The Centers for Disease Control and Prevention's public health response to monitoring Tdap safety in pregnant women in the United States

Abstract

In 2010, in response to a widespread pertussis outbreak and neonatal deaths, California became the first state to recommend routine administration of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine during pregnancy. In 2011, the Advisory Committee on Immunization Practices (ACIP) followed with a similar recommendation for Tdap vaccination during pregnancy for previously unvaccinated women. In 2012, this recommendation was expanded to include Tdap vaccination of every pregnant woman during each pregnancy. These recommendations were based on urgent public health needs and available evidence on the safety of other inactivated vaccines during pregnancy. However, there were limited data on the safety of Tdap during pregnancy. In response to the new ACIP recommendations, the Centers for Disease Control and Prevention (CDC) implemented ongoing collaborative studies to evaluate whether vaccination with Tdap during pregnancy adversely affects the health of mothers and their offspring and provide the committee with regular updates. The current commentary describes the public health actions taken by CDC to respond to the ACIP recommendation to study and monitor the safety of Tdap vaccines in pregnant women and describes the current state of knowledge on the safety of Tdap vaccines in pregnant women. Data from the various monitoring activities support the safety of Tdap use during pregnancy.

Keywords:

• epidemiology
• pregnancy
• surveillance
• Tdap
• vaccine safety

Background

In 2010, in response to a widespread pertussis outbreak and pertussis-related infant deaths, California became the first state to recommend routine administration of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine during pregnancy.¹ In 2011, the Advisory Committee on Immunization Practices (ACIP) followed with a similar recommendation that Tdap be administered during pregnancy, at 20 weeks gestation or later, to women who had not been previously vaccinated in order to provide the young infant with maternal transplacental passive antibody protection against pertussis during the early postnatal months.² In October 2012, ACIP expanded this recommendation to include vaccination of all pregnant women during each pregnancy, preferably between 27-36 weeks gestation.³ These recommendations were based on urgent public health needs and available evidence on the safety of other inactivated vaccines (e.g., influenza) during pregnancy. However, there were limited data on the safety of Tdap during pregnancy when these recommendations were made. As with most vaccines and medications, pre-licensure trials for Tdap did not include pregnant women and few post-marketing safety studies had been conducted.⁴ Important evidence gaps in Tdap safety data relate to potential increased reactogenicity of multiple versus single Tdap doses and whether vaccination affects fetal growth and/or is associated with adverse maternal and/or birth outcomes. It is important to be aware of background rates of pregnancy outcomes when looking at the safety of a particular vaccine administered to pregnant women. Spontaneous abortion (SAB) is a relatively frequent event in pregnancy, with a rate as high as 22.4% in women aged 34 years old or older and 10.4% in women younger than age 25 years.⁵ Stillbirths occur at a background rate of 0.4% of all pregnancies or 6.05 per 1000 live births and fetal deaths.⁶ Preterm delivery (<37 weeks gestation) occurs in 10.4–11.5% of pregnancies⁵ and major birth defects occur at an overall background rate of 3%.⁷ In response to the ACIP recommendation, the Centers for Disease Control and Prevention (CDC) implemented a multifaceted approach to evaluate whether vaccination with Tdap during pregnancy adversely affects the health of mothers and their offspring and provided the ACIP with regular updates. The objectives of the current commentary are: 1) to describe the public health actions taken by CDC to monitor the safety of Tdap vaccines in pregnant women; and 2) to describe the current state of knowledge on the safety of Tdap vaccines in pregnant women.

Vaccine Safety Monitoring at the Centers for Disease Control and Prevention

Vaccine adverse event reporting system (VAERS)

