Scolaris Content Display Scolaris Content Display

Vacunas para las mujeres para la prevención del tétanos neonatal

Collapse all Expand all

References

References to studies included in this review

Black 1980 {published data only}

Black RE, Huber DH, Curlin GT. Reduction of neonatal tetanus by mass immunization of non‐pregnant women: duration of protection provided by one or two doses of aluminium‐adsorbed tetanus toxoid. Bulletin of the World Health Organization 1980;58(6):927‐30.

Munoz 2014 {published data only}

Leibson T, St‐Onge M, Koren G. TDM Journal Club: Safety and immunogenicity of tetanus diphtheria and acellular pertussis immunization during pregnancy. Therapeutic Drug Monitoring 2015;37(3):283‐4.
Munoz FM, Bond NH, Maccato M, Pinell P, Hammill HA, Swamy GK, et al. Safety and immunogenicity of tetanus diphtheria and acellular pertussis (Tdap) immunization during pregnancy in mothers and infants: a randomized clinical trial. JAMA 2014;311(17):1760‐9.

Newell 1966 {published data only}

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. Bulletin of the World Health Organization 1966;35(6):863‐71.
Newell KW, Duenas Lehmann A, LeBlanc DR, Garces Osorio N. The use of toxoid for the prevention of tetanus neonatorum: preliminary report of a double‐blind controlled field trial. Bulletin of the World Health Organization 1964;30:439‐44.

References to studies excluded from this review

Abu Raya 2014 {published data only}

Abu Raya B, Srugo I, Kessel A, Peterman M, Bader D, Gonen R. The effect of timing of maternal tetanus, diphtheria, and acellular pertussis (Tdap) immunization during pregnancy on newborn pertussis antibody levels ‐ A prospective study. Vaccine 2014;32(44):5787‐93.

Abuwa 1997 {published data only}

Abuwa PN, Alikor EA, Gbaraba PV, Mung KS, Oruamabo RS. Epidemiology of neonatal tetanus in the Rivers State of Nigeria: a community based study. Journal of Epidemiology and Community Health 1997;51(3):336.

Al‐Safi 2011 {published data only}

Al‐Safi ZA, Shavell VI, Gonik B. Vaccination in pregnancy. Womens Health 2011;7(1):109‐19.

Anh 1999 {published data only}

Anh NQ, Hong HA, Nhon TN, Thinh ND, Van NT, Hendriks J. Tetanus antibodies measured by the toxin binding inhibition test (ToBI) in mothers and children in the Neonatal Tetanus Program in Vietnam. Developments in Biological Standardization 1999;101:247‐53.

Axelsson 2002 {published data only}

Axelsson I. A Cochrane review on the umbilical cord care and prevention of infections. Antiseptic solutions are not necessary in developed countries but life‐saving in developing countries [Cochrane‐oversikt om att forebygga navelinfektioner. Antiseptisk losning ar onodig i i‐lander men livraddande i u‐lander.]. Lakartidningen 2002;99(14):1563‐6.

Aylward 1996 {published data only}

Aylward RB, Mansour E, Oon el‐S A, Tawfik SA, Makar S, Abu el Kheir A, et al. The role of surveillance in a 'high risk' approach to the elimination of neonatal tetanus in Egypt. International Journal of Epidemiology 1996;25(6):1286‐91.

Baltazar 1994 {published data only}

Baltazar JC, Sarol JN. Prenatal tetanus immunization and other practices associated with neonatal tetanus. Southeast Asian Journal of Tropical Medicine and Public Health 1994;25(1):132‐8.

Basher 2010 {published data only}

Basher MS. Knowledge and practice about TT vaccination among undergraduate female medical students. Mymensingh Medical Journal 2010;19(4):520‐3.

Berggren 1971 {published data only}

Berggren WL, Berggren GM. Changing incidence of fatal tetanus of the newborn. A retrospective study in a defined rural Haitian populations. American Journal of Tropical Medicine And Hygiene 1971;20(3):491‐4.

Blencowe 2010 {published data only}

Blencowe H, Lawn J, Vandelaer J, Roper M, Cousens S. Tetanus toxoid immunization to reduce mortality from neonatal tetanus. International Journal of Epidemiology 2010;39(Suppl 1):i102‐9.

Canning 2011 {published data only}

Canning D, Razzaque A, Driessen J, Walker DG, Streatfield PK, Yunus M. The effect of maternal tetanus immunization on children's schooling attainment in Matlab, Bangladesh: follow‐up of a randomized trial. Social Science & Medicine 2011;72(9):1429‐36.

Chai 2004 {published data only}

Chai F, Prevots DR, Wang X, Birmingham M, Zhang R, Chai F. Neonatal tetanus incidence in China, 1996‐2001, and risk factors for neonatal tetanus, Guangxi Province, China. International Journal of Epidemiology 2004;33(3):551‐7.

Chongsuvivatwong 1993 {published data only}

Chongsuvivatwong V, Bujakorn L, Kanpoy V, Treetrong R. Control of neonatal tetanus in southern Thailand. International Journal of Epidemiology 1993;22(5):931‐5.

de Walque 2008 {published data only}

de Walque D. Do unsafe tetanus toxoid injections play a significant role in the transmission of HIV/AIDS? Evidence from seven African countries. Sexually Transmitted Infections 2008;84(2):122‐5.

Dhillon 1975 {published data only}

Dhillon H, Menon PS. Active immunization of women in pregnancy with two injections of adsorbed tetanus toxoid for prevention of tetanus neonatorum in Punjab, India. Indian Journal of Medical Research 1975;63(4):583‐9.

Dietz 1996 {published data only}

Dietz V, Milstien JB, van Loon F, Cochi S, Bennett J. Performance and potency of tetanus toxoid: implications for eliminating neonatal tetanus. Bulletin of the World Health Organization 1996;74(6):619‐28.

Erener‐Ercan 2014 {published data only}

Erener‐Ercan T, Aslan M, Vural M, Erginoz E, Kocazeybek B, Ercan G. Tetanus and diphtheria immunity among term and preterm infant‐mother pairs in Turkey, a country where maternal and neonatal tetanus have recently been eliminated. European Journal of Pediatrics 2015;174(3):339‐44.

Gupta 1998 {published data only}

Gupta SD, Keyl PM. Effectiveness of prenatal tetanus toxoid immunization against neonatal tetanus in a rural area in India. Pediatric Infectious Disease Journal 1998;17(4):316‐21.

