Key PointsQuestion
Does maternal immunization with Tdap vaccine during the third trimester of pregnancy yield high concentrations of pertussis antibodies at birth? Is there an optimal gestational age for immunization?
Findings
In this prospective cohort study of 626 pregnancies, neonates whose mothers received Tdap immunization in the third trimester compared with those whose mothers received no Tdap vaccine during pregnancy had a geometric mean concentration of pertussis toxin antibodies in cord blood of 47.3 IU/mL vs 12.9 IU/mL, a difference that was statistically significant. Concentrations of cord blood antibodies were highest when immunization occurred at 27 to 30 weeks and declined thereafter.
Meaning
Maternal immunization with Tdap vaccine during the third trimester was associated with higher pertussis toxin antibody concentrations in neonates than no maternal immunization; immunization early in the third trimester was associated with the highest concentrations.
Importance
Immunization with tetanus, diphtheria, and acellular pertussis (Tdap) vaccine is recommended in the United States during weeks 27 through 36 of pregnancy to prevent life-threatening infant pertussis. The optimal gestation for immunization to maximize concentrations of neonatal pertussis toxin antibodies is unknown.
Objective
To determine pertussis toxin antibody concentrations in cord blood from neonates born to women immunized and unimmunized with Tdap vaccine in pregnancy and optimal gestational age for immunization to maximize concentrations of neonatal antibodies.
Design, Setting, and Participants
Prospective, observational, cohort study of term neonates in Houston, Texas (December 2013-March 2014).
Exposures
Tdap immunization during weeks 27 through 36 of pregnancy or no Tdap immunization.
Main Outcomes and Measures
Primary outcome was geometric mean concentrations (GMCs) of pertussis toxin antibodies in cord blood of Tdap-exposed and Tdap-unexposed neonates and proportions of Tdap-exposed and Tdap-unexposed neonates with pertussis toxin antibody concentrations of 15 IU/mL or higher, 30 IU/mL or higher, and 40 IU/mL or higher, cutoffs representing quantifiable antibodies or levels that may be protective until the infant immunization series begins. Secondary outcome was the optimal gestation for immunization to achieve maximum pertussis toxin antibodies.
Results
Six hundred twenty-six pregnancies (mean maternal age, 29.7 years; 41% white, 27% Hispanic, 26% black, 5% Asian, 1% other; mean gestation, 39.4 weeks) were included. Three hundred twelve women received Tdap vaccine at a mean gestation of 31.2 weeks (range, 27.3-36.4); 314 were unimmunized. GMC of neonatal cord pertussis toxin antibodies from the Tdap-exposed group was 47.3 IU/mL (95% CI, 42.1-53.2) compared with 12.9 IU/mL (95% CI, 11.7-14.3) in the Tdap-unexposed group, for a GMC ratio of 3.6 (95% CI, 3.1-4.2; P < .001). More Tdap-exposed than Tdap-unexposed neonates had pertussis toxin antibody concentrations of 15 IU/mL or higher (86% vs 37%; difference, 49% [95% CI, 42%-55%]), 30 IU/mL or higher (72% vs 17%; difference, 55% [95% CI, 49%-61%]), and 40 IU/mL or higher (59% vs 12%; difference, 47% [95% CI, 41%-54%]); P < .001 for each analysis. GMCs of pertussis toxin antibodies were highest when Tdap vaccine was administered during weeks 27 through 30 and declined thereafter, reaching a peak at week 30 (57.3 IU/mL [95% CI, 44.0-74.6]).
Conclusions and Relevance
Immunization with Tdap vaccine during the third trimester of pregnancy, compared with no immunization, was associated with higher neonatal concentrations of pertussis toxin antibodies. Immunization early in the third trimester was associated with the highest concentrations.