CDC and the Food and Drug Administration (FDA) established the Vaccine Adverse Events Reporting System (VAERS) in 1990 to monitor vaccine safety.⁸ VAERS is a national spontaneous reporting system that accepts reports from healthcare providers, vaccine manufacturers, the public, and other individuals, on adverse events (AEs) associated with vaccines licensed in the United States. VAERS data are monitored to detect new, unusual, or rare vaccine adverse events, increases in known adverse events, and possible safety signals which may be evaluated in other studies. VAERS plays an important role as the frontline system for monitoring AEs as part of routine post-licensure vaccine safety surveillance and following new vaccine recommendations.⁹ The VAERS form requests demographic information about the vaccine recipient and past history of AEs following vaccination, description of the AE, information on the type of vaccine received; the timing of the vaccination; and current illnesses or medications. While VAERS has a number of strengths, such as its broad national scope and timely reporting, important limitations include over or under reporting, biased reporting, and inconsistency in quality and completeness of reports.⁹ Importantly, VAERS generally cannot assess causality between an AE and receipt of a vaccine. VAERS does not collect information on the total number of vaccinees, therefore it is not possible to calculate the incidence or prevalence of an AE. Crude reporting rates for certain AEs may sometimes be estimated using vaccine doses distributed as a proxy denominator. The VAERS form does not collect specific information about the pregnancy status of the vaccine recipient. However, it is possible to search for pregnancy reports in the VAERS system by searching for specific pregnancy Medical Dictionary for Regulatory Activities (MedDRA) codes.¹⁰ This has enabled monitoring of AEs after several vaccines given to pregnant women such as trivalent inactivated influenza vaccines, 2009 H1N1 inactivated influenza vaccines, Tdap vaccines, meningococcal vaccines, human papillomavirus vaccines, and hepatitis A and hepatitis B vaccines.^4,11-15

Vaccine safety datalink (VSD)

The Vaccine Safety Datalink (VSD) is a collaborative project between CDC and 9 integrated health care systems.^16,17 The VSD was established in 1990 and is a vital resource informing policy makers and the public about the safety of vaccines used in the United States. Large linked databases are used to identify and evaluate safety of vaccines and conduct studies about rare and serious AEs following immunization. The VSD captures comprehensive medical and immunization histories for over 9 million people annually, approximately 3% of the US population. The VSD uses electronic medical records and other administrative sources at each site to gather data on enrollees including demographics, vaccinations, and medical outcomes.^16,17 The VSD conducts vaccine safety studies based on questions or concerns raised from the medical literature and reports to VAERS. Additionally, when there are new vaccines that have been recommended for use in the United States or changes in vaccine recommendations, the VSD monitors the safety of these vaccines. In the past 5 years, as part of efforts to monitor the safety of vaccines in pregnant women, the VSD has developed an algorithm to search for and identify pregnant vaccine recipients who can be further evaluated for adverse pregnancy outcomes.¹⁸ VSD investigators have published important studies on vaccine safety in pregnant women.^18-24 Ongoing VSD studies are evaluating acute outcomes following Tdap vaccine in pregnancy, safety of Tdap administration according to time since receipt of prior tetanus toxoid containing vaccines in pregnant women, and the safety of co-administration of Tdap and influenza vaccines in pregnancy.

Clinical immunization safety assessment (CISA) project

The Clinical Immunization Safety Assessment (CISA) Project is a national network of vaccine safety experts from CDC, 7 medical research centers, and other partners. CISA was established in 2001 to address unmet vaccine safety clinical research needs. CISA's mission is to improve understanding of AEs following immunization at the individual patient level. CISA serves as a vaccine safety resource providing expert consultation on clinical vaccine safety issues and with its partners conducts studies to identify risk factors and preventive strategies for vaccine AEs, particularly in special populations.^25,26 A strength of CISA is its ability to collect detailed clinical data and biological specimens through prospective research studies. CISA was used to enhance vaccine safety monitoring during the 2009-2010 H1N1 influenza pandemic.^27,28 Ongoing CISA studies are evaluating the safety of Tdap in pregnant women²⁹ and the feasibility of text messaging to monitor pregnancy outcomes after inactivated influenza vaccine.³⁰

