Safety of tetanus, diphtheria, and acellular pertussis vaccination among pregnant active duty U.S. military women

Vaccine xxx (xxxx) xxx

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Safety of tetanus, diphtheria, and acellular pertussis vaccination among pregnant active duty U.S. military women Clinton Hall a,b,⇑, Lisa M. Abramovitz a,b, Anna T. Bukowinski a,b, Ashley A. Ricker b,c, Zeina G. Khodr a,b, Gia R. Gumbs a,b, Natalie Y. Wells b, Ava Marie S. Conlin b a b c

Leidos, Inc., 140 Sylvester Road, San Diego, CA 92106, USA Deployment Health Research Department, Naval Health Research Center, 140 Sylvester Road, San Diego, CA 92106, USA Innovative Employee Solutions, 140 Sylvester Road, San Diego, CA 92106, USA

a r t i c l e

i n f o

Article history: Received 30 October 2019 Received in revised form 1 January 2020 Accepted 4 January 2020 Available online xxxx Keywords: Vaccine safety Pregnancy Tdap Maternal immunization Military

a b s t r a c t Background: The tetanus, diphtheria, and acellular pertussis (Tdap) vaccine was approved for U.S. adults in 2005 and recommended for administration in every pregnancy in 2012, with optimal timing between 27 and 36 weeks’ gestation. In the military, however, a current Tdap vaccination status is compulsory for service, and active duty women may be inadvertently exposed in early pregnancy. Safety data in this population are limited. Objectives: To assess safety of inadvertent (0–13 weeks’ gestation) and recommended (27–36 weeks’ gestation) exposure to the Tdap vaccine in pregnancy. Methods: Pregnancies and live births from Department of Defense Birth and Infant Health Research program data were linked with military personnel immunization records to determine pregnancy Tdap vaccine exposure among active duty women, 2006–2014. Multivariable Cox and generalized linear regression models estimated associations between Tdap vaccine exposure and adverse pregnancy or infant outcomes. Results: Of 145,883 pregnancies, 1272 were exposed to the Tdap vaccine in the first trimester and 9438 between 27 and 36 weeks’ gestation. Neither inadvertent nor recommended vaccine exposure were associated with spontaneous abortion, preeclampsia, or preterm labor. Among 117,724 live born infants, 984 were exposed to the Tdap vaccine in the first trimester and 9352 between 27 and 36 weeks’ gestation. First trimester exposure was not associated with birth defects, growth problems in utero, growth problems in infancy, preterm birth, or low birth weight. Tdap vaccine exposure between 27 and 36 weeks’ gestation was not associated with any adverse infant outcome. Conclusions: Among a population of active duty women in the U.S. military who received the Tdap vaccine during pregnancy, we detected no increased risks for adverse maternal, fetal, or infant outcomes. Our findings corroborate existing literature on the safety of exposure to the Tdap vaccine in pregnancy. Ó 2020 Elsevier Ltd. All rights reserved.

1. Introduction Pertussis is a highly contagious respiratory infection associated with infant morbidity and mortality [1]; however, the vaccination series against pertussis is not routinely initiated until two months of age. Beginning October 2012, the Advisory Committee on Immunization Practices (ACIP) recommended that pregnant women receive the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine between 27 and 36 weeks’ gestation for every pregnancy, regardless of whether they received a pre⇑ Corresponding author at: Deployment Health Research Department, Naval Health Research Center, 140 Sylvester Road, San Diego, CA 92106-3521, USA. E-mail address: [email protected] (C. Hall).

pregnancy Tdap vaccine [2]. This approach increases transplacental passive immunity and effectively reduces infant risk for pertussis infection [3–12]. Existing safety studies have not detected any clinically meaningful associations with exposure to the Tdap vaccine during pregnancy and adverse maternal, fetal, or infant outcomes [13–26], but few have examined inadvertent exposures in early pregnancy [24– 26]. In the U.S. military, a current Tdap vaccination status is compulsory for service. Consequently, military women may be more likely than civilian women to be inadvertently exposed in early pregnancy, but safety evidence in this population is lacking. Using a linked database of administrative medical claims and military personnel data, this study assessed the safety of Tdap vaccine exposure among a cohort of pregnant active duty women in

https://doi.org/10.1016/j.vaccine.2020.01.009 0264-410X/Ó 2020 Elsevier Ltd. All rights reserved.

