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Safety of meningococcal polysaccharide-protein conjugate vaccine in pregnancy: a review of the Vaccine Adverse Event Reporting System
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OBSTETRICS
Safety of meningococcal polysaccharide-protein conjugate vaccine in pregnancy: a review of the Vaccine Adverse Event Reporting System Yenlik Zheteyeva, MD; Pedro L. Moro, MD; Xin Yue, MS; Karen Broder, MD 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).
ports. 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).
STUDY DESIGN: We searched VAERS for reports of pregnant women
CONCLUSION: Our comprehensive review of reports to VAERS in preg-
who received MenACWY-D from Jan. 1, 2005 through Dec. 31, 2011. We conducted clinical review of reports and available medical records.
nant women after MenACWY-D did not identify any concerning patterns in maternal, infant, or fetal outcomes.
RESULTS: Of 103 identified reports, 38 (36.7%) did not describe any
Key words: adverse events, epidemiology, meningococcal polysaccharide-protein conjugate vaccine, pregnancy, surveillance, vaccine safety
AE. No maternal or infant deaths were reported. The most frequent pregnancy-specific AE was spontaneous abortion in 17 (16.5%) re-
Cite this article as: Zheteyeva Y, Moro PL, Yue X, et al. Safety of meningococcal polysaccharide-protein conjugate vaccine in pregnancy: a review of the Vaccine Adverse Event Reporting System. Am J Obstet Gynecol 2013;208:478.e1-6.
M
eningococcal disease, caused by Neisseria meningitidis, a gramnegative aerobic diplococci, can result in serious complications, such as brain damage, hearing loss, or learning disabilities; 11.3% of cases are fatal.1,2 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 2007.3 However, since
From the Immunization Safety Office, Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA (all authors); and the Epidemic Intelligence Service, Office of Workforce and Career Development, Centers for Disease Control and Prevention, Atlanta, GA (Dr Zheteyeva). Received Sept. 20, 2012; revised Jan. 11, 2013; accepted Feb. 18, 2013. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. The authors report no conflict of interest. Reprints are not available from the authors. 0002-9378/$36.00 © 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2013.02.027
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1991, localized outbreaks have been occurring more frequently,4 and the use of meningococcal vaccine to control these outbreaks has increased.5 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.6 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.7 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 MCV4.8 ACIP further recommended that all adolescents receive a booster dose of the vaccine at age 16 years.9 Data support the safety of MCV4 among nonpregnant per-
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sons aged 11-55 years,6 however, data on pregnant women are lacking and because of this MCV4 is not routinely recommended in pregnancy.6,10 Because pregnant women may be exposed to MCV4 inadvertently or as part of outbreak control measures, assessing safety in pregnancy is important.8 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.
M ATERIALS AND M ETHODS 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.11 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 man-
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www.AJOG.org ufacturers are required to report all AEs of which they become aware11,12; its primary purpose is to detect potential vaccine safety concerns that may be further investigated through controlled studies in defined populations.11 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).13 Reports are classified as serious based on the Code of Federal Regulations14 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 governmentsponsored 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 (ⱖ28 weeks).15 Spontaneous abortion (SAB) was defined as fetal demise ⬍20 weeks’ gestation, stillbirth was defined as fetal demise ⱖ20 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)16 compared with inactivated influenza vaccines that have an acceptable safety profile in pregnancy.17,18 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
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studies.17,18 We excluded reports from analysis if no AE was reported or if live vaccines (contraindicated during pregnancy19) or anthrax vaccine (not recommended during pregnancy in a pre-event situation20) were administered concomitantly. We identified MedDRA terms with disproportionately higher reporting after MenACWY-D by applying criteria of Evans et al16 (PRR ⱖ2.0, Yates 2 ⱖ4.0, and number of reports ⱖ3 in the MCV4 group).
R ESULTS 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
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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.21,22 Thirteen (12.6%) reports were classified as serious. Reports of serious events in the mother or with delivery included 2 reports of preeclampsia and 1 report each of: premature delivery and maternal depressive and anxiety disorder; arrest of descent and failed attempt of vacuum delivery; and pyelonephritis and depression. Serious reports in the newborns diagnosed within 1 month after birth included the aqueductal stenosis report described above; seizures in premature newborns; respiratory distress, pleural effusion, umbilical hernia, and mild jaundice; respiratory distress, hypovolemia, and prematurity; respiratory syncytial virus bronchitis and bronchiolitis; hereditary spherocytosis; and severe prematurity, respiratory distress, necrotizing enterocolitis, sepsis, and patent ductus arteriosus in a very premature newborn (24-26 weeks).
