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The optimal gestation for pertussis vaccination during pregnancy: a prospective cohort study

Published:March 08, 2016DOI:https://doi.org/10.1016/j.ajog.2016.03.002

      Background

      There is an increasing incidence of pertussis infection in infants too young to be adequately protected via vaccination. Maternal pertussis vaccination during the third trimester of pregnancy is a new strategy to provide protection to newborn infants.

      Objective

      This study sought to determine the optimal gestational window for vaccination in the third trimester.

      Study Design

      This prospective study recruited 3 groups of women: an early vaccination group, vaccinated between 28-32 weeks’ gestation; a late vaccination group, vaccinated between 33-36 weeks’ gestation; and an unvaccinated control group. Maternal venous blood was taken prior to pertussis vaccination. At birth, infant cord blood was collected to determine antibody levels to pertussis toxin (PT), pertactin (PRN), and filamentous hemagglutinin (FHA).

      Results

      In all, 154 women were recruited from April through September 2014. There was no significant difference between maternal PRN and FHA antibody levels among the 3 groups, however, PT was higher in the early compared to late vaccination group (P = .05). Cord blood antibody levels to PT, PRN, and FHA were significantly higher in those born to vaccinated women compared with unvaccinated controls (P < .001, P = .001, and P < .001, respectively). Vaccination between 28-32 weeks’ gestation resulted in significantly higher cord blood PT (4.18.0 vs 3.50 IU/mL, P = .009), PRN (5.83 vs 5.31 IU/mL, P = .03), and FHA (5.56 vs 5.03 IU/mL, P = .03) antibody levels than vaccination between 33-36 weeks’ gestation. When adjusted for maternal prevaccination antibody levels, PT levels in early vs late vaccination approached significance (P = .06). PRN levels were significantly higher in the early vaccination group (P = .003). There was no significant difference for FHA antibody levels between the 2 groups (P = .16).

      Conclusion

      Maternal vaccination during the third trimester is effective in affording higher levels of pertussis antibody protection to the newborn infant. Vaccination early in the third trimester appears more effective than later in pregnancy.