Please cite this article as: C. Hall, L. M. Abramovitz, A. T. Bukowinski et al., Safety of tetanus, diphtheria, and acellular pertussis vaccination among pregnant active duty U.S. military women, Vaccine, https://doi.org/10.1016/j.vaccine.2020.01.009

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C. Hall et al. / Vaccine xxx (xxxx) xxx

the U.S. military. We examined associations with select adverse maternal, fetal, and infant outcomes, focusing on inadvertent (0– 13 weeks’ gestation) and recommended (27–36 weeks’ gestation) Tdap vaccine exposure during pregnancy. 2. Materials and methods 2.1. Data sources and study population This study utilized data from the Department of Defense Birth and Infant Health Research (BIHR) program, which identifies pregnancies, live births, and associated health outcomes among TRICARE beneficiaries (i.e., those enrolled in the Military Health System [MHS]). Methods for developing BIHR data have been described in detail elsewhere [27]. Briefly, demographic and military personnel data are obtained from the Defense Manpower Data Center (DMDC) and linked with electronic administrative encounter data extracted from the MHS Data Repository, which includes all care covered by TRICARE at both domestic and overseas duty locations. Medical encounter records are coded with International Classification of Diseases, Ninth/Tenth Revision, Clinical Modification (ICD-9/10-CM) diagnostic and procedure codes and Current Procedural Terminology (CPT) codes, which are used to identify pregnancies and define outcomes during pregnancy and through an infant’s first year of life. In this study, ICD-10-CM codes are only used for infant encounters October–December 2015. Same-sex multiples are excluded from BIHR data due to difficulties distinguishing their neonatal records. For pregnancies ending in a live birth, estimated gestational age (EGA) is derived from ICD codes, and estimated date of last menstrual period (LMP) is calculated by subtracting EGA from delivery date. For pregnancies ending in a loss, LMP is estimated by subtracting the median number of days between LMP and start of pregnancy care for live births from the pregnancy loss case’s earliest date of pregnancy care. EGA of pregnancy losses is then determined by calculating the difference between estimated LMP and pregnancy end date. For all pregnancies, estimated date of conception is calculated by adding 2 weeks to date of LMP. This study assessed separate pregnancy and infant populations. Because the Tdap vaccine was approved for use in adults in 2005 [28], the pregnancy population included pregnancies from 2006 to 2014 among military women who were on active duty status for the duration of their pregnancy. Pregnancies for which outcomes could not be ascertained were excluded from analyses (‘‘unknown outcomes”), as were ectopic and molar pregnancies, pregnancies ending in elective abortions, pregnancies in which women received more than one Tdap vaccine, and multiple gestations. Unknown outcomes include pregnancies that could not be defined as live deliveries or losses due to loss to follow-up (e.g., the woman did not stay enrolled in TRICARE or discontinued pregnancy care) or conflicting pregnancy data (e.g., implausible time between pregnancies, indication of a pregnancy loss with subsequent continuing pregnancy care and no additional information on outcome). The infant population was derived from resulting live born singletons who were also captured in BIHR data. This study was approved by the institutional review board at the Naval Health Research Center (protocol number NHRC.2013.0015), and informed consent was waived in accordance with 32 CFR § 219.116(d). 2.2. Exposure Two mutually exclusive Tdap exposure windows were assessed: inadvertent exposure (receipt of the Tdap vaccine between 0 and 13 weeks’ gestation, i.e., the first trimester) and rec-

