Advertisement

Adverse event reports after tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccines in pregnant women

      Objective

      We sought to characterize reports to the Vaccine Adverse Event Reporting System (VAERS) of pregnant women who received tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap).

      Study Design

      We searched VAERS for reports of pregnant women who received Tdap from Jan. 1, 2005, through June 30, 2010. We conducted a clinical review of reports and available medical records.

      Results

      We identified 132 reports of Tdap administered to pregnant women; 55 (42%) described no adverse event (AE). No maternal or infant deaths were reported. The most frequent pregnancy-specific AE was spontaneous abortion in 22 (16.7%) reports. Injection site reactions were the most frequent non-pregnancy–specific AE found in 6 (4.5%) reports. One report with a major congenital anomaly (gastroschisis) was identified.

      Conclusion

      During a time when Tdap was not routinely recommended in pregnancy, review of reports to VAERS in pregnant women after Tdap did not identify any concerning patterns in maternal, infant, or fetal outcomes.

      Key words

      Administration of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) to a pregnant woman induces formation of maternal antibodies against pertussis that are transferred to the fetus across the placenta.
      • Gall S.A.
      • Myers J.
      • Pichichero M.
      Maternal immunization with tetanus-diphtheria-pertussis vaccine: effect on maternal and neonatal serum antibody levels.
      Transplacentally transferred antibodies might provide protection against pertussis infection in young infants.
      • Gall S.A.
      • Myers J.
      • Pichichero M.
      Maternal immunization with tetanus-diphtheria-pertussis vaccine: effect on maternal and neonatal serum antibody levels.
      • Leuridan E.
      • Hens N.
      • Peeters N.
      • de Witte L.
      • Van der Meeren O.
      • Van Damme P.
      Effect of a pre-pregnancy pertussis booster dose on maternal antibody titers in young infants.
      In addition, Tdap vaccination of pregnant women and other family members directly prevents pertussis in these individuals and may indirectly protect infants by reducing the risk for pertussis transmission, a strategy known as cocooning.
      • Healy C.M.
      • Rench M.A.
      • Baker C.J.
      Implementation of cocooning against pertussis in a high-risk population.
      Infants <3 months of age are too young to receive the primary pertussis vaccination series and have the highest risk for death from pertussis. Therefore, strategies to prevent pertussis in these infants are essential.
      • Cortese M.M.
      • Baughman A.L.
      • Zhang R.
      • Srivastava P.U.
      • Wallace G.S.
      Pertussis hospitalizations among infants in the United States, 1993 to 2004.
      For Editors' Commentary, see Contents
      Tdap was licensed by the Food and Drug Administration (FDA) in 2005 for booster immunization against tetanus, diphtheria, and pertussis for individuals 10-64 years of age, and is available in the United States from 2 manufacturers: Adacel (Sanofi Pasteur, Swiftwater, PA)
      Food and Drug Administration
      Vaccines and Related Biological Products Advisory Committee, March 15, 2005: FDA Adacel briefing information.
      and Boostrix (GlaxoSmithKline Biologicals, Rixensart, Belgium).
      Food and Drug Administration
      Vaccines and Related Biological Products Advisory Committee, March 15, 2005: FDA Boostrix briefing information.
      Since 2008 the Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) has recommended using Tdap in the immediate postpartum period in women who did not previously receive Tdap to protect both mothers and infants from pertussis.
      • Murphy T.V.
      • Slade B.A.
      • Broder K.R.
      • et al.
      Prevention of pertussis, tetanus, and diphtheria among pregnant and postpartum women and their infants: recommendations of the Advisory Committee on Immunization Practices (ACIP).
      ACIP did not routinely recommend use of Tdap in pregnant women, but recommended that providers consider use in certain situations that included instances when a pregnant woman has insufficient tetanus or diphtheria protection until delivery, or is at increased risk for pertussis (eg, adolescents aged 11-18 years, health care personnel, and women employed in institutions or living in a community in which a pertussis outbreak is occurring).
      • Murphy T.V.
      • Slade B.A.
      • Broder K.R.
      • et al.
      Prevention of pertussis, tetanus, and diphtheria among pregnant and postpartum women and their infants: recommendations of the Advisory Committee on Immunization Practices (ACIP).
      In 2011 ACIP assessed that the strategy focusing on cocooning had not achieved the intended goal of reducing the burden of pertussis in infants. In October 2011, CDC published an updated ACIP recommendation that health care providers administer Tdap during the third or late second trimester (>20 weeks' gestation) to women who have not previously received Tdap.
      Centers for Disease Control and Prevention (CDC)
      Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) in pregnant women and persons who have or anticipate having close contact with an infant aged <12 months–Advisory Committee on Immunization Practices (ACIP), 2011.
      To provide safety evidence to help inform the ACIP deliberations for Tdap use in pregnant women, we conducted a review of reports to the Vaccine Adverse Event Reporting System (VAERS) of pregnant women given Tdap from 2005 through 2010.

