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Vaccines for women to prevent neonatal tetanus

  1. Vittorio Demicheli1,*,
  2. Antonella Barale2,
  3. Alessandro Rivetti1

Editorial Group: Cochrane Pregnancy and Childbirth Group

Published Online: 31 MAY 2013

Assessed as up-to-date: 31 JAN 2013

DOI: 10.1002/14651858.CD002959.pub3


How to Cite

Demicheli V, Barale A, Rivetti A. Vaccines for women to prevent neonatal tetanus. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD002959. DOI: 10.1002/14651858.CD002959.pub3.

Author Information

  1. 1

    Azienda Sanitaria Locale ASL AL, Servizio Regionale di Riferimento per l'Epidemiologia, SSEpi-SeREMI - Cochrane Vaccines Field, Alessandria, Piemonte, Italy

  2. 2

    ASL VC, Struttura di Epidemiologia, Vercelli, Piemonte, Italy

*Vittorio Demicheli, Servizio Regionale di Riferimento per l'Epidemiologia, SSEpi-SeREMI - Cochrane Vaccines Field, Azienda Sanitaria Locale ASL AL, Via Venezia 6, Alessandria, Piemonte, 15100, Italy. vdemicheli@aslal.it. vittoriodemicheli@gmail.com.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 31 MAY 2013

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This is not the most recent version of the article. View current version (06 JUL 2015)

 
Characteristics of included studies [ordered by study ID]
Black 1980

MethodsVolunteers received 1 of the 2 treatments on a double-blind basis, there was no information about the adopted manner of randomisation.


ParticipantsChildren between 1 and 14 years of age and non-pregnant women at least 15 years old from Matlab, a community in rural Bangladesh. Altogether 92,928 participants were immunised and their 8641 infants followed up.


Interventions1 or 2 doses of adult dose Al-adsorbed tetanus-diphtheria toxoid versus cholera toxoid. Both as 0.5 mL dose, intramuscular, double-blind.


OutcomesNeonatal mortality on days 4-14 (as indicator for neonatal tetanus).
Neonatal mortality. Both assessed on 2 following birth cohorts.


NotesImmunisations carried out between July 1974 and August 1974. Neonatal outcomes were assessed during 'censuses' between April 1975 and March 1977. Government supported.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescibed as randomised but no description about sequence generation is present.

Allocation concealment (selection bias)Unclear riskAllocation concealment not described.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDescribed as double-blind but reported details do not allow to state whether the study was really carried out under blind conditions.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes of interest (death cases occurred among newborns during the first 28 days) assessed by means of demographic surveillance system.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo lost from follow-up (infants).

Selective reporting (reporting bias)Unclear riskNot assessed.

Other biasUnclear riskMortality between 4 and 14 days is only an indicator outcome for neonatal tetanus death.

Newell 1966

MethodsRCT (all registered were allotted a code number according to their ascertainment, which was previously randomly divided in 2 groups, A and B. Those who declined to participate were placed in a third group C, n = 1158).


ParticipantsWomen between 13 and 45 years of age from Corregimiento of Guacene (Colombia) were immunised with TT or polyvalent influenza vaccine (n = 1618). Follow-up was carried out on 1182 infants.


Interventions1 or 2 doses of 10 LF AlPO4 adsorbed tetanus toxoid vs polyvalent influenza vaccine, 1 mL intramuscularly, both preparations were not perfectly undistinguishable.


OutcomesIncidence of neonatal tetanus cases or deaths.
Non-tetanus death among the newborns in the 5 years following the immunisation.


NotesCarried out between 1961 and 1965. Lederle Laboratories provided TT.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom sampling number.

Allocation concealment (selection bias)Low riskEven if formally adequate (i.e. code numbers allotted to participant women by order of ascertainment; code numbers were previously randomised to treatment and control arm), injected preparation were not perfectly indistinguishable (see below).

Blinding of participants and personnel (performance bias)
All outcomes
High riskVial labels were of different colours. It was noted early by both participants and personnel that 1 of the 2 preparation was more painful after inoculation. This might have caused an higher refusal rate in intervention group (about 10%).

Blinding of outcome assessment (detection bias)
All outcomes
Low riskEven if not described, it is plausible that outcome assessors were unaware of the immunisation status of the women.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot estimable.

