 M. RAHMAN ET AL. the neonatal mortality experience of children born to mothers who were immunized with tetanus toxoid during pregnancy, before pregnancy, or never immunized. MATERIALS AND METHODS The data for this study come from the field station of the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B, formerly the Cholera Research Laboratory), located in Matlab thana, Comilla district, about 45 km south-east of Dacca. The field surveillance area consisted of 149 villages with a population of about 177 000 persons. Since 1963, the ICDDR,B has operated a field research programme in this area involving the provision of diarrhoeal disease treatment services, and a continuous household registration of births, deaths, marriages, and niigrations. Details of the field surveillance area, its people, and field research pro- cedures have been reported in several previous publi- cations (9, 10). Registration of vital events in the field area was ensured through a three-tier surveillance system. Primary detection of births, deaths, marriages, and migrations was the responsibility of 110 literate female village workers (FVWs). In half of the field surveillance area, where a maternal and child health family planning (MCH-FP) programme has been operating since 1977, there were 80 FVWs, each responsible for a population of about 1100; the remaining half of the study population (comparison area) was covered by 30 FVWs, each responsible for a population of about 2800 people. During their visits to each household, fortnightly in the MCH-FP area and weekly in the comparison area, the FVWs enquired about vital events and recorded the events in a register. The FVWs worked independently and were supervised by 12 male field assistants (FAs) with secondary school education. The FAs accompanied by the FVWs visited each household monthly to check on the completeness of the registration and to record vital events on standard registration forms. The death registration form contained the following infor- mation: village, family, and individual identification numbers, age at death, sex, and probable cause of death. The work of the FAs was independently checked by 6 male senior field assistants who visited each household at least five times annually. The entire registration work was supervised and coordinated by a field supervisor and 3 assistant supervisors. During July and August 1974, the protective effect of cholera toxoid vaccine was evaluated in the Matlab field surveillance area. Children 1 -14 years old and non-pregnant women 15 years old and over were vaccinated after informed consent was obtained. On a double-blind basis, volunteers received 0.5 ml of cholera toxoid or 0.5 ml of aluminium phosphate tetanus-diphtheria toxoid. Attempts were made to give a second injection of the same vaccine to all vaccinees 42 days later, and 74% actually received a second dose (8). The MCH-FP programme was initiated in October 1977. The study design, field operations, and health services of the programme have been reported pre- viously (11). Initially, only family planning services were offered, but subsequently other services (immunization, oral rehydration therapy for diar- rhoea, and nutritional education) were introduced. In June 1978, immunization of pregnant women with 3 injections of aluminium-adsorbed tetanus toxoid was initiated, with a schedule of 0.5 ml at the 6th month, a second 0.5 ml at the 7th month, and a third 0.5 ml at the 8th month of pregnancy. As from July 1979, the three-dose schedule was modified to a two-dose schedule as follows: 0.5 ml any time after the 5th month of pregnancy and another 0.5 ml at least 4 weeks later, preferably at least one month before the expected delivery date. Vaccine was procured from the Bangladesh Government with the assistance of the World Health Organization Office in Dacca. Vaccine stock was stored in Dacca in a refrigerator and shipped monthly to the Matlab field station in a specially-designed vaccuum flask. At the field station, the vaccine was stored in a refrigerator, which often had to be main- tained by a local generator during power failures. Vaccines were consistently stored and transported at 4- 8 °C, and were discarded if the temperature exceeded 8 °C for a cumulative period of 72 hours. In fortnightly meetings at the subcentres, the FVWs sub- mitted lists of pregnant women willing to accept the vaccine. Accordingly, vaccines were despatched from Matlab centre to the subcentres for distribution among the FVWs. Since the subcentres had no elec- tricity, cold boxes with refreshed freezer packs were rotated to the subcentres every two days. Moving from the subcentres, the