      Materials and Methods

      Data sources

      VAERS is a spontaneous reporting system coadministered by CDC and FDA.
      US Department of Health and Human Services
      Vaccine Adverse Event Reporting System (VAERS).
      Established in 1990, VAERS monitors vaccine safety and accepts adverse event (AE) reports following receipt of any US-licensed vaccine.
      • Varricchio F.
      • Iskander J.
      • DeStefano F.
      Understanding vaccine safety information from the Vaccine Adverse Event Reporting System.
      VAERS is not designed to assess causal associations between vaccines and AEs; its primary purpose is to detect potential vaccine safety concerns that may be further investigated in defined populations.
      • Chen R.T.
      • Rastogi S.C.
      • Mullen J.R.
      • et al.
      The Vaccine Adverse Event Reporting System (VAERS).
      The VAERS report form collects demographic and health information, including information about the vaccination and AE experience.
      US Department of Health and Human Services
      Vaccine Adverse Event Reporting System form.
      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).
      Northrop Grumman Corporation
      Medical Dictionary for Regulatory Activities maintenance and support services organization.
      Each report can be coded with ≥1 MedDRA term. Reports are also classified as “serious” based on the Code of Federal Regulations
      US Food and Drug Administration
      21 Code of Federal Regulation Part 600.80 Postmarketing reporting of adverse experiences.
      if they contain information that the AE resulted in death, hospitalization, prolongation of hospitalization, life-threatening illness, persistent or significant disability, or congenital anomalies. For this study, the definition of “serious” was slightly modified and did not include reports on hospitalizations for delivery unless they required prolonged stay in a hospital due to delivery complications or postpartum conditions. Medical records are routinely requested for nonmanufacturer serious VAERS reports.
      We searched the VAERS database for reports of pregnant women vaccinated in the United States with Tdap, with or without other vaccines, from Jan. 1, 2005, through June 30, 2010. We conducted an automated search using the following criteria: MedDRA terms in 2 System Organ Classes “Pregnancy, Puerperium, and Perinatal Conditions” and “Congenital, Familial, and Genetic Disorders”; MedDRA term “Drug Exposure During Pregnancy”; and a text string search for the term “preg” in the report. Reports that had at least one of these criteria were included in the data set for further evaluation.

      Clinical reviews

      CDC and FDA medical officers reviewed all US reports identified in the VAERS database using the automated search to confirm pregnancy status at time of vaccination, calculate gestational age, and characterize AEs. We included reports on infants born to women vaccinated with Tdap during pregnancy. For each report we assigned a primary diagnosis. If >1 AE was reported for the same individual, we assigned the diagnosis based on what we believed was the primary clinical event of concern and assumed the primary event was the pregnancy-specific event unless information suggested otherwise. Complex reports were reviewed by physicians on the study team with expertise in obstetrics and neonatology. If a VAERS report described AEs in >1 person, we treated each person as a separate report. Reports that indicated the reported subject was not pregnant or that Tdap was administered prior to the last menstrual period were excluded.
      Gestational age at the time of vaccination and at the time of the AE was calculated based on: (1) clinical determination of health care provider, (2) earliest ultrasound assessment (if the former was not available), or (3) last menstrual period, estimated delivery date, or estimated date of conception (if the first 2 options were not available) found in VAERS report and/or medical records. We used the following definition for trimesters: first (0-13 weeks), second (14-27 weeks), and third (≥28 weeks).
      Prenatal care.
      Spontaneous abortion (SAB) was defined as fetal demise <20 weeks' gestation, stillbirth was defined as fetal demise ≥20 weeks' gestation, and preterm delivery was defined as a live birth <37 weeks' gestation. Causality between reported AEs and Tdap was not assessed.