Vaccine Safety Studies Prior to the ACIP Recommendations

Prior to the October 2011 ACIP maternal recommendation for Tdap, several studies supported the safety of administering tetanus toxoid-containing vaccine to pregnant women,³¹ but few studies had been conducted on the safety of Tdap in pregnant women (Table 1). A prospective, randomized trial to assess the immunogenicity and reactogenicity of Tdap in adolescents and adults enrolled 4,480 subjects, 2,936 of whom received Tdap and 1,365 tetanus, diphtheria (Td) vaccine.³² Pregnant women were excluded from the trial. However, 30 women had one or more pregnancies during the study, 23 in the Tdap treatment arm and 7 in the Td group. Each woman tested negative for pregnancy at enrollment. Five in the Tdap arm experienced a SAB, and one in the Td group had a therapeutic abortion. Four had preterm deliveries, 2 in each treatment group. At birth, 23 newborns, including the 4 preterm newborns, were reported to be normal. In addition, a study from 2005 through 2011 of the Adacel^® (Tdap) Vaccine Pregnancy Registry reported 539 pregnant women who received Tdap during pregnancy. Among the 480 spontaneous prospective reports included in this series, 27 (5.6%) were classified as serious AEs and there were 16 (3.3%) SAB and 8 (1.7%) preterm deliveries.³³ In another study of 4524 health care workers who were vaccinated with Tdap during a mass vaccination campaign, 16 women received Tdap during pregnancy, all of whom gave birth to normal full-term infants.³⁴

A postmarketing study was also conducted on the safety of Tdap vaccination in pregnant women and/or their infants during 2005 through 2010 whose reports were submitted to VAERS.⁴ This study provided safety evidence that helped inform the ACIP deliberations for Tdap use in pregnant women in 2011-2012. A total of 132 reports were submitted to VAERS regarding pregnant women who received Tdap during pregnancy. The majority (77.3%) of women from these reports were vaccinated in the first trimester. Fifty-five (42%) reports did not describe any AE, and the reason for submitting the report to VAERS was because vaccine was administered during pregnancy at a time when Tdap in pregnancy was not routinely recommended. No maternal or infant deaths were reported. The most common pregnancy-specific AE was spontaneous abortion (22 reports; 16.7%) and the most common non-pregnancy–specific AE was injection site reaction (6 reports; 4.5%). One case of a major congenital anomaly (gastroschisis) in an infant born to a 15-year-old mother who received concomitant quadrivalent human papillomavirus vaccine (HPV4) was reported. No unusual or unexpected pattern of maternal, infant, or fetal adverse events were found.

CDC Actions to Monitor the Safety of Tdap Vaccine in Pregnancy After the 2012 ACIP Recommendation

Beginning in late 2012, CDC initiated enhanced safety surveillance of Tdap in pregnant women using VAERS for the period from October 2011 through March 2015. Maternal, Medical, delivery, and/or infant records (if appropriate) were requested for all pregnancy and/or infant reports. Compared to the period before the October 2012 recommendation, there was an increase in the proportion of certain pregnancy-specific outcomes that occurred after the first trimester (e.g., stillbirths, preterm deliveries), as well as certain non-pregnancy specific outcomes (e.g., injection site reactions).³⁵ A decrease in the number of reports describing no AE was noted and most Tdap vaccinations occurred during the second and third trimester. These changes in reporting patterns were likely due to the new routine ACIP Tdap recommendation for pregnant women resulting in predominant vaccination during the second and third trimester of pregnancy. No new or unexpected vaccine safety concerns were noted among pregnant women who received Tdap (or their infants). There were a limited number of pregnancy reports with repeat Tdap doses reported to VAERS, therefore no safety assessment could be made of repeat Tdap administration during pregnancy.

Also in late 2012, CDC implemented studies in VSD to evaluate Tdap vaccine safety in pregnant women. A retrospective, observational, cohort study by Kharbanda et al.³⁶ from 2010-2012 in 2 California VSD sites that included 123,494 pregnant women, found no increased risk for adverse birth outcomes, including preterm birth, among pregnant women vaccinated with Tdap. A small but statistically significant increased risk was found for chorioamnionitis (RR 1.19; 95% CI, 1.13-1.26) comparing pregnant women receiving Tdap with unvaccinated pregnant women after adjusting for maternal age and comorbidities, although no adjustment for risk factors for chorioamnionitis was done. Chorioamnionitis is often found associated with preterm birth,^37,38 but Kharbanda et al., found most of the women who had chorioamnionitis following Tdap vaccination did not have preterm births. Moreover, chart review was able to confirm only 50% of the chorioamnionitis diagnoses.³⁶ Chorioamnionitis has been described in a few other studies, but no previous statistically significant association has been observed with any vaccine. Although not meeting strict criteria for statistical significance, a VSD study of the 2002–2009 influenza seasons found a small increased risk of chorioamnionitis among women who received influenza vaccine.²² Following the VSD finding for chorioamnionitis, a review of the VAERS database was conducted covering a period of 24 years to assess for this condition; few cases of chorioamnionitis following receipt of any vaccine were found.³⁹