Halperin 2011 {published data only}

Halperin BA, Morris A, Mackinnon‐Cameron D, Mutch J, Langley JM, McNeil SA, et al. Kinetics of the antibody response to tetanus‐diphtheria‐acellular pertussis vaccine in women of childbearing age and postpartum women. Clinical Infectious Diseases 2011;53(9):885‐92.

Hardy‐Fairbanks 2013 {published data only}

Hardy‐Fairbanks AJ, Pan SJ, Decker MD, Johnson DR, Greenberg DP, Kirkland KB. Immune responses in infants whose mothers received Tdap vaccine during pregnancy. Pediatric Infectious Diseases Journal 2013;32(11):1257‐60.

Hasnain 2007 {published data only}

Hasnain S, Sheikh NH. Causes of low tetanus toxoid vaccination coverage in pregnant women in Lahore district, Pakistan. Eastern Mediterranean Health Journal 2007;13(5):1142‐52.

Heredia 1968 {published data only}

Heredia AF, Borkar MB, Rao SS. Active immunization in pregnancy with fluid tetanus toxoid. Indian Journal of Medical Sciences 1968;22(4):209‐13.

Hlady 1992 {published data only}

Hlady WG, Bennett JV, Samadi AR, Begum J, Hafez A, Tarafdar AI, et al. Neonatal tetanus in rural Bangladesh: risk factors and toxoid efficacy. American Journal of Public Health 1992;82(10):1365‐9.

Hurmez 2012 {published data only}

Hurmez L, Habeeb QS, Al‐Derzi NA. Seroprevalence of tetanus antibodies among pregnant women in Duhok Governorate, Iraq [Seroprevalence des anticorps antitetaniques chez des femmes enceintes dans le Gouvernorat de Duhok (Iraq)]. Eastern Mediterranean Health Journal 2012;18(6):573‐8.

Juan‐Giner 2014 {published data only}

Juan‐Giner A, Domicent C, Langendorf C, Roper MH, Baoundoh P, Fermon F, et al. A cluster randomized non‐inferiority field trial on the immunogenicity and safety of tetanus toxoid vaccine kept in controlled temperature chain compared to cold chain. Vaccine 2014;32(47):6220‐6.

Kielmann 1977 {published data only}

Kielmann AA, Vohra SR. Control of tetanus neonatorum in rural communities‐‐immunization effects of high‐dose calcium phosphate‐absorbed tetanus toxoid. Indian Journal of Medical Research 1977;66(6):906‐16.

Koenig 1998 {published data only}

Koenig MA, Roy NC, McElrath T, Shahidullah M, Wojtyniak B. Duration of protective immunity conferred by maternal tetanus toxoid immunization: further evidence from Matlab, Bangladesh. American Journal of Public Health 1998;88(6):903‐7.

Krishnan 2013 {published data only}

Krishnan A, Srivastava R, Dwivedi P, Ng N, Byass P, Pandav CS. Non‐specific sex‐differential effect of DTP vaccination may partially explain the excess girl child mortality in Ballabgarh, India. Tropical Medicine and International Health 2013;18(11):1329‐37.

Lassi 2010 {published data only}

Lassi ZS, Haider BA, Bhutta ZA. Community‐based intervention packages for reducing maternal and neonatal morbidity and mortality and improving neonatal outcomes. Cochrane Database of Systematic Reviews 2010, Issue 11. [DOI: 10.1002/14651858.CD007754.pub2]

MacLennan 1965 {published data only}

Hardegree MC, Barile MF, Pittman M, Schofield FD, Maclennan R, Kelly A. Immunization against neonatal tetanus in New Guinea. Bulletin of the World Health Organization 1970;43(3):439‐51.
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. Bulletin of the World Health Organization 1965;32(5):683‐97.

Mulholland 1996 {published data only}

Mulholland K, Suara RO, Siber G, Roberton D, Jaffar S, N'Jie J, et al. Maternal immunization with Haemophilus influenzae type b polysaccharide‐tetanus protein conjugate vaccine in the Gambia. JAMA 1996;275(15):1182‐8.

Nohynek 1999 {published data only}

Nohynek H, Gustafsson L, Capeding MR, Kayhty H, Olander RM, Pascualk L, et al. Effect of transplacentally acquired tetanus antibodies on the antibody responses to haemophilus influenzae type b‐tetanus toxoid conjugate and tetanus toxoid vaccines in Filipino infants. Pediatric Infectious Disease Journal 1999;18(1):25‐30.

Orozova‐Bekkevold 2007 {published data only}

Orozova‐Bekkevold I, Jensen H, Stensballe L, Olsen J. Maternal vaccination and preterm birth: using data mining as a screening tool. Pharmacy World and Science 2007;29(3):205‐12.

Perry 1998 {published data only}

Perry H, Weierbach R, Hossain I, Islam R. Tetanus toxoid immunization coverage among women in zone 3 of Dhaka city: the challenge of reaching all women of reproductive age in urban Bangladesh. Bulletin of the World Health Organization 1998;76(5):449‐57.

Rahman 1982a {published data only}

Rahman M, Chen LC, Chakraborty J, Yunus M, Chowdhury AI, Sarder AM, et al. 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 1982;60(2):261‐7.

Rahman 1982b {published data only}

Rahman M, Chen LC, Chakraborty J, Yunus M, Faruque AS, Chowdhury AI. Use of tetanus toxoid for the prevention of neonatal tetanus. 2. Immunization acceptance among pregnant women in rural Bangladesh. Bulletin of the World Health Organization 1982;60(2):269‐77.

Relyveld 1991 {published data only}

Relyveld E, Bengounia A, Huet M, Kreeftenberg JG. Antibody response of pregnant women to two different absorbed tetanus toxoids. Vaccine 1991;9(5):369‐72.

Salama 2009 {published data only}

Salama MM, Hady OA, Ashour W, Mostafa A, El Alkamy S, El Sayed N, et al. A randomized controlled trial of oral administration of tetanus toxoid (TT) versus tetanus and reduced diphtheria (Td) in pregnant women. Journal of Clinical Immunology 2009;29(4):524‐31.

Schofield 1961 {published data only}

Schofield FD, Tucker VM, Westbrook GR. Neonatal tetanus in New Guinea. Effect of active immunization in pregnancy. BMJ 1961;5255:785‐9.