      Proportional reporting ratios

      To assess for disproportionately higher reporting of AEs after Tdap administered to pregnant women, we calculated proportional reporting ratios (PRRs)
      • Evans S.J.W.
      • Waller P.C.
      • Davis S.
      Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports.
      • Banks D.
      • Woo E.J.
      • Burwen D.R.
      • Perucci P.
      • Braun M.M.
      • Ball R.
      Comparing data mining methods on the VAERS database.
      compared to inactivated influenza vaccines, which have been determined to have an acceptable safety profile in pregnancy.
      • Moro P.L.
      • 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.
      • Moro P.L.
      • 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).
      We compared proportions of MedDRA terms after Tdap with proportions of the same MedDRA terms after trivalent inactivated influenza vaccines (TIV) and influenza A (H1N1) 2009 monovalent vaccine (used during the 2009 through 2010 pandemic) administered without Tdap to pregnant women. For TIV and monovalent vaccine administered in pregnancy, we used VAERS reports identified for previously conducted and published studies.
      • Moro P.L.
      • 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.
      • Moro P.L.
      • 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).
      We excluded reports from analysis if no AE was reported or if live vaccines (contraindicated during pregnancy
      • Kroger A.T.
      • Atkinson W.L.
      • Marcuse E.K.
      • Pickering L.K.
      Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC)
      General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP).
      ) or anthrax vaccine (not recommended during pregnancy
      • Wright J.G.
      • Quinn C.P.
      • Shadomy S.
      • Messonnier N.
      Centers for Disease Control and Prevention (CDC)
      Use of anthrax vaccine in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009.
      ) were administered concomitantly. We identified MedDRA terms with disproportionately higher reporting after Tdap by applying criteria of Evans et al
      • Evans S.J.W.
      • Waller P.C.
      • Davis S.
      Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports.
      (PRR ≥2.0, Yates χ2 ≥4.0, and number of reports ≥3 in the Tdap group). Clinical reviews were conducted for all MedDRA terms with a PRR ≥2.0.
      Because VAERS is a routine, government-sponsored surveillance system that does not meet the definition of research, this investigation was not subject to institutional review board review and informed consent requirements.