Quiz Ref IDPertussis incidence is highest in infants too young to have completed their primary immunization series (6 months or younger), who are at highest risk of developing life-threatening complications.1 In high-income countries, pertussis-related mortality occurs predominantly in infants 3 months or younger.1-3 Immunization of pregnant women can induce sufficient levels of maternal antibodies, leading to passive protection of infants.3,4 Serologic correlates of protection against pertussis in infants are unknown, but substantial concentrations of maternal antibodies to pertussis toxin, the pertussis antigen associated with severe disease, are likely critical in preventing severe disease.5
Quiz Ref IDIn 2013, the Centers for Disease Control and Prevention (CDC) in the United States recommended that pregnant women receive tetanus, diphtheria, and acellular pertussis (Tdap) vaccine in every pregnancy during weeks 27 through 36 of gestation.1 Studies have demonstrated that immunizing before or early in pregnancy resulted in pertussis toxin antibody concentrations likely insufficient to protect infants.1,6 Third-trimester Tdap immunization was shown to be safe, allowed efficient placental transport of induced maternal antibodies, and did not interfere significantly with infant antibody response to pertussis toxin during the primary immunization series.7-12 However, data on pertussis antibody concentrations following maternal Tdap immunization are limited because of small cohort size or differing immunization schedules.13-15 No study, to our knowledge, has specifically evaluated pertussis antibody concentrations in a large cohort of infants based on current US policy or, based on this policy, assessed the interval during pregnancy when immunization would maximize infant cord blood concentrations.
This study measured pertussis toxin antibody concentrations in umbilical cord sera of neonates born to women who received Tdap vaccine during weeks 27 through 36 of pregnancy compared with neonates born to unimmunized women and the optimal timing of immunization to maximize concentration of maternally derived antibodies in infant cord blood.
This prospective cohort study was approved by the institutional review board of Baylor College of Medicine. CDC human participants review determined that CDC investigators were not engaged in human participants research for this study, and CDC institutional review board approval was not required. The study met criteria for waiver of informed consent.
The study population was term newborns born at the Pavilion for Women at Texas Children’s Hospital in Houston, a tertiary referral center for obstetrics with approximately 5000 deliveries annually, including low- and high-risk pregnancies. Participants were eligible for inclusion if they delivered at term (≥37 weeks’ gestation); there was documentation (lot number and administration record) that the mother received Tdap vaccine during gestation weeks 27 through 36 (Tdap-exposed group) and 14 days or more before delivery (to allow for antibody response) or there was specific documentation in the medical record that the mother had not received Tdap vaccine during pregnancy (Tdap-unexposed group); and residual umbilical cord serum was available in sufficient quantity for serologic testing. Infants born to mothers who tested positive for HIV or syphilis were excluded.
Cord serum samples were collected from infants from December 9, 2013, through March 15, 2014. Maternal age, self-reported race/ethnicity (fixed-category questions), date and gestation at Tdap vaccine administration, infant date of birth, and length of gestation were abstracted from the medical record. Race/ethnicity was included because pertussis incidence varies by this factor.1,2,16,17 Prior Tdap receipt was not recorded because studies have demonstrated that prepregnancy immunization was not associated with sufficient concentrations of pertussis toxin antibodies at birth.1,6
The primary outcome was pertussis toxin antibody concentrations in cord blood from infants of Tdap-immunized mothers compared with those of Tdap-unimmunized mothers. The secondary outcome was optimal gestation to administer Tdap vaccine that resulted in maximum infant pertussis toxin antibody concentration at birth. For both primary and secondary outcomes, the estimated pertussis toxin antibody concentrations in infants of Tdap-immunized mothers at age 2 months, when the infant primary immunization series is initiated, was calculated using the published half-life of passively acquired maternal levels.18
Umbilical cord blood specimens were processed to collect serum, aliquoted, coded, and frozen at −80°C until testing. Serologic testing for pertussis toxin antibody concentrations was performed at the CDC by enzyme-linked immunosorbent assay as previously described.19,20 CDC laboratory analysts (M.H.M., M.D.M.) were blinded to identification of samples. In each assay, samples were tested at a 1:100 dilution and the concentrations of IgG antibodies were quantified using internal standards calibrated to the World Health Organization International Standard 06/140 (NIBSC). The lower and upper limits of quantitation were 15 and 480 IU/mL, respectively. Per accepted practice, values less than the lower limit of quantitation were halved and those greater than the upper limit of quantitation were doubled.
