Objective
We sought to characterize reports to the Vaccine Adverse Event Reporting System (VAERS) of pregnant women who received tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap).
Study Design
We searched VAERS for reports of pregnant women who received Tdap from Jan. 1, 2005, through June 30, 2010. We conducted a clinical review of reports and available medical records.
Results
We identified 132 reports of Tdap administered to pregnant women; 55 (42%) described no adverse event (AE). No maternal or infant deaths were reported. The most frequent pregnancy-specific AE was spontaneous abortion in 22 (16.7%) reports. Injection site reactions were the most frequent non-pregnancy–specific AE found in 6 (4.5%) reports. One report with a major congenital anomaly (gastroschisis) was identified.
Conclusion
During a time when Tdap was not routinely recommended in pregnancy, review of reports to VAERS in pregnant women after Tdap did not identify any concerning patterns in maternal, infant, or fetal outcomes.
Administration of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) to a pregnant woman induces formation of maternal antibodies against pertussis that are transferred to the fetus across the placenta. Transplacentally transferred antibodies might provide protection against pertussis infection in young infants. In addition, Tdap vaccination of pregnant women and other family members directly prevents pertussis in these individuals and may indirectly protect infants by reducing the risk for pertussis transmission, a strategy known as cocooning. Infants <3 months of age are too young to receive the primary pertussis vaccination series and have the highest risk for death from pertussis. Therefore, strategies to prevent pertussis in these infants are essential.
For Editors’ Commentary, see Contents
Tdap was licensed by the Food and Drug Administration (FDA) in 2005 for booster immunization against tetanus, diphtheria, and pertussis for individuals 10-64 years of age, and is available in the United States from 2 manufacturers: Adacel (Sanofi Pasteur, Swiftwater, PA) and Boostrix (GlaxoSmithKline Biologicals, Rixensart, Belgium). Since 2008 the Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) has recommended using Tdap in the immediate postpartum period in women who did not previously receive Tdap to protect both mothers and infants from pertussis. ACIP did not routinely recommend use of Tdap in pregnant women, but recommended that providers consider use in certain situations that included instances when a pregnant woman has insufficient tetanus or diphtheria protection until delivery, or is at increased risk for pertussis (eg, adolescents aged 11-18 years, health care personnel, and women employed in institutions or living in a community in which a pertussis outbreak is occurring). In 2011 ACIP assessed that the strategy focusing on cocooning had not achieved the intended goal of reducing the burden of pertussis in infants. In October 2011, CDC published an updated ACIP recommendation that health care providers administer Tdap during the third or late second trimester (>20 weeks’ gestation) to women who have not previously received Tdap.
To provide safety evidence to help inform the ACIP deliberations for Tdap use in pregnant women, we conducted a review of reports to the Vaccine Adverse Event Reporting System (VAERS) of pregnant women given Tdap from 2005 through 2010.
Materials and Methods
Data sources
VAERS is a spontaneous reporting system coadministered by CDC and FDA. Established in 1990, VAERS monitors vaccine safety and accepts adverse event (AE) reports following receipt of any US-licensed vaccine. VAERS is not designed to assess causal associations between vaccines and AEs; its primary purpose is to detect potential vaccine safety concerns that may be further investigated in defined populations. The VAERS report form collects demographic and health information, including information about the vaccination and AE experience. It does not specifically collect information on pregnancy status. AE signs and symptoms recorded in each VAERS report are coded by trained staff using an internationally standardized terminology from the Medical Dictionary for Regulatory Activities (MedDRA). Each report can be coded with ≥1 MedDRA term. Reports are also classified as “serious” based on the Code of Federal Regulations if they contain information that the AE resulted in death, hospitalization, prolongation of hospitalization, life-threatening illness, persistent or significant disability, or congenital anomalies. For this study, the definition of “serious” was slightly modified and did not include reports on hospitalizations for delivery unless they required prolonged stay in a hospital due to delivery complications or postpartum conditions. Medical records are routinely requested for nonmanufacturer serious VAERS reports.
We searched the VAERS database for reports of pregnant women vaccinated in the United States with Tdap, with or without other vaccines, from Jan. 1, 2005, through June 30, 2010. We conducted an automated search using the following criteria: MedDRA terms in 2 System Organ Classes “Pregnancy, Puerperium, and Perinatal Conditions” and “Congenital, Familial, and Genetic Disorders”; MedDRA term “Drug Exposure During Pregnancy”; and a text string search for the term “preg” in the report. Reports that had at least one of these criteria were included in the data set for further evaluation.