      Results

      During Jan. 1, 2005, through June 30, 2010, VAERS received a total of 106,573 US reports after Tdap; 163 reports met criteria of pregnancy reports using the automated search. Of these reports, 33 were excluded: 28 reports indicated that the subject was not pregnant, 2 reports indicated that Tdap was received postpartum, 2 reports indicated vaccination in children, and 1 report was a duplicate. Two reports described AEs in infant and mother; each of these reports was treated as 2 separate reports (1 for infant and 1 for mother). After the clinical review, 132 reports were identified as true pregnancy reports and were used for further analysis. Six (4.5%) reports were classified as serious and included 2 reports of ruptured ectopic pregnancies that required laparotomy; and 1 report each of stillbirth at 37 weeks' gestation due to placental abruption, influenza, gastroschisis in a newborn, and laryngotracheomalacia in a 3-month-old infant. In all these reports, the serious classification was based on the person requiring hospitalization. No maternal or infant deaths were reported.
      Characteristics of VAERS reports are presented in Table 1. A majority of the reports (69, 52.3%) were received from manufacturers. In 48 (36.4%) reports Tdap was the only vaccine received. The median maternal age was 22 years. Information to determine the trimester of Tdap exposure was available for 110 (83.3%) reports. In most of the reports where trimester at time of vaccination was known, 85 (77.3%), indicated that Tdap was administered during the first trimester of pregnancy. A total of 95 (72.0%) reports indicated administration of Adacel.
      TABLE 1US VAERS reports following Tdap in pregnant women (n = 132)
      CharacteristicValue
      Serious reports, n (%)6 (4.5)
      Tdap administered alone,
      Other vaccines given with Tdap included meningococcal conjugate (7; 5.4%); human papillomavirus (7; 5.4%); measles, mumps, and rubella (4; 3.1%); and influenza (3; 2.3%);
      n (%)
      48 (36.4)
      Median maternal age, y (range)
      Missing for 1 pregnant woman;
      22 (13–42)
      Median interval from vaccination to adverse event, d (range)
      Unknown for 61 reports;
      7 (0–268)
      Median gestational age at time of vaccination, wk (range)
      Unknown for 43 reports;
      6 (1–37)
      Trimester of pregnancy at time of vaccination (n = 110),
      Unknown for 22 reports;
      n (%)
       First (0–13 wk)85 (77.3)
       Second (14–27 wk)21 (19.1)
       Third (≥28 wk)4 (3.6)
      Brand name of Tdap, n (%)
       Adacel
      Sanofi Pasteur, Swiftwater, PA;
      95 (72.0)
       Boostrix
      GlaxoSmithKline Biologicals, Rixensart, Belgium.
      20 (15.2)
       Unknown17 (12.9)
      Type of reporter, n (%)
       Manufacturer69 (52.3)
       Provider42 (31.8)
       Other20 (15.2)
       Patient/parent1 (0.8)
      Characteristics of Vaccine Adverse Event Reporting System (VAERS) reports received following Tdap vaccine in pregnant women, United States, Jan. 1, 2005, through June 30, 2010 (n = 132).
      Tdap, tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis.
      Zheteyeva. Safety of Tdap in pregnancy. Am J Obstet Gynecol 2012.
      a Other vaccines given with Tdap included meningococcal conjugate (7; 5.4%); human papillomavirus (7; 5.4%); measles, mumps, and rubella (4; 3.1%); and influenza (3; 2.3%);
      b Missing for 1 pregnant woman;
      c Unknown for 61 reports;
      d Unknown for 43 reports;
      e Unknown for 22 reports;
      f Sanofi Pasteur, Swiftwater, PA;
      g GlaxoSmithKline Biologicals, Rixensart, Belgium.
      In all, 55 (41.7%) reports did not describe any AE; these reports were submitted because vaccine had been administered during pregnancy at a time period when Tdap in pregnancy was not routinely recommended (Table 2). The most frequent pregnancy-specific outcome was SAB in 22 (16.7%) reports. The median gestational age at the time of SAB was 9 weeks (range, 5–16 weeks). The median onset interval between vaccination and SAB was 33 days (range, 9–61 days). We did not observe any temporal clustering of SAB reports. Two stillbirth cases were reported. One case occurred in a 20-year-old woman at 37 weeks of gestation and was reported to be due to placental abruption; Tdap was administered several hours before the outcome. The other case was in a 27-year-old woman at 22 weeks of gestation (46 days after exposure to Tdap) with no other pregnancy complications reported before fetal demise.
      TABLE 2Adverse events
      Based on primary reported diagnosis identified during clinical review–1 diagnosis assigned to 1 report;
      in pregnant women following Tdap vaccine, VAERS
      Adverse eventsn%
      Pregnancy-specific adverse events
       Spontaneous abortion
      Pregnancy outcomes were not reported in 65 (42%) reports–other pregnancy outcomes included 4 (3.0%) elective termination of pregnancy, 24 (18.2%) vaginal deliveries, and 8 (6.1%) cesarean deliveries;
      2216.7
       Gestational diabetes75.3
       Oligohydramnios
      2 cases with oligohydramnios had induction of labor as secondary diagnosis and 1 case had threatened abortion in early pregnancy as secondary diagnosis;
      32.3
       Induction of labor
      Chorioamnionitis was reported as secondary to labor induction;
      21.5
       Stillbirth21.5
       Ruptured ectopic pregnancy21.5
       Preterm delivery21.5
       Subchorionic hemorrhage by ultrasound10.8
       Cesarean delivery10.8
       Low-lying placenta on ultrasound10.8
       Placental abruption and fetal intolerance10.8
       Preeclampsia
      Preterm delivery reported as secondary diagnosis for this case;
      10.8
       Prolonged labor10.8
       Toxemia
      Threatened abortion in early pregnancy is reported for this case as secondary diagnosis.
      10.8
       Total4735.6
      Non-pregnancy–specific outcomes
       Injection site reactions64.5
       Anemia53.8
       Headache or fever with abdominal pain32.3
       Urinary tract infection21.5
       Syncope21.5
       Upper respiratory infection21.5
       Influenza10.8
       Nausea and vomiting10.8
       Rash on arms/thigh10.8
       Superficial thrombophlebitis10.8
       Total2418.2
      Infant outcomes
       Gastroschisis10.8
       Laryngotracheomalacia (diagnosed at age 3 mo)
      Preterm delivery reported as secondary diagnosis for this case;
      10.8
       Patent foramen ovale and peripheral pulmonic stenosis10.8
       Mild physiologic jaundice10.8
       Transient tachypnea and infiltrates in lower lobes10.8
       Bilateral hydrocele10.8
       Total64.5
      No adverse events5541.7
      Reported adverse events
      Based on primary reported diagnosis identified during clinical review–1 diagnosis assigned to 1 report;
      in pregnant women following receipt of Tdap vaccine, Vaccine Adverse Event Reporting System (VAERS), Jan. 1, 2005, through June 30, 2010 (n = 132).
      Tdap, tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis.
      Zheteyeva. Safety of Tdap in pregnancy. Am J Obstet Gynecol 2012.
      a Based on primary reported diagnosis identified during clinical review–1 diagnosis assigned to 1 report;
      b Pregnancy outcomes were not reported in 65 (42%) reports–other pregnancy outcomes included 4 (3.0%) elective termination of pregnancy, 24 (18.2%) vaginal deliveries, and 8 (6.1%) cesarean deliveries;
      c 2 cases with oligohydramnios had induction of labor as secondary diagnosis and 1 case had threatened abortion in early pregnancy as secondary diagnosis;
      d Chorioamnionitis was reported as secondary to labor induction;
      e Preterm delivery reported as secondary diagnosis for this case;
      f Threatened abortion in early pregnancy is reported for this case as secondary diagnosis.
      There were 3 infants born preterm: (1) the first to a 22-year-old woman with a cesarean section at 36 weeks of gestation, described as being indicated because of a history of having a cesarean section delivery; the woman delivered a normal infant; (2) the second case was in a 40-year-old woman with multiple previous pregnancies who also had preeclampsia; she delivered a normal infant at 35 weeks of gestation; and (3) the third case was in an 18-year-old woman who delivered a normal infant at 35 weeks of gestation.
      The most frequent non-pregnancy-specific outcomes were injection site reactions, in 6 (4.5%) reports (Table 2).
      Six (4.5%) reports indicated adverse infant outcomes, including 1 report each of gastroschisis, patent foramen ovale and peripheral pulmonic stenosis, physiologic neonatal jaundice, transient tachypnea and infiltrates in the lower lobes, bilateral hydrocele, and laryngotracheomalacia (Table 2). Only 1 of these infants had a major birth defect (gastroschisis). This infant was born to a 15-year-old mother who received Tdap and quadrivalent human papillomavirus vaccines concomitantly at approximately 8 weeks' gestation; additional information regarding the maternal history was not available.
      In all, 24 (18.2%) pregnancies resulted in vaginal deliveries (including 2 preterm). Eight (6.1%) pregnancies resulted in cesarean deliveries, which included 1 preterm delivery in a 22-year-old woman (described above). Reasons for cesarean deliveries were described in 5 of 8 reports and included 2 reports of severe fetal bradycardia and placental abruption; and 1 report each of macrosomia, arrest of descent, and prolonged labor. Four elective abortions were reported. These reports did not describe any AEs and reasons for elective termination of pregnancy were not indicated.