Proportional reporting ratios The PRRs screening criteria were met for higher proportional reporting after MenACWY-D in pregnancy for the MedDRA term “anemia.” No disproportionality was found in reporting for SAB, stillbirth, preterm deliveries, or congenital anomalies. Among the 3 reports coded for anemia with MedDRA, 1 report was of the woman who had the child with ventriculomegaly described above. The second case of severe anemia occurred in a 13year-old female with hematocrit of 29.4% and hemoglobin of 9.3 g/dL. Ultrasound examination of her infant at 27 weeks’ gestation showed normal fetal anatomy, normal amniotic fluid index (13.7 cm), and a normal placenta. No 478.e3
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TABLE 1
US VAERS reports received following MCV4 in pregnant women or their infants, VAERS, 2005-2011 (N ⴝ 103) Characteristic
Value
Serious reports, n (%)
13 (12.6)
Median (range) maternal age, y (n ⫽ 98)
17 (13–31)
.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. a
Median (range) gestational age at time of vaccination, wk (n ⫽ 67)
5 (1–35)
Median (range) onset interval, d (n ⫽ 43)
3 (0–163)
.............................................................................................................................................................................................................................................. b ..............................................................................................................................................................................................................................................
Most common vaccines given with MCV4, n (%)
.....................................................................................................................................................................................................................................
HPV4
64 (62.1)
Tdap
36 (34.9)
..................................................................................................................................................................................................................................... .............................................................................................................................................................................................................................................. a
Gestational age at time of vaccination, n (%) (n ⫽ 67)
.....................................................................................................................................................................................................................................
First trimester (0-13 wk)
52 (77.6)
Second trimester (14-27 wk)
13 (19.4)
..................................................................................................................................................................................................................................... .....................................................................................................................................................................................................................................
Third trimester (ⱖ28 wk)
2 (3.0)
..............................................................................................................................................................................................................................................
Reporter, n (%) (n ⫽ 103)
.....................................................................................................................................................................................................................................
Manufacturer
50 (48.5)
Provider
39 (37.9)
Other
14 (13.6)
..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................
HPV4, Human papilloma virus vaccine; MCV4, meningococcal polysaccharide-protein conjugate vaccine; Tdap, tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine; VAERS, Vaccine Adverse Event Reporting System. 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.
Zheteyeva. Meningococcal polysaccharide-protein conjugate vaccine safety in pregnancy. Am J Obstet Gynecol 2013.
further information regarding the pregnancy outcome was provided. A third nonserious report involved a 15-yearold female who presented with anemia at an unspecified time during pregnancy. The patient underwent a cesarean section due to occiput posterior descent and failure to progress and delivered a healthy male infant at 38 weeks’ gestation.
C OMMENT During 2005 through 2011, pregnancyrelated reports accounted for 1.1% of the 9120 reports to VAERS following MenACWY-D. Our review of the VAERS database did not find any unusual or unexpected pattern of maternal, infant, or fetal AEs after administration of MenACWY-D vaccine in pregnant women. SAB was the most frequent pregnancyspecific outcome. SAB is a relatively common event that occurs in about 1520% of all pregnancies.23 SAB was also the most frequent pregnancy-specific AE reported in VAERS studies of safety of
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seasonal inactivated influenza trivalent vaccine and influenza A (H1N1) 2009 monovalent vaccine that are recommended for use during pregnancy.17,18 Cohort studies of monovalent H1N1 inactivated influenza vaccines in Europe did not identify an increased risk for SAB or stillbirth after vaccination.24,25 Additionally, we did not find disproportional reporting of SAB in VAERS for MenACWY-D compared with influenza vaccines. UTI and fever with vomiting were the most common nonpregnancy-specific AEs. Pregnant women are generally at increased risk for UTIs due to pregnancy-related physiological changes such as urinary stasis and vesicoureteral reflux, and UTI incidence in pregnant women can be as high as 8%.26 In prelicensure clinical trials involving nonpregnant subjects aged 18-55 years, systemic reactions, which included fever or vomiting, were observed in as many as 62% of cases.8 Aqueductal stenosis occurs in 1 in 2000 deliveries. Genetic causes of aque-
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TABLE 2
Adverse events in pregnant women following receipt of MCV4, VAERS, 2005-2011 (N ⴝ 103) Adverse eventa
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
4 (3.9)
Stillbirth
2 (1.0)
Preeclampsia
2 (1.9)
Gestational hypertension
1 (1.0)
Vaginal bleeding
2 (1.9)
Abortion (unspecified)
1 (1.0)
Arrest of descent
1 (1.0)
..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... b,c ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... c ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... c ..............................................................................................................................................................................................................................................