Clinical reviews
CDC and FDA medical officers reviewed all US reports identified in the VAERS database using the automated search to confirm pregnancy status at time of vaccination, calculate gestational age, and characterize AEs. We included reports on infants born to women vaccinated with Tdap during pregnancy. For each report we assigned a primary diagnosis. If >1 AE was reported for the same individual, we assigned the diagnosis based on what we believed was the primary clinical event of concern and assumed the primary event was the pregnancy-specific event unless information suggested otherwise. Complex reports were reviewed by physicians on the study team with expertise in obstetrics and neonatology. If a VAERS report described AEs in >1 person, we treated each person as a separate report. Reports that indicated the reported subject was not pregnant or that Tdap was administered prior to the last menstrual period were excluded.
Gestational age at the time of vaccination and at the time of the AE was calculated based on: (1) clinical determination of health care provider, (2) earliest ultrasound assessment (if the former was not available), or (3) last menstrual period, estimated delivery date, or estimated date of conception (if the first 2 options were not available) found in VAERS report and/or medical records. We used the following definition for trimesters: first (0-13 weeks), second (14-27 weeks), and third (≥28 weeks). Spontaneous abortion (SAB) was defined as fetal demise <20 weeks’ gestation, stillbirth was defined as fetal demise ≥20 weeks’ gestation, and preterm delivery was defined as a live birth <37 weeks’ gestation. Causality between reported AEs and Tdap was not assessed.
Proportional reporting ratios
To assess for disproportionately higher reporting of AEs after Tdap administered to pregnant women, we calculated proportional reporting ratios (PRRs) compared to inactivated influenza vaccines, which have been determined to have an acceptable safety profile in pregnancy. We compared proportions of MedDRA terms after Tdap with proportions of the same MedDRA terms after trivalent inactivated influenza vaccines (TIV) and influenza A (H1N1) 2009 monovalent vaccine (used during the 2009 through 2010 pandemic) administered without Tdap to pregnant women. For TIV and monovalent vaccine administered in pregnancy, we used VAERS reports identified for previously conducted and published studies. We excluded reports from analysis if no AE was reported or if live vaccines (contraindicated during pregnancy ) or anthrax vaccine (not recommended during pregnancy ) were administered concomitantly. We identified MedDRA terms with disproportionately higher reporting after Tdap by applying criteria of Evans et al (PRR ≥2.0, Yates χ 2 ≥4.0, and number of reports ≥3 in the Tdap group). Clinical reviews were conducted for all MedDRA terms with a PRR ≥2.0.
Because VAERS is a routine, government-sponsored surveillance system that does not meet the definition of research, this investigation was not subject to institutional review board review and informed consent requirements.
Results
During Jan. 1, 2005, through June 30, 2010, VAERS received a total of 106,573 US reports after Tdap; 163 reports met criteria of pregnancy reports using the automated search. Of these reports, 33 were excluded: 28 reports indicated that the subject was not pregnant, 2 reports indicated that Tdap was received postpartum, 2 reports indicated vaccination in children, and 1 report was a duplicate. Two reports described AEs in infant and mother; each of these reports was treated as 2 separate reports (1 for infant and 1 for mother). After the clinical review, 132 reports were identified as true pregnancy reports and were used for further analysis. Six (4.5%) reports were classified as serious and included 2 reports of ruptured ectopic pregnancies that required laparotomy; and 1 report each of stillbirth at 37 weeks’ gestation due to placental abruption, influenza, gastroschisis in a newborn, and laryngotracheomalacia in a 3-month-old infant. In all these reports, the serious classification was based on the person requiring hospitalization. No maternal or infant deaths were reported.
Characteristics of VAERS reports are presented in Table 1 . A majority of the reports (69, 52.3%) were received from manufacturers. In 48 (36.4%) reports Tdap was the only vaccine received. The median maternal age was 22 years. Information to determine the trimester of Tdap exposure was available for 110 (83.3%) reports. In most of the reports where trimester at time of vaccination was known, 85 (77.3%), indicated that Tdap was administered during the first trimester of pregnancy. A total of 95 (72.0%) reports indicated administration of Adacel.