ommended exposure (receipt of the Tdap vaccine between 27 and 36 weeks’ gestation). Maternal military vaccination history was ascertained from DMDC immunization data; Tdap vaccine exposure was identified by the vaccine administered code 115. 2.3. Pregnancy outcomes Adverse pregnancy outcomes of interest were preeclampsia, preterm labor, and spontaneous abortion. Case definitions for preeclampsia and preterm labor in this population have been described previously [29]. Spontaneous abortions were identified from maternal inpatient and outpatient records on or before 22 weeks’ EGA, using ICD-9-CM codes for missed or spontaneous abortion (632 and 634.xx), and/or CPT codes for treatment of incomplete, missed, or septic abortion (59812, 59820, 59821, 59830). If diagnosis codes for other loss types (e.g., stillbirth) appeared on the same record, the loss was not considered a spontaneous abortion. 2.4. Infant outcomes Adverse infant outcomes of interest were low birth weight (LBW; birth weight under 2500 g), preterm birth (birth before 37 weeks’ gestation), growth problems in utero, growth problems in infancy, and major birth defects. Infant sex was also assessed as an indicator of overall reproductive health [30]. Methods for defining LBW and preterm birth in this population have been previously described [31]. Growth problems in utero were defined by ICD-9-CM codes in infant records indicating slow fetal growth and fetal malnutrition (764.xx). Growth problems in infancy were defined by ICD-9/10-CM codes in infant records indicating failure to thrive (ICD-9-CM codes 779.34, 783.41; ICD-10-CM codes P92.6, R62.51), lack of normal physiological development (ICD-9CM code 783.40; ICD-10-CM codes R62.50, R62.59), or short stature (ICD-9-CM code 783.43; ICD-10-CM code R62.52). Major birth defects were selected for inclusion in analyses based on definitions from the Vaccine Safety Datalink and the National Birth Defects Prevention Network [32,33], in combination with input from a physician (A.S.C.) and a certified medical coder (see Supplementary Table 1 for ICD-9/10-CM codes and details); categories of birth defects required relevant diagnoses in the first year of life, either on one inpatient record or two outpatient records on different days. Major birth defects were assessed overall and by affected organ system as sample size allowed. 2.5. Statistical analyses Frequencies and percentages were calculated to describe select maternal characteristics for the pregnancy and infant study populations, stratified by Tdap vaccine exposure status (none, vaccinated 0–13 weeks’ gestation [first trimester, inadvertent], or vaccinated 27–36 weeks’ gestation [recommended]). The analytic approach differed by the outcome under study. Time-dependent Cox proportional hazards models, using EGA as the time scale and left truncated at the start of pregnancy care, were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all pregnancy outcomes and infant preterm birth. For analyses of maternal preterm labor and infant preterm birth, observations were censored at the outcome date or 37 weeks’ gestation. For analyses of spontaneous abortion, observations were censored at the outcome date or 22 weeks’ gestation. Because preeclampsia does not typically develop until 20 weeks’ gestation, pregnancies that ended prior to 20 weeks’ gestation were excluded from those analyses. A Poisson regression with robust error variance was used to estimate risk ratios (RRs) and 95% CIs for analyses of LBW, growth problems in utero, growth problems in infancy,

Please cite this article as: C. Hall, L. M. Abramovitz, A. T. Bukowinski et al., Safety of tetanus, diphtheria, and acellular pertussis vaccination among pregnant active duty U.S. military women, Vaccine, https://doi.org/10.1016/j.vaccine.2020.01.009

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and birth defects [34]. A log-binomial regression estimated RRs for analyses of male infant sex. For spontaneous abortion and birth defect models, only first trimester exposure was assessed. For all analyses and each exposure window, Tdap vaccine exposure was assessed dichotomously. For all models, the reference group consisted of women who did not receive the Tdap vaccine during pregnancy. Women who received the Tdap vaccine in pregnancy, but not during the time windows of interest, were excluded from respective analyses (i.e., between weeks 14 and 26, or in week 37 and later). Potential confounding variables were assessed based on a priori knowledge and associations observed in previous BIHR program studies [3,35,36]. Most multivariable models adjusted for the same covariate set: maternal age at conception (continuous), marital status (married or unmarried/unknown), military rank (enlisted or officer), military service branch (Army, Navy, Air Force, Marine Corps, or Coast Guard), and receipt of vaccines not routinely recommended in pregnancy (yes or no), which was included as a proxy for lack of pregnancy recognition (see Supplementary Table 2 for details). Analyses of all pregnancy outcomes and infant preterm birth modeled receipt of vaccines not routinely recommended in pregnancy as time varying, otherwise it was assessed dichoto-

mously. In this population, prevalence of birth defects, growth problems in utero, and growth problems in infancy increased over time; therefore, respective analyses additionally adjusted for infant birth year. For all other outcomes under study, we considered adjustment for year of pregnancy outcome due to changes in Tdap recommendations over time, but estimates did not change by more than 10% so this variable was left out of final models. Analyses of infant male sex only adjusted for maternal age due to limited a priori knowledge of risk factors for altered offspring sex ratios. All statistical analyses were performed using SAS, version 9.4 (SAS Institute Inc., Cary, NC, USA).