FVWs carried the vaccine to the homes of pregnant women and delivered the vaccine using 1-ml disposable needles and syringes. All unused vaccines left over at the end of a day were discarded. The field record system for the tetanus immunization programme is described in detail else- where (12). In the present analysis, all live births registered in the MCH-FP and comparison areas during the period from 1 September 1978 until 31 December 1979 were identified. These records were linked with any deaths recorded within 28 days of birth. The acceptance of tetanus vaccination during the 1974 cholera vaccine trial, by the mothers of these live births, was ascer- tained from the 1974 vaccine registers. The accep- tance of vaccination during the 1978 - 79 programme 262 PREVENTION OF NEONATAL TETANUS. 1. was obtained from the FVWs field registers, which contained in addition to other information, an up-to- date list of pregnant women, their census identifi- cation number, and date and number of tetanus injections. RESULTS Table 1 presents selected vital events in the MCH- FP and comparison areas for the calendar year 1979. The lower crude birth and death rates in the MCH-FP area presumably reflect the impact of the family planning services of the MCH-FP programme. During the period under study, in the MCH-FP area about 30%0 of married women of reproductive age used contraceptives, as compared with about 407% in the comparison area (11). The lower crude death rate in MCH-FP area was mainly due to differences in the age structure of the two populations, because of the reduced number of births in the MCH-FP area. The contribution of health services, including tetanus immunization, to the reduced death rate in the MCH- FP area is not quantified, although as demonstrated later (in Table 3), tetanus immunization of pregnant women did contribute to lowered neonatal mortality. Table 2 presents the number of live births in this study analysed according to maternal tetanus immun- ization status. The mothers of 956 infants (9.77o) had accepted full immunization (2 injections) while non- pregnant during the July-August 1974 programme and 934 (9.5%) accepted full immunization during pregnancy in the 1978 - 79 programme. The mothers of the remaining infants (729 or 7.47o) accepted partial immunization (1 injection in one or other pro- Table 1. Mid-year population and numbers and rates of selected vital events in Matlab, Bangladesh (1979), by area MCH-FP area Comparison area Vital events No. Rate' No. Rate" Total population (estimated mid-1979) 90 134 - 86 649 Live births 3 131 34.7 4 061 46.9 Deaths: All ages 1 080 12.0 1 342 15.5 Infant 358 114.3 477 117.4 Neonatal 221 70.6 298 73.4 Postneonatal 137 43.8 179 44.1 a Crude birth and death rates are per 1000 population. Infant, neonatal, and postneonatal mortality rates are per 1000 related live births. Table 2. Number of live births between 1 September 1978 and 31 December 1979 according to immunization status of their mothers Immunization status MCH-FP Comparison of mothers area area Total' Fully immunized" While non- pregnant in 1974 436 520 956 (9.7) During pregnancy in 1978-79 934 - 934(9.5) Mixed or partially immunized' 495 234 729 (7.4) Non-immunized 2379 4858 7237 (73.4) Total no. of live births 4244 5612 98561100.0) Figures in parentheses represent percentage. Acceptance of 2 injections either in the 1 974 programme or in the 1978 - 79 programme. " Partial immunization means acceptance of 1 injection either in 1974 or in 1978 - 79. Mixed immunization means acceptance of 1 or 2 injections in 1974 and again 1 or 2 injections in 1 978 - 79. gramme, or partial immunization in one programme and full immunization in the other, or full immunization in both the programmes). None of the study mothers was exposed to any other national or local tetanus immunization programme. Examination of the neonatal mortality rates (data not shown here) for the study infants according to the day of death and the immunization status of the mother, suggests that the infants whose mothers had received full immunization while not pregnant in 1974 and the infants whose mothers had received full immunization during pregnancy in 1978 - 79 had lower death rates between days 5 and 12 and 6 and 15, respectively, compared with the infants whose mothers had not accepted immunization on either occasion. The three-day moving averages are shown in Fig. 1, and a similar pattern emerges, differences in mortality rate being observed between day 4 and day 16 between the non-immunized group and the group immunized in 1978 - 79 and between day 4 and day 13 between the non-immunized and the group immu- nized in 1974. The prominent increase in deaths on days 19-21 in the 1978-79 immunized group was due to the death of two pairs of twins. Table 3 shows the overall rates of neonatal mortality (days 0- 28) and the neonatal mortality on days 4- 14, when tetanus is considered to be the main cause of death (4). The differences in neonatal mor- tality rates (both 0- 28 and 4- 14 days) between the 1978 - 79 fully immunized group and the non-immu- nized group were statistically significant (P < 0.01). 