| Characteristic | Value |
|---|---|
| Serious reports, n (%) | 6 (4.5) |
| Tdap administered alone, a n (%) | 48 (36.4) |
| Median maternal age, y (range) b | 22 (13–42) |
| Median interval from vaccination to adverse event, d (range) c | 7 (0–268) |
| Median gestational age at time of vaccination, wk (range) d | 6 (1–37) |
| Trimester of pregnancy at time of vaccination (n = 110), e n (%) | |
| First (0–13 wk) | 85 (77.3) |
| Second (14–27 wk) | 21 (19.1) |
| Third (≥28 wk) | 4 (3.6) |
| Brand name of Tdap, n (%) | |
| Adacel f | 95 (72.0) |
| Boostrix g | 20 (15.2) |
| Unknown | 17 (12.9) |
| Type of reporter, n (%) | |
| Manufacturer | 69 (52.3) |
| Provider | 42 (31.8) |
| Other | 20 (15.2) |
| Patient/parent | 1 (0.8) |
a Other vaccines given with Tdap included meningococcal conjugate (7; 5.4%); human papillomavirus (7; 5.4%); measles, mumps, and rubella (4; 3.1%); and influenza (3; 2.3%);
b Missing for 1 pregnant woman;
f Sanofi Pasteur, Swiftwater, PA;
In all, 55 (41.7%) reports did not describe any AE; these reports were submitted because vaccine had been administered during pregnancy at a time period when Tdap in pregnancy was not routinely recommended ( Table 2 ). The most frequent pregnancy-specific outcome was SAB in 22 (16.7%) reports. The median gestational age at the time of SAB was 9 weeks (range, 5–16 weeks). The median onset interval between vaccination and SAB was 33 days (range, 9–61 days). We did not observe any temporal clustering of SAB reports. Two stillbirth cases were reported. One case occurred in a 20-year-old woman at 37 weeks of gestation and was reported to be due to placental abruption; Tdap was administered several hours before the outcome. The other case was in a 27-year-old woman at 22 weeks of gestation (46 days after exposure to Tdap) with no other pregnancy complications reported before fetal demise.
| Adverse events | n | % |
|---|---|---|
| Pregnancy-specific adverse events | ||
| Spontaneous abortion b | 22 | 16.7 |
| Gestational diabetes | 7 | 5.3 |
| Oligohydramnios c | 3 | 2.3 |
| Induction of labor d | 2 | 1.5 |
| Stillbirth | 2 | 1.5 |
| Ruptured ectopic pregnancy | 2 | 1.5 |
| Preterm delivery | 2 | 1.5 |
| Subchorionic hemorrhage by ultrasound | 1 | 0.8 |
| Cesarean delivery | 1 | 0.8 |
| Low-lying placenta on ultrasound | 1 | 0.8 |
| Placental abruption and fetal intolerance | 1 | 0.8 |
| Preeclampsia e | 1 | 0.8 |
| Prolonged labor | 1 | 0.8 |
| Toxemia f | 1 | 0.8 |
| Total | 47 | 35.6 |
| Non-pregnancy–specific outcomes | ||
| Injection site reactions | 6 | 4.5 |
| Anemia | 5 | 3.8 |
| Headache or fever with abdominal pain | 3 | 2.3 |
| Urinary tract infection | 2 | 1.5 |
| Syncope | 2 | 1.5 |
| Upper respiratory infection | 2 | 1.5 |
| Influenza | 1 | 0.8 |
| Nausea and vomiting | 1 | 0.8 |
| Rash on arms/thigh | 1 | 0.8 |
| Superficial thrombophlebitis | 1 | 0.8 |
| Total | 24 | 18.2 |
| Infant outcomes | ||
| Gastroschisis | 1 | 0.8 |
| Laryngotracheomalacia (diagnosed at age 3 mo) e | 1 | 0.8 |
| Patent foramen ovale and peripheral pulmonic stenosis | 1 | 0.8 |
| Mild physiologic jaundice | 1 | 0.8 |
| Transient tachypnea and infiltrates in lower lobes | 1 | 0.8 |
| Bilateral hydrocele | 1 | 0.8 |
| Total | 6 | 4.5 |
| No adverse events | 55 | 41.7 |
a Based on primary reported diagnosis identified during clinical review–1 diagnosis assigned to 1 report;
b Pregnancy outcomes were not reported in 65 (42%) reports–other pregnancy outcomes included 4 (3.0%) elective termination of pregnancy, 24 (18.2%) vaginal deliveries, and 8 (6.1%) cesarean deliveries;
c 2 cases with oligohydramnios had induction of labor as secondary diagnosis and 1 case had threatened abortion in early pregnancy as secondary diagnosis;
d Chorioamnionitis was reported as secondary to labor induction;
e Preterm delivery reported as secondary diagnosis for this case;
f Threatened abortion in early pregnancy is reported for this case as secondary diagnosis.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
