Objective
We characterized reports to the Vaccine Adverse Event (AE) Reporting System (VAERS) of pregnant women who received meningococcal polysaccharide-protein conjugate vaccine Menactra (MenACWY-D; Sanofi Pasteur Inc., Swiftwater, PA).
Study Design
We searched VAERS for reports of pregnant women who received MenACWY-D from Jan. 1, 2005 through Dec. 31, 2011. We conducted clinical review of reports and available medical records.
Results
Of 103 identified reports, 38 (36.7%) did not describe any AE. No maternal or infant deaths were reported. The most frequent pregnancy-specific AE was spontaneous abortion in 17 (16.5%) reports. Urinary tract infections and fever with vomiting were the most frequent nonpregnancy-specific AEs found in 4 (3.9%) and 3 (2.9%) reports, respectively. We identified 1 report with a major congenital anomaly (aqueductal stenosis and severe ventriculomegaly).
Conclusion
Our comprehensive review of reports to VAERS in pregnant women after MenACWY-D did not identify any concerning patterns in maternal, infant, or fetal outcomes.
Meningococcal disease, caused by Neisseria meningitidis , a gram-negative aerobic diplococci, can result in serious complications, such as brain damage, hearing loss, or learning disabilities; 11.3% of cases are fatal. The annual incidence of meningococcal disease decreased from 0.92 per 100,000 population in 1998 to 0.33 cases per 100,000 population in 2007. However, since 1991, localized outbreaks have been occurring more frequently, and the use of meningococcal vaccine to control these outbreaks has increased.
In January 2005, a quadrivalent meningococcal polysaccharide-protein conjugate vaccine (MCV4) Menactra (MenACWY-D) (Sanofi Pasteur Inc., Swiftwater, PA) was licensed for use in the United States among persons aged 11-55 years. Meningococcal conjugate vaccines, through conjugation of polysaccharide to a protein carrier, change the immune response from T-cell independent to T-cell dependent, leading to improved immunogenicity over polysaccharide vaccines. The Advisory Committee on Immunization Practices (ACIP) recommended that persons aged 2-55 years at increased risk for meningococcal disease (eg, college freshmen, travelers to N meningitidis hyperendemic countries, persons with terminal complement component deficiencies, persons with anatomic or functional asplenia, and microbiologists routinely exposed to isolates of N meningitidis ) and all adolescents aged 11-18 years be immunized with MCV4. ACIP further recommended that all adolescents receive a booster dose of the vaccine at age 16 years. Data support the safety of MCV4 among nonpregnant persons aged 11-55 years, however, data on pregnant women are lacking and because of this MCV4 is not routinely recommended in pregnancy.
Because pregnant women may be exposed to MCV4 inadvertently or as part of outbreak control measures, assessing safety in pregnancy is important. To evaluate the safety of MCV4 in pregnant women, we reviewed reports to the Vaccine Adverse Event (AE) Reporting System (VAERS) of pregnant women who received MenACWY-D or infants born to women who received MenACWY-D in pregnancy during 2005 through 2011.
Materials and Methods
Data source
The VAERS is a national spontaneous reporting surveillance system, established in 1990 and coadministered by the Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration, which accepts reports of AEs following receipt of any US-licensed vaccine. VAERS is not designed to assess causal associations between vaccines and AEs. VAERS reports may be submitted voluntarily by any health care provider or member of the public. Vaccine manufacturers are required to report all AEs of which they become aware ; its primary purpose is to detect potential vaccine safety concerns that may be further investigated through controlled studies in defined populations. In VAERS, AE signs and symptoms recorded in each report are coded by trained staff using internationally standardized terminology from the Medical Dictionary for Regulatory Activities (MedDRA). Reports are classified as serious based on the Code of Federal Regulations if one of the following is reported: death, hospitalization, prolongation of hospitalization, life-threatening illness, persistent or significant disability, or congenital anomalies. For serious reports from sources other than the manufacturer, medical records are routinely requested by VAERS personnel for review. The VAERS form does not contain a field for pregnancy status, therefore a specialized search strategy is needed to look for reports in pregnant women. We searched the VAERS database for reports of pregnant women vaccinated in the United States with MenACWY-D from Jan. 1, 2005, through Dec. 31, 2011. We first conducted an automated search using 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. VAERS is a government-sponsored surveillance system and is not subject to institutional review board or consent requirements.
Clinical reviews
CDC medical officers with obstetrical expertise 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 MenACWY-D 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 that contained several significant outcomes were reviewed by physicians on the study team with clinical background in obstetrics and neonatology (specializing in birth defects). 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 MenACWY-D 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 (eg, 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). Spontaneous abortion (SAB) was defined as fetal demise <20 weeks’ gestation, stillbirth was defined as fetal demise ≥20 weeks’ gestation, and premature delivery was defined as a live birth <37 weeks’ gestation. Causality between reported AEs and MCV4 vaccine was not assessed.
Proportional reporting ratios
To assess for disproportionately higher reporting of AEs after MenACWY-D administered to pregnant women, we calculated proportional reporting ratios (PRRs) compared with inactivated influenza vaccines that have an acceptable safety profile in pregnancy. We compared proportions of MedDRA terms after MenACWY-D with proportions of the same MedDRA terms after trivalent inactivated influenza vaccines and influenza A (H1N1) 2009 monovalent vaccine (used during the 2009 through 2010 pandemic) administered without MCV4 vaccine to pregnant women. For trivalent inactivated influenza and monovalent vaccines 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 in a pre-event situation ) were administered concomitantly. We identified MedDRA terms with disproportionately higher reporting after MenACWY-D by applying criteria of Evans et al (PRR ≥2.0, Yates χ 2 ≥4.0, and number of reports ≥3 in the MCV4 group).