3. Results 3.1. Population characteristics After exclusions, the analytic population included 145,883 pregnancies identified among active duty women, 2006–2014 (Fig. 1). Of these, 1272 (0.9%) were exposed to the Tdap vaccine during the first trimester, and 9438 (6.5%) during 27–36 weeks’ gestation. The prevalence of first trimester exposure ranged from

279,929 pregnancies to active duty women, 2002–2015

134,046 Excluded 82,703 pregnancies that started before 1 Jan 2006 or after 31 Dec 2014 39,978 pregnancies with unknown outcomes 7021 ectopic or molar pregnancies 1915 known elective abortions 2194 pregnancies that resulted in multiples 235 pregnancies where women received more than one Tdap vaccine

117,724 infants born to women whose pregnancies resulted in live births

145,883 pregnancies to active duty women, 2006–2014

131,450 No Tdap vaccine exposure during pregnancy

14,433 Tdap vaccine exposure during pregnancy

1272 vaccinated between 0–13 weeks’ gestation

9438 vaccinated between 27–36 weeks’ gestation

103,729 No Tdap vaccine exposure during mother’s

13,995 Tdap vaccine exposure during mother’s pregnancy

984 vaccinated between 0–13 weeks’ gestation

9352 vaccinated between 27–36 weeks’ gestation

Fig. 1. Study population flowchart detailing pregnancies and exclusions among active duty U.S. military women, Department of Defense Birth and Infant Health Research Program, 2006–2014.

Please cite this article as: C. Hall, L. M. Abramovitz, A. T. Bukowinski et al., Safety of tetanus, diphtheria, and acellular pertussis vaccination among pregnant active duty U.S. military women, Vaccine, https://doi.org/10.1016/j.vaccine.2020.01.009

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Tdap vaccine prior to pregnancy, while women exposed during 27–36 weeks’ gestation were more likely to have received a Tdap vaccine prior to pregnancy and less likely to have received a vaccine not routinely recommended in pregnancy. Women vaccinated during 27–36 weeks’ gestation were more likely to initiate prenatal care in the first trimester compared with unvaccinated women, while women vaccinated in the first trimester were less likely.

0.3% to 2.0% over the study period, while the prevalence of exposure during 27–36 weeks’ gestation increased from <1.0% before 2012 to 40.0% for pregnancies that ended in 2014. Of 117,724 identified infants, 984 (0.8%) had mothers who received the Tdap vaccine during the first trimester, and 9352 (7.9%) during 27–36 weeks’ gestation. Compared with women not exposed to the Tdap vaccine in pregnancy, women exposed in the first trimester or between 27 and 36 weeks’ gestation were older and more likely to be married, military officers, or in a healthcare occupation (Table 1). The distribution of race/ethnicity was similar for all vaccination groups. Women vaccinated in the first trimester were more likely to be in the Air Force, in a healthcare occupation, and exposed to a vaccine not routinely recommended in pregnancy compared with women vaccinated during 27–36 weeks’ gestation. Compared with women unexposed to the Tdap vaccine during pregnancy, women exposed in the first trimester were less likely to have received a

3.2. Multivariable analyses Receipt of the Tdap vaccine during either pregnancy exposure window was not associated with an increased risk for preeclampsia or preterm labor (Table 2). In unadjusted models, first trimester exposure to the Tdap vaccine was associated with a 15% increased risk for spontaneous abortion (HR = 1.15, 95% CI = 1.05–1.30), but this association was attenuated after adjustment for maternal demographic characteristics (i.e., age, marital status, military rank,

Table 1 Characteristics of the U.S. active duty military female study population and live born infants, stratified by tetanus, diphtheria, and acellular pertussis (Tdap) vaccine exposure status during pregnancy, Department of Defense Birth and Infant Health Research Program, 2006–2014. Tdap vaccine exposure status and timing during pregnancy Pregnancies (N = 145,883)

Infants (N = 117,724)

Unvaccinated (N = 131,450)

Vaccinated, 0– 13 weeks’ gestation (N = 1272)

Vaccinated, 27–36 weeks’ gestation (N = 9438)

Unvaccinated (N = 103,729)

Vaccinated, 0–13 weeks’ gestation (N = 984)

Vaccinated, 27–36 weeks’ gestation (N = 9352)

Maternal characteristics

N

(%)

N

(%)

N

(%)

N

(%)

N

(%)

N

(%)

Age at conception (years) 17–24 25–29 30–34 35+

65,574 36,780 19,378 9718

(49.9) (28.0) (14.7) (7.4)

299 572 260 141

(23.5) (45.0) (20.4) (11.1)

3949 2900 1868 721

(41.8) (30.7) (19.8) (7.6)

52,437 29,582 15,237 6473

(50.6) (28.5) (14.7) (6.2)

247 447 201 89

(25.1) (45.4) (20.4) (9.0)

3917 2861 1859 715

(41.9) (30.6) (19.9) (7.7)

Race/ethnicity White non-Hispanic Black non-Hispanic Hispanic Other/unknown

62,833 35,215 18,350 15,052

(47.8) (26.8) (14.0) (11.5)

625 348 148 151

(49.1) (27.4) (11.6) (11.9)