      Key words

      Introduction

      Although preventable through vaccination, the incidence of pertussis infection has been on the increase over recent years. The group most vulnerable to significant morbidity (including hospitalization) and mortality, are infants <3 months of age.
      • Paddock C.D.
      • Sanden G.N.
      • Cherry J.D.
      • et al.
      Pathology and pathogenesis of fatal Bordetella pertussis infection in infants.
      In recent years, an increasing number of pertussis cases have been diagnosed in this age group despite widespread access to the pertussis vaccine.
      • De Melker H.E.
      • Schellekens J.F.
      • Neppelenbroek S.E.
      • Mooi F.R.
      • Rümke H.C.
      • Conyn-van Spaendonck M.A.
      Reemergence of pertussis in the highly vaccinated population of The Netherlands: observations on surveillance data.
      • Celentano L.P.
      • Massari M.
      • Paramatti D.
      • Salmaso S.
      • Tozzi A.E.
      EUVAC-NET Group
      Resurgence of pertussis in Europe.
      • Cherry J.D.
      Epidemic pertussis in 2012–the resurgence of a vaccine-preventable disease.
      Several deaths have also been reported in resource-rich settings,
      • Vitek C.R.
      • Pascual F.B.
      • Baughman A.L.
      • Murphy T.V.
      Increase in deaths from pertussis among young infants in the United States in the 1990s.
      triggering a review of vaccination policy.
      Newborn infants are most at risk as their immune system is functionally immature and they do not acquire protective levels of antibodies until at least 4 months of age (usually after the second dose of pertussis vaccine). The newborn is therefore reliant on IgG antibodies, acquired through passive transplacental transfer, and IgA antibodies, in breast milk, for protection.
      • Heininger U.
      • Riffelmann M.
      • Bär G.
      • Rudin C.
      • von König C.-H.W.
      The protective role of maternally derived antibodies against Bordetella pertussis in young infants.
      Studies have shown low levels of maternal pertussis antibodies available for infant protection in the majority of women of childbearing age.
      • Healy C.M.
      • Munoz F.M.
      • Rench M.A.
      • Halasa N.B.
      • Edwards K.M.
      • Baker C.J.
      Prevalence of pertussis antibodies in maternal delivery, cord, and infant serum.
      • Englund J.A.
      • Anderson E.L.
      • Reed G.F.
      • et al.
      The effect of maternal antibody on the serologic response and the incidence of adverse reactions after primary immunization with acellular and whole-cell pertussis vaccines combined with diphtheria and tetanus toxoids.
      Furthermore, the mother has been identified as the main source of pertussis infection to the newborn.
      • Wendelboe A.M.
      • Njamkepo E.
      • Bourillon A.
      • et al.
      Transmission of Bordetella pertussis to young infants.
      Maternal vaccination is a strategy that has the potential to afford protection to the neonate via passive transplacental transfer of maternal antibodies. These antibodies protect infants in the first few months of life, prior to the development of active immunity through routine vaccination.
      Studies in pregnant women with whole-cell and acellular pertussis vaccine demonstrate safety for mother and fetus.
      • Englund J.A.
      • Anderson E.L.
      • Reed G.F.
      • et al.
      The effect of maternal antibody on the serologic response and the incidence of adverse reactions after primary immunization with acellular and whole-cell pertussis vaccines combined with diphtheria and tetanus toxoids.
      • Munoz F.M.
      • Bond N.H.
      • Maccato M.
      • et al.
      Safety and immunogenicity of tetanus diphtheria and acellular pertussis (Tdap) immunization during pregnancy in mothers and infants: a randomized clinical trial.
      • Donegan K.
      • King B.
      • Bryan P.
      Safety of pertussis vaccination in pregnant women in UK: observational study.
      • Zheteyeva Y.A.
      • Moro P.L.
      • Tepper N.K.
      • et al.
      Adverse event reports after tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccines in pregnant women.
      Recent studies confirm that active placental transfer of pertussis-specific antibodies occurs, with peak transfer occurring in the third trimester of pregnancy.
      • Saji F.
      • Samejima Y.
      • Kamiura S.
      • Koyama M.
      Dynamics of immunoglobulins at the feto-maternal interface.
      • Simister N.E.
      Placental transport of immunoglobulin G.
      The durability of passively acquired pertussis antibodies has also been calculated and data suggest that maternal antibody protection may last up to 4 months of age.
      • Van Savage J.
      • Decker M.D.
      • Edwards K.M.
      • Sell S.H.
      • Karzon D.T.
      Natural history of pertussis antibody in the infant and effect on vaccine response.
      • Edwards K.M.
      Pertussis: an important target for maternal immunization.
      Efficacy of maternal vaccination in protecting infants <3 months of age has been reported to be 91%.
      • Amirthalingam G.
      • Andrews N.
      • Campbell H.
      • et al.
      Effectiveness of maternal pertussis vaccination in England: an observational study.
      These observations make maternal vaccination an attractive intervention to protect newborn infants from pertussis and its complications. In 2011, the United States and the United Kingdom recommended maternal vaccination during pregnancy as a strategy to increase newborn protection.
      Centers for Disease Control and Prevention (CDC)
      Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) in pregnant women and persons who have or anticipate having close contact with an infant aged <12 months–Advisory Committee on Immunization Practices (ACIP), 2011.

      Davies S; Department of Health. Whooping cough vaccination program for pregnant women. Available at: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/212947/CMO-Pertussis-27-09-2012-FINAL.pdf. Accessed October 19, 2015.

      These guidelines recommend vaccination in the third trimester but the optimal gestation window remains unknown. The aim of this study is to examine cord blood pertussis antibody levels comparing early third-trimester vaccination with late third-trimester vaccination.