Results
From Jan. 1, 2005 through Dec. 31, 2011, VAERS received a total of 9120 reports after MenACWY-D in the United States. Of these, 156 reports met criteria of pregnancy reports using the automated search. After the clinical review, 103 reports were identified as reporting actual MenACWY-D vaccination during pregnancy or infant outcomes following maternal vaccination during pregnancy and were used for further analysis. Median maternal age was 17 years ( Table 1 ). Thirty-eight (36.7%) reports did not describe any AEs and the reason for submission was vaccine exposure during pregnancy. No maternal or infant deaths were reported. The most frequent pregnancy-related AE was SAB described in 17 (16.5%) reports. The median gestational age of SAB was 9 weeks (range, 5–17), we did not find any clustering in particular years or by gestational age. The most frequent nonpregnancy-related AE was urinary tract infection (UTI) in 4 (3.9%) reports followed by fever with vomiting in 3 (2.9%) reports. Ten (9.7%) reports described a variety of neonatal outcomes ( Table 2 ). One of the infants had a major congenital anomaly: aqueductal stenosis and severe ventriculomegaly of third and lateral ventricles. This infant was born to an 18-year-old mother who received MenACWY-D without other vaccines at 7 weeks’ gestation. During her pregnancy the mother took prenatal vitamins, acetaminophen, nitrofurantoin for pyelonephritis, and bupropion for depression. Pregnancy complications included anemia, pyelonephritis, and polyhydramnios from which the mother recovered. At 20 weeks’ gestation the infant was diagnosed with ventriculomegaly. A male infant was delivered by cesarean section at 38 weeks, with Apgar scores of 9 at both 1 and 5 minutes. At day 2 of life a magnetic resonance imaging examination was consistent with aqueductal stenosis with severe ventriculomegaly involving the third and lateral ventricles. Review of pediatric records from 2 months to 5 years of age revealed normal growth and development. This report was also described in the manufacturer’s prelicensure studies.
| Characteristic | Value |
|---|---|
| Serious reports, n (%) | 13 (12.6) |
| Median (range) maternal age, y (n = 98) | 17 (13–31) |
| Median (range) gestational age at time of vaccination, wk (n = 67) a | 5 (1–35) |
| Median (range) onset interval, d (n = 43) b | 3 (0–163) |
| Most common vaccines given with MCV4, n (%) | |
| HPV4 | 64 (62.1) |
| Tdap | 36 (34.9) |
| Gestational age at time of vaccination, n (%) (n = 67) a | |
| First trimester (0-13 wk) | 52 (77.6) |
| Second trimester (14-27 wk) | 13 (19.4) |
| Third trimester (≥28 wk) | 2 (3.0) |
| Reporter, n (%) (n = 103) | |
| Manufacturer | 50 (48.5) |
| Provider | 39 (37.9) |
| Other | 14 (13.6) |
a Gestational age information available for 67 reports;
b Median onset interval for 13 spontaneous abortion reports with available data was 19 d (range, 0–95 d)–onset interval for 1 stillbirth report with available data was 162 d–onset interval is difference between date of adverse event onset and vaccination date.
| Adverse event a | n (%) |
|---|---|
| Pregnancy-specific outcomes | 39 (37.9) |
| Spontaneous abortion | 17 (16.5) |
| Elective termination | 5 (4.9) |
| Nausea with/without vomiting | 4 (3.9) |
| Preterm delivery b , c | 4 (3.9) |
| Stillbirth | 2 (1.0) |
| Preeclampsia c | 2 (1.9) |
| Gestational hypertension | 1 (1.0) |
| Vaginal bleeding | 2 (1.9) |
| Abortion (unspecified) | 1 (1.0) |
| Arrest of descent c | 1 (1.0) |
| Outcomes not specific to pregnancy | 16 (15.5) |
| Urinary tract infection | 4 (3.9) |
| Fever with vomiting or abdominal pain | 3 (2.9) |
| Hypoesthesia, aphasia | 1 (1.0) |
| Injured arm | 1 (1.0) |
| Rash | 1 (1.0) |
| Severe anemia | 1 (1.0) |
| Iron-deficient anemia | 1 (1.0) |
| Syncope | 1 (1.0) |
| Tonsillitis | 1 (1.0) |
| Major depressive disorder, anxiety disorder, urinary tract infection c | 1 (1.0) |
| Pyelonephritis, depression c | 1 (1.0) |
| Neonatal outcomes | 10 (9.7) |
| Extra digit(s) on hand | 2 (1.9) |
| Aqueductal stenosis and severe ventriculomegaly of third and lateral ventricles in newborn c | 1 (1.0) |
| Seizures in premature newborn (born at 36 wks’ gestation) c | 1 (1.0) |
| Respiratory distress, pleural effusion, umbilical hernia, and mild jaundice c | 1 (1.0) |
| Respiratory distress, hypovolemia, and prematurity c | 1 (1.0) |
| Respiratory syncytial virus bronchitis and bronchiolitis in newborn c | 1 (1.0) |
| Hereditary spherocytosis c | 1 (1.0) |
| Severe prematurity (born at 25 wk’ gestation), respiratory distress, necrotizing enterocolitis, sepsis, and patent ductus arteriosus c , d | 1 (1.0) |
| Grunting, crying, and flatulence | 1 (1.0) |
| No adverse event | 38 (36.7) |
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