Statistical analyses were performed using SPSS version 24.0 (IBM/SPSS Inc) and SAS version 9.4 (SAS Institute Inc). Baseline comparison between the Tdap-exposed and Tdap-unexposed groups used 2-sided Fisher exact test, χ2 test, and Cochran Mantel-Haenszel test for categorical outcomes and either t test or Mann-Whitney test, depending on normality, for continuous outcomes. Serum pertussis toxin antibody values were reported as geometric mean concentrations (GMCs) with 95% CIs. The difference between Tdap-exposed vs Tdap-unexposed groups with respect to GMC was assessed by t test of log-transformed serum IgG levels.
Pertussis toxin antibody concentrations estimated to be present in infants at age 2 months were calculated using the published half-life of passively acquired maternal levels (36 days).18 The proportions of cord samples with pertussis toxin antibody concentrations 15 IU/mL or higher, 30 IU/mL or higher, and 40 IU/mL or higher were calculated. These arbitrary cutoffs were chosen to further define the population with quantifiable antibodies in this cohort (≥15 IU/mL) and because studies identified levels 30 IU/mL or higher and 40 IU/mL or higher at birth to define infants who would be “seropositive” or potentially protected at the start of the immunization series.14,15 Using the published half-life, pertussis toxin antibody concentrations at the start of the primary immunization series were estimated to be 3.75 IU/mL or higher when concentration at birth was 15 IU/mL or higher, 7.5 IU/mL or higher when concentration at birth was 30 IU/mL or higher, and 10 IU/mL or higher when concentration at birth was 40 IU/mL or higher.
The association of timing of maternal Tdap vaccine administration with infant cord concentrations of pertussis toxin antibodies was determined by calculating the GMC (with 95% CI) and proportions of samples with pertussis toxin antibody concentrations of 15 IU/mL or higher, 30 IU/mL or higher, and 40 IU/mL or higher by gestation week immunized. GMC was graphed by gestation week at immunization. This graph was examined for possible point of inflection visually and using Join Point Regression Program version 4.6 (Statistical Research and Application Branch, National Cancer Institute).21 Two separate regression models were run with mean GMC as the outcome variable and gestation week for immunization as the independent variable for gestation less than 30 weeks and 30 weeks or more.
Differences in antibody concentrations at birth between infants who received Tdap vaccine during the early third trimester (gestation weeks 27-31) vs late third trimester (gestation weeks 32-36) were also determined. This post hoc comparison was chosen because the biology of placental transport suggests the early third trimester as the optimal time to administer a vaccine in pregnancy, and it is the midpoint of the recommended gestational window for Tdap administration. In addition, these immunization windows are of sufficient duration to allow at least 2 health care visits—and thus opportunities to administer Tdap vaccine—during pregnancy, rendering this comparison helpful in practice without being overly restrictive for clinicians.
Generalized linear mixed models (PROC GLIMMIX [SAS version 9.4]) were used for estimation of adjusted geometric mean concentrations and corresponding 95% CIs. PROC GENMOD (SAS version 9.4) was used for estimation of proportion differences and associated 95% CIs. Results were adjusted for age and ethnicity, which are known to be associated with variations in the incidence of pertussis1,2,16,17 and thus could affect antibody levels through natural infection. Results were also adjusted for gestation at delivery, since the time interval from vaccination for those immunized each week could vary by up to 5 weeks, depending on whether the term infant delivered at 37 or 42 weeks. P < .05 (2-sided) was considered statistically significant.
Of 954 patients evaluated for eligibility, 328 were excluded (no cord sample [141], delivery at <37 weeks’ gestation [105], no documentation of Tdap immunization status [50], received Tdap vaccine outside of recommended gestation period [17], received Tdap vaccine <14 days before delivery [14], abnormal laboratory screening values [1]). Umbilical cord sera were thus collected from 626 neonates—those whose mothers had received Tdap vaccine (n = 312) and those whose mothers were unimmunized (n = 314).
