The study protocol was reviewed and approved by institutional review boards at Emory University, the CDC, and the 7 Vaccine Safety Datalink (VSD) sites and was determined exempt from requiring participant consent. The study cohort included pregnant women enrolled in the VSD (Figure). The VSD is a collaborative project between the CDC and 9 integrated health care organizations.¹⁵ The VSD includes data on more than 9 million individuals annually (approximately 3% of the US population), with an annual birth cohort of approximately 90 000. Data are collected from standardized files prepared at each site that contain individual demographic, enrollment, immunization, hospitalization, emergency department visits, and outpatient visits. For this study, 7 VSD sites contributed data: Group Health Cooperative (Washington), Kaiser Permanente Northwest (Oregon and Washington), Kaiser Permanente Northern California, Southern California Kaiser Permanente, HealthPartners (Minnesota), Marshfield Clinic (Wisconsin), and Kaiser Permanente Colorado. These sites were chosen because they contribute pregnancy data on a yearly basis. Although the majority of the VSD data comes from the 2 California sites, and thus the western United States, the demographic characteristics of the VSD population have been shown to be generally comparable with that of the entire US population.¹⁶

We conducted a retrospective cohort study among pregnant women vaccinated with Tdap by evaluating medically attended acute adverse events (occurring in outpatient, inpatient, and emergency department settings) in mothers and adverse birth outcomes in their neonates. We compared adverse events between women receiving a prior tetanus-containing vaccine less than 2 years before and 2 to 5 years before with women who had received a prior tetanus-containing vaccine more than 5 years before (controls). We chose these comparisons based on intervals used in prior studies comparing acute adverse events following multiple tetanus-containing vaccines in nonpregnant individuals.^12–14 Prior vaccination status was irrespective of pregnancy status at the time of vaccination.

We identified pregnancies ending between January 1,2007, and November 15, 2013, in automated data using a validated pregnancy algorithm¹⁷ that has been used in prior VSD pregnancy studies.^18,19 This pregnancy episode algorithm uses claims, administrative, and birth data from the electronic medical record to identify pregnancies, pregnancy outcomes, and gestational age at pregnancy outcome, and has been shown to be accurate within 28 days in confirming the estimated pregnancy start date for 99% of live births and in confirming the pregnancy outcome date for 96% of live births.¹⁷

We included women aged 14 through 49 years who received Tdap vaccine during pregnancy and had continuous insurance coverage from 6 months prior to pregnancy to 6 weeks postpartum with no more than a 30-day gap in enrollment. We excluded women who had no documentation of prior tetanus-containing vaccines, women who received live vaccines during pregnancy, and women with a multiple gestation pregnancy. We also excluded pregnancies with non-live birth outcomes (stillborn, spontaneous abortion, therapeutic abortion, trophoblastic disease, and ectopic pregnancy) because we did not have the resources to access medical records to confirm the timing of these outcomes in relation to vaccination, which could result in inaccurate findings. Finally, we excluded all women who received non-Tdap tetanus-containing vaccines during pregnancy (ie, tetanus diphtheria [Td]).

We identified vaccinations using electronic medical record and insurance claims data that are captured in the standardized VSD vaccine file. We defined a vaccine administered during pregnancy as one given from 7 days after the woman’s last menstrual period through 7 days before the date the pregnancy ended. We used these cutoffs to avoid misclassification of vaccines that might have been given prior to pregnancy or postpartum.^10,19

We compared International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for fever, local reactions (limb pain, limb swelling, cellulitis, lymphadenitis, and Arthus reaction), and allergic reactions (allergy, urti-caria, and anaphylaxis) occurring in intervals of 0 through 3 days and 0 through 7 days following Tdap vaccine, excluding duplicate diagnoses that had been given in the previous 30 days to capture incident cases associated with a health care visit. The day of vaccination was considered day 0, and we excluded any diagnoses on day 0 occurring in the outpatient setting, as they were likely present before the vaccination. As some allergic reactions may occur on day 0 in the outpatient setting, we performed a sensitivity analysis including diagnoses of allergic reactions in the outpatient setting on the day of vaccination. We compared the risk of incident cases of Guillain-Barré syndrome in the inpatient setting, using a 1-through 42-day time window following vaccination. We also examined the following adverse birth outcomes: preterm delivery (defined as gestational age <37 weeks), low birth weight (birth weight <2500 g), and small for gestational age (weight <10th percentile for gestational age and sex).²⁰

