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DeSilva M, Vazquez-Benitez G, Nordin JD, et al. Tdap Vaccination During Pregnancy and Microcephaly and Other Structural Birth Defects in Offspring. JAMA. 2016;316(17):1823–1825. doi:10.1001/jama.2016.14432
Copyright 2016 American Medical Association. All Rights Reserved.
In 2012, the US Advisory Committee on Immunization Practices recommended tetanus, diphtheria, and acellular pertussis (Tdap) vaccine be administered during every pregnancy, ideally between 27 and 36 weeks’ gestation.1 Previously, Tdap was recommended for unvaccinated pregnant women since 2010 in California and since 2011 across the United States.
Cases of microcephaly in Brazil increased substantially during 2015, likely associated with maternal Zika virus infections. However, these cases overlapped with the November 2014 initiation of Brazil’s maternal Tdap program.2 Previous small observational studies reported no increased risks for birth defects following maternal Tdap vaccination; none focused on microcephaly.3 This large study examined associations between maternal Tdap vaccination and structural birth defects, including microcephaly, in offspring.
This study was approved by all sites’ institutional review boards and the Centers for Disease Control and Prevention (CDC), with waivers of informed consent. This retrospective cohort study of singleton live births at 7 Vaccine Safety Datalink (VSD)4 sites (Northern California, Southern California, Colorado, Minnesota, Oregon, Washington, and Wisconsin) from January 1, 2007, through September 30, 2013, compared prevalence of structural birth defects between infants born to women who received Tdap during pregnancy and unvaccinated women. VSD, a collaboration between the CDC and several health care organizations, conducts postmarketing safety evaluations for vaccines administered in the United States.4
Pregnancies were identified from electronic health care data using a validated algorithm.5 Women were required to be continuously insured from 6 months prior to their last menstrual period through 6 weeks postpartum, with 1 or more outpatient visit(s) during pregnancy, to ensure complete capture of diagnoses. Infants were required to have birth weight and gestational age data and to be enrolled in health insurance for 4 months or more during the first year of life, with 1 or more outpatient visit(s). Insurance and health utilization criteria were not applied for infant deaths at less than 1 year. Infants with exposures increasing risk for structural birth defects (maternal diabetes or use of teratogenic medications, infant congenital infections, and chromosomal abnormalities) were excluded.
Three maternal vaccination exposure windows were examined: less than 14 weeks’ gestation (first trimester), 27 to 36 weeks’ gestation (current recommendation), and any gestational week. Analyses of maternal Tdap vaccination from 27 to 36 weeks’ gestation were limited to 2010-2013 for California sites and to 2012-2013 for other sites. Any structural defect, selected major structural defects (based on US and European birth defect surveillance systems), and microcephaly alone were identified from diagnostic codes assigned at medical visits during the first year of life (until the end of data collection, December 31, 2013). Algorithms based on expected timing of diagnosis, selected medical record review validation, and comparison of background rates were applied to increase specificity for major structural defects.
Covariates are listed in Table 1. A generalized linear model with Poisson distribution and log link was used to estimate prevalence ratios with 95% CIs, and Poisson distribution with identity link with robust variance estimation was used to estimate prevalence differences with 95% CIs. Adjusted estimates were obtained by estimating propensity scores using logistic regression, then adding propensity scores to models as quintiles. Variables in the propensity scores are listed in Table 2. SAS version 9.3 (SAS Institute Inc) was used for analysis.
Analyses included 324 463 singleton live births. Maternal Tdap was not significantly associated with increased risk for microcephaly for vaccinations occurring at less than 14 weeks’ gestation (n = 3321; adjusted prevalence ratio [APR], 0.96 [95% CI, 0.36-2.58]), between 27 and 36 weeks’ gestation (n = 20 568; APR, 1.01 [95% CI, 0.63-1.61]), or during any week of pregnancy (n = 41 654; APR, 0.86 [95% CI, 0.60-1.24]). Adjusted analyses were similar for any structural defect and selected structural defects (Table 2).
These results expand upon what is known about maternal Tdap vaccination safety6 to include information about structural birth defects and microcephaly in offspring. The findings are potentially limited by incomplete data on Tdap vaccinations (making it possible to misclassify women’s immunization status), diagnosed structural birth defects, and important covariates (including maternal alcohol use), as well as inability to study birth defects resulting in pregnancy loss or elective termination. The findings support recommendations for routine Tdap administration during pregnancy.
Corresponding Author: Malini DeSilva, MD, MPH, HealthPartners Institute, PO Box 1524, MS 21111R, Minneapolis, MN 55440-1524 (email@example.com).
Author Contributions: Drs DeSilva and Kharbanda had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: All Authors.
Acquisition, analysis, or interpretation of data: DeSilva, Vazquez-Benitez, Romitti, Kharbanda.
Drafting of the manuscript: DeSilva, Vazquez-Benitez, Kharbanda.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Vazquez-Benitez.
Obtained funding: Nordin, Kharbanda.
Administrative, technical, or material support: DeStefano.
Study supervision: Nordin, Lipkind, DeStefano, Kharbanda.
Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Funding/Support: This work was funded by the Centers for Disease Control and Prevention (CDC).
Role of the Funder/Sponsor: The CDC participated in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.
Additional Contributions: We thank Nicola P. Klein, MD (Kaiser Permanente Northern California); T. Craig Cheetham, PharmD, MS (Kaiser Permanente Southern California); Allison Naleway, PhD (Kaiser Permanente Northwest); Saad B. Omer, MPH (Emory University); Simon J. Hambidge, MD (Institute for Health Research); Grace M. Lee, MD (Harvard Pilgrim Health Care Institute); James G. Donahue, PhD (Marshfield Clinic); and Michael L. Jackson, PhD (Group Health Cooperative), for providing subject matter expertise, technical assistance, and review of the study; Leslie Kuckler, MPH, Beth Molitor, MBA, and Avalow Olsen, BS (all from HealthPartners Institute), for their assistance with data collection; and Natalie McCarthy, MPH (CDC), for her assistance with data collection and management and administrative and technical support. Compensation for all contributors was received through the CDC.