Maternal and infant characteristics are summarized in the Table. Immunized women were older, more likely to be white, and less likely to be black than unimmunized women; there were no differences in infant birth weight or gestation at delivery. The mean gestation at maternal Tdap vaccine administration was 31.2 weeks (range, 27.3-36.4); most women (80%) received Tdap vaccine during weeks 28 through 32 of gestation. The mean interval between immunization and delivery was 57 days (range, 21-90 days); 77% of women received Tdap vaccine 8 weeks or more before delivery.
The GMC of pertussis toxin antibodies at birth for infants born to Tdap-immunized women was 47.3 IU/mL (95% CI, 42.1-53.2 [range, 7.5-960]) and to Tdap-unimmunized women was 12.9 IU/mL (95% CI, 11.7-14.3 [range, 7.5-402]), for a ratio of 3.6 (95% CI, 3.1-4.2) (P < .001) (Figure 1). This ratio remained significant after controlling for maternal age, ethnicity, and gestational age at delivery. More infants born to Tdap-immunized women than to Tdap-unimmunized women had pertussis toxin antibody concentrations of 15 IU/mL or higher (86% vs 37%; difference, 49% [95% CI, 42%-55%]), 30 IU/mL or higher (72% vs 17%; difference, 55% [95% CI, 49%-61%]), and 40 IU/mL or higher (59% vs 12%; difference, 47% [95% CI, 41%-54%]) (P < .001 for each analysis).
When adjusted for potential confounders (maternal age, ethnicity, and gestational age at delivery), all results remained significant (P < .001), with a difference of 50% (95% CI, 44%-57%) for infants with pertussis toxin antibody concentrations of 15 IU/mL or higher, 57% (95% CI, 50%-63%) for those with concentrations 30 IU/mL or higher, and 48% (95% CI, 40%-54%) for those with concentrations 40 IU/mL or higher.
The GMC of pertussis toxin antibodies in cord sera increased sequentially each week when Tdap vaccine was administered during 27 through 29 weeks of gestation, was highest when given at week 30 (GMC, 57.3 IU/mL [95% CI, 44.0-74.6]; range, 7.5-424), and declined thereafter (Figure 2; eTable in the Supplement). One outlier for week 36 (of the 6 participants who received Tdap vaccine during gestation week 36) that was more than 2 standard deviations from the mean was excluded. Using 5000 permutations and overall significance of .05, gestation week 30 appeared to be the point at which a change in the direction of slope was occurring. On join point analysis, the parameter estimate (beta) for less than 30 weeks was 0.04, P = .58 (nonsignificant positive slope) and for 30 weeks or more was −0.05, P = .01 (significant negative slope). This analysis indicated that after 30 weeks, GMC decreased significantly with increasing gestation age at immunization. When Tdap vaccine was given during 27 through 30 weeks, no significant difference in GMC at birth was seen. Proportions of samples with pertussis toxin antibody concentrations of 15 IU/mL or higher, 30 IU/mL or higher, and 40 IU/mL or higher were highest when Tdap vaccine was administered between weeks 28 through 31 (eTable in the Supplement).
The estimated GMC of serum pertussis toxin antibody at age 2 months was 11.8 IU/mL (95% CI, 10.5-13.3) among infants born to Tdap-immunized mothers and 3.2 IU/mL (95% CI, 2.9-3.6) among those born to Tdap-unimmunized mothers, for a GMC ratio of 3.7 (95% CI, 3.2-4.2) (P < .001). Estimated GMC of pertussis toxin antibodies at infant age 2 months was highest when Tdap vaccine was administered during week 30 (14.3 IU/mL (95% CI, 11.0-18.7), followed, in descending order, by weeks 29, 28, 31, 27, 32, 33, 36, 34, and 35 (eTable in the Supplement).
The GMC ratio of pertussis toxin antibodies was 1.4 (95% CI, 1.1-1.7; P = .02) when mothers were immunized at weeks 27 through 31 (52.5 IU/mL [95% CI, 45.5-60.6]; range, 7.5-960) compared with weeks 32 through 36 (39.0 IU/mL [95% CI, 32.1-47.4]; range, 7.5-433). When adjusted for maternal age, ethnicity, and gestation at delivery, the GMC ratio was 1.4 (95% CI, 1.1-1.8; P = .007).