      Materials and Methods

      This prospective study evaluated maternal and newborn pertussis-specific antibody levels prior to and following diphtheria, tetanus, and acellular pertussis (dTpa) immunization. Pregnant women at a tertiary obstetric hospital were recruited from April through September 2014. Inclusion criteria were healthy pregnant women with a singleton pregnancy between 28-36+6 weeks who consented to receive dTpa. Women unimmunized for pertussis during their current pregnancy served as controls. Exclusion criteria included women already vaccinated with dTpa in the current pregnancy; immunosuppressed women, such as those with HIV infection; and women considered at high risk for preterm delivery. Women were approached during the third trimester and invited to participate in the study. If they agreed to vaccination then they were allocated to either the early or late group according to their gestation at the time of vaccination. Women vaccinated between 28-32+6 weeks’ gestation comprised the early vaccination group and women vaccinated between 33-36+6 weeks’ gestation comprised the late vaccination group. Women who declined the vaccination but were willing to participate in the study comprised the control group. A prevaccination maternal venous sample was taken from all participants and infant cord blood was collected at delivery.
      Prior to the study a sample size calculation based on the effect sizes and associated variances reported by Healy et al
      • Healy C.M.
      • Rench M.A.
      • Baker C.J.
      Importance of timing of maternal combined tetanus, diphtheria, and acellular pertussis (Tdap) immunization and protection of young infants.
      was undertaken. We estimated that a minimum sample of 42 patients per group would be required to be able to demonstrate at least a 10% difference in antibody levels between early and late vaccination groups, with 80% power at the 5% significance level. The study of Healy et al,
      • Healy C.M.
      • Rench M.A.
      • Baker C.J.
      Importance of timing of maternal combined tetanus, diphtheria, and acellular pertussis (Tdap) immunization and protection of young infants.
      however, did not account for maternal prevaccination levels.
      Monash Health Human Research Ethics Committee approved the study and all participants provided informed, signed consent. Demographic data were collected from the women’s medical records and a participant questionnaire upon recruitment and following delivery was completed.
      Participants were vaccinated with dTpa containing ≥2 IU diphtheria toxoid, ≥20 IU tetanus toxoid, 8 μg pertussis toxin (PT), 8 μg filamentous hemagglutinin (FHA), and 2.5 μg pertactin (PRN).
      All blood samples were processed at the time of collection and stored at –80°C prior to analysis of samples. At birth, infant cord blood was collected to determine antibody levels to PT, PRN, and FHA using a commercially available IgG-specific enzyme-linked immunosorbent assay (Alpha Diagnostic International, San Antonio, TX). Results were reported in IU/mL using the World Health Organization reference 06/142.
      All continuous variables were assessed for normality. All maternal and cord antibody body levels were skewed and were therefore log transformed prior to further analysis. Time between vaccination and birth was computed by subtracting the gestational week of the vaccine from the gestational age at birth. The characteristics of the population and cord blood antibody concentrations were tabulated. Data are presented as means and SD or counts and percentages as appropriate. Differences in characteristics and outcomes between the early and late vaccination group were compared using independent t tests or χ2 tests and across the control, early, and late group with χ2 tests or analysis of variance. The association between timing of vaccination and the log-transformed cord antibody levels was determined using linear regression. The residuals of the regression model were assessed for normality. Maternal prevaccination antibody levels differed between groups, therefore this was included in the multivariate adjustment. No effect of mode of birth on antibody levels was observed so mode of birth was not included in the final model. Cord antibody levels were plotted against time between vaccination and birth and the correlation was determined using Pearson correlation coefficient. A P value <.05 (2-tailed) was regarded as statistically significant. All analyses were performed using statistical software (Stata, Release 12.1; StataCorp LP, College Station, TX).

      Results

      A total of 115 women (53 between 28-32+6 weeks’ and 62 between 33-36+6 weeks’ gestation) were vaccinated with dTpa. There were 39 nonvaccinated control subjects. A total of 82 paired maternal and infant cord blood samples were available from dTpa-immunized mothers, and 27 unimmunized mothers for analysis (Figure 1).
      Figure thumbnail gr1
      Figure 1Study participants according to allocated vaccination or control group
      Flow chart of study participants.
      dTpa, diphtheria, tetanus, and acellular pertussis.
      Naidu et al. Pertussis vaccination during pregnancy. Am J Obstet Gynecol 2016.
      The demographic and clinical characteristics of the study population are presented in Table 1, along with the pertussis antibodies in maternal serum prior to vaccination.
      Table 1Population characteristics
      Vaccinated 28–32 wk

      N = 53
      Vaccinated 33–36 wk

      N = 62
      P value
      Difference in means between early and late vaccination
      Control group