We compared baseline characteristics between the 3 groups of pregnant women who received Tdap vaccine. We used χ² tests to compare categorical variables, and analysis of variance to compare continuous variables. We identified all adverse events using ICD-9-CM codes. We used log-binomial regression analysis to calculate the relative risks (RRs) for both rare and non-rare events. Akaike Information Criterion measurements are included as assessments of model fit (eTable1 in the Supplement). We adjusted for differences in gestational age at time of vaccination and VSD site (Kaiser Permanente Northern California, Southern California Kaiser Permanente, or other site) when comparing acute events. When comparing birth outcomes, we also adjusted for maternal age, length of enrollment (in months) in the health plan prior to pregnancy, risk factors for pregnancy adverse events, pregnancy complications, and prenatal care utilization, because these are likely to independently affect birth outcomes. Prenatal care utilization was assessed using the Kotelchuck Adequacy of Prenatal Care Utilization Index, which takes into account the number of prenatal care visits from the time of the first prenatal care visit until delivery.²¹ Comorbidities (asthma, diabetes, hypertension, and cardiovascular disease) and pregnancy complications were identified usingICD-9-CM codes. Only records that contained information on the neonate (ie, weight and gestational age) were used when analyzing birth outcomes. In addition, only vaccinations given prior to 37 weeks of gestation were included, so as to not bias the results for preterm delivery and low birth weight. All analyses were performed using SAS (SAS Institute), version 9.3.

We performed a priori power calculations based on an expected sample size of 24 000 women and determined that we had 80% or higher power to detect an RR greater than 2 for all of our birth outcomes. However, analyses for medically attended acute adverse outcomes, which are rare, were under-powered. To detect an RR greater than 2 for local reactions, 10 000 participants would be needed in each cohort; for fever, 37 000 participants; and for allergic reactions, 75 000 participants. We considered results to be statistically significant at an a error less than .05 using 2-tailed tests.

Overall, acute adverse events after vaccination were rare (eTables 2–3 in the Supplement). There were no statistically significant differences in fever, allergic reactions, or local reactions among women who had received their prior tetanus-containing vaccine less than 2 years before and 2 to 5 years before compared with controls (Table 2). Fever beginning 0 through 3 days after vaccination occurred at a rate (per 10 000 women) of 2.1 in those who received Tdap and had a prior tetanus-containing vaccine less than 2 years before compared with 3.5 among controls (adjusted RR, 0.66 [95% CI, 0.07–5.77]; P = .70). Allergic reactions beginning 0 through 3 days after vaccination occurred at a rate (per 10 000 women) of 2.1 in women who received Tdap and had a prior tetanus-containing vaccine less than 2 years before (adjusted RR, 1.55 [95% CI, 0.13–18.45]; P = .73) and 1.0 in those receiving it 2 to 5 years before (adjusted RR, 0.71 [95% CI, 0.06–8.13]; P = .78) compared with 1.4 among controls. Local reactions beginning 0 through 3 days after vaccination occurred at a rate (per 10 000 women) of 4.2 in women who received Tdap and had a prior tetanus-containing vaccine less than 2 years before (adjusted RR, 0.49 [95% CI, 0.112.20]; P = .35) and 7.0 in those receiving it 2 to 5 years before (adjusted RR, 0.77 [95% CI, 0.31–1.95]; P = .59) compared with 11.2 among controls. There was no increased risk of allergic reactions based on the sensitivity analysis including outpatient diagnoses occurring on day 0 (eTable 4 in the Supplement). There were no cases of anaphylaxis, Arthus reactions, or Guillain-Barré syndrome following vaccination.

There were no statistically significant differences in adverse birth outcomes among women who had received their prior tetanus-containing vaccine less than 2 years before and 2 to 5 years before compared with controls (Table 3). Preterm delivery occurred in 6.6% of women who received Tdap and had a prior tetanus-containing vaccine less than 2 years before (adjusted RR, 1.15 [95% CI, 0.98–1.34]; P = .08) and 6.4% of those receiving it 2 to 5 years before (adjusted RR, 1.06 [95% CI, 0.94–1.19]; P = .33) compared with 6.8% of controls. Low-birth-weight delivery occurred in 4.7% of women who received Tdap and had a prior tetanus-containing vaccine less than 2 years before (adjusted RR, 1.10 [95% CI, 0.92–1.32]; P = .31) and4.7% of those receiving it2to5 years before (adjusted RR, 1.03 [95% CI, 0.89–1.18]; P = .72) compared with 5.1% of controls. Small for gestational age delivery occurred in 9.0% of women who received Tdap and had a prior tetanus-containing vaccine less than 2 years before (adjusted RR, 0.99 [95% CI, 0.87–1.13]; P = .88) and 8.7% of those receiving it2to5 years before (adjusted RR, 0.96 [95% CI, 0.87–1.06]; P = .45) compared with 9.1% of controls.