Shakib 2013 {published data only}

Shakib JH, Korgenski K, Sheng X, Varner MW, Pavia AT, Byington CL. Tetanus, diphtheria, acellular pertussis vaccine during pregnancy: pregnancy and infant health outcomes. Journal of Pediatrics 2013;63(5):1422‐6.e1‐4.

Silveira 1995 {published data only}

Silveira CM, Caceres VM, Dutra MG, Lopes‐Camelo J, Castilla EE. Safety of tetanus toxoid in pregnant women: a hospital‐based case‐control study of congenital anomalies. Bulletin of the World Health Organization 1995;73(5):605‐8.

Stanfield 1973 {published data only}

Stanfield JP, Gall D, Bracken PM. Single‐dose antenatal tetanus immunisation. Lancet 1973;1(7797):215‐9.

Suri 1964 {published data only}

Suri JC, Dhillon H, Grewal HS. Active immunization of women in pregnancy for prevention of neonatal tetanus. Bulletin of the World Health Organization 1964;31:349‐57.

Tall 1991 {published data only}

Tall F, Prazuck T, Roisin A, Sanou J, Nacro B, Traore A, et al. Risk factors for neonatal tetanus in western Burkina Faso. Case‐control study [Facteurs de risque du tetanos neonatal dans l'ouest du Burkina Faso. Etude cas temoin]. Bulletin de la Societe de Pathologie Exotique 1991;84(5 Pt 5):558‐61.

Traverso 1991 {published data only}

Traverso HP, Kamil S, Rahim H, Samadi AR, Boring JR, Bennett JV. A reassessment of risk factors for neonatal tetanus. Bulletin of the World Health Organization 1991;69(5):573‐9.

Yala 1980 {published data only}

Yala PF. Prevention of neonatal tetanus by active immunization of pregnant women in Brazzaville. Practical evalation and a comparison of single‐dose and triple‐dose vaccinations. Bulletin de la Societe de Pathologie Exotique et de ses Fil 1980;73(1):15‐22.

Yusuf 1991 {published data only}

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 Journal of Tropical Medicine and Public Health 1991;22(3):351‐6.

Borrow 2006

Borrow R, Balmer P, Roper MH. The immunological basis for immunization series Module 3: Tetanus Update 2006. Immunisation, Vaccines and Biologicals ‐ WHOhttp://whqlibdoc.who.int/publications/2007/9789241595551_eng.pdf (accessed on May 4th, 2015).

Descombey 1924

Descombey P. L'anatoxine tetanique. Comptes rendus des séances de la Société de biologie et de ses filiales 1924;91:239‐41.

Dietz 1996

Dietz V, Milstein JB, van Loon F, Cochi S, Bennet J. Performance and potency of tetatus toxoid: implications for eliminating neonatal tetanus. Bulletin of the World Health Organization 1996;74(6):619‐28.

GRADE 2014 [Computer program]

McMaster University. GRADEpro. [Computer program on www.gradepro.org]. Version 2015. McMaster University, 2014.

Higgins 2011

Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.

Jefferson 1996

Jefferson TO, Jefferson VM. The quest for trials on the efficacy of human vaccines. Results of the handsearch of "Vaccine". Vaccine 1996;14:461‐4.

Jefferson 1998

Jefferson TO. Vaccine trial data systematically assembled, pooled and disseminated by the Cochrane Collaboration. Vaccine 1998;16:1487‐95.

Liu 2015

Liu L, Oza S, Hogan D, Perin J, Rudan I, Lawn JE, et al. Global, regional, and national causes of child mortality in 2000–13, with projections to inform post‐2015 priorities: an updated systematic analysis. Lancet 2015;385(9966):430‐40.

Prevots 1998

Prevots DR. Neonatal tetanus. Bulletin of the World Health Organization 1998;76 Suppl 2:135‐6. [PUBMED: 10063693]

RevMan 2014 [Computer program]

The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Schunemann 2009

Schunemann HJ. GRADE: from grading the evidence to developing recommendations. A description of the system and a proposal regarding the transferability of the results of clinical research to clinical practice [GRADE: Von der Evidenz zur Empfehlung. Beschreibung des Systems und Losungsbeitrag zur Ubertragbarkeit von Studienergebnissen]. Zeitschrift fur Evidenz, Fortbildung und Qualitat im Gesundheitswesen 2009;103(6):391‐400.

UNICEF/WHO/UNFPA 2000

UNICEF, WHO, UNFPA. Maternal and Neonatal TetanusElimination by 2005. Strategies for achieving and maintaining elimination. http://www.unfpa.org/sites/default/files/pub‐pdf/maternal_health_2000.pdf [accessed April 29th, 2015].

UNICEF/WHO/UNFPA 2015

UNICEF, WHO, UNFPA. Achieving and Sustaining Maternal and NeonatalTetanus Elimination. Strategic Plan 2012–2015. http://www.who.int/immunization/diseases/MNTEStrategicPlan_E.pdf [accessed on April 29th, 2015].

WHO 1999

World Health Organization. Progress towards the global elimination of neonatal tetanus, 1990‐1998. Weekly Epidemiological Record 1999;74(10):73‐80.

WHO 2006

World Health Organization. Tetanus vaccine. WHO position paper. Weekly Epidemiological Record 2006;81(20):198‐208.

WHO 2015

World Health Organization. Maternal and Neonatal Tetanus (MNT) elimination. http://www.who.int/immunization/diseases/MNTE_initiative/en/ (accessed April 29th, 2015).

References to other published versions of this review

Demicheli 2001

Demicheli V, Barale A. Vaccines for preventing neonatal tetanus. Cochrane Database of Systematic Reviews 2001, Issue 1. [DOI: 10.1002/14651858.CD002959]

Demicheli 2005

Demicheli V, Barale A, Rivetti A. Vaccines for women to prevent neonatal tetanus. Cochrane Database of Systematic Reviews 2005, Issue 4. [DOI: 10.1002/14651858.CD002959.pub2]

Demicheli 2013

Demicheli V, Barale A, Rivetti A. Vaccines for women to prevent neonatal tetanus. Cochrane Database of Systematic Reviews 2013, Issue 5. [DOI: 10.1002/14651858.CD002959.pub3]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Jump to:

Black 1980

Methods

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

Participants

Children 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.

Interventions

1 or 2 doses of adult dose Al‐adsorbed tetanus‐diphtheria toxoid vs cholera toxoid. Both as 0.5 mL dose, intramuscular, double‐blind.

Outcomes

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

Notes

Immunisations 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

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Descibed as randomised but no description about sequence generation is present.