4446 2200 1362 1430

(47.1) (23.3) (14.4) (15.2)

50,018 27,354 14,383 11,974

(48.2) (26.4) (13.9) (11.5)

495 258 109 122

(50.3) (26.2) (11.1) (12.4)

4407 2179 1349 1417

(47.1) (23.3) (14.4) (15.2)

Marital status Not married Married

37,821 93,629

(28.8) (71.2)

319 953

(25.1) (75.0)

2169 7269

(23.0) (77.0)

27,561 76,168

(26.6) (73.4)

222 762

(22.6) (77.4)

2158 7194

(23.1) (76.9)

Service branch Army Navy Air Force Marine Corps Coast Guard

47,158 32,560 37,983 10,485 3264

(35.9) (24.8) (28.9) (8.0) (2.5)

421 200 580 46 25

(33.1) (15.7) (45.6) (3.6) (2.0)

3031 3139 2331 823 114

(32.1) (33.3) (24.7) (8.7) (1.2)

36,128 25,918 30,570 8416 2697

(34.8) (25.0) (29.5) (8.1) (2.6)

320 157 456 32 19

(32.5) (16.0) (46.3) (3.3) (1.9)

3006 3111 2311 811 113

(32.1) (33.3) (24.7) (8.7) (1.2)

Military rank Enlisted Officer

113,606 17,844

(86.4) (13.6)

988 284

(77.7) (22.3)

7695 1743

(81.5) (18.5)

89,620 14,109

(86.4) (13.6)

764 220

(77.6) (22.4)

7627 1725

(81.6) (18.5)

Military occupation Healthcare Combat Other/unknown

24,562 7561 99,327

(18.7) (5.8) (75.6)

387 65 820

(30.4) (5.1) (64.5)

2018 560 6860

(21.4) (5.9) (72.7)

19,353 5961 78,415

(18.7) (5.8) (75.6)

309 52 623

(31.4) (5.3) (63.3)

2000 553 6799

(21.4) (5.9) (72.7)

Timing of Tdap vaccine exposure prior to pregnancy None 72,157 <1 year 17,749 1–<3 years 28,299 3–5 years 10,419 >5 years 2826

(54.9) (13.5) (21.5) (7.9) (2.2)

1222 17 23 8 2

(96.1) (1.3) (1.8) (0.6) (0.2)

1406 1370 3599 1993 1070

(14.9) (14.5) (38.1) (21.1) (11.3)

58,389 13,951 21,902 7652 1835

(56.3) (13.5) (21.1) (7.4) (1.8)

947 10 20 7 0

(96.2) (1.0) (2.0) (0.7) (0.0)

1394 1355 3565 1976 1062

(14.9) (14.5) (38.1) (21.1) (11.4)

Receipt of vaccines not routinely recommended in pregnancy No 115,386 (87.8) Yes 16,064 (12.2)

1001 271

(78.7) (21.3)

8580 858

(90.9) (9.1)

90,176 13,553

(86.9) (13.1)

768 216

(78.1) (22.0)

8501 851

(90.9) (9.1)

First trimester initiation of prenatal care No Yes Estimated gestational age (days) at start of pregnancy care, mean ± standard deviation

9529 (7.2) 121,921 (92.8) 55.3 ± 26.5

106 (8.3) 1166 (91.7) 56.5 ± 25.3

577 (6.1) 8861 (93.9) 52.9 ± 23.9

9334 (9.0) 94,395 (91.0) 55.8 ± 29.4

102 (10.4) 882 (89.6) 57.2 ± 28.2

572 (6.1) 8780 (93.9) 52.9 ± 23.9

Please cite this article as: C. Hall, L. M. Abramovitz, A. T. Bukowinski et al., Safety of tetanus, diphtheria, and acellular pertussis vaccination among pregnant active duty U.S. military women, Vaccine, https://doi.org/10.1016/j.vaccine.2020.01.009

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Table 2 Hazard ratios and 95% confidence intervals for maternal tetanus, diphtheria, and acellular pertussis (Tdap) vaccine exposure during pregnancy and adverse pregnancy outcomes, Department of Defense Birth and Infant Health Research program, 2006–2014. Maternal outcomes

Timing of Tdap vaccine exposure in pregnancy 0–13 weeks’ gestation

Preeclampsia Preterm labor Spontaneous abortion

27–36 weeks’ gestation

Unexposed Case N (%)

Exposed Case N (%)

HRa (95% CI)

aHRb (95% CI)

Unexposed Case N (%)

Exposed Case N (%)

HRa (95% CI)

aHRb (95% CI)