      N = 39
      P value
      Differences across 3 groups.
      Maternal age, years30.4 (4.28)30.3 (4.82).9032.3 (5.2).09
      Maternal body mass index26.2 (7.0)26.7 (7.6).7725.9 (5.5).88
      Nulliparous26 (49.1%)32 (51.6%).7910 (25.6%).03
      Maternal ethnicity
      Australian born28 (52.8%)27 (43.6%).3221 (53.9%).49
      Gestation at birth, week38.8 (2.06)39.3 (1.3).1338.6 (1.2).08
      Time between vaccination and birth, week8.72 (2.29)4.48 (1.54)N/A
      Pertussis vaccination history
      Not vaccinated ever?21 (39.6%)25 (40.3%).4314 (36.8%)<.001
      Vaccinated <5 years2 (3.8)6 (9.68%)14 (36.8%)
      Not sure30 (56.6%)31 (50%)10 (26.3%)
      Primary antenatal care provider
      Obstetrician25 (47.2%)32 (51.6%).5224 (63.2%).26
      Midwife23 (43.4%)24 (38.7%)9 (23.7%)
      General practitioner5 (9.43%)4 (6.45%)5 (13.2%)
      Mode of delivery
      Normal vaginal28 (52.8%)35 (56.5%).708 (20.5%)<.001
      Instrumental12 (22.6%)11 (17.7%)4 (10.3%)
      Elective cesarean3 (5.7%)7 (11.3%)25 (64.1%)
      Emergency cesarean10 (18.9%)9 (14.5%)2 (5.13%)s
      Mean birthweight, grams (SD)3365 (651)3460 (514).383432 (484).09
      Maternal prevaccination level
      lnPRN5.51 (1.3)5.35 (1.30).565.56 (1.12).73
      lnFHA3.75 (1.08)3.32 (1.1).083.62 (0.90).17
      lnPT1.95 (1.17)1.42 (1.24).051.96 (1.01).07
      InFHA, log transformed filamentous hemagglutinin; InPRN, log transformed pertactin; InPT, log transformed pertussis toxin; SD, standard deviation.
      Naidu et al. Pertussis vaccination during pregnancy. Am J Obstet Gynecol 2016.
      a Difference in means between early and late vaccination
      b Differences across 3 groups.
      Cord antibody levels by groups are demonstrated in Table 2. Cord blood levels were significantly higher in the vaccinated group compared to control irrespective of timing of maternal vaccination in the third trimester.
      Table 2Venous cord blood antibody levels by groups
      Vaccinated 28–32 wk

      N = 38
      Vaccinated 33–36 wk

      N = 44
      Control group

      N = 27
      P value
      Analysis of variance for differences across 3 groups.
      Cord blood postvaccination
      lnPRN5.83 (0.93)5.31 (1.17)4.9 (1.04).001
      lnFHA5.56 (0.99)5.03 (1.19)4.21 (1.06)<.001
      lnPT4.18 (1.10)3.50 (1.25)2.80 (1.2)<.001
      InFHA, log transformed filamentous hemagglutinin; InPRN, log transformed pertactin; InPT, log transformed pertussis toxin; SD, standard deviation.
      Naidu et al. Pertussis vaccination during pregnancy. Am J Obstet Gynecol 2016.
      a Analysis of variance for differences across 3 groups.
      The relationship among maternal age, body mass index, vaccination history, parity, and maternal prevaccination levels with each respective cord blood antibody was examined. Only prevaccination maternal pertussis antibody levels were associated with cord blood pertussis antibody levels.
      When prevaccination maternal antibody levels were taken into account PT antibody levels approached significance in the early vs late vaccination group (P = .06). PRN antibody levels were significantly higher in the early vs late vaccination group (P = .03) and no significant difference was found for FHA antibody levels between the 2 groups (Table 3).
      Table 3Timing of vaccination and antibody levels
      Univariate β coefficient (95% CI)P valueMultivariate β coefficient (95% CI)P value
      PT
      28–32 wk0.67 (0.17–1.18).0090.44 (–0.02 to 0.90).06
      33–36 wk11
      PRN
      28–32 wk0.52 (0.05–0.98).030.44 (0.05–0.83).03
      33–36 wk11
      FHA
      28–32 wk0.53 (0.04–1.01).030.36 (–0.1 to 0.81).12
      33–36 wk11
      CI, confidence interval; FHA, filamentous hemagglutinin; PRN, pertactin; PT, pertussis toxin.
      Adjusted for maternal prevaccination levels.
      Naidu et al. Pertussis vaccination during pregnancy. Am J Obstet Gynecol 2016.
      A significant correlation was also found for PT, PRN, and FHA for the number of weeks of exposure and pertussis IgG antibody levels (Figure 2).
      Figure thumbnail gr2
      Figure 2Weeks exposed to vaccine and cord blood levels
      Weeks exposed to vaccine and cord blood levels. Log of pertussis toxin (LN_PT_CB), pertactin (LN_PRN_CB), and filamentous hemagglutinin (LN_FHA_CB) antibody levels in IU/mL.
      Naidu et al. Pertussis vaccination during pregnancy. Am J Obstet Gynecol 2016.