Allocation concealment (selection bias)

Unclear risk

Allocation concealment not described.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Described 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 risk

Outcomes 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 risk

No loss from follow‐up (infants).

Selective reporting (reporting bias)

Low risk

Not detected.

Other bias

Unclear risk

Mortality between 4 and 14 days is only an indicator outcome for neonatal tetanus death.

Overall risk of bias

Unclear risk

Indirect estimate of effectiveness.

Munoz 2014

Methods

Phase 1‐2 randomised, double‐blind, placebo‐controlled, cross‐over trial (see notes) carried out through 3 National Institutes of Health in Houston, Durham, Seattle (USA) between October 2008 and May 2012. Both academic and private obstetric office practices were included.

Participants

Healthy pregnant women aged 18 to 45 years and at low risk for obstetrical complications, with no underlying chronic medical conditions, a singleton pregnancy, and prenatal evaluation that predicted an uncomplicated pregnancy with normal first or second trimester screening test results and detailed anatomic fetal ultrasound at 18 to 22 weeks' gestation were invited to participate. Out of the 172 who agreed 76 were excluded because they met exclusion criteria (prior receipt of Tdap, medical condition, high‐risk pregnancy, mental illness, smoker, receipt of blood products, receipt of TT or tetanus and diphtheria vaccine during the past 2 years), a further 18 were excluded because they did not meet inclusion criteria. The remaining 48 were randomised (2:1) to receive 1 dose of Tdap or saline placebo between the 30th and 32nd gestation week.

An age‐matched comparison group of healthy non‐pregnant women was open label immunised with Tdap. Children were also immunised with DTaP (Pentacel, Sanfi) and Hib at 2, 4, 6, and 12 months of age.

Interventions

Participants were randomised 2:1 within each centre (block randomisation) in order to receive 1 intramuscular dose of either:

Licensed Tdap vaccine (Adacel, Sanofi Pasteur): 1 a 0.5‐mL injection containing 5 Lf TT, 2 Lf diphtheria toxoid, 2.5 μg detoxified pertussis toxin, 5 μg filamentous hemagglutinin, 3 μg pertactin, and 5 μg fimbriae types 2 and 3 in a sterile liquid suspension adsorbed onto aluminium phosphate in single‐dose vials.
Saline control (Hospira Inc): 0.9% sodium chloride. Each vial (2 mL) was used for a single intramuscular dose of 0.5 mL.

Women who received saline during pregnancy (n = 15) were given Tdap vaccine postpartum prior to hospital discharge, and women who received Tdap during pregnancy (n = 33) were given saline postpartum.

Outcomes

1) Injection site reactions: pain, erythema/redness, induration/swelling.
2) Systemic reactions: fever (oral temperature ≥ 38°C), headache, malaise, myalgia.

Assessed by 30‐minute observation and completion of a 7‐day symptom diary after each injection.

3) Adverse events and serious adverse events:
for pregnant women they were recorded from the day of antepartum vaccination to 4 months postpartum;
for infants they were recorded from birth to approximately 13 months of age;

for non‐pregnant women, for 6 months after Tdap immunisation.

Attribution of an adverse event to vaccination was judged by the investigators considering temporality, biologic plausibility, and identification of alternative etiologies for each event.

4) Pregnancy outcomes: documented for mothers and infants at the time of delivery through review of delivery records.

5) Infant growth: weight, length, and fronto‐occipital circumference were assessed at each study visit at ages 2, 7 and 13 months, Bayley‐III Scales of Infant and Toddler Development at the last study visit.

6) Immunogenicity assessment (ELISA).

Notes

For the review's purpose, only the first part of the study (i.e. vaccine administration during pregnancy) is included and considered as parallel group trial.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

The study is reported as randomised, but no description of the method of randomisation or about generation of allocation sequence is present in the text.

Allocation concealment (selection bias)

Low risk

From the "Methods" section:"Randomization was stratified by site with random block sizes. Each participant was assigned a unique treatment number that corresponded to her treatment allocation". 1 woman received pharmacy stock vaccine outside randomisation. No information about block size, also considering the small number of participants at each site.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

From the "Methods" section:"Only the unblinded vaccine administrator had access to the treatment allocation". Not clear whether vaccine and placebo were distinguishable for their appearance.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Local and systemic adverse event were reported on a diary symptoms card. Bias in detection should instead be low for adverse events and pregnancy outcomes.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All mothers accounted for safety assessment. 1 child born from a vaccinated mother and 2 children born from mothers who received saline placebo as first were lost from follow‐up.

Selective reporting (reporting bias)

Low risk

All outcomes in the methods has been assessed.

Other bias

High risk

Sample size. Authors did not power the study to test any specific hypothesis. The study was designed and preformed as cross‐over trial: only the first part of the study was included in the review and considered as parallel group trial.

Overall risk of bias

High risk

Not conceived and not powered to detect possible important safety issue or consequence of tetanus immunisation during pregnancy.

Newell 1966

Methods

RCT (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).

Participants

Women 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.

Interventions

1 or 2‐3 doses of 10 LF AlPO4 adsorbed TT vs polyvalent influenza vaccine, 1 mL intramuscularly, both preparations were not perfectly undistinguishable.

Outcomes

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

Notes

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

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Random sampling number.

Allocation concealment (selection bias)

Unclear risk

Even 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 preparations were not perfectly indistinguishable (see below). Refusal of immunisation could have introduced some bias in selection.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Vial labels were of different colours. It was noted early by both participants and personnel that 1 of the 2 preparations was more painful after inoculation. This together with refusal (see above) might have caused an higher refusal rate in intervention group (about 10%).

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Even 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 risk

Not estimable.

Selective reporting (reporting bias)

Low risk

Not detected.

Other bias

Unclear risk

The method of cutting and dressing the umbilical cord by birth attendant could have had an effect on outcome.

Overall risk of bias

Unclear risk

Apart from possible bias in selection, this study could provide a reliable estimate of effectiveness.

ELISA: enzyme‐linked immunoabsorbent assay
Hib: H. Influenza
RCT: randomised controlled trial
Tdap: tetanus‐diphtheria acellular pertussis vaccine
TT: tetanus toxoid
vs: versus
10 LF AlPO4: aluminium phosphate absorbed tetanus toxoid

Characteristics of excluded studies [ordered by study ID]

Jump to:

Study

Reason for exclusion

Abu Raya 2014

Not a trial. Serological outcomes only: antibody titre against tetanus and diphtheria in paired maternal cord sera.