      Proportional reporting ratios

      The PRR screening criteria were met for higher proportional reporting after Tdap in pregnancy for the following MedDRA terms: anemia, antepartum hemorrhage, gestational diabetes, oligohydramnios, and upper respiratory tract infection (Table 3). No disproportionality was found in reporting SAB, stillbirth, or preterm deliveries.
      TABLE 3MedDRA terms among pregnant women after Tdap vaccines compared to inactivated influenza vaccines
      MedDRA termTdap reports, no. (%) (n = 71)MIV + TIV, no. (%) (n = 467)PRR (95% CI)
      Anemia3 (4.2)1 (0.2)19.73 (2.1–187.1)
      Antepartum hemorrhage3 (4.2)1 (0.2)19.73 (2.1–187.1)
      Gestational diabetes7 (9.9)3 (0.6)15.35 (4.1–58.0)
      Oligohydramnios3 (4.2)3 (0.6)6.58 (1.4–32.0)
      Upper respiratory tract infection3 (4.2)3 (0.6)6.58 (1.4–32.0)
      CI, confidence interval; MedDRA, Medical Dictionary for Regulatory Activities; MIV, monovalent inactivated vaccine (H1N1); PRR, proportional reporting ratio; Tdap, tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis; TIV, trivalent inactivated influenza vaccine.
      Zheteyeva. Safety of Tdap in pregnancy. Am J Obstet Gynecol 2012.
      The 3 reports with the MedDRA code for anemia were nonserious reports. The lowest hemoglobin values listed in 3 reports ranged from 9.3–10 g/dL. All anemia cases were treated with iron supplements and prenatal vitamins.
      The 3 antepartum hemorrhage reports were nonserious: 1 case of vaginal bleeding/threatened abortion in early pregnancy that subsequently resolved (pregnancy resulted in full-term delivery without complications), 1 subchorionic hemorrhage detected by ultrasound at 12 weeks' gestation that occurred before Tdap, and 1 subchorionic hemorrhage detected by ultrasound at 6 weeks' gestation that was described as “small.”
      Seven reports were coded as gestational diabetes, all of which were nonserious. Among these cases, the median age of the women was 31 years (range, 25–38 years). Four of the 7 reports described at least 1 risk factor for gestational diabetes that included a body mass index reported as “high” in 3 reports, and history of gestational diabetes in a previous pregnancy in 1 report. One report coded as gestational diabetes described history of type 2 diabetes mellitus and did not refer to the current pregnancy.
      Three mothers had oligohydramnios occurring at 33, 40, and 36 weeks of gestation. However, 2 reports did not appear to meet clinical criteria for oligohydramnios (amniotic fluid index <5 cm)
      • Moore T.R.
      • Cayle J.E.
      The amniotic fluid index in normal human pregnancy.
      as these patients had an amniotic fluid index >5 cm. All 3 women delivered term normal infants with normal birth weight. In one case, a nuchal cord had to be reduced and brief intubation of the newborn was performed.
      +Three women developed upper respiratory infection at 3, 23, and 20 weeks of gestation. The first 2 pregnancies resulted in SAB at 9 weeks and term vaginal delivery, respectively, and the outcome of the third pregnancy was not reported.