5949 (5.6) 8099 (7.7) 22,931 (17.6)

54 (5.3) 68 (6.7) 233 (18.6)

0.95 (0.72–1.24) 0.88 (0.69–1.11) 1.15 (1.01–1.30)

1.02 (0.78–1.34) 0.94 (0.74–1.19) 1.07 (0.94–1.22)

5963 (5.6) 8160 (7.7) –

494 (5.3) 463 (4.9) –

1.00 (0.92–1.10) 0.93 (0.85–1.02) –

1.07 (0.97–1.17) 0.97 (0.88–1.07) –

a

Unadjusted models. Multivariable models adjusted for maternal age at conception, marital status, military rank, military service branch, and receipt of vaccines not routinely recommended in pregnancy. b

and military service branch) and receipt of vaccines not routinely recommended in pregnancy (HR = 1.07, 95% CI = 0.94–1.22). First trimester exposure to the Tdap vaccine was not associated with infant preterm birth, LBW, growth problems in utero, growth problems in infancy, or birth defects (Table 3). For infants whose mothers received the Tdap vaccine in the first trimester, 54.8% were male compared with 51.3% of infants whose mothers did not receive the Tdap vaccine in pregnancy (adjusted RR = 1.07, 95% CI = 1.01–1.13). Maternal exposure to the Tdap vaccine during 27–36 weeks’ gestation was not associated with infant preterm birth, LBW, or male sex. Unadjusted models estimated positive associations between receipt of the Tdap vaccine during 27– 36 weeks’ gestation and growth problems in utero as well as growth problems in infancy, but these associations were fully attenuated in adjusted models (RR = 1.03, 95% CI = 0.91–1.16 and RR = 0.95, 95% CI = 0.85–1.06, respectively).

4. Discussion In this large, administrative claims-based study of active duty women in the U.S. military, we detected no clinically meaningful associations between Tdap vaccine exposure in pregnancy and adverse maternal, fetal, or infant outcomes. These findings corroborate existing studies of Tdap vaccination in pregnancy [13–26]. Our study is novel in that it assessed the safety of in-pregnancy Tdap vaccine exposure among active duty women in the U.S. military, a population for which a current Tdap vaccination status is compulsory. Further, our study is one of few to specifically assess the safety of Tdap vaccine exposure in early pregnancy (0–13 weeks’ gestation).

DeSilva et al. also examined the association between first trimester Tdap vaccine exposure (defined as <14 weeks’ gestation) and infant birth defects, and no increased risks were detected [24]. Similar to our study, DeSilva et al. used diagnostic codes from administrative claims data to identify birth defect cases [33]. While our case definition has specificity than DeSilva et al. because we did not employ outcome-specific algorithms, we did not observe an increased risk for infant birth defects among women exposed to the Tdap vaccine during 0–13 weeks’ gestation. Our results corroborate DeSilva et al. and other existing studies that assessed infant birth defects and Tdap vaccination in pregnancy [19–25]. Based on data from May 2005 through August 2009 (i.e., before the current ACIP recommendations were implemented), Shakib et al. reported that among 138 women exposed to the Tdap vaccine during pregnancy, 87 (63%) were vaccinated in the first trimester [25]. While associations with first trimester exposure were not separately assessed, Shakib et al. reported no differences in preterm delivery, gestational age, or birth weight by exposure status. Further, a lower prevalence of spontaneous abortions and congenital anomalies was found among women exposed to the Tdap vaccine compared with controls. In our study, a slightly higher percentage of women with first trimester Tdap vaccine exposure experienced a spontaneous abortion or gave birth to an infant with a birth defect compared with unexposed women, but our regression-based analyses did not demonstrate that exposure increased risks for these outcomes. Layton et al., using more recent data (2010–2014) from a large insurance claims database, separately assessed ‘‘early prenatal” Tdap vaccine exposure, defined as receipt of the Tdap vaccine before 27 weeks’ gestation [26]. Modest positive associations were

Table 3 Relative risks and 95% confidence intervals for maternal tetanus, diphtheria, and acellular pertussis (Tdap) vaccine exposure during pregnancy and adverse infant outcomes, Department of Defense Birth and Infant Health Research program, 2006–2014. Infant outcomes

Preterm birthc Growth problems in uterod Growth problems in infancyd Low birth weight Male sexe Any major structural birth defectd Cardiovascular birth defectsd Genitourinary birth defectsd

Timing of Tdap vaccine exposure in pregnancy Unexposed

0–13 weeks’ gestation

Case N (%)

Case N (%)

RRa (95% CI)

aRRb (95% CI)