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
1 (1.0)
Pyelonephritis, depression
1 (1.0)
..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... c ..................................................................................................................................................................................................................................... c ..............................................................................................................................................................................................................................................
Neonatal outcomes
10 (9.7)
.....................................................................................................................................................................................................................................
Extra digit(s) on hand
2 (1.9)
Aqueductal stenosis and severe ventriculomegaly of third and lateral ventricles in newbornc
1 (1.0)
Seizures in premature newborn (born at 36 wks’ gestation)
1 (1.0)
Respiratory distress, pleural effusion, umbilical hernia, and mild jaundicec
1 (1.0)
Respiratory distress, hypovolemia, and prematurity
1 (1.0)
Respiratory syncytial virus bronchitis and bronchiolitis in newborn
1 (1.0)
Hereditary spherocytosis
1 (1.0)
Severe prematurity (born at 25 wk’ gestation), respiratory distress, necrotizing enterocolitis, sepsis, and patent ductus arteriosusc,d
1 (1.0)
Grunting, crying, and flatulence
1 (1.0)
.....................................................................................................................................................................................................................................
..................................................................................................................................................................................................................................... c .....................................................................................................................................................................................................................................
..................................................................................................................................................................................................................................... c ..................................................................................................................................................................................................................................... c ..................................................................................................................................................................................................................................... c .....................................................................................................................................................................................................................................
..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................
No adverse event
38 (36.7)
..............................................................................................................................................................................................................................................
MCV4, meningococcal polysaccharide-protein conjugate vaccine; VAERS, Vaccine Adverse Event Reporting System. a
Adverse events are based on primary reported diagnosis identified during clinical review–1 diagnosis assigned to 1 report; Includes 1 serious report; c Serious reports; d Maternal complications included chorioamnionitis, hypertension, and placental abruption.
b
Zheteyeva. Meningococcal polysaccharide-protein conjugate vaccine safety in pregnancy. Am J Obstet Gynecol 2013.
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ductal stenosis include X-linked and autosomal recessive disorders. Acquired causes include intrauterine infection and intraventricular hemorrhage. Most cases are considered multifactorial without an identifiable cause.27 In our review we found only 1 aqueductal stenosis case; this finding is not informative and no inferences can be made. The mother was not reported to be exposed to any potential teratogens, but had kidney infection (pyelonephritis) during the pregnancy. “Anemia” was the only MedDRA term that was disproportionately more frequently reported after MenACWY-D compared with influenza vaccines. Two of the anemia reports were nonserious and in another the patient was hospitalized for conditions other than anemia. In 2 reports, information available indicated the patients recovered and had an uneventful pregnancy. Anemia is a relatively common medical condition during pregnancy occurring in 30% of pregnant women.28 Iron or folate deficiencies are the main causes of anemia in pregnancy, and adequate intake of dietary supplements can correct the condition. In addition to MenACWY-D, 2 other vaccines are licensed for prevention of meningococcal disease in the United States: MCV4 Menveo (MenACWYCRM) (licensed 2010; Novartis Vaccines and Diagnostics, Inc., Cambridge, MA) and quadrivalent meningococcal polysaccharide vaccine (MPSV4) Menomune (licensed 1981; Sanofi Pasteur). Pregnant women were excluded from prelicensure trials for these meningococcal vaccines, and the limited safety data come from women who were inadvertently exposed during pregnancy in the prelicensure clinical trials.29 Among 1113 recipients of MenACWY-D in prelicensure trials, 6 pregnancies were reported (no SAB, 1 congenital anomaly [hydrocephalus]).22 The case of hydrocephalus was verified with the manufacturer and was found to be the same case as reported to VAERS (described above). For MenACWY-CRM, 37 pregnancies occurred among 3952 women given the vaccine. Seven of them experienced SAB, no congenital anomalies were reported. Studies of vaccination with MPSV4 (Menomune) during pregnancy did not document AEs among pregnant