Abuwa 1997

Not a trial.

Al‐Safi 2011

Narrative review.

Anh 1999

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

Axelsson 2002

Review on umbilical cord care and prevention of infections.

Aylward 1996

Surveillance study.

Baltazar 1994

Case‐control study on efficacy of prenatal TT immunisation in preventing neonatal tetanus.

Basher 2010

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

Berggren 1971

Retrospective survey.

Blencowe 2010

Systematic review.

Canning 2011

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

Chai 2004

Case‐control study.

Chongsuvivatwong 1993

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

de Walque 2008

Not comparative.

Dhillon 1975

Not a trial. Only serological outcomes.

Dietz 1996

Review.

Erener‐Ercan 2014

Not a trial. Serological outcomes only: antibody titre against tetanus and diphtheria in paired maternal cord sera.

Gupta 1998

Cohort study.

Halperin 2011

Interventions (vaccine or placebo) were administered after delivery (post‐partum study)

Hardy‐Fairbanks 2013

Not a trial (cohort study). Antibody titre in maternal, cord blood and infant.

Hasnain 2007

Survey assessing the reasons for low vaccination coverage.

Heredia 1968

Not a trial. Only serological assessment.

Hlady 1992

Case‐control study.

Hurmez 2012

Not a comparative study. Seroprevalence and TT vaccine coverage assessed on a sample of 600 pregnant women in Iraq.

Juan‐Giner 2014

Trial assessing antibody response to 2 TT vaccines that underwent either controlled temperature chain or standard cold chain in women between 14 and 49 years.

Kielmann 1977

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

Koenig 1998

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

Krishnan 2013

Study assessing whether differential excess mortality among Indian girl children could be associated with vaccinations (GBS, DTP, measles).

Lassi 2010

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

MacLennan 1965

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

Mulholland 1996

No intervention: trial with polyribosylribitol phosphate‐tetanus vaccine.

Nohynek 1999

No 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 2007

Not about tetanus immunisation.

Perry 1998

Report on TT immunisation coverage.

Rahman 1982b

Consensus to vaccination.

Rahman 1982a

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

Relyveld 1991

Only serological outcomes.

Salama 2009

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

Schofield 1961

Not a trial.

Shakib 2013

Cohort study.

Silveira 1995

Case‐control to assess relationship between exposition to TT in pregnancy and malformation in the newborns.

Stanfield 1973

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

Suri 1964

Not a trial. Different TT preparations were administered and antitoxins in cord blood were measured.

Tall 1991

Case‐control study.

Traverso 1991

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

Yala 1980

Not a trial.

Yusuf 1991

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

DTP: diphtheria, tetanus and pertussis
GBS: group B streptococcus
Hib: H. Influenza
TT: tetanus toxoid

Data and analyses

Open in table viewer
Comparison 1. Tetanus toxoid versus influenza vaccine

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Neonatal tetanus deaths Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 1.1

Comparison 1 Tetanus toxoid versus influenza vaccine, Outcome 1 Neonatal tetanus deaths.

Comparison 1 Tetanus toxoid versus influenza vaccine, Outcome 1 Neonatal tetanus deaths.

1.1 One dose

1

494

Risk Ratio (M‐H, Fixed, 95% CI)

0.57 [0.26, 1.24]

1.2 Two or three doses

1

688

Risk Ratio (M‐H, Fixed, 95% CI)

0.02 [0.00, 0.30]

2 All causes of death Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 1.2

Comparison 1 Tetanus toxoid versus influenza vaccine, Outcome 2 All causes of death.

Comparison 1 Tetanus toxoid versus influenza vaccine, Outcome 2 All causes of death.

2.1 One dose

1

494

Risk Ratio (M‐H, Fixed, 95% CI)

1.08 [0.65, 1.79]

2.2 Two or three doses

1

688

Risk Ratio (M‐H, Fixed, 95% CI)

0.31 [0.17, 0.55]

3 Neonatal tetanus cases Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 1.3

Comparison 1 Tetanus toxoid versus influenza vaccine, Outcome 3 Neonatal tetanus cases.

Comparison 1 Tetanus toxoid versus influenza vaccine, Outcome 3 Neonatal tetanus cases.

3.1 Any dose

1

1182

Risk Ratio (M‐H, Fixed, 95% CI)

0.20 [0.10, 0.40]

4 Deaths from non‐neonatal tetanus causes (not prespecified) Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 1.4

Comparison 1 Tetanus toxoid versus influenza vaccine, Outcome 4 Deaths from non‐neonatal tetanus causes (not prespecified).

Comparison 1 Tetanus toxoid versus influenza vaccine, Outcome 4 Deaths from non‐neonatal tetanus causes (not prespecified).

4.1 One dose

1

494

Risk Ratio (M‐H, Fixed, 95% CI)

2.14 [0.97, 4.76]

4.2 Two or three doses

1

688

Risk Ratio (M‐H, Fixed, 95% CI)

0.75 [0.38, 1.47]

Open in table viewer
Comparison 2. Tetanus diphtheria toxoid versus cholera toxoid

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Neonatal mortality Show forest plot

1

8641

Risk Ratio (M‐H, Fixed, 95% CI)

0.68 [0.56, 0.82]

Analysis 2.1

Comparison 2 Tetanus diphtheria toxoid versus cholera toxoid, Outcome 1 Neonatal mortality.

Comparison 2 Tetanus diphtheria toxoid versus cholera toxoid, Outcome 1 Neonatal mortality.

2 Four to 14 days neonatal mortality Show forest plot

1

8641

Risk Ratio (M‐H, Fixed, 95% CI)

0.38 [0.27, 0.55]

Analysis 2.2

Comparison 2 Tetanus diphtheria toxoid versus cholera toxoid, Outcome 2 Four to 14 days neonatal mortality.

Comparison 2 Tetanus diphtheria toxoid versus cholera toxoid, Outcome 2 Four to 14 days neonatal mortality.

Open in table viewer
Comparison 3. Tetanus Diphtheria Acellular pertussis versus saline placebo local and systemic reactions

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Injection site reactions Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 3.1

Comparison 3 Tetanus Diphtheria Acellular pertussis versus saline placebo local and systemic reactions, Outcome 1 Injection site reactions.

Comparison 3 Tetanus Diphtheria Acellular pertussis versus saline placebo local and systemic reactions, Outcome 1 Injection site reactions.