Selective reporting (reporting bias)Unclear riskNot assessed.

Other biasUnclear riskNot relevant.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Abuwa 1997Not a trial.

Al-Safi 2011Narrative review.

Anh 1999Not a trial. Serological measurement with means of the Toxin Binding Inhibition Test on pregnant women and children after 2 doses TT.

Axelsson 2002Review on umbilical cord care and prevention of infections.

Aylward 1996Surveillance study.

Baltazar 1994Case-control study on efficacy of prenatal TT immunisation in preventing neonatal tetanus.

Basher 2010Cross-sectional study assessing vaccination coverage and educational status in a sample of undergraduate female students in Bangladesh.

Berggren 1971Retrospective survey.

Blencowe 2010Systematic review.

Canning 2011Follow-up study assessing schooling attainment on babies born from mothers who were immunised several years earlier (Black 1980).

Chai 2004Case-control study.

Chongsuvivatwong 93Incidence of neonatal tetanus mortality before and after mass immunisation in Thailand.

de Walque 2008Not comparative.

Dhillon 1975Not a trial. Only serological outcomes.

Dietz 1996Review.

Gupta 1998Cohort study.

Halperin 2011Serological outcomes only.

Hardegree 1970Continuation of the study of MacLennan 1965. 2 TT vaccine with different adjuvants were administered. Serological only.

Hasnain 2007Survey assessing the reasons for low vaccination coverage.

Heredia 1968Not a trial. Only serological assessment.

Hlady 1992Case-control study.

Kielmann 1977Not a trial. Administration of TT with 2 different adjuvants in women of childbearing age. Only serological outcomes.

Koenig 1998Not a trial. 10-year follow up conducted on half of the area where Black 1980 was carried out.

Lassi 2010Cochrane review about efficacy of community-based intervention packages to prevent neonatal tetanus. Vaccination is not included.

MacLennan 1965No intervention: administration of vaccines containing same toxoids but different adjuvants in women of childbearing age. Efficacy outcomes are only serological.

Mulholland 1996No intervention: trial with polyribosylribitol phosphate-tetanus vaccine.

Nohynek 1999No intervention: participants were children receiving conjugate Hib and DTP vaccine, who were born from mother immunised with different doses of TT (0, 1, 2, 3 and more).

Orozova-Bekkevold 2007Not about tetanus immunisation.

Perry 1998Report on tetanus toxoid immunisation coverage.

Rahman 1982bConsensus to vaccination.

Rahman 1982Not a trial. Vaccination of pregnant women with 3 doses of TT. Immunisation program conducted in half of the Matlab area after Black 1980.

Relyveld 1991Only serological outcomes.

Salama 2009Efficacy outcome is not of interest : immune response to vaccination assessed in women after immunisation.

Schofield 1961Not a trial.

Silveira 1995Case-control to assess relationship between exposition to TT in pregnancy and malformation in the newborns.

Stanfield 1973Not a trial. Variation of seral antitoxin after administration of different TT preparation to pregnant women.

Suri 1964Not a trial. Different TT preparation were administered and antitoxin in cord blood were measured.

Tall 1991Case-control study.

Traverso 1991Case-control study for assessing risk of developing neonatal tetanus, TT immunisation of the mothers was not evaluated as associated factor.

Yala 1980Not a trial.

Yusuf 1991Follow-up survey to determine incidence of neonatal tetanus before and after a vaccination campaign in Indonesia.

 
Comparison 1. Tetanus toxoid versus influenza vaccine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Neonatal tetanus deaths11182Risk Ratio (M-H, Random, 95% CI)0.12 [0.00, 7.88]

