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Cochrane Database of Systematic Reviews

Vaksin untuk wanita bagi mencegah tetanus neonatal

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DOI:
https://doi.org/10.1002/14651858.CD002959.pub4Copiar DOI
Base de datos:
  1. Cochrane Database of Systematic Reviews
Versión publicada:
  1. 06 julio 2015see what's new
Tipo:
  1. Intervention
Etapa:
  1. Review
Grupo Editorial Cochrane:
  1. Grupo Cochrane de Embarazo y parto

Copyright:
  1. Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Autores

  • Vittorio Demicheli

    Correspondencia a: Servizio Regionale di Riferimento per l'Epidemiologia, SSEpi‐SeREMI ‐ Cochrane Vaccines Field, Azienda Sanitaria Locale ASL AL, Alessandria, Italy

    [email protected]

    [email protected]

  • Antonella Barale

    Struttura di Epidemiologia, ASL VC, Vercelli, Italy

  • Alessandro Rivetti

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

Contributions of authors

For the present update, Alessandro Rivetti updated the searches, applied inclusion criteria and commented on the report. Vittorio Demicheli applied inclusion criteria and assessed methodological quality, extracted data and drafted the report. Antonella Barale assessed methodological quality, extracted data and commented on the report. All authors contributed to the final draft.

Sources of support

Internal sources

  • ASL 20 Alessandria, Italy.

External sources

  • UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research (RHR), World Health Organization, Switzerland.

Declarations of interest

None known.

Acknowledgements

We would like to thank the many people that contributed to this review.

For the 2015 update, the editorial staff for preparing the draft for updating, and Lynn Hampson, who performed the searches of Cochrane Pregnancy and Childbirth Group’s Trials Register.

For the 2012 update, Sonja Henderson revised the methods section and Lynn Hampson updated the searches of Cochrane Pregnancy and Childbirth Group’s Trials Register.

In the first version of the review published in 2005, Lynn Hampson revised our search strategies and Gabriella Morandi ran some of the searches and helped us retrieve the papers. Carlo Di Pietrantonj assisted us in evaluating and interpreting the statistical content of the papers. Rebecca Smyth and Jim Neilson revised the review and provided us with lots of useful comments and suggestions that led to publication of the review.

This project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to Cochrane Pregnancy and Childbirth. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.

Version history

Published

Title

Stage

Authors

Version

2015 Jul 06

Vaccines for women for preventing neonatal tetanus

Review

Vittorio Demicheli, Antonella Barale, Alessandro Rivetti

https://doi.org/10.1002/14651858.CD002959.pub4

2013 May 31

Vaccines for women to prevent neonatal tetanus

Review

Vittorio Demicheli, Antonella Barale, Alessandro Rivetti

https://doi.org/10.1002/14651858.CD002959.pub3

2005 Oct 19

Vaccines for women to prevent neonatal tetanus

Review

Vittorio Demicheli, Antonella Barale, Alessandro Rivetti

https://doi.org/10.1002/14651858.CD002959.pub2

2001 Jan 22

Vaccines for preventing neonatal tetanus

Protocol

Vittorio Demicheli, Antonella Barale

https://doi.org/10.1002/14651858.CD002959

Open in table viewer
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

Differences between protocol and review

Subgroup analysis based on number of doses of vaccine was not specified in the original protocol. Methods for assessing subgroup differences were updated and carried out using interaction tests now available within RevMan (RevMan 2014). One of the included studies (Newell 1966) also reports as an outcome the cases of deaths not due to neonatal tetanus. It has been included in the analysis as a non pre‐specified outcome.

Keywords

MeSH

PICO

Population
Intervention
Comparison
Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

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

Figuras y tablas -
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.

Figuras y tablas -
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.

Figuras y tablas -
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

Figuras y tablas -
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

Figuras y tablas -
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]

Figuras y tablas -
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]

Figuras y tablas -
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]

Figuras y tablas -
Comparison 3. Tetanus Diphtheria Acellular pertussis versus saline placebo local and systemic reactions