1.1 Pain at injection site

1

48

Risk Ratio (M‐H, Fixed, 95% CI)

5.68 [1.54, 20.94]

1.2 Erythema ‐ redness

1

48

Risk Ratio (M‐H, Fixed, 95% CI)

1.36 [0.15, 12.05]

1.3 Induration ‐ swelling

1

48

Risk Ratio (M‐H, Fixed, 95% CI)

3.29 [0.18, 60.05]

1.4 Any injection site symptoms

1

48

Risk Ratio (M‐H, Fixed, 95% CI)

3.94 [1.41, 11.01]

2 Systemic reactions Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

Analysis 3.2

Comparison 3 Tetanus Diphtheria Acellular pertussis versus saline placebo local and systemic reactions, Outcome 2 Systemic reactions.

Comparison 3 Tetanus Diphtheria Acellular pertussis versus saline placebo local and systemic reactions, Outcome 2 Systemic reactions.

2.1 Fever (oral temperature ≥ 38°C)

1

48

Risk Ratio (M‐H, Fixed, 95% CI)

1.41 [0.06, 32.78]

2.2 Headache

1

48

Risk Ratio (M‐H, Fixed, 95% CI)

1.67 [0.54, 5.11]

2.3 Malaise

1

48

Risk Ratio (M‐H, Fixed, 95% CI)

0.91 [0.19, 4.43]

2.4 Myalgia

1

48

Risk Ratio (M‐H, Fixed, 95% CI)

5.18 [0.30, 88.02]

2.5 Any systemic symptoms

1

48

Risk Ratio (M‐H, Fixed, 95% CI)

1.82 [0.60, 5.51]

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figures and Tables -
Figure 1

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 2

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Comparison 1 Tetanus toxoid versus influenza vaccine, Outcome 1 Neonatal tetanus deaths.
Figures and Tables -
Analysis 1.1

Comparison 1 Tetanus toxoid versus influenza vaccine, Outcome 1 Neonatal tetanus deaths.

Comparison 1 Tetanus toxoid versus influenza vaccine, Outcome 2 All causes of death.
Figures and Tables -
Analysis 1.2

Comparison 1 Tetanus toxoid versus influenza vaccine, Outcome 2 All causes of death.

Comparison 1 Tetanus toxoid versus influenza vaccine, Outcome 3 Neonatal tetanus cases.
Figures and Tables -
Analysis 1.3

Comparison 1 Tetanus toxoid versus influenza vaccine, Outcome 3 Neonatal tetanus cases.

Comparison 1 Tetanus toxoid versus influenza vaccine, Outcome 4 Deaths from non‐neonatal tetanus causes (not prespecified).
Figures and Tables -
Analysis 1.4

Comparison 1 Tetanus toxoid versus influenza vaccine, Outcome 4 Deaths from non‐neonatal tetanus causes (not prespecified).

Comparison 2 Tetanus diphtheria toxoid versus cholera toxoid, Outcome 1 Neonatal mortality.
Figures and Tables -
Analysis 2.1

Comparison 2 Tetanus diphtheria toxoid versus cholera toxoid, Outcome 1 Neonatal mortality.

Comparison 2 Tetanus diphtheria toxoid versus cholera toxoid, Outcome 2 Four to 14 days neonatal mortality.
Figures and Tables -
Analysis 2.2

Comparison 2 Tetanus diphtheria toxoid versus cholera toxoid, Outcome 2 Four to 14 days neonatal mortality.

Comparison 3 Tetanus Diphtheria Acellular pertussis versus saline placebo local and systemic reactions, Outcome 1 Injection site reactions.
Figures and Tables -
Analysis 3.1

Comparison 3 Tetanus Diphtheria Acellular pertussis versus saline placebo local and systemic reactions, Outcome 1 Injection site reactions.

Comparison 3 Tetanus Diphtheria Acellular pertussis versus saline placebo local and systemic reactions, Outcome 2 Systemic reactions.
Figures and Tables -
Analysis 3.2

Comparison 3 Tetanus Diphtheria Acellular pertussis versus saline placebo local and systemic reactions, Outcome 2 Systemic reactions.

Summary of findings for the main comparison. Tetanus toxoid versus influenza vaccine for women to prevent neonatal tetanus

Tetanus toxoid versus influenza vaccine for women to prevent neonatal tetanus

Patient or population: women aged between 13 and 45 years.

Setting: rural community
Intervention: tetanus toxoid versus influenza vaccine.

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Tetanus toxoid versus influenza vaccine

Neonatal tetanus deaths ‐ 1 dose
Follow‐up: 30 days

Study population

RR 0.57
(0.26 to 1.24)

494
(1 study)

⊕⊕⊝⊝
low1,2

70 per 1000

40 per 1000
(18 to 87)

Moderate

70 per 1000

40 per 1000
(18 to 87)

Neonatal tetanus deaths ‐ 2 or 3 doses
Follow‐up: 30 days

Study population

RR 0.02
(0 to 0.3)

688
(1 study)

⊕⊕⊕⊝
moderate1

78 per 1000

2 per 1000
(0 to 23)

Moderate

78 per 1000

2 per 1000
(0 to 23)

All causes of deaths ‐ 1 dose
Follow‐up: 30 days

Study population

RR 1.08
(0.65 to 1.79)

494
(1 study)

⊕⊕⊝⊝
low1,2

About 57% of non‐tetanus deaths were observed in the first 7 days of life.

104 per 1000

112 per 1000
(67 to 186)

Moderate

104 per 1000

112 per 1000
(68 to 186)

All causes of deaths ‐ 2 or 3 doses
Follow‐up: 30 days

Study population

RR 0.31
(0.17 to 0.55)

688
(1 study)

⊕⊕⊕⊝
moderate1

133 per 1000

41 per 1000
(23 to 73)

Moderate

133 per 1000

41 per 1000
(23 to 73)

Neonatal tetanus cases ‐ Any dose
Follow‐up: 30 days

Study population

RR 0.2
(0.1 to 0.4)

1182
(1 study)

⊕⊕⊕⊝
moderate1

Only 3 non fatal tetanus cases observed (all in the control group).