    1.1 One dose
1494Risk Ratio (M-H, Random, 95% CI)0.57 [0.26, 1.24]

    1.2 Two or three doses
1688Risk Ratio (M-H, Random, 95% CI)0.02 [0.00, 0.30]

 2 Deaths from non-neonatal tetanus causes11182Risk Ratio (M-H, Random, 95% CI)1.24 [0.44, 3.47]

    2.1 One dose
1494Risk Ratio (M-H, Random, 95% CI)2.14 [0.97, 4.76]

    2.2 Two or three doses
1688Risk Ratio (M-H, Random, 95% CI)0.75 [0.38, 1.47]

 3 All causes of death11182Risk Ratio (M-H, Random, 95% CI)0.58 [0.17, 1.99]

    3.1 One dose
1494Risk Ratio (M-H, Random, 95% CI)1.08 [0.65, 1.79]

    3.2 Two or three doses
1688Risk Ratio (M-H, Random, 95% CI)0.31 [0.17, 0.55]

 4 Neonatal tetanus cases1Risk Ratio (M-H, Random, 95% CI)Subtotals only

    4.1 Any dose
11182Risk Ratio (M-H, Random, 95% CI)0.20 [0.10, 0.40]

 
Comparison 2. Tetanus diphtheria toxoid versus cholera toxoid

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Neonatal mortality1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 2 Four to 14 days neonatal mortality1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 
Table 1. Studies evaluating safety outcomes

ReferencesStudy designStudy populationInterventionSafety outcomesResults

MacLennan 19652 studies are reported in this paper:
a) 1 cluster-RCT evaluating reactogenicity and side-effects;
b) 1 RCT assessing safety only, with a 24-weeks' follow-up.
Both studies were performed in New Guinea on indigenous populations.
a) Pregnant women belonging to the Abelam tribe (n = 179).
b) Non-pregnant women from the Maprik area (n = 999).
a) Tetanus toxoid prepared by Parke Davis & co with different adjuvants and administered in different doses (Drakeol, 1 dose vs H - 24, 1 dose vs AlPO4, 2 doses vs none, 3 doses) or TT prepared by the Commonwealth Serum Laboratories without adjuvant, 3 doses.
b) TT prepared by Parke Davis & co with Drakeol (A, 1 dose) vs H - 24 (B, 1 dose) vs AlPO4 (C, 2 doses).
a) Swelling (severe or no tender).
b) Abscess (A = 103 /327; B = 96/332; C = 2/340 at the 14th week after immunisation).
c) Fever between 37.8-38.3 °C.
d) Swelling.
Although oil-adjuvated preparations provide longer persistence of antitoxin and require to be administered only once, they caused frequently severe side-effects. The Al-adjuvated preparations, administered in 2 doses, appeared to be the best way at the time of the study to prevent the occurrence of NNT.

Silveira 1995Case-control study.Cases (n = 34,293): newborn with congenital malformation. The 10 most frequent in South America were considered.
Controls (n = 34,777): non-malformed babies of the same sex, born in the same hospital immediately after the malformed ones.
Data were obtained from examination of 1,282,403 neonates in 173 hospitals in 105 cities across 9 different countries in South America.
Immunisation of the mothers with TT during pregnancy.Cleft lip, pes equinovarus, postaxial polydactyly, hip subluxation, haemangioma, periauricular tag, fistula auris, pigmented naevus, other skin defects, multiple malformed.No association for each of the examined factors was found.

Salama 2009RCT.Healthy pregnant Egyptian women at about 20 weeks of gestational age (n = 122).Subjects were randomised to :

a) 0.5 ml of tetanus toxoid (TT, 5Lf, n = 62).

b) 0.5 ml of combined tetanus and reduced diphtheria (Td, 5 Lf of each toxoids, n = 60).

First dose at 20-26 weeks of pregnancy, 2nd and 3rd administered respectively 8 and 4 weeks apart.
Systemic (fever, malaise, headache,
or body aches) and local reactions at the site of
injection (pain, redness, swelling) within 3 days after each immunisation.
Pain at the site of injection was complained more frequently in Td group after both first (P < 0.01) and second (P < 0.04) dose.

 Lf: limit of flocculation units
RCT = randomised controlled trial
TT: tetanus toxoid
vs: versus
 
Table 2. Non-randomised studies

ReferencesDesignStudy PopulationTreatmentOutcomesResults

Baltazar 1994Case-control study.54 neonates admitted to hospital diagnosed with neonatal tetanus. 50
controls 1-4 months old admitted for causes other than neonatal tetanus.
Manila.
Immunisation with tetanus toxoid, considered immunised if received at least 2 doses of tetanus toxoid during pregnancy, otherwise not.Incidence of immunisation: cases (1/54), controls (12/49).Protective effect against neonatal tetanus if at least 2 doses of tetanus toxoid.