CDC also recently implemented a prospective observational clinical study in CISA at Vanderbilt University and Duke University with the following primary goals: 1) to compare rates of local and systemic reactions after Tdap in pregnant vs. non-pregnant women; and 2) to assess rates of preterm birth and SGA in women who received Tdap. Secondary goals are: 1) to explore differences in reactogenicity rates in pregnant women who receive multiple Tdap doses vs. single dose Tdap; 2) to assess rates of additional obstetrical and infant outcomes in pregnant women receiving Tdap; and 3) to describe health outcomes and growth parameters among infants born to women who received Tdap during pregnancy. Maternal serological samples are also being collected at baseline and 28 days after vaccination for immunogenicity analyses. This study is currently ongoing.²⁹

Non-CDC Led Studies on the Safety of Tdap Vaccine in Pregnancy

A phase 1-2 clinical trial assessed the safety and immunogenicity of Tdap vaccine during pregnancy and its effect on infant responses to DTaP vaccine.⁴⁰ The study conducted from 2008 to 2012, enrolled 48 pregnant women aged 18 to 45 years who received Tdap (n = 33) or placebo (n = 15) at 30 to 32 weeks' gestation, with crossover immunization postpartum. No Tdap-associated serious AEs occurred in women or infants. Injection site reactions after Tdap immunization were reported in 26 (78.8% [95% CI, 61.1%–91.0%]) and 12 (80% [95% CI, 51.9%–95.7%]) pregnant and postpartum women, respectively (P > 0.99). Systemic symptoms were reported in 12 [36.4% (95% CI, 20.4%–54.9%)] and 11 (73.3% [95% CI, 44.9%–92.2%]) pregnant and postpartum women, respectively (P = 0.03). Growth and development were assessed to be similar in both infant groups. This preliminary assessment did not find an increased risk of AEs among women who received Tdap vaccine during pregnancy or their infants.

A retrospective cohort study of pregnant women aged 12 to 45 years in a healthcare maintenance organization in Utah from May 2005 through August 2009 assessed pregnancy and infant outcomes following receipt of Tdap vaccine.⁴¹ Among 162,448 pregnancies, 138 women who received Tdap were identified and were compared with an unvaccinated control group of 552 pregnant women. Most of the vaccinated women (63%) received Tdap during the first trimester. The incidence of spontaneous or elective abortion was no greater in Tdap vaccinated than in unvaccinated women (4/138; 2.9% vs. 49/552; 8.9%). There were no significant differences in preterm delivery, gestational age at birth, or birth weight between the groups. Five (3.7%) congenital anomalies were identified among 134 infants exposed to Tdap during pregnancy and 22 (4.4%) of 505 infants born to unvaccinated mothers. No increase in adverse outcomes was identified in infants born to women receiving Tdap compared with infants of unexposed mothers.

An observational cohort study in the UK Clinical Practice Research Datalink examined the safety of pertussis vaccination in 20,074 pregnant women compared to a matched historical unvaccinated control group. The primary outcome of interest in this study was stillbirth, but other predefined AEs of interest occurring in the third trimester were also assessed (maternal and neonatal death, pre-eclampsia and eclampsia, antepartum and postpartum hemorrhage, fetal distress, uterine rupture, placenta previa, vasa previa, caesarean delivery, low birth weight, and neonatal renal failure). Two analyses were done: vaccinated pregnant women were compared to unvaccinated historical controls and all eligible women were compared to unvaccinated controls. No increased risk of stillbirth or of other predefined AEs were observed.⁴²

A retrospective cohort study of pregnant women from June 2013-July 2014 compared pregnancy outcomes among 7,152 women who received Tdap at 32 weeks gestation or later and 226 who declined to receive Tdap.⁴³ There was no difference in stillbirths, major malformations, chorioamnionitis, 5-minute Apgar score, cord blood pH, or rates of neonatal complications. Rates of preterm birth, small for gestational age, and length of neonatal hospitalization were all significantly increased in the unvaccinated group. A subgroup analysis of multiparous women found no difference in neonatal outcomes between women who were given at least 2 doses of Tdap in the past 5 years (N=1,229) and those who received a single dose (N=4,159).