79 per 1000

16 per 1000
(8 to 32)

Moderate

79 per 1000

16 per 1000
(8 to 32)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Design & Implementation (selection bias): Different aspect of the vials used for intervention and control vaccine could have introduced a certain bias in selection.
2 Imprecision: Wide confidence interval including clinical important effect and no effect

Figures and Tables -
Summary of findings for the main comparison. Tetanus toxoid versus influenza vaccine for women to prevent neonatal tetanus
Summary of findings 2. Tetanus diphtheria toxoid immunisation of women of reproductive age compared with cholera toxoid for preventing neonatal mortality

Tetanus diphtheria toxoid immunisation of women of reproductive age compared with cholera toxoid for preventing neonatal mortality

Patient or population: women of reproductive age ≥ 15 years.
Setting: rural community

Intervention: tetanus diphtheria toxoid versus cholera toxoid.

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Tetanus diphtheria toxoid

Neonatal mortality in the first 28 days of life
Follow‐up: 28 days

Study population

RR 0.68
(0.56 to 0.82)

8641
(1 study)

⊕⊕⊝⊝
low1,2

60 per 1000

41 per 1000
(33 to 49)

Moderate

60 per 1000

41 per 1000
(34 to 49)

Neonatal mortality between day 4‐14 of life
Follow‐up: 10 days

Study population

RR 0.38
(0.27 to 0.55)

8641
(1 study)

⊕⊕⊝⊝
low1,2

25 per 1000

10 per 1000
(7 to 14)

Moderate

25 per 1000

9 per 1000
(7 to 14)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Design & Implementation (selection bias): Even if several important methodological details are missing, the possibility of a certain bias in selection could not be totally excluded.
2 Indirectness: Authors consider mortality between days 4 and 14 of life as proxy outcome for neonatal tetanus.

Figures and Tables -
Summary of findings 2. Tetanus diphtheria toxoid immunisation of women of reproductive age compared with cholera toxoid for preventing neonatal mortality
Summary of findings 3. Local and systemic reactions after administration of Tetanus Diphtheria acelluar Pertussis vaccine versus saline placebo in pregnant women

Local and systemic reactions after administration of Tetanus Diphtheria acelluar Pertussis vaccine versus saline placebo in pregnant women

Patient or population: patients with local and systemic reactions
Settings: community
Intervention: Tetanus Diphtheria acellular Pertussis vaccine
Comparison: saline placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Saline placebo

Tetanus Diphtheria acellular Pertussis vaccine

Injection site reactions ‐ pain at injection site
Follow‐up: 7 days

Study population

RR 5.68
(1.54 to 20.94)

48
(1 study)

⊕⊕⊕⊝
moderate1

133 per 1000

757 per 1000
(205 to 1000)

Moderate

133 per 1000

755 per 1000
(205 to 1000)

Injection site reactions ‐ erythema ‐ redness
Follow‐up: 7 days

Study population

RR 1.36
(0.15 to 12.05)

48
(1 study)

⊕⊕⊕⊝
moderate1

67 per 1000

91 per 1000
(10 to 803)

Moderate

67 per 1000

91 per 1000
(10 to 807)

Injection site reactions ‐ induration ‐ swelling
Follow‐up: 7 days

Study population

RR 3.29
(0.18 to 60.05)

48
(1 study)

⊕⊕⊕⊝
moderate1

0 per 1000

0 per 1000
(0 to 0)

Moderate

0 per 1000

0 per 1000
(0 to 0)

Systemic reactions ‐ fever (oral temperature ≥ 38°C)
Follow‐up: 7 days

Study population

RR 1.41
(0.06 to 32.78)

48
(1 study)

⊕⊕⊕⊝
moderate1

0 per 1000

0 per 1000
(0 to 0)

Moderate

0 per 1000

0 per 1000
(0 to 0)

Systemic reactions ‐ headache
Follow‐up: 7 days

Study population

RR 1.67
(0.54 to 5.11)

48
(1 study)

⊕⊕⊕⊝
moderate1

200 per 1000

334 per 1000
(108 to 1000)

Moderate

200 per 1000

334 per 1000
(108 to 1000)

Systemic reactions ‐ malaise
Follow‐up: 7 days

Study population

RR 0.91
(0.19 to 4.43)

48
(1 study)

⊕⊕⊕⊝
moderate1

133 per 1000

121 per 1000
(25 to 591)

Moderate

133 per 1000

121 per 1000
(25 to 589)

Systemic reactions ‐ myalgia
Follow‐up: 7 days

Study population

RR 5.18
(0.3 to 88.02)

48
(1 study)

⊕⊕⊕⊝
moderate1

0 per 1000

0 per 1000
(0 to 0)

Moderate

0 per 1000

0 per 1000
(0 to 0)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Imprecision: Small sample size. The study was not powered to test any specific hypotheses.

Figures and Tables -
Summary of findings 3. Local and systemic reactions after administration of Tetanus Diphtheria acelluar Pertussis vaccine versus saline placebo in pregnant women
Table 2. Non‐randomised studies

References

Design

Study Population

Treatment

Outcomes

Results

Baltazar 1994

Case‐control study.

54 neonates admitted to hospital diagnosed with NT. 50
controls 1 to 4 months old admitted for causes other than NT.
Manila.

Immunisation with TT, considered immunised if received at least 2 doses of TT during pregnancy, otherwise not.

Incidence of immunisation: cases (1/54), controls (12/49).

Protective effect against NT if at least 2 doses of TT.

Chai 2004

Case‐control study.
Surveillance data after TT mass immunisation campaign carried out 1995 to 1996 in 320 out of 560 countries reaching about 23 million women aged 18 to 35 years, were also reported. Coverage with 2 doses of TT was estimate 10%. Surveillance data of 1996 to 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 information (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 1998

Survey.

1688 pregnant women. India.

Immunisation with TT, considered immunised if received 2 doses of TT at least 4 weeks apart or a booster dose. Partially immunised, if received 1 dose of TT either during the current pregnancy or in the past 3 years.

Deaths from NT within 3 to 30 days of birth.

Immunisation during the antenatal period is highly protective against occurrence of NT.

Hlady 1992

Case‐control study.

Infants with clinically‐diagnosed tetanus. 3 controls. Bangladesh.

Immunisation with TT, 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 1991

Follow‐up survey.

Women aged 10 to 45 years. Indonesia.

Immunisation with TT, 1 or 2 doses.

Deaths from NT within 3 to 28 days of birth.

Immunisation caused an 85% reduction of NT.

Chongsuvivatwong 1993

Survey study.

Women aged 15 to 45 years. Thailand.

Immunisation with TT.

Cases of NT.

Immunisation caused a 8 to 10 times reduction of NT.

Rahman 1982a

Surveillance study.