Quiz Ref IDThis study demonstrated that immunization with Tdap vaccine during weeks 27 through 36 of pregnancy, as recommended by the CDC to prevent life-threatening pertussis in young infants, compared with no immunization was associated with significantly higher concentrations of pertussis toxin antibodies in neonates at birth. Concentrations were highest when Tdap vaccine was administered during weeks 27 through 30 and declined thereafter.
Quiz Ref IDThese findings may be important for a number of reasons. Pertussis toxin is the pertussis antigen most associated with severe infant disease. Although no definitive serologic correlate of immunity for pertussis has been established, it is likely that antibody concentrations needed to protect young infants are higher than those required for older children and adults.3,4 Older children and adults, who are likely primed through prior immunization, natural infection, or both and whose ability to mount humoral and cell-mediated immune responses is more developed than in young infants, have alternative mechanisms for mounting a robust immunologic response. Pertussis toxin antibody concentrations measured in cord sera from infants in this cohort born to Tdap-immunized mothers were higher than concentrations reported from the pre-Tdap booster era22-24 and than concentrations from cord sera of infants born to mothers who received Tdap vaccine within 15 months before or in early pregnancy.6 Pertussis toxin antibody concentrations at birth were sufficiently high in infants born to Tdap-immunized mothers that, even allowing for the natural decay of maternal antibodies, most infants would have had substantial antibody levels until initiation of the primary vaccine series, thus reducing their risk of pertussis-related mortality and morbidity.
This study is the first, to our knowledge, to evaluate a large cohort of newborn infants born at term to mothers who received Tdap vaccine in accordance with the current US recommendations. These serologic findings may help to explain why epidemiologic studies demonstrated reduction in infant pertussis following third-trimester immunization in the United States11,12,25 and in the United Kingdom, where pertussis booster vaccine was given during weeks 28 to 38 of pregnancy and resulted in a 91% reduction in pertussis in infants 3 months or younger.26
Determination of the optimal gestation for maternal immunization is complex. Placental transfer of antibodies is a dynamic process beginning around week 17 of gestation.4,27 The efficiency of antibody transfer is low until 32 to 34 weeks and is dependent on maternal antibody levels, placental function, absence of maternal co-infections that diminish transfer, and IgG subclass induced by vaccine antigens.4,27 Protein antigens, such as those found in the Tdap vaccine, induce IgG1 antibodies, which are transported more efficiently than those induced by polysaccharide antigens (IgG2).28Quiz Ref ID Decisions on the timing of maternal immunizations should consider the interval required for a maternal vaccine immune response (approximately 10-14 days for pertussis antigens), timing of peak response, duration of maternal antibody levels after birth, and disease risk for mother and infant.1,29 These factors are especially important when considering pertussis maternal immunization strategies, because pertussis antibodies wane quickly and disease burden is far greater in infants than in pregnant women.
