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Department of Obstetrics and Gynecology, Monash University, Melbourne, AustraliaRitchie Center, Hudson Institute of Medical Research, Melbourne, Australia
Department of Obstetrics and Gynecology, Monash University, Melbourne, AustraliaRitchie Center, Hudson Institute of Medical Research, Melbourne, AustraliaMonash Health, Melbourne, Australia
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.
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.
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.
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.
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.
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.
Safety and immunogenicity of tetanus diphtheria and acellular pertussis (Tdap) immunization during pregnancy in mothers and infants: a randomized clinical trial.
Recent studies confirm that active placental transfer of pertussis-specific antibodies occurs, with peak transfer occurring in the third trimester of pregnancy.
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.
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.
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
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,
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 1Study participants according to allocated vaccination or control group
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.
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
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).
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.
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.
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.
The effect of timing of maternal tetanus, diphtheria, and acellular pertussis (Tdap) immunization during pregnancy on newborn pertussis antibody levels–a prospective study.
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.
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.
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,
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.
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.
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.
References
Paddock C.D.
Sanden G.N.
Cherry J.D.
et al.
Pathology and pathogenesis of fatal Bordetella pertussis infection in infants.
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.
Safety and immunogenicity of tetanus diphtheria and acellular pertussis (Tdap) immunization during pregnancy in mothers and infants: a randomized clinical trial.
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.
The effect of timing of maternal tetanus, diphtheria, and acellular pertussis (Tdap) immunization during pregnancy on newborn pertussis antibody levels–a prospective study.
National Institute for Health and Excellence 2008. Antenatal care (NICE clinical guideline 62). Available at: guidance.nice.org.uk/cg62. Accessed October 19, 2015.
Cite this article as: Naidu MA, Muljadi R, Davies-Tuck ML, et al. The optimal gestation for pertussis vaccination during pregnancy: a prospective cohort study. Am J Obstet Gynecol 2016;215:237.e1-6.
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