Women from surveillance area. Bangladesh.

Immunised with TT at 6th, 7th, 8th month. Considered immunised if received 2 injections in 1974 or in the 1978 to 1979 programme.
Partially immunised, if received 1 injection in 1974 or 1978 to 1979.
Mixed immunised if received 1 or 2 doses in 1974 and again 1 or 2 doses in 1978 to 1979.

Deaths attributed to NT within 4 to 14 days after birth.

Full immunisation reduced neonatal mortality rates by about one half and mortality rates on days 4 to 14 by about 70%.

Koenig 1998

Survey.

Children between 1 to 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 NT within 4 to 14 days after birth.

2 injections provided significant protection. Protection of 1 dose not significant.

Schofield 1961

Observational.

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 TT (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 NT 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.
3 times immunised: 1/175.
From the history‐taking survey it results that during the examination period 184 deaths due to NT occurred out of 3017 live births.

3 doses of formalinised TT administered during pregnancy afforded substantial protection against NT. Immunisation with only 2 doses provided also a significant protection level. No reactions to the vaccine were noticed.

NT: neonatal tetanus
TT: tetanus toxoid

Figures and Tables -
Table 2. Non‐randomised studies
Table 1. Studies evaluating safety outcomes

References

Study design

Study population

Intervention

Safety outcomes

Results

MacLennan 1965

2 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) TT 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 to 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 1995

Case‐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 1282,403 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, hemangioma, periauricular tag, fistula auris, pigmented naevus, other skin defects, multiple malformed.

No association for each of the examined factors was found.

Salama 2009

RCT.

Healthy pregnant Egyptian women at about 20 weeks of gestational age (n = 122).

Participants were randomised to :

a) 0.5 mL of TT (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 to 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.

Shakib 2013

Retrospective Cohort study

‐ Exposed cohort: 138 women aged between 12 and 45 years with documented Tdap immunisation during pregnancy. They were identified among the 162,448 pregnancies occurred within the Intermountain Healthcare facilities (Salt Lake, Utah) between May 2005 and August 2009.

‐ Not exposed cohort: 552 randomly selected women from the same population (without documented vaccination during pregnancy).

In the exposed cohort Tdap immunisation occurred more frequently within 1st (63%), than during 2nd (17%) and 3rd (20%) pregnancy trimester. Immunisation with Tdap occurred mainly as prophylactic measure in consequence of wound, trauma or routine health supervision.

Spontaneous or elective abortion

Stillbirth

Preterm delivery (<37 weeks)

Gestational age

Birth weight

Congenital anomalies

Incidence of spontaneous or elective abortion was no greater in Tdap cases than in controls.

No significant differences in preterm delivery, gestational age, or birth weight between groups.

Frequence of ICD‐9‐CM codes diagnosis for congenital anomalies reported among children born to Tdap exposed women do not differ significantly from that observed among born to not Tdap exposed women.

Lf: limit of flocculation units
RCT = randomised controlled trial
Tdap: Tetanus‐diphtheria acellular pertussis vaccine
TT: tetanus toxoid
vs: versus

Figures and Tables -
Table 1. Studies evaluating safety outcomes
Comparison 1. Tetanus toxoid versus influenza vaccine

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Neonatal tetanus deaths Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.1 One dose

1

494

Risk Ratio (M‐H, Fixed, 95% CI)

0.57 [0.26, 1.24]

1.2 Two or three doses

1

688

Risk Ratio (M‐H, Fixed, 95% CI)

0.02 [0.00, 0.30]

2 All causes of death Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.1 One dose

1

494

Risk Ratio (M‐H, Fixed, 95% CI)

1.08 [0.65, 1.79]

2.2 Two or three doses

1

688

Risk Ratio (M‐H, Fixed, 95% CI)

0.31 [0.17, 0.55]

3 Neonatal tetanus cases Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

3.1 Any dose

1

1182

Risk Ratio (M‐H, Fixed, 95% CI)

0.20 [0.10, 0.40]

4 Deaths from non‐neonatal tetanus causes (not prespecified) Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

4.1 One dose

1

494

Risk Ratio (M‐H, Fixed, 95% CI)

2.14 [0.97, 4.76]

4.2 Two or three doses

1

688

Risk Ratio (M‐H, Fixed, 95% CI)

0.75 [0.38, 1.47]

Figures and Tables -
Comparison 1. Tetanus toxoid versus influenza vaccine
Comparison 2. Tetanus diphtheria toxoid versus cholera toxoid

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Neonatal mortality Show forest plot

1

8641

Risk Ratio (M‐H, Fixed, 95% CI)

0.68 [0.56, 0.82]

2 Four to 14 days neonatal mortality Show forest plot

1

8641

Risk Ratio (M‐H, Fixed, 95% CI)

0.38 [0.27, 0.55]

Figures and Tables -
Comparison 2. Tetanus diphtheria toxoid versus cholera toxoid
Comparison 3. Tetanus Diphtheria Acellular pertussis versus saline placebo local and systemic reactions

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Injection site reactions Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.1 Pain at injection site

1

48

Risk Ratio (M‐H, Fixed, 95% CI)

5.68 [1.54, 20.94]

1.2 Erythema ‐ redness

1

48

Risk Ratio (M‐H, Fixed, 95% CI)

1.36 [0.15, 12.05]

1.3 Induration ‐ swelling

1

48

Risk Ratio (M‐H, Fixed, 95% CI)

3.29 [0.18, 60.05]

1.4 Any injection site symptoms

1

48

Risk Ratio (M‐H, Fixed, 95% CI)

3.94 [1.41, 11.01]

2 Systemic reactions Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.1 Fever (oral temperature ≥ 38°C)

1

48

Risk Ratio (M‐H, Fixed, 95% CI)

1.41 [0.06, 32.78]

2.2 Headache

1

48

Risk Ratio (M‐H, Fixed, 95% CI)

1.67 [0.54, 5.11]

2.3 Malaise

1

48

Risk Ratio (M‐H, Fixed, 95% CI)

0.91 [0.19, 4.43]

2.4 Myalgia

1

48

Risk Ratio (M‐H, Fixed, 95% CI)

5.18 [0.30, 88.02]

2.5 Any systemic symptoms

1

48

Risk Ratio (M‐H, Fixed, 95% CI)

1.82 [0.60, 5.51]

Figures and Tables -
Comparison 3. Tetanus Diphtheria Acellular pertussis versus saline placebo local and systemic reactions