Case N (%)

RRa (95% CI)

aRRb (95% CI)

8421 (8.1) 3316 (3.2) 3840 (3.7) 5111 (4.9) 53,168 (51.3) 3091 (3.0) 990 (1.0) 1261 (1.2)

60 (6.1) 25 (2.5) 33 (3.4) 33 (3.4) 539 (54.8) 33 (3.4) 11 (1.1) 15 (1.5)

0.74 0.80 0.91 0.68 1.07 1.13 1.17 1.25

0.77 0.85 0.85 0.71 1.07 1.15 1.15 1.28

569 (6.1) 408 (4.4) 526 (5.6) 318 (3.4) 4754 (50.8) – – –

0.91 1.37 1.52 0.69 0.99 – – –

0.95 1.03 0.95 0.69 0.99 – – –

(0.58–0.96) (0.54–1.17) (0.65–1.27) (0.49–0.95) (1.01–1.13) (0.80–1.58) (0.65–2.12) (0.76–2.08)

27–36 weeks’ gestation

(0.60–0.99) (0.58–1.25) (0.61–1.20) (0.51–0.99) (1.01–1.13) (0.82–1.61) (0.63–2.08) (0.77–2.12)

(0.84–1.00) (1.23–1.51) (1.39–1.66) (0.62–0.77) (0.97–1.01)

(0.87–1.04) (0.91–1.16) (0.85–1.06) (0.61–0.77) (0.97–1.01)

a

Unadjusted models. Multivariable models adjusted for maternal age at conception, marital status, military rank, military service branch, and receipt of vaccines not routinely recommended in pregnancy. c Hazard ratios are presented for preterm birth. d Multivariable models additionally adjusted for infant birth year. e Multivariable model only adjusted for maternal age at conception. b

Please cite this article as: C. Hall, L. M. Abramovitz, A. T. Bukowinski et al., Safety of tetanus, diphtheria, and acellular pertussis vaccination among pregnant active duty U.S. military women, Vaccine, https://doi.org/10.1016/j.vaccine.2020.01.009

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estimated with chorioamnionitis (RR = 1.19, 95% CI = 1.11–1.28), premature rupture of membranes (RR = 1.08, 95% CI = 1.02–1.15), and postpartum hemorrhage (RR = 1.34, 95% CI = 1.23–1.44). While we did not study these outcomes, Layton et al. called for a cautious interpretation of their findings because receipt of the Tdap vaccine prior to the recommended timing might indicate atypical care or anticipated premature birth [26]. However, similar to our study, Layton et al. did not observe an increased risk for preeclampsia with early prenatal exposure, nor did they estimate positive associations between early prenatal exposure and any adverse infant outcome in fully adjusted analyses. In our study, the only potentially adverse signal detected was a higher proportion of male infants born to women with Tdap vaccine exposure in early pregnancy—54.8% of births to these women were male, compared with 50.8% among women vaccinated during 27–36 weeks’ gestation and 51.3% among women not vaccinated during pregnancy (of all U.S. births 2007–2017, 51.2% were male [37]). However, the magnitude of the observed association was small (RR = 1.07) and the finding itself is not clinically meaningful. Because the sex ratio at birth is a relatively stable measure [30], there are suggestions that a skewed offspring sex ratio is indicative of exposure to reproductive hazards. However, affected sex ratios are typically female-biased, as male fetuses are more vulnerable to adverse environmental stressors [38]. If Tdap vaccine exposure in early pregnancy were a reproductive hazard, we might expect to observe a preponderance of female live births in addition to increased risks for adverse outcomes such as spontaneous abortions and/or birth defects, but we did not. Given the relatively small number of women who received the Tdap vaccine between 0 and 13 weeks’ gestation in this study, the association we observed with male infant sex is likely due to chance. Because this study relied on administrative data, exposure and outcome status are misclassified to a certain extent. While formal validation efforts have not been conducted for all variables of interest, a previous study by our group showed that ICD-9-CM codes provide an accurate assessment of birth weight and gestational age in this military population [39]. For pregnancies that end in a live birth, this also indicates that estimated date of LMP (and therefore the exposure window used for assessment) is also fairly accurate, as it is derived from gestational age as coded in medical claims data. However, pregnancies that do not end in a live birth have not been validated, so the accuracy of estimated date of LMP for pregnancy losses is unknown. Additionally, we were unable to conduct a clinical review of spontaneous abortion cases and therefore could not determine the precise date of fetal demise; Tdap vaccine exposure may have occurred after the actual date of fetal death for some cases. Also, it is possible that spontaneous abortion was diagnosed even though alternate diagnoses (e.g., chemical pregnancy) could not be ruled out; however, we attempted to limit such misclassification by excluding cases from being considered a spontaneous abortion if diagnostic/procedure codes for other loss types appeared on the same record. We also lacked information on some potential confounders, such as maternal smoking and alcohol use during pregnancy. This could have differentially biased our results away from the null as inadvertent vaccination may be positively associated with these factors while recommended vaccination may be negatively associated; however, we tried to control for behaviors associated with unrecognized pregnancy by adjusting for a proxy, i.e., receipt of vaccines not routinely recommended in pregnancy. Further, our results for recommended Tdap vaccine exposure may be subject to healthy user bias as women who adhere to ACIP guidelines might be more likely to comply with other healthy recommended behaviors (e.g., vitamin supplementation) that could induce or inflate protective associations. Lastly, our outcomes of growth problems in utero and major birth defects were only assessed