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women or newborns.30,31 Pregnancy registries are available for 2 of these vaccines. Sanofi Pasteur has developed a MenACWY-D vaccine pregnancy registry to prospectively collect data from health care providers of patients who received MenACWY-D vaccine during pregnancy.21 Similarly, Novartis Vaccines and Diagnostics Inc maintains a pregnancy registry to monitor the fetal outcomes of pregnant women exposed to MenACWYCRM.22 VAERS is a national surveillance system that is used to detect signals of potential vaccine safety concerns, which are further explored in carefully designed epidemiological studies. VAERS has inherent limitations of all passive surveillance systems including underreporting, reporting biases, and inconsistency in quality of reports. Additionally, the VAERS form does not contain a field for pregnancy status, making it necessary to use sophisticated search strategies to look for these reports. VAERS does not collect data on the number of pregnant women vaccinated, therefore it is not possible to directly calculate incidence/ prevalence or reporting rates of AEs. Events that occur temporally closer to the time of vaccination are more likely to be reported to VAERS11; conversely, events (eg, birth defects) diagnosed months after the vaccination may be underreported. Therefore, VAERS data must be interpreted with caution and cannot generally be used to assess causality.11 The regulatory definition of a serious report in VAERS can have limitations as it may not reflect the true severity of an outcome. For example, in our review 2 stillbirth reports in women vaccinated at 3 and 24 weeks were coded as nonserious because the patients were seen in the emergency department but were not hospitalized. Since MCV4 is not routinely recommended for use in pregnancy no national survey has been conducted to assess MCV4 coverage in pregnant women. Therefore, because there are no data on the number of MenACWY-D doses administered to pregnant women, reporting rates cannot be estimated and findings are difficult to interpret. 478.e5
www.AJOG.org In our review of reports to VAERS in pregnant women who received MenACWY-D we did not identify any safety concerns. This review, while limited, supports the ACIP recommendations that MenACWY-D vaccine may be used in pregnant women at increased risk for meningococcal disease.8 This information is particularly important because of a pregnancy rate in teenagers of 70.6 per 1000 females in 200532 who are the main group to receive MCV4 and who may inadvertently receive this vaccine while pregnant. Obstetricians and gynecologists are an important source of health information for pregnant women, and can play a crucial role in preventing disease in adolescent and adult pregnancies through the implementation of vaccine recommendations. This information may also be informative to global efforts to prevent and control meningococcal disease in pregnant women who reside in highly endemic countries.33 f ACKNOWLEDGMENTS We thank Dr Janet Cragan from the Division of Birth Defects and Developmental Disabilities at the Centers for Disease Control and Prevention (CDC) for her valuable expert advice. We also thank the CDC’s Immunization Safety Office staff whose work allowed the activity to be conducted.
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29. Food and Drug Administration. Vaccines licensed for immunization and distribution in the US with supporting documents. Available at: http://www.fda.gov/BiologicsBloodVaccines/ Vaccines/ApprovedProducts/ucm093830.htm. Accessed Sept. 17, 2012. 30. Leston GW, Little JR, Ottman J, Miller GL. Meningococcal vaccine in pregnancy: an assessment of infant risk. Pediatr Infect Dis J 1998;17:261-3. 31. de Andrade Carvalho A, Giampaglia CM, Kimura H, et al. Maternal and infant antibody response to meningococcal vaccination in pregnancy. Lancet 1977;2:809-11. 32. Martinez G, Copen CE, Abma JC. Teenagers in the United States: sexual activity, contraceptive use, and childbearing, 2006-2010 national survey of family growth. Vital Health Stat 23 2011;(31):1-35. 33. Djingarey MH, Barry R, Bonkoungou M, et al. Effectively introducing a new meningococcal A conjugate vaccine in Africa: the Burkina Faso experience. Vaccine 2012;30: B40-5.
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OBSTETRICS
Safety of meningococcal polysaccharide-protein conjugate vaccine in pregnancy: a review of the Vaccine Adverse Event Reporting System Yenlik Zheteyeva, MD; Pedro L. Moro, MD; Xin Yue, MS; Karen Broder, MD 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).
ports. 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).
STUDY DESIGN: We searched VAERS for reports of pregnant women
CONCLUSION: Our comprehensive review of reports to VAERS in preg-
who received MenACWY-D from Jan. 1, 2005 through Dec. 31, 2011. We conducted clinical review of reports and available medical records.
nant women after MenACWY-D did not identify any concerning patterns in maternal, infant, or fetal outcomes.
