VAERS is a spontaneous reporting system co-administered by the Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA).⁸ Established in 1990, VAERS monitors vaccine safety and accepts adverse event (AE) reports following receipt of any US-licensed vaccine ⁹ VAERS is not designed to assess causal associations between vaccines and AEs; its primary purpose is to detect potential vaccine safety concerns that may warrant further investigations in defined populations.¹⁰ VAERS accepts reports from vaccine manufacturers, healthcare providers, vaccine recipients, and others. Healthcare providers are required to report any AE from the reportable events table ¹¹ and are encouraged to report any AE they consider to be clinical significant, whether or not they believe it was caused by the vaccine. Manufacturers are required to report all AEs of which they become aware. The VAERS report form collects patients’ demographic and past medical history as well as details of the AEs and information on vaccinations.¹² 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).¹³ Each report can be coded with one or more MedDRA terms. Reports are also classified as serious based on the Code of Federal Regulations ¹⁴ if they contain information that the AE resulted in death, hospitalization, prolongation of hospitalization, life-threatening illness, or resulted in a persistent or significant disability. For this study, we excluded reports on routine hospitalizations for delivery from the “serious” category. Medical records are routinely requested for all serious VAERS reports except those submitted by the vaccine manufacturer. Some reports only describe exposure to vaccine during pregnancy without an AE.

We searched the VAERS database for reports involving pregnant women who had received Hep A or Hep AB in the United States, with or without other vaccines, during January 1, 1996 through April 5, 2013. We conducted an automated search using the following criteria: MedDRA terms in System Organ Classes (SOC) “Pregnancy, Puerperium, and Perinatal Conditions” and “Congenital, Familial and Genetic Disorders”, the MedDRA terms “Drug Exposure during Pregnancy” or “Maternal Exposure During Pregnancy”, and a text string search for the term “preg” in the report. Reports of pregnant women or their infants exposed in utero that had at least one of these criteria were included in the dataset for further evaluation.

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 estimated gestational age and characterize AEs. For each report we assigned a primary diagnosis. If more than one 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 a pregnancy-specific event unless information suggested otherwise. Complex reports (e.g. major birth defect, pre-eclampsia) were reviewed by physicians on the study team with expertise in obstetrics and neonatology. For purposes of AE description, if a VAERS report described AEs in more than one person (e.g., mother and exposed infant), we treated each person as a separate report. Reports that indicated the reported subject was not pregnant or that Hep A or Hep AB vaccine 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 the last menstrual period or estimated delivery date found in the VAERS report or medical records. If this information was not provided, we used other information available from the VAERS report or medical record indicative of gestational age (e.g., ultrasound report, reporter’s note, hospital records). We used the following definition for trimesters: first (0-13 weeks), second (14-27 weeks), and third (28+ weeks).¹⁵ Spontaneous abortion (SAB) was defined as a fetal demise prior to 20 weeks gestation, stillbirth was defined as fetal demise at or after 20 weeks gestation, and pre-term delivery was defined as a live birth before 37 weeks gestation. Causality between reported AEs and Hep A or Hep AB was not assessed.

In order to assess for disproportionately higher reporting of AEs after Hep A or Hep AB administered to pregnant women, we calculated proportional reporting ratios (PRRs) ^16,17 compared with inactivated influenza vaccines, which have been determined to have an acceptable safety profile in pregnancy.^18,19 We combined Hep A and Hep AB vaccine reports and compared proportions of MedDRA terms after these vaccines with proportions of the same MedDRA terms after trivalent inactivated influenza vaccines (TIV) and influenza A (H1N1) 2009 monovalent vaccine (MIV) (used during the 2009-10 pandemic) administered without Hep A or Hep AB vaccine to pregnant women. For TIV and MIV administered in pregnancy, we used VAERS reports analyzed in previous studies^{18, 19} as well as reports received during 2010-2013. We excluded reports from analysis if no AE was reported or if live vaccines (contraindicated during pregnancy ³), or anthrax vaccine (not recommended during pregnancy ²⁰) were administered concomitantly. We identified MedDRA terms with disproportionately higher reporting after Hep A or Hep AB by applying Evans’ criteria (PRR ≥ 2.0, Yates-chi-square ≥ 4.0, and number of reports ≥ 3 in reports of HEP A or Hep AB).¹⁶ 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 nor informed consent requirements.

Among 35 reports of Hep AB, 14 (40%) reports did not describe an adverse event, 16 (45.7%) were maternal events, and 5 (14.3%) were infant/neonatal events. Adverse events included: among pregnancy-specific AEs: 3 reports of SAB and elective termination each, 2 reports of premature delivery, and one report each of oligohydramnios, abruption placentae and uterine and abdominal cramps; among non-pregnancy specific AEs: one report each of pelvic pain, sinusitis, nausea and dizziness, paleness, and injection site pain; five reports of infant AEs: 3 reports of jaundice, and one report each of fetal distress, growth under lower lip. Two serious reports after Hep AB included oligohydramnios and neonatal jaundice noted above.