      Comment

      While public health policies are increasingly recommending maternal pertussis vaccination as the most effective strategy to reduce infant pertussis infection, the best time to vaccinate the pregnant mother is not known. In this study, we have shown that vaccination early in the third trimester is associated with higher antipertussis antibody levels in cord blood at birth than maternal vaccination later in the third trimester. We suggest that based on this finding women should be advised to have pertussis vaccination at around 28 weeks of pregnancy.
      Our finding of higher levels of pertussis-specific antibodies in cord blood of babies born to women vaccinated in pregnancy compared to those from babies born to an unvaccinated mother is consistent with previous reports.
      • Healy C.M.
      • Munoz F.M.
      • Rench M.A.
      • Halasa N.B.
      • Edwards K.M.
      • Baker C.J.
      Prevalence of pertussis antibodies in maternal delivery, cord, and infant serum.
      • Munoz F.M.
      • Bond N.H.
      • Maccato M.
      • et al.
      Safety and immunogenicity of tetanus diphtheria and acellular pertussis (Tdap) immunization during pregnancy in mothers and infants: a randomized clinical trial.
      Centers for Disease Control and Prevention (CDC)
      Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) in pregnant women and persons who have or anticipate having close contact with an infant aged <12 months–Advisory Committee on Immunization Practices (ACIP), 2011.

      Davies S; Department of Health. Whooping cough vaccination program for pregnant women. Available at: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/212947/CMO-Pertussis-27-09-2012-FINAL.pdf. Accessed October 19, 2015.

      • Healy C.M.
      • Rench M.A.
      • Baker C.J.
      Importance of timing of maternal combined tetanus, diphtheria, and acellular pertussis (Tdap) immunization and protection of young infants.
      • Gall S.A.
      • Myers J.
      • Pichichero M.
      Maternal immunization with tetanus-diphtheria-pertussis vaccine: effect on maternal and neonatal serum antibody levels.
      • Hardy-Fairbanks A.J.
      • Pan S.J.
      • Decker M.D.
      • et al.
      Immune responses in infants whose mothers received Tdap vaccine during pregnancy.
      • Abu Raya B.
      • Srugo I.
      • Kessel A.
      • et al.
      The effect of timing of maternal tetanus, diphtheria, and acellular pertussis (Tdap) immunization during pregnancy on newborn pertussis antibody levels–a prospective study.
      While the level of protection from Bordetella pertussis infection is thought to correlate with high titres of PT, PRN, and FHA,
      • Heininger U.
      • Riffelmann M.
      • Bär G.
      • Rudin C.
      • von König C.-H.W.
      The protective role of maternally derived antibodies against Bordetella pertussis in young infants.
      • Leuridan E.
      • Hens N.
      • Peeters N.
      • de Witte L.
      • Van der Meeren O.
      • Van Damme P.
      Effect of a prepregnancy pertussis booster dose on maternal antibody titers in young infants.
      • Storsaeter J.
      • Hallander H.O.
      • Gustafsson L.
      • Olin P.
      Levels of anti-pertussis antibodies related to protection after household exposure to Bordetella pertussis.
      • Taranger J.
      • Trollfors B.
      • Lagergård T.
      • et al.
      Correlation between pertussis toxin IgG antibodies in postvaccination sera and subsequent protection against pertussis.
      the minimum antibody level associated with adequate protection is not clear.
      • Gall S.A.
      • Myers J.
      • Pichichero M.
      Maternal immunization with tetanus-diphtheria-pertussis vaccine: effect on maternal and neonatal serum antibody levels.
      • Leuridan E.
      • Hens N.
      • Peeters N.
      • de Witte L.
      • Van der Meeren O.
      • Van Damme P.
      Effect of a prepregnancy pertussis booster dose on maternal antibody titers in young infants.
      • Storsaeter J.
      • Hallander H.O.
      • Gustafsson L.
      • Olin P.
      Levels of anti-pertussis antibodies related to protection after household exposure to Bordetella pertussis.
      As such, anti-PT, anti-PRN, and anti-FHA levels have been used as surrogate markers of protection. That maternal vaccination increases those levels suggests that this approach will confer better protection against infection to the newborn, prior to development of its own active immunization. Indeed, the recent observation that maternal vaccination was associated with a 90% decrease in reported infant pertussis infections confirms the effectiveness of this approach.
      What has been less clear is whether there is an optimal time in pregnancy to offer maternal vaccination with a view to maximizing newborn protection. That we found cord blood levels of antipertussis antibodies to be higher in those babies whose mothers had been vaccinated at 28-32 weeks suggests that earlier, rather than later, vaccination will be more effective. This supports the post hoc finding from another recent study of maternal pertussis vaccination.
      • Abu Raya B.
      • Srugo I.
      • Kessel A.
      • et al.
      The effect of timing of maternal tetanus, diphtheria, and acellular pertussis (Tdap) immunization during pregnancy on newborn pertussis antibody levels–a prospective study.
      While that study was not designed to specifically explore timing of vaccination, the authors suggested that maternal vaccination at 27-31 weeks was associated with the highest cord blood titres of PT, PRN, and FHA antibodies.
      • Abu Raya B.
      • Srugo I.
      • Kessel A.
      • et al.
      The effect of timing of maternal tetanus, diphtheria, and acellular pertussis (Tdap) immunization during pregnancy on newborn pertussis antibody levels–a prospective study.
      We were able to show a positive correlation between the number of weeks exposed to the vaccine and cord blood levels of PT, PRN, and FHA. This suggests that longer exposure to the vaccine allows for higher PT, PRN, and FHA antibody levels to be produced in the mother and transferred across the placenta to the infant in the third trimester of pregnancy prior to delivery. It also suggests that even earlier maternal vaccination would be worth exploring. That said, 28 weeks’ gestation is an attractive time to vaccinate women because other routine pregnancy interventions are offered at that gestation, such as testing for gestational diabetes, rhesus prophylaxis, and hemoglobin measurement.