RESULTS: Of 103 identified reports, 38 (36.7%) did not describe any
Key words: adverse events, epidemiology, meningococcal polysaccharide-protein conjugate vaccine, pregnancy, surveillance, vaccine safety
AE. No maternal or infant deaths were reported. The most frequent pregnancy-specific AE was spontaneous abortion in 17 (16.5%) re-
Cite this article as: Zheteyeva Y, Moro PL, Yue X, et al. Safety of meningococcal polysaccharide-protein conjugate vaccine in pregnancy: a review of the Vaccine Adverse Event Reporting System. Am J Obstet Gynecol 2013;208:478.e1-6.
M
eningococcal disease, caused by Neisseria meningitidis, a gramnegative aerobic diplococci, can result in serious complications, such as brain damage, hearing loss, or learning disabilities; 11.3% of cases are fatal.1,2 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 2007.3 However, since
From the Immunization Safety Office, Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA (all authors); and the Epidemic Intelligence Service, Office of Workforce and Career Development, Centers for Disease Control and Prevention, Atlanta, GA (Dr Zheteyeva). Received Sept. 20, 2012; revised Jan. 11, 2013; accepted Feb. 18, 2013. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. The authors report no conflict of interest. Reprints are not available from the authors. 0002-9378/$36.00 © 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2013.02.027
478.e1
1991, localized outbreaks have been occurring more frequently,4 and the use of meningococcal vaccine to control these outbreaks has increased.5 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.6 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.7 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 MCV4.8 ACIP further recommended that all adolescents receive a booster dose of the vaccine at age 16 years.9 Data support the safety of MCV4 among nonpregnant per-
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sons aged 11-55 years,6 however, data on pregnant women are lacking and because of this MCV4 is not routinely recommended in pregnancy.6,10 Because pregnant women may be exposed to MCV4 inadvertently or as part of outbreak control measures, assessing safety in pregnancy is important.8 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.
M ATERIALS AND M ETHODS 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.11 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 man-
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www.AJOG.org ufacturers are required to report all AEs of which they become aware11,12; its primary purpose is to detect potential vaccine safety concerns that may be further investigated through controlled studies in defined populations.11 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).13 Reports are classified as serious based on the Code of Federal Regulations14 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 governmentsponsored 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 (ⱖ28 weeks).15 Spontaneous abortion (SAB) was defined as fetal demise ⬍20 weeks’ gestation, stillbirth was defined as fetal demise ⱖ20 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)16 compared with inactivated influenza vaccines that have an acceptable safety profile in pregnancy.17,18 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
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studies.17,18 We excluded reports from analysis if no AE was reported or if live vaccines (contraindicated during pregnancy19) or anthrax vaccine (not recommended during pregnancy in a pre-event situation20) were administered concomitantly. We identified MedDRA terms with disproportionately higher reporting after MenACWY-D by applying criteria of Evans et al16 (PRR ⱖ2.0, Yates 2 ⱖ4.0, and number of reports ⱖ3 in the MCV4 group).
R ESULTS 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
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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.21,22 Thirteen (12.6%) reports were classified as serious. Reports of serious events in the mother or with delivery included 2 reports of preeclampsia and 1 report each of: premature delivery and maternal depressive and anxiety disorder; arrest of descent and failed attempt of vacuum delivery; and pyelonephritis and depression. Serious reports in the newborns diagnosed within 1 month after birth included the aqueductal stenosis report described above; seizures in premature newborns; respiratory distress, pleural effusion, umbilical hernia, and mild jaundice; respiratory distress, hypovolemia, and prematurity; respiratory syncytial virus bronchitis and bronchiolitis; hereditary spherocytosis; and severe prematurity, respiratory distress, necrotizing enterocolitis, sepsis, and patent ductus arteriosus in a very premature newborn (24-26 weeks).
Proportional reporting ratios The PRRs screening criteria were met for higher proportional reporting after MenACWY-D in pregnancy for the MedDRA term “anemia.” No disproportionality was found in reporting for SAB, stillbirth, preterm deliveries, or congenital anomalies. Among the 3 reports coded for anemia with MedDRA, 1 report was of the woman who had the child with ventriculomegaly described above. The second case of severe anemia occurred in a 13year-old female with hematocrit of 29.4% and hemoglobin of 9.3 g/dL. Ultrasound examination of her infant at 27 weeks’ gestation showed normal fetal anatomy, normal amniotic fluid index (13.7 cm), and a normal placenta. No 478.e3
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TABLE 1
US VAERS reports received following MCV4 in pregnant women or their infants, VAERS, 2005-2011 (N ⴝ 103) Characteristic
Value
Serious reports, n (%)
13 (12.6)
Median (range) maternal age, y (n ⫽ 98)
17 (13–31)
.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. a
Median (range) gestational age at time of vaccination, wk (n ⫽ 67)
5 (1–35)
Median (range) onset interval, d (n ⫽ 43)
3 (0–163)
.............................................................................................................................................................................................................................................. b ..............................................................................................................................................................................................................................................