Chai 2004Case-control study.
Surveillance data after TT mass immunisation campaign carried out 1995-96 in 320 out of 560 countries reaching about 23 million women aged 18-35 years, were also reported. Coverage with 2 doses of TT was estimate 10%. Surveillance data of 1996-2001 were analysed.
Cases: 60 children with NT (WHO case definition) reported by cards and hospital record in Bobai country (province of Guangxi, China) to the National Notifiable Disease Reporting System (NNDRS) from 1.1.97 to 30.4.98. Only children with accurate locating information were included. Controls: 60 infants born in the same village as the cases.Mother of children were immunised with TT. No information about the number of administered doses is reported.TT immunisation status of the mothers and other informations (maternal: age, education level, annual income < 1000 Yuan; infant: gender, order of birth, home delivery; parental knowledge and attitude regarding NT) were assessed by means of a detailed questionnaire given to parents of both cases and controls. TT immunisation history was based only of mother's recall because they were not provided with vaccinal records. Mothers of 7 cases and 17 controls received previously TT.Receiving of 1 or more of TT was significant protective against NT. Maternal age, education, family income, birth order, parental knowledge, were also significantly associated with NT.

Gupta 1998Survey.1688 pregnant women. India.Immunisation with tetanus toxoid, considered immunised if received 2 doses of tetanus toxoid at least 4 weeks apart or a booster dose. Partially immunised, if received 1 dose of tetanus toxoid either during the current pregnancy or in the past 3 years.Deaths from neonatal tetanus within 3 to 30 days of birth.Immunisation during the antenatal period is highly protective against occurrence of neonatal tetanus.

Hlady 1992Case-control study.Infants with clinical diagnosed tetanus. 3 controls. Bangladesh.Immunisation with tetanus toxoid, 2 doses 4 weeks apart, with second dose administered at least 30 days before delivery.Incidence of immunisation: cases (33/112), controls (122/336).Immunisation failed to provide the expected high level of protection.

Yusuf 1991Follow-up survey.Women aged 10-45 years. Indonesia.Immunisation with tetanus toxoid, 1 or 2 doses.Deaths from neonatal tetanus within 3 to 28 days of birth.Immunisation caused an 85% reduction of neonatal tetanus.

Chongsuvivatwong 93Survey study.Women aged 15-45 years. Thailand.Immunisation with tetanus toxoid.Cases of neonatal tetanus.Immunisation caused a 8-10 times reduction of neonatal tetanus.

Rahman 1982Surveillance study.Women from surveillance area. Bangladesh.Immunised with tetanus toxoid at 6th, 7th, 8th month. Considered immunised if received 2 injections in 1974 or in the 1978-79 programme.
Partially immunised, if received 1 injection in 1974 or 1978-79.
Mixed immunised if received 1 or 2 doses in 1974 and again 1 or 2 doses in 1978-79.
Deaths attributed to neonatal tetanus within 4-14 days after birth.Full immunisation reduced neonatal mortality rates by about one half and mortality rates on days 4-14 by about 70%.

Koenig 1998Survey.Children between 1-14 years and non-pregnant women at least 15 years. Bangladesh.Immunised with cholera toxoid (1 or 2 0.5 ml doses) vs tetanus - diphtheria toxoid (1 or 2 0.5 ml doses).Deaths attributed to neonatal tetanus within 4-14 days after birth.2 injections provided significant protection. Protection of 1 dose not significant.

Schofield 1961Observational.Pregnant women from 62 villages in New Guinea (Maprik, Wingei and Wosera areas). A retrospective "history-taking survey" on children born from 1945 to the time of the study was also performed in the Maprik area.3 doses of fluid formalinised tetanus toxoid (Commonwealth Serum Laboratories, Melbourne). The first dose was administered as early as possible in pregnancy, the second 6 weeks later and the third between 6 weeks and 6 months after the second.Cases of neonatal tetanus observed in children born from mothers who received different number of doses of TT during pregnancy.
Not immunised: 8/86.
Once immunised: 8/74.
Twice immunised: 8/234.
Three times immunised: 1/175.
From the history-taking survey it results that during the examination period 184 deaths due to neonatal tetanus occurred out of 3017 live births.
3 doses of formalinised TT administered during pregnancy afforded substantial protection against neonatal tetanus. Immunisation with only 2 doses provided also a significant protection level. No reactions to the vaccine were noticed.

 NT: neonatal tetanus
TT: tetanus toxoid