The Association of Prenatal Tetanus, Diphtheria, and Acellular Pertussis (Tdap) Vaccination With Attention-Deficit/Hyperactivity Disorder

Tracy A. Becerra-Culqui; Darios Getahun; Vicki Chiu; Lina S. Sy; Hung Fu Tseng

Disclosures

Am J Epidemiol. 2020;189(10):1163-1172. 

In This Article

Discussion

In this large, sociodemographically diverse, population-based retrospective cohort study of pregnant women and their children, we found no association between in utero exposure to the Tdap vaccine and ADHD. Subanalyses supported the overall results showing minimal variability by child's year of birth and maternal parity and when additional covariates were added to the propensity score model. To our knowledge, no study has published results examining the risk of ADHD following maternal exposure to the Tdap vaccine. These findings are consistent with our previous research of no increased risk of the neurodevelopmental outcome of autism following in utero exposure to Tdap vaccination.[13]

Recent evidence of an inflammatory pathway during pregnancy adds to the current literature on environmental risk factors for ADHD.[31] For example, diabetes during pregnancy or severe hyperglycemia might potentially predispose fetuses to chronic inflammation, which in turn might interfere with fetal brain development.[32] A thorough assessment of the link between neuroinflammation and brain development points to the involvement of mechanisms that include glial activation, increased oxidative stress, abnormal neuronal development, reduced neurotropic support, and altered neurotransmitter function.[17] In one study, maternal fever during early pregnancy and genitourinary infections in late pregnancy were reported to be associated with ADHD in offspring.[33] Though the latter study is the only known study to have evaluated this relationship, there is robust research about prenatal immune activation and the risk of autism, suggesting that infections during pregnancy (e.g., rubella and influenza) and prolonged episodes of fever are likely to alter fetal brain development through cytokine responses and proinflammatory pathways.[34–40] ADHD and autism might share a common inflammatory pathway, but more research is needed on the timing of perinatal insults and the areas they affect.[17]

In this observational study based in a health-care setting where patient and practice characteristics are associated with vaccine receipt, use of propensity score and IPTW methods enabled us to achieve balance of measured covariates across the Tdap-exposed and -unexposed groups. However, much like traditional confounding adjustment methods, these methods are limited to Tdap vaccination relationships with known and measured covariates. A handful of studies have found a few predictors of low prenatal Tdap uptake, finding associations with maternal age (<30 years), Black race/ethnicity, having other children, nonvaccination against influenza during pregnancy, giving birth preterm, and visiting the emergency room during pregnancy.[27,28,41] Additional factors were included if they were determined to feasibly influence Tdap receipt based on known changes in vaccination practice over time (year of birth) and indicators of health-care use (maternal education, history of ADHD diagnosis, Medicaid insurance, medical center, start of prenatal care, and influenza vaccination during pregnancy). Austin and Stuart[42] have argued that it is important to include factors associated with the outcome (ADHD diagnosis) in propensity score models. Risk factors for ADHD, including child's birth before 37 weeks' gestation, male sex, non-Hispanic White or Black maternal race/ethnicity, household income or public health insurance (Medicaid), and maternal education were included in the main model, and additional variables were included in the sensitivity analysis (i.e., maternal body mass index, smoking, drinking).[25,26,43] In addition, genetic and familial risk factors seem to account for the majority of the variance (60%–90%) in ADHD.[16,31] In the present study, maternal history of ADHD was taken into account; it was present in 1.2% of the Tdap-vaccinated and -unvaccinated mothers. However, residual confounding might have occurred, since we did not account for extended familial risk.

Our findings have some strengths and potential limitations. ADHD was determined by recorded diagnoses and dispensed medications in the EMR and was not validated by a study-specific standardized assessment. In addition, misclassification of ADHD diagnosis could have occurred among children with dual insurance or limited health-care use, if parents sought care for ADHD elsewhere. However, incident ADHD diagnoses were probably captured consistently given systematic procedures for diagnosis within the KPSC health-care system. In addition, the diagnosis of ADHD is made by qualified mental health professionals (child/adolescent psychiatrists, developmental/behavioral pediatricians, child psychologists, or neurologists). Yet, the combined prevalence of ADHD in this study was 1.0%, lower than the estimated parent-reported 4.9% prevalence among 4- to 10-year-old children on ADHD medication in the United States (43). Because the study follow-up time was dependent on the child's birth year, children in this study had different opportunities for receiving an ADHD diagnosis. For example, children born in 2011 had maximum potential follow-up of 4–5 years after turning 3 years of age, whereas children born in 2014 had 1–2 years. Based on a previous study of ADHD in this population, 1.0% prevalence is consistent for children aged 5 years, and ADHD diagnosis rates quickly accelerate during the elementary school years, with rates peaking at age 10 years, an age the children in this study did not reach.[32] Similarly, maternal uptake of Tdap vaccine varied by birth year because of evolving ACIP recommendations and pertussis epidemics in California.[44–46] Because we identified minimal variability in study results when stratifying by birth year, these variations probably did not affect our results. However, we cannot rule out the potential for residual confounding. One additional strength is that maternal Tdap vaccination and ADHD information was not subject to recall bias.

We conclude that Tdap vaccination during the prenatal period is not associated with an increased risk of ADHD in offspring. This study provides additional evidence supporting the long-term safety of ACIP's recommendation to vaccinate pregnant women in order to protect infants, who are at highest risk of morbidity and mortality following pertussis infection.

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