Most common vaccines given with MCV4, n (%)
.....................................................................................................................................................................................................................................
HPV4
64 (62.1)
Tdap
36 (34.9)
..................................................................................................................................................................................................................................... .............................................................................................................................................................................................................................................. a
Gestational age at time of vaccination, n (%) (n ⫽ 67)
.....................................................................................................................................................................................................................................
First trimester (0-13 wk)
52 (77.6)
Second trimester (14-27 wk)
13 (19.4)
..................................................................................................................................................................................................................................... .....................................................................................................................................................................................................................................
Third trimester (ⱖ28 wk)
2 (3.0)
..............................................................................................................................................................................................................................................
Reporter, n (%) (n ⫽ 103)
.....................................................................................................................................................................................................................................
Manufacturer
50 (48.5)
Provider
39 (37.9)
Other
14 (13.6)
..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................
HPV4, Human papilloma virus vaccine; MCV4, meningococcal polysaccharide-protein conjugate vaccine; Tdap, tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine; VAERS, Vaccine Adverse Event Reporting System. 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.
Zheteyeva. Meningococcal polysaccharide-protein conjugate vaccine safety in pregnancy. Am J Obstet Gynecol 2013.
further information regarding the pregnancy outcome was provided. A third nonserious report involved a 15-yearold female who presented with anemia at an unspecified time during pregnancy. The patient underwent a cesarean section due to occiput posterior descent and failure to progress and delivered a healthy male infant at 38 weeks’ gestation.
C OMMENT During 2005 through 2011, pregnancyrelated reports accounted for 1.1% of the 9120 reports to VAERS following MenACWY-D. Our review of the VAERS database did not find any unusual or unexpected pattern of maternal, infant, or fetal AEs after administration of MenACWY-D vaccine in pregnant women. SAB was the most frequent pregnancyspecific outcome. SAB is a relatively common event that occurs in about 1520% of all pregnancies.23 SAB was also the most frequent pregnancy-specific AE reported in VAERS studies of safety of
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seasonal inactivated influenza trivalent vaccine and influenza A (H1N1) 2009 monovalent vaccine that are recommended for use during pregnancy.17,18 Cohort studies of monovalent H1N1 inactivated influenza vaccines in Europe did not identify an increased risk for SAB or stillbirth after vaccination.24,25 Additionally, we did not find disproportional reporting of SAB in VAERS for MenACWY-D compared with influenza vaccines. UTI and fever with vomiting were the most common nonpregnancy-specific AEs. Pregnant women are generally at increased risk for UTIs due to pregnancy-related physiological changes such as urinary stasis and vesicoureteral reflux, and UTI incidence in pregnant women can be as high as 8%.26 In prelicensure clinical trials involving nonpregnant subjects aged 18-55 years, systemic reactions, which included fever or vomiting, were observed in as many as 62% of cases.8 Aqueductal stenosis occurs in 1 in 2000 deliveries. Genetic causes of aque-
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TABLE 2
Adverse events in pregnant women following receipt of MCV4, VAERS, 2005-2011 (N ⴝ 103) Adverse eventa
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
4 (3.9)
Stillbirth
2 (1.0)
Preeclampsia
2 (1.9)
Gestational hypertension
1 (1.0)
Vaginal bleeding
2 (1.9)
Abortion (unspecified)
1 (1.0)
Arrest of descent
1 (1.0)
..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... b,c ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... c ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... c ..............................................................................................................................................................................................................................................
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
1 (1.0)
Pyelonephritis, depression
1 (1.0)
..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... ..................................................................................................................................................................................................................................... c ..................................................................................................................................................................................................................................... c ..............................................................................................................................................................................................................................................
Neonatal outcomes
10 (9.7)
.....................................................................................................................................................................................................................................