      Comment

      During 2005 through 2010 when Tdap was not routinely recommended for use in pregnant women, we found 132 reports submitted to VAERS after receipt of Tdap in pregnant women, accounting for approximately 0.1% of all US reports after Tdap during this period. Our review did not find any unusual or unexpected pattern of maternal, infant, or fetal AEs. A sizable minority of reports (42%) did not describe an AE other than the exposure to Tdap during pregnancy. About 5% of reports met the definition of serious, which is lower than observed in the pregnancy registry of one of the Tdap manufacturers.
      • Wang M.
      • Khromava A.
      • Mahmood A.
      • Dickinson N.
      Pregnant women receiving tetanus-diphtheria-acellular pertussis (Tdap) vaccine: 6 years of Adacel vaccine pregnancy registry data.
      SAB was the most frequent pregnancy-specific outcome, reported in 16.7% of reports. SAB is a relatively common event that occurs in about 15-20% of all pregnancies.
      • Black S.
      • Eskola J.
      • Siegrist C.A.
      • et al.
      Importance of background rates of disease in assessment of vaccine safety during mass immunization with pandemic H1N1 influenza vaccines.
      SAB was also the most frequent pregnancy-specific AE reported in studies of influenza vaccine safety.
      • Moro P.L.
      • 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.
      • Moro P.L.
      • 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).
      Our analysis did not reveal disproportionate reporting for SAB in VAERS for Tdap compared with influenza vaccines. We identified only 1 infant with a major birth defect in our review: an infant with gastroschisis born to a 15-year-old mother who concomitantly received Tdap with human papillomavirus vaccine. The prevalence of gastroschisis in the United States is 3.73 cases per 10,000 live births
      • Canfield M.A.
      • Honein M.A.
      • Yuskiv N.
      • et al.
      National estimates and race/ethnic-specific variation of selected birth defects in the United States, 1999-2001.
      and the risk factor most consistently identified for gastroschisis is younger maternal age.
      • Rasmussen S.A.
      • Frias J.L.
      Non-genetic risk factors for gastroschisis.
      Because the total number of pregnant women vaccinated with Tdap is not known, it is difficult to interpret the VAERS findings. No other infants with major birth defects were reported.
      As expected, the most frequent non-pregnancy-specific outcome was injection site reaction found in 4.5% of reports; injection site reactions have been identified as a common AE in prelicensure trials in non-pregnant persons.
      Food and Drug Administration
      Vaccines and Related Biological Products Advisory Committee, March 15, 2005: FDA Adacel briefing information.
      Food and Drug Administration
      Vaccines and Related Biological Products Advisory Committee, March 15, 2005: FDA Boostrix briefing information.
      Disproportionality analysis for reports in pregnant women revealed that gestational diabetes, anemia, antepartum hemorrhage, oligohydramnios, and upper respiratory infection were reported to VAERS more frequently after Tdap than after inactivated influenza vaccines. However, further clinical review found that most of these conditions were minor, and there were no concerning patterns for these outcomes that required additional investigation. Because most VAERS reports were from women vaccinated during the first trimester, we were not able to separately evaluate VAERS reports of vaccinations in second and third trimesters of pregnancy. As a national surveillance system, VAERS may be used to detect signals of potential vaccine safety concerns, which can