Higher PRRs were identified for the MedDRA terms ‘Abortion’ and ‘Neonatal disorder’. Six reports contained the code ‘Abortion’ and comprised 3 reports each of spontaneous abortion and elective termination. Two of the spontaneous abortion reports were after Hep A and one after Hep AB. The three elective termination reports were after Hep AB vaccine. One report did not provide information regarding the reason for the procedure. The other two reports of elective termination were scheduled before vaccination for reasons unrelated to vaccination. Three reports after Hep A contained the code ‘Neonatal disorder’ but two referred to the same infant (one report for the mother and the other for her infant). The diagnosis in the two neonatal reports with this code were a report of respiratory syncytial virus infection, and the serious report of laryngotracheomalacia, both described above. No disproportionality was found in reporting of stillbirth, preterm deliveries or the specific MedDRA terms for SAB (in distinction to the overall ‘Abortion’ code described above).

During the period of this review from 1996 through 2013, 134 pregnancy reports after Hep A or Hep AB were submitted to VAERS. Our review did not find any unusual or unexpected pattern of maternal, infant or fetal AEs. Close to half of reports (47%) did not describe an adverse event other than the exposure to Hep A or Hep AB during pregnancy. We conducted two levels of analysis to assess the safety of Hep A or Hep AB in pregnancy: clinical review of VAERS reports and available medical records and disproportionality analysis using proportional reporting ratios. The MedDRA codes ‘Abortion’ and ‘Neonatal disorder’ were disproportionally reported, however, reports with the code ‘Abortion’ included both spontaneous abortion and elective termination, and the code for spontaneous abortion alone was not disproportionally reported. Two of the three elective termination reports indicated the procedure was done for reasons unrelated to vaccination. Clinical review of reports did not identify any concerning cluster of maternal or infant AEs following Hep A or Hep AB administration. The most common pregnancy-specific outcome was spontaneous abortion (SAB), observed in 11% of all reports. SAB is a relatively frequent event during pregnancy with rates that vary from 10.4% in women younger than 25 years to 22.4% in women aged 34 years or older. ²¹ SAB has also been found to be the most common pregnancy-specific outcome in several studies assessing other vaccines administered to pregnant women reported to VAERS. ^{18, 19, 22}

Although few studies have assessed the safety of Hep A or Hep AB in pregnant women, one study evaluated the risk of SAB in 3,599 pregnant women who inadvertently received either bivalent human papillomavirus vaccine (HPV2) (Cervarix) or Hep A vaccine during pregnancy²³ Investigators reported the risk of SAB was 11.5% of 1,786 pregnant women who received HPV2, compared with 10.2% in a control group of 1,813 pregnant women who received Hep A.²³ In this same study, the rates for stillbirth and premature delivery were 0.8% and 7.5% for HPV2 and 0.7% and 8.5% for Hep A. These findings are reassuring and do not suggest any evidence for an increased risk of SAB, stillbirths, or premature delivery in either group of women when compared to background rates for these conditions.^21,24,25 Among non-pregnancy specific AEs in our review, urinary tract infection and nausea/vomiting were the most common with 3 non-serious reports each. Urinary tract infection is a frequent medical condition which can affect 20% of pregnancies.²⁶

One major birth defect was reported, an infant born without both lower limbs. Absence of limb(s) or congenital amelia is a rare birth defect. A multi-center descriptive epidemiologic international study by Bermejo-Sanchez et al ²⁷ found a total prevalence of Amelia (either one or more limbs) to be 1.41 per 100,000 births. In the Bermejo-Sanchez study absence of both lower extremities accounted for approximately 10% of all amelia cases. Amelia has been described in several infants exposed to thalidomide. It is not known what other risk factors and causes may be responsible for this condition. Polydactyly, or presence of an extra digit, presented by one of the infants in this review may be considered a major birth defect if it can be demonstrated that the extra digit is a complete appendage. No medical records were available for this report and the information provided in the VAERS form was very limited therefore we had insufficient information to classify this report as a major birth defect. Both infants received HPV4 concomitantly, and this coupled with lack of denominator data to calculate reporting rates for these conditions, makes it difficult to make any assessment. Major birth defects occur in 3% of live births ²⁸ and we observed no unusual clustering of birth defects in our review.

Any finding in VAERS needs to be interpreted with caution, given its inherent limitations. VAERS is a passive surveillance system that may be prone to biased reporting (over- or underreporting) and inconsistency in the quality and completeness of reports. Because VAERS accepts reports from any reporter, the information provided by individuals with little or no medical training, may adversely affect the quality of the report. Events that occur close to the time of vaccination are more likely to be reported to VAERS. Birth defects may be diagnosed several months after vaccination and may be underreported. VAERS also generally cannot determine whether a vaccine caused an AE.^{9, 10} Stimulated reporting can occur following publicity around a potential AE. For example, although the reporting rate for SAB after influenza A (H1N1) 2009 monovalent vaccine reports was below the background rate for SAB in the US pregnant population, it was 25 times higher than the reporting rate to VAERS for SABs after the seasonal influenza vaccine during the period 1990-2009, likely reflecting stimulated reporting.^{18, 19} VAERS does not collect data on the number of individuals vaccinated therefore it is not possible to calculate the incidence or prevalence of adverse events.⁹