      National Institute for Health and Excellence 2008. Antenatal care (NICE clinical guideline 62). Available at: guidance.nice.org.uk/cg62. Accessed October 19, 2015.

      It was also interesting to note that the response to maternal vaccination was not uniform for all 3 pertussis antibodies. In particular, while levels of the PRN and PT antibodies increased, levels of the FHA antibody were not increased when we accounted for prevaccination levels. This may not be critical for conferring newborn protection. PT has been identified as the most important virulence factor of the B pertussis bacterium,
      • Paddock C.D.
      • Sanden G.N.
      • Cherry J.D.
      • et al.
      Pathology and pathogenesis of fatal Bordetella pertussis infection in infants.
      with the highest correlate to disease protection in infants. It has been suggested that PT alone confers immunity against pertussis, although not complete protection.
      Ad Hoc Group for the Study of Pertussis Vaccines
      Placebo-controlled trial of two acellular pertussis vaccines in Sweden–protective efficacy and adverse events.
      • Trollfors B.
      • Taranger J.
      • Lagergård T.
      • et al.
      A placebo-controlled trial of a pertussis-toxoid vaccine.
      Furthermore individuals who lack PT antibodies are susceptible to pertussis.
      When maternal age, body mass index, vaccination history, parity, and maternal prevaccination levels were analyzed, only prevaccination maternal pertussis antibody levels were associated with higher cord blood pertussis antibody levels. Some guidelines are now recommending vaccination with every pregnancy irrespective of the timing of previous pregnancy and vaccination.
      Australian Technical Advisory Group on Immunisation (ATAGI)
      Our findings support this approach, and provide evidence that maintaining high maternal antibody levels aids maximal cord blood levels at the time of labor.
      One potential limitation of this study is the generalizability of the findings to other pertussis vaccines. It is possible that immunization responses to a 5-valent vaccine may differ from those to the tri-valent dTpa vaccine used in this study.

      Conclusion

      We have shown that maternal vaccination during the third trimester of pregnancy affords higher levels of pertussis antibody protection to the newborn infant than in nonvaccinated women. Furthermore the optimal window of vaccination to confer the highest level of pertussis antibody protection to the infant appears to be between 28-32 weeks’ gestation. Our findings support earlier vaccination in the third trimester of pregnancy to maximize protection provided to newborns through a maternal vaccination strategy. These findings should be considered in national guidelines and when implementing vaccination programs across maternity services.

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