Extra digit(s) on hand
2 (1.9)
Aqueductal stenosis and severe ventriculomegaly of third and lateral ventricles in newbornc
1 (1.0)
Seizures in premature newborn (born at 36 wks’ gestation)
1 (1.0)
Respiratory distress, pleural effusion, umbilical hernia, and mild jaundicec
1 (1.0)
Respiratory distress, hypovolemia, and prematurity
1 (1.0)
Respiratory syncytial virus bronchitis and bronchiolitis in newborn
1 (1.0)
Hereditary spherocytosis
1 (1.0)
Severe prematurity (born at 25 wk’ gestation), respiratory distress, necrotizing enterocolitis, sepsis, and patent ductus arteriosusc,d
1 (1.0)
Grunting, crying, and flatulence
1 (1.0)
.....................................................................................................................................................................................................................................
..................................................................................................................................................................................................................................... c .....................................................................................................................................................................................................................................
..................................................................................................................................................................................................................................... c ..................................................................................................................................................................................................................................... c ..................................................................................................................................................................................................................................... c .....................................................................................................................................................................................................................................
..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................
No adverse event
38 (36.7)
..............................................................................................................................................................................................................................................
MCV4, meningococcal polysaccharide-protein conjugate vaccine; VAERS, Vaccine Adverse Event Reporting System. a
Adverse events are based on primary reported diagnosis identified during clinical review–1 diagnosis assigned to 1 report; Includes 1 serious report; c Serious reports; d Maternal complications included chorioamnionitis, hypertension, and placental abruption.
b
Zheteyeva. Meningococcal polysaccharide-protein conjugate vaccine safety in pregnancy. Am J Obstet Gynecol 2013.
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ductal stenosis include X-linked and autosomal recessive disorders. Acquired causes include intrauterine infection and intraventricular hemorrhage. Most cases are considered multifactorial without an identifiable cause.27 In our review we found only 1 aqueductal stenosis case; this finding is not informative and no inferences can be made. The mother was not reported to be exposed to any potential teratogens, but had kidney infection (pyelonephritis) during the pregnancy. “Anemia” was the only MedDRA term that was disproportionately more frequently reported after MenACWY-D compared with influenza vaccines. Two of the anemia reports were nonserious and in another the patient was hospitalized for conditions other than anemia. In 2 reports, information available indicated the patients recovered and had an uneventful pregnancy. Anemia is a relatively common medical condition during pregnancy occurring in 30% of pregnant women.28 Iron or folate deficiencies are the main causes of anemia in pregnancy, and adequate intake of dietary supplements can correct the condition. In addition to MenACWY-D, 2 other vaccines are licensed for prevention of meningococcal disease in the United States: MCV4 Menveo (MenACWYCRM) (licensed 2010; Novartis Vaccines and Diagnostics, Inc., Cambridge, MA) and quadrivalent meningococcal polysaccharide vaccine (MPSV4) Menomune (licensed 1981; Sanofi Pasteur). Pregnant women were excluded from prelicensure trials for these meningococcal vaccines, and the limited safety data come from women who were inadvertently exposed during pregnancy in the prelicensure clinical trials.29 Among 1113 recipients of MenACWY-D in prelicensure trials, 6 pregnancies were reported (no SAB, 1 congenital anomaly [hydrocephalus]).22 The case of hydrocephalus was verified with the manufacturer and was found to be the same case as reported to VAERS (described above). For MenACWY-CRM, 37 pregnancies occurred among 3952 women given the vaccine. Seven of them experienced SAB, no congenital anomalies were reported. Studies of vaccination with MPSV4 (Menomune) during pregnancy did not document AEs among pregnant