This study demonstrated that, following US immunization recommendations and in accordance with current understanding of the kinetics of placental transfer, optimal time to administer Tdap vaccine to maximize pertussis toxin antibodies at birth may be early in the third trimester, with the window of 27 through 30 weeks of gestation yielding the highest cord blood levels. Pertussis toxin antibody concentrations in cord sera increased gradually during weeks 27 through 30, were highest when Tdap vaccine was given at 30 weeks, and declined thereafter, particularly after 33 weeks. Consistent with these findings, mean pertussis toxin antibody concentrations and fold differences between infants of Tdap-immunized mothers and infants of unimmunized mothers were higher in randomized clinical trials and prospective cohort studies using a narrow window during the third trimester for Tdap vaccine administration (30-32 weeks),10 compared with those using longer intervals (22-33 weeks).8,30
These results are also consistent with published observational studies.11-13,15 A study by Eberhardt et al found that immunization during the second trimester was superior to immunization during the third trimester from a serologic standpoint and postulated that this unexpected finding suggested that prolonged maternofetal transfer cumulatively results in higher IgG levels than transfer over shorter periods during a time when placental transfer is most efficient.14 Forty-six women (14%) in the study by Eberhardt et al received Tdap vaccine during gestation weeks 26 through 33, compared with 285 who received Tdap vaccine during weeks 27 through 33 in the current study. Although the current study provides a more robust analysis of the value of immunizing during the early third trimester, direct comparison between these 2 studies is challenging. Together, they suggest that prospective studies are needed to determine if late second- or early third-trimester immunization is preferable from a serologic standpoint for infants born at term, those born at late preterm (34 through 36 weeks’ gestation), or both. Additional considerations for further study include assessment of whether there is a threshold concentration of maternal pertussis toxin antibody in infants beyond which infant immune response to the primary immunization series is blunted, as has been reported in a number of studies.8,30-33
This study has several limitations. First, the observational study design precludes a causal interpretation of the findings. Second, this was a single-center study and was exploratory in nature without any formal power calculation, so results need to be verified in future large studies. Third, maternal preimmunization and postimmunization serum samples were not collected; thus, the study could not determine how many women may have had boosting through natural infection or who did not mount an anamnestic response. However, specimens from Tdap-immunized and Tdap-unimmunized women were collected over 3 months, reducing the potential confounding effect of seasonal variations of pertussis disease, and there was no increase in cases reported in the hospital referral area during the quarter before, during, or after this study period (Rachel Wiseman, MPH, epidemiologist, Texas Department of State Health Services, written communication, August 9, 2016). Fourth, no women were immunized during the second trimester, and the numbers immunized in late pregnancy were low, limiting the conclusions that can be drawn about maternal immunization during these intervals.
Immunization with Tdap vaccine during the third trimester of pregnancy, compared with no immunization, was associated with higher neonatal concentrations of pertussis toxin antibodies. Immunization early in the third trimester was associated with the highest concentrations.
Corresponding Author: C. Mary Healy, MD, Infectious Disease Section, Department of Pediatrics, Baylor College of Medicine, 1102 Bates St, Ste 1120, Houston, TX 77030 (chealy@bcm.edu).
Accepted for Publication: September 10, 2018.
Author Contributions: Dr Healy had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Healy, Rench, Baker.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Healy, Smith.
Critical revision of the manuscript for important intellectual content: Healy, Rench, Swaim, Sangi-Haghpeykar, Mathis, Martin, Baker.
Statistical analysis: Healy, Smith, Sangi-Haghpeykar, Mathis.
Obtained funding: Healy.
Administrative, technical, or material support: Healy, Rench, Swaim, Martin, Baker.
Supervision: Healy, Baker.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Healy reported receiving research grants from Sanofi Pasteur and Novartis Vaccines and serving on advisory boards for Novartis Vaccines, Pfizer Inc, and Novavax Inc. Dr Baker reported serving on scientific advisory boards for Seqirus Inc and as a consultant for Pfizer Inc. No other authors reported disclosures.
Funding/Support: This article was made possible by award CDC-CI10-101203PPHF12 from the Centers for Disease Control and Prevention (CDC), through the Houston Department of Health and Human Services (HDHHS).
Role of the Funder/Sponsor: The sponsor was involved in the design of the study, performance of laboratory assays, interpretation of the data, and critical review of the manuscript. The sponsor had no role in collection, management, or statistical analysis of the data and did not have the right to prevent publication of the study.
Additional Contributions: We thank Lucia Pawloski, PhD (research biologist, Pertussis and Diphtheria Laboratory, CDC), and Maria Lucia Tondella, PhD (team lead, Pertussis and Diphtheria Laboratory, CDC), for their assistance in performing the study. We thank Robin Schroeder (administrative coordinator, Baylor College of Medicine) for her assistance in manuscript preparation. Drs Pawloski and Tondella received no compensation for their role in the study. Baylor College of Medicine received salary support for Ms Schroeder for her role in the study.
Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC or HDHHS.
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