Comment

Rapid, comprehensive, reliable assessment of the safety of the Tdap vaccine during pregnancy was a public health priority after the ACIP made its recommendation for the vaccine's use with every pregnancy. It is important to note that this was the first time a vaccination has been expressly recommended during pregnancy to provide transplacental fetal protection in the United States. In addition, no pre-licensure trials for Tdap were conducted in pregnant women; Tdap is not licensed for repeat doses; and ACIP had not previously recommended repeat doses in other populations. The ACIP recommendation for Tdap vaccination during each pregnancy was based on urgent public health needs, and the information from CDC's complementary, comprehensive and timely domestic surveillance investigations and research was critical in evaluating the vaccine policy and in developing consistent and coherent communication messages to reassure public health officials, providers and the lay public on the risks and benefits of Tdap vaccine in pregnancy. In addition, safety data collected through systems outside CDC were valuable.

To date, 2 years after current recommendations on Tdap vaccination during pregnancy were made, CDC's public health response has done much to address knowledge gaps and increase our understanding of the safety of Tdap vaccine in pregnant women. CDC's findings have been complemented by safety data from non-US government institutions. Results from all monitoring activities point to the safety of Tdap vaccine in pregnancy, providing support to the ACIP recommendations for routine Tdap vaccination of pregnant women. Maternal vaccination offers promise to help protect mothers and infants in the United States and globally and new vaccines, such as the group B Streptococcus vaccine, are in development.⁴⁴ The Tdap vaccine safety monitoring experience, in which multiple systems and partners assessed the safety using diverse methods, may serve as a model for future vaccine safety monitoring efforts in pregnant women.