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women or newborns.30,31 Pregnancy registries are available for 2 of these vaccines. Sanofi Pasteur has developed a MenACWY-D vaccine pregnancy registry to prospectively collect data from health care providers of patients who received MenACWY-D vaccine during pregnancy.21 Similarly, Novartis Vaccines and Diagnostics Inc maintains a pregnancy registry to monitor the fetal outcomes of pregnant women exposed to MenACWYCRM.22 VAERS is a national surveillance system that is used to detect signals of potential vaccine safety concerns, which are further explored in carefully designed epidemiological studies. VAERS has inherent limitations of all passive surveillance systems including underreporting, reporting biases, and inconsistency in quality of reports. Additionally, the VAERS form does not contain a field for pregnancy status, making it necessary to use sophisticated search strategies to look for these reports. VAERS does not collect data on the number of pregnant women vaccinated, therefore it is not possible to directly calculate incidence/ prevalence or reporting rates of AEs. Events that occur temporally closer to the time of vaccination are more likely to be reported to VAERS11; conversely, events (eg, birth defects) diagnosed months after the vaccination may be underreported. Therefore, VAERS data must be interpreted with caution and cannot generally be used to assess causality.11 The regulatory definition of a serious report in VAERS can have limitations as it may not reflect the true severity of an outcome. For example, in our review 2 stillbirth reports in women vaccinated at 3 and 24 weeks were coded as nonserious because the patients were seen in the emergency department but were not hospitalized. Since MCV4 is not routinely recommended for use in pregnancy no national survey has been conducted to assess MCV4 coverage in pregnant women. Therefore, because there are no data on the number of MenACWY-D doses administered to pregnant women, reporting rates cannot be estimated and findings are difficult to interpret. 478.e5
www.AJOG.org In our review of reports to VAERS in pregnant women who received MenACWY-D we did not identify any safety concerns. This review, while limited, supports the ACIP recommendations that MenACWY-D vaccine may be used in pregnant women at increased risk for meningococcal disease.8 This information is particularly important because of a pregnancy rate in teenagers of 70.6 per 1000 females in 200532 who are the main group to receive MCV4 and who may inadvertently receive this vaccine while pregnant. Obstetricians and gynecologists are an important source of health information for pregnant women, and can play a crucial role in preventing disease in adolescent and adult pregnancies through the implementation of vaccine recommendations. This information may also be informative to global efforts to prevent and control meningococcal disease in pregnant women who reside in highly endemic countries.33 f ACKNOWLEDGMENTS We thank Dr Janet Cragan from the Division of Birth Defects and Developmental Disabilities at the Centers for Disease Control and Prevention (CDC) for her valuable expert advice. We also thank the CDC’s Immunization Safety Office staff whose work allowed the activity to be conducted.
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www.fda.gov/downloads/biologicsbloodvaccines/ vaccines/approvedproducts/ucm131170.pdf. Accessed Sept. 17, 2012. 7. Terranella A, Cohn A, Clark T. Meningococcal conjugate vaccines: optimizing global impact. Infect Drug Resist 2011;4:161-9. 8. Bilukha OO, Rosenstein N; National Center for Infectious Diseases, Centers for Disease Control and Prevention (CDC). Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2005;54(RR-7):1-21. 9. Centers for Disease Control and Prevention (CDC). Updated recommendations for use of meningococcal conjugate vaccines–Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Morb Mortal Wkly Rep 2011;60: 72-6. 10. National Center for Immunization and Respiratory Diseases. General recommendations on immunization–recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2011;60:1-64. 11. Varricchio F, Iskander J, DeStefano F. Understanding vaccine safety information from the Vaccine Adverse Event Reporting System. Pediatr Infect Dis J 2004;23:287-94. 12. Chen RT, Rastogi SC, Mullen JR, et al. The Vaccine Adverse Event Reporting System (VAERS). Vaccine 1994;12:542-50. 13. International Federation of Pharmaceutical Manufacturers and Associations (IFPMA). Medical dictionary for regulatory activities (MedDRA). Available at: http://www.meddramsso. com/. Accessed March 1, 2013. 14. Food and Drug Administration. 21 Code of Federal Regulation Part 600.80. Postmarketing reporting of adverse experiences. 1997;62: Federal Register: 52252-3. Available at: http:// www.accessdata.fda.gov/scripts/cdrh/cfdocs/ cfcfr/CFRSearch.cfm?fr⫽600.80. Accessed Sept. 17, 2012. 15. Prenatal care. In: Cunningham G, Leveno KJ, Bloom SL, Hauth JC, Gilstrap LC, Wenstrom KD, eds. Williams obstetrics. New York: McGraw-Hill Companies Inc; 2001:221-47. 16. Evans SJW, Waller PC, Davis S. Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports. J Pharmacoepidemiol Drug Saf 2001;10:483-6. 17. Moro PL, Broder K, Zheteyeva Y, et al. Adverse events in pregnant women following administration of trivalent inactivated influenza vaccine and live attenuated influenza vaccine in the Vaccine Adverse Event Reporting System, 1990-2009. Am J Obstet Gynecol 2011; 204:e1-7. 18. Moro PL, Broder K, Zheteyeva Y, et al. Adverse events in pregnant women following administration of influenza A (H1N1) 2009 monovalent vaccine reported to the Vaccine Adverse Event Reporting System (VAERS). Am J Obstet Gynecol 2011;205:e1-9. 19. Kroger AT, Atkinson WL, Marcuse EK, Pickering LK; Advisory Committee on Immu-
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