among live born infants, which is a limitation as some pregnancies affected by these conditions may have ended in an adverse outcome. Our study was strengthened by the availability of detailed immunization records for active duty personnel, which allowed us to ascertain information on the timing of Tdap vaccine exposure during pregnancy and adjust for other vaccines administered during pregnancy. Additionally, we employed appropriate analytic approaches that were dependent on the outcome under study. For example, for analyses of fetal loss, we used a time-varying survival analysis model that was left truncated at the start of pregnancy care. Because women present for pregnancy care at different gestational ages—and because an unknown proportion of the source population will experience a pregnancy loss prior to presenting for care—women whose pregnancies ended in a live birth had a greater opportunity to be included in our study [40]. Because we only had visibility of pregnancy losses for which TRICARE-covered care was sought, accounting for time under observation in a left truncated model minimized bias related to differential presentation for care by outcome status. This model also minimized bias introduced by differential presentation for care by exposure status, which would have mostly affected analyses of first trimester Tdap vaccine exposure. 5. Conclusions Our findings add to an established body of literature that has demonstrated the safety of Tdap vaccination in pregnancy. Because a current Tdap vaccination status is compulsory for military service, our results are reassuring for active duty military women in particular, as they may be more likely than civilian women to be inadvertently exposed in early pregnancy. 6. Disclaimer I am a military service member or employee of the U.S. Government. This work was prepared as part of my official duties. Title 17, U.S.C. §105 provides that copyright protection under this title is not available for any work of the U.S. Government. Title 17, U.S.C. §101 defines a U.S. Government work as work prepared by a military service member or employee of the U.S. Government as part of that person’s official duties. Report No. 19–74 was supported by the U.S. Navy Bureau of Medicine and Surgery under work unit no. 60504 and the Defense Health Agency Immunization Healthcare Division (proposal ID#42). The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the U.S. Government. The study protocol was approved by the Naval Health Research Center Institutional Review Board in compliance with all applicable Federal regulations governing the protection of human subjects. Research data were derived from an approved Naval Health Research Center Institutional Review Board protocol, number NHRC.2013.0015. CRediT authorship contribution statement Clinton Hall: Methodology, Formal analysis, Writing - original draft. Lisa M. Abramovitz: Methodology, Formal analysis, Writing - original draft. Anna T. Bukowinski: Methodology, Writing review & editing. Ashley A. Ricker: Methodology, Writing - review & editing. Zeina G. Khodr: Methodology, Writing - review & editing. Gia R. Gumbs: Writing - review & editing, Project administration. Natalie Y. Wells: Writing - review & editing. Ava

Please cite this article as: C. Hall, L. M. Abramovitz, A. T. Bukowinski et al., Safety of tetanus, diphtheria, and acellular pertussis vaccination among pregnant active duty U.S. military women, Vaccine, https://doi.org/10.1016/j.vaccine.2020.01.009

C. Hall et al. / Vaccine xxx (xxxx) xxx

Marie S. Conlin: Conceptualization, Writing - review & editing, Supervision.

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Declaration of Competing Interest [17]

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Acknowledgement We would like to acknowledge Katherine J. Snell, BS, from the Department of Defense Birth and Infant Health Research program, for her contributions to this study. Appendix A. Supplementary material

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Supplementary data to this article can be found online at https://doi.org/10.1016/j.vaccine.2020.01.009.

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Please cite this article as: C. Hall, L. M. Abramovitz, A. T. Bukowinski et al., Safety of tetanus, diphtheria, and acellular pertussis vaccination among pregnant active duty U.S. military women, Vaccine, https://doi.org/10.1016/j.vaccine.2020.01.009