Table 1. Summary of findings of vaccine safety studies of Tdap in pregnant women

Study	Data Source	Study participants	Study period	Main findings and conclusions
Pichichero et al., 2005 ^32	Women who became pregnant during a prospective, randomized trial of Tdap or Td vaccines	30 women were negative on pregnancy testing at enrollment but became pregnant during the study; 23 pregnant women among 2,936 adolescents and adults receiving Tdap; 7 pregnant women among 1,365 Td recipients	August 2001 – August 2002	• 5 spontaneous abortions and 2 preterm births in Tdap group • 1 therapeutic abortion and 2 preterm births in Td group • 23 newborns were reported normal in both groups
Talbot et al., 2010 ^34	Tdap exposure during a mass vaccination campaign	16 pregnant women among 4,524 healthcare workers vaccinated with Tdap	April 1 – May 31, 2006	• All 16 women gave birth to full-term infants who had normal newborn evaluations.
Wang et al., 2011 ^33	Adacel^® (Tdap) Vaccine Pregnancy Registry – Prospective reports	480 prospective reports	2005 – 2011	• 16 (3.3%) spontaneous abortions and 8 (1.7%) preterm deliveries
Zheteyeva et al, 2012 ^14	VAERS	132 spontaneous reports of pregnant women or their infants exposed to Tdap	2005 – 2010	• 22 spontaneous abortions, 2 preterm births, and one major birth defect (gastroschisis) • No unusual or unexpected pattern of maternal, infant or fetal adverse events
Moro, 2014 ^35	VAERS	90 spontaneous reports of pregnant women or their infants exposed to Tdap	October 2011 – February 2014	• Expected increase in the proportion of certain adverse events observed: stillbirths, preterm deliveries, injection site reactions • No new unexpected vaccine safety concerns were noted among pregnant women who received Tdap
Shakib et al., 2013 ^41	Retrospective cohort from a HMO	From 162,448 pregnancies, 138 Tdap recipients were compared to 552 unvaccinated (controls)	May 2005 – August 2009	• Incidence of spontaneous or elective abortions was no greater in Tdap cases than controls (4/138; 2.9% vs. 49/552; 8.9%) • No significant differences in preterm delivery, small for gestational age, or birth weight between groups • Five (3.7%) major birth defects in 134 infants in Tdap group compared to 22 (4.4%) of 505 infants among controls • No increase in in adverse outcomes noted among infants from Tdap group compared with control infants
Kharbanda et al., 2014 ^36	Retrospective cohort of pregnant women from 2 VSD sites	26,229 pregnant women who received Tdap were compared to 97,265 unvaccinated	2010 – 2012	• Rate of preterm delivery were 6.3% among vaccinated and 7.8% among unvaccinated (adjusted RR, 1.03; 95% CI, 0.97-1.09) • Rate of small for gestational age were 8.4% for vaccinated and 8.3% for unvaccinated (adjusted RR, 1.00; 95% CI, 0.96-1.06) • Chorioamnionitis was diagnosed in 6.1% of vaccinated and 5.5% of unvaccinated women (adjusted RR, 1.19; 95% CI, 1.13-1.26) • Receipt of Tdap during pregnancy was not associated with increased risk of hypertensive disorders of pregnancy or preterm or SGA birth • Small but statistically significant increased risk of chorioamnionitis diagnosis was observed
Muñoz et al., 2014 ^40	Phase 1-2 clinical trial	48 pregnant women enrolled; 33 received Tdap; 15 received placebo with cross-over immunization post-partum	2008 – 2012	• Injection site reactions after Tdap occurred in 26 (78.8%[95%CI, 61.1%–91.0%]) and 12 (80%[95%CI; 51.9-95.7]) pregnant and postpartum women • Systemic symptoms occurred in 12 (36.4%[95% CI; 20.4-54.9]) and 11 (73.3%[95%CI; 44.9-92.2]) pregnant and postpartum women • Growth and development were similar in both infant groups • No increased risk of adverse events was observed among women who received Tdap or their infants
Donegan, 2014 ^42	Retrospective cohort of pregnant women in the UK Clinical Practice Research Datalink	20,074 pregnant women who received DTaP-IPV (Repevax^®) vaccination compared to matched historical unvaccinated control group	October 1, 2012 – March 31, 2013	• Incidence rate ratio of stillbirths 0.69 (95% CI, 0.23 – 1.62) was compared with historical national rates. No increased risk observed • Compared with a matched historical cohort of unvaccinated pregnant women, there was no evidence that vaccination accelerated the time to delivery (hazard ratio 1.00, 0.97 – 1.02) • No evidence of an increased risk of stillbirth, maternal or neonatal death, pre-eclampsia or eclampsia, hemorrhage, fetal distress, uterine rupture, placenta or vasa previa, caesarean delivery, low birth weight, or neonatal renal failure
Morgan, 2015 ^43	Retrospective cohort of pregnant women from a single institution	7,152 pregnant women who received Tdap were compared to 226 who declined Tdap	June 2013 – July 2014	• There was no difference in stillbirths, major malformations, chorioamnionitis, 5-minute Apgar score, or cord blood pH • Rates of neonatal complications (e.g., ventitaltion requirement, sepsis, intraventricular hemorrhage, neonatal death) were also similar • Preterm birth rates at ≤ 36 weeks (6% compared to 12%, P<0.001), incidence of small for gestational age (10% compared with 15%, P=0.03), and length of neonatal hospitalization (3.9 compared to 4.7 days, P<0.001) were all significantly increased in the unvaccinated group • No difference in neonatal outcomes was noted between women who were given at least 2 doses of Tdap in the past 5 years (N=1,229) and those who received a single dose (N=4,159)

^† VAERS = Vaccine Adverse Event Reporting System; VSD= Vaccine Safety Datalink.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Disclaimer

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention (CDC).

Acknowledgments

We are especially thankful to Dr. Frank DeStefano for a thorough review of the manuscript and for providing valuable comments in its development. We also thank VAERS, VSD, and CISA colleagues for their work in monitoring the safety of Tdap vaccine in pregnant women.

Funding

Dr. Lakshmi Sukumaran was funded as a Vaccine Safety Fellow by the National Institutes of Health award number T32AI074492.