263 M. RAHMAN ET AL. The difference between the 4 -14 day neonatal mortality rates for the 1974 fully-immunized group and the non-immunized group was statistically signi- 10- ficant (P < 0.05) in the MCH-FP area only. All other comparisons were not significant. Table 4 presents neonatal mortality rates and mortality rates between day 4 and day 14 for the small numbers of births in the mixed or partially immunized groups. None of the differences were statistically significant, but the 4- 14 day mortality among those born to mothers who received two immunizations 0 \he 24 during pregnancy in 1978 - 79 (with either one or two z o,9 ,,0\SX previous injections in 1974) was very low. The 4- 14 \d\%,,_,%v < day mortality among the births to the mothers partially immunized in 1978 - 79 was higher than the corresponding rate for the non-immunized group (see 0 Table 3). There seem to be two possible explanations 5 20 25 28 for higher mortality rate among the neonates of this Day after birth who partially immunized during nancy. Several previous studies have shown that Fig. 1. Number of infant deaths (per 1000 surviving successful protection against tetanus neonatorum is infants), according to day after birth (3-day moving unlikely if maternal immunization is incomplete (4, average) and maternal tetanus immunization status, for 5). It is also possible that the partially immunizedinfants born between 1 September 1978 and 31 Decem- go also a ther proportion imaparasber 1979, in Matlab, Bangladesh. -* immunized group contained a higher proportion of primaparas during pregnancy, 1978-79;o----O immunized while who experience comparatively higher neonatal non-pregnant, 1974;0-O non-immunized. mortality rates. This possibility was confirmed in a Table 3. Neonatal and 4 - 14 day mortality among the live birth cohort (1 September 1978 - 31 December 1979) according to maternal immunization status MCH-FP area Comparison area Total Immunization status No. Rate No. Rate No. Rate Fully immunized while non-pregnant (1974) Live births 436 - 520 - 956 Neonatal 10- 28 day) deaths 28 64.2 33 63.5 61 63.8 4-14daydeaths 7 16.1' 12 23.1 19 19.9 Fully immunized during pregnancy (1978 - 79) Live births 934 - - - 934 Neonatal 10- 28 day) deaths 40 42.8' - 40 42.8" 4 - 14 day deaths 10 10.7" - - 10 10.7" Non-immunized Live births 2379 - 4858 - 7237 Neonatal (0- 28 day) deaths 199 83.6' 368 75.7 567 78.3u 4 - 14 day deaths 82 34.5" 164 33.8 246 34.0" P < 0.01 for comparisons of the pairs of figures marked a, b, c, and d. P < 0.05 for comparison of the pair of figures marked e. All the other comparisons were not significant. 264 PREVENTION OF NEONATAL TETANUS. 1. Table 4. Neonatal and 4- 14 day mortality among the live birth cohort (1 September 1978 -31 DecenYber 1979) according to mixed or partial maternal immunization status' Immunization status of mothers No. of injections No. of injections No. of Neonatal deaths Deaths 4- 14 days received while received during live non-pregnant in 1974 pregnancy in 1978-79 births" No. Rate No. Rate 2 2 142 9 63.4 1 7.0 2 1 25 2 80.0 1 40.0 1 2 64 2 31.2 1 1 5.6 1 1 12 1 83.3 0 0 1 0 362 1 8 49.7 9 24.9 0 1 124 15 121.0 6 48.4 Total 729 47 64.5 1 8 24.7 For definition see Table 2. MCH-FP and comparison areas combined. sample survey, which showed that the main reason for failure to accept a second immunization was the departure of the women from their usual residence to their parents' house (12). This practice is more common among young women experiencing preg- nancy for the first time. Table 5 shows still-birth ratios for the group that was fully immunized in 1974, the group that was fully immunized in 1978 - 79, and the non-immunized group. The difference between still-birth ratios of the 1978 - 79 immunized group and the other two groups was statistically significant (P< 0.05). Table 5. Still-birth ratio (per 1000 live births) among the birth cohort (1 September 1978 -31 December 1979) according to maternal immunization status Immunization No. of Still-births status live of mothers births" No. Ratio Fully immunized while non-pregnant (1974) 956 44 46.0" Fully immunized during pregnancy (1978 - 79) 934 24 2 5.7"' Non-immunized 7237 313 43.3' MCH-FP and comparison areas combined. P < 0.05 for comparison of the pairs of figures marked b and c. DISCUSSION Some of the limitations of this study deserve mention. The first concerns the comparability of the three study groups: those immunized in 1974, those immunized in 1978-79, and tho non-immunized group. While the group immunized in 1974 comprised women who were selected in a double-blind manner, those immunized in 1978 - 79 were women who voluntarily accepted tetanus immunization during pregnancy. Any biases introduced by this motiv- ational difference, however, may not be large. An examination of age, parity, number of living children, education, occupation, and other socio-demographic variables failed to demonstrate statistically signifi- cant differences between the acceptors and non- acceptors of vaccination in the 1978 - 79 programme (12). Another constraint was the lack of direct diagnosis of neonatal deaths due to tetanus. The current regis- tration of the cause of death relies on the description of symptoms and circumstances provided by the family and relatives of the deceased and ascertain- ment by an unskilled field worker, and thus it was not possible to assess directly the effectiveness of immunization against neonatal tetanus deaths. This problem was compounded by the fact that tetanus neonatorum in Matlab is known as "takuria", which includes not only tetanus deaths but also other undiagnosed deaths which people believe to be caused by evil spirits (12). A third limitation is the possible contamination effect of other health intervention activities in the 265 M. RAHMAN ET AL. MCH-FP area. Oral therapy for diarrhoea, nutritional education, and family planning services were also provided to the population during the 1978 - 79 study period. The crude birth rate of 34.7 per 1000 in the MCH-FP area in contrast with 46.9 in the comparison area is one example of the effects of these services. None of these other health measures, however, appears to have affected the neonatal mor- tality rate (Table 1), nor was there evidence of differ- ential effects of these interventions on the 1978 - 79 immunized and non-immunized groups. Despite these limitations the study was unique in several respects. The delivery system employed in Matlab in 1978 - 79 provided uniform availability of tetanus immunization services to the target popu- lation. Secondly, the availability of reliable vital regis- tration data, particularly concerning very early infant deaths, is unusual for populations in developing countries. Finally, the detection of neonatal deaths was conducted independently of the immunization programme, thereby reducing possible reporting bias of clinic-based or health programme staff. A previous Matlab paper demonstrated that for infants whose mothers had received two tetanus injec- tions 9- 32 months before giving birth, the neonatal death rate was 20 per 1000 live births lower than the rate for those whose mothers were not immunized (8). The present study shows that even after an average of four and a half years (48 - 64 months), the immunized group (2 injections) had a neonatal mortality rate 14.5 per 1000 live births lower than that for the non-immu- nized group. This difference, however, was not statis- tically significant, although there was a significant difference in the mortality rate 4 - 14 days after birth. This finding implies that mass immunization programmes covering non-pregnant women should consider booster immunization within 4- 6 years of the initial immunizations. Another major finding of this study concerns the impact of active immunization of pregnant women on neonatal mortality. Full immunization of pregnant women with two tetanus injections reduced neonatal mortality rates by about one half and neonatal mortality on days 4- 14 by about 70%. Given the apparent homogeneity of immunized and non-immu- nized groups of women, in respect to their socio- demographic characteristics and the fact that almost all births in the Matlab area are delivered at home by untrained midwives and relatives, maternal immuniz- ation probably explains most of this significant reduction in neonatal mortality. The magnitude of the effect, however, suggests that the reduction noted may be inflated and may have been biased by an unquantifiable difference between the immunized and non-immunized groups. A nationally represen- tative retrospective sample survey of infant mortality conducted by WHO in the period 1975 - 77, indicated that neonatal tetanus caused 25 deaths per 1000 live births in Bangladesh (14). The net mortality effect of a successful programme immunizing all pregnant women may be crudely esti- mated as follows. In Bangladesh and similar coun- tries, infant mortality may contribute about 25% of all deaths, and neonatal mortality may constitute up to two-thirds of all infant deaths (13). An optimistic, but plausible, reduction of neonatal mortality by one- third may therefore be expected to reduce overall infant mortality by 22% and the overall death rate by about 6%. Interestingly, data in Table 1 fail to document such a high impact on neonatal, infant, and crude death rates, in part because only one-third of the eligible women in this programme accepted the vaccine. The factors responsible for this modest immunization acceptance rate are analysed in a separate paper (12). Another finding in this study, tentative because of small sample size, is the limited impact of partial maternal immunization during pregnancy. This observation is consistent with several other previous studies (3, 4, 8). Unfortunately, again owing to sample size, this study did not provide clear evidence regarding the impact of a booster dose during preg- nancy in previously immunized women. The study also addresses the effect of tetanus immunization during pregnancy on pregnancy out- come. Since women were given the first tetanus injec- tion after the fifth month of pregnancy, the present study only examines still-birth (> 7 months) ratios and not early miscarriages. The data show that the immunized group had significantly lower still-birth ratio then the non-immunized group. The reasons for this difference are not known. The finding is never- theless extremely reassuring regarding a possible negative effect of tetanus immunization during preg- nancy on late foetal outcome. A significant number of women did not accept vaccination for fear of harming the foetus (12). 266 PREVENTION OF NEONATAL TETANUS. 1. 267 RESUME UTILISATION DE L'ANATOXINE TETANIQUE POUR LA PREVENTION DU TETANOS NEONATAL. 1. REDUCTION DE LA MORTALITE NEONATALE PAR LA VACCINATION DE FEMMES ENCEINTES ET NON ENCEINTES DANS UNE REGION RURALE DU BANGLADESH Au cours d'un essai sur le terrain du vaccin a base d'ana- toxine cholerique effectue en 1974 dans la zone de surveil- lance de Matlab, au Bangladesh, par le Centre international de recherche sur les maladies diarrheiques du Bangladesh, deux doses d'anatoxine tetanique adsorbee sur aluminium ont e administrees a un groupe temoin de femmes non enceintes choisies au hasard. Par ailleurs, a partir de juin 1978, un programme de vaccination des femmes enceintes par l'anatoxine tetanique a debute, paralleement a la mise en aeuvre, au niveau des villages, d'un programme de sante maternelle et infantile et de planification familiale, dans la moitie de cette zone de surveillance de Matlab. Pendant toute la duree de ces deux programmes, le Centre a poursuivi l'application de son systeme longitudinal de registre inde- pendant d'etat civil, permettant de repertorier toutes les naissances et les deces dans la zone etudiee. La presente etude analyse les taux de mortalite neonatale (O- 28 jours) pour une cohorte d'enfants nes vivants entre le 1er septembre 1978 et le 31 decembre 1979 suivant que leurs meres avaient e vaccinees contre le tetanos ou non (et si oui, quand) lors des programmes lances en 1974 et en 1978 - 79. Une precedente etude effectuee dans la region de Matlab avait montre que le taux de mortalite neonatale des nouveau-nes dont les meres avaient recu deux doses de vaccin antitetanique 9 a 32 mois avant l'accouchement etait inferieur de 20 pour 1000 naissances vivantes a celui des nouveau-nes dont les meres n'avaient pas e vaccinees. La presente etude a reve1l que meme apres un laps de temps de 48 a 64 mois, le groupe immunise presentait un taux de mortalite neonatale inferieur de 14,5 pour 1000 a celui du groupe non immunise. La difference n'etait toutefois pas statistiquement significative, bien qu'elle soit assez importante (18,4 pour 1000 naissances vivantes) pour le taux de mortalite parmi les nourrissons de 4 a 14 jours, age ou le tetanos est la principale cause de dec&s. Le taux de mortalite des nouveau-nes dont les meres avaient recu deux doses de vaccin antitetanique au cours de leur grossesse etait pres de deux fois inferieur, et pour les nourrissons de 4 a 14 jours inferieur de pres de 70Wo a celui des enfants de meres non vaccinees. L'administration d'une seule dose d'anatoxine tetanique au cours de la grossesse ne semble pas conferer de protection contre le tetanos neonatal. REFERENCES 1. BYTCHENKO, B. Geographical distribution of tetanus in the world, 1951 -60: a review of the problem. 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