Prenatal Tdap immunization and risk of maternal and newborn adverse events

Abstract

Many countries recommend combined tetanus toxoid, reduced diphtheria toxoid and acellular pertussis immunization (Tdap) during pregnancy to stimulate transplacental transmission of pertussis antibodies to newborns. The immune system can be altered during pregnancy, potentially resulting in differing immunization risks in pregnant women. The safety of widespread Tdap immunization during pregnancy needs to be established. Our objective was to assess whether prenatal Tdap immunization was associated with adverse birth outcomes, and to evaluate the effect of timing of Tdap administration on these outcomes.

We identified pregnancies at delivery in a large insurance claims database (2010–2014). Tdap immunization was categorized as optimal prenatal (27 + weeks), early prenatal (<27 weeks), postpartum (≤7 days post-delivery), or none. Medical claims were searched to identify maternal adverse immunization reactions (e.g. anaphylaxis, fever, Guillian-Barre syndrome [GBS]), adverse birth outcomes (e.g. preeclampsia/eclampsia, premature rupture or membranes, chorioamnionitis) and newborn outcomes (e.g. respiratory distress, pulmonary hypertension, neonatal jaundice). Women with optimal or early prenatal Tdap were compared to those not immunized in pregnancy, using propensity score-weighted log-binomial regression and Cox proportional hazards models to estimate risk ratios (RR) and hazard ratios (HR). We identified 1,079,034 deliveries and 677,075 linked newborns; 11.5% were immunized optimally and 2.3% immunized early. There were 1 case of post-immunization anaphylaxis, and 12 cases of maternal encephalopathy (all post- delivery); there were no cases of GBS. Optimally-timed immunization was associated with small increased relative risks of: chorioamnionitis [RR = 1.11, (95% CI: 1.07–1.15), overall risk = 2.8%], and postpartum hemorrhage [RR = 1.23 (95% DI: 1.18–1.28), overall risk = 2.4%]; however, these relative increases corresponded to low absolute risk increases. Tdap was not associated with increased risk of any adverse newborn outcome. Overall, prenatal Tdap immunization was not associated with newborn adverse events, but potential associations with chorioamnionitis consistent with one previous study and postpartum hemorrhage require further investigation.

Introduction

Tetanus toxoid, reduced diphtheria toxoid and acellular pertussis immunization (Tdap) administered during pregnancy conveys passive pertussis immunity to newborns via transplacental transmission of maternal pertussis antibodies [1], [2], [3], [4], [5], [6]; thus, several countries recommend Tdap during every pregnancy, including closely spaced pregnancies [7], [8], [9]. Despite international efforts to prevent infant pertussis through maternal Tdap, prenatal uptake remains sub-optimal [10], [11], [12], [13], [14], due in part to concerns about safety [15], [16]. While generally accepted as safe, widespread prenatal Tdap requires careful scrutiny to establish the safety for the mother and newborn.

Tdap has not been associated with clinically significant harms for the fetus or neonate such as preterm birth, small for gestational age, stillbirth, low birth weight, or congenital anomalies [17]. Similarly, there is no evidence of increased risk of serious adverse events in pregnancy, with the exception of unreplicated findings of increased chorioamnionitis risk from one retrospective study [17], [18]. Previous non-experimental studies have been limited by small sample size, unclear immunization timing, and confounding due to comparing guideline-adherent immunized versus non-adherent unimmunized populations. Given that a strong understanding of the safety of Tdap during pregnancy may be central to increasing uptake, additional studies are needed.

Furthermore, considerable uncertainty persists about the optimal timing of prenatal Tdap administration. The CDC recommends administration at any time during pregnancy, though preferably between gestational weeks 27–36 [19] to maximize maternal antibody response and passive antibody transfer; other countries recommend administration during the second [8] or third trimesters [9] to improve immunization coverage for preterm deliveries. Safety studies which account for the timing of immunization are limited [17].

To examine the safety of Tdap administration during pregnancy, we conducted a large-scale, cohort study comparing the risks of adverse outcomes in the infant and mother associated with Tdap and examined the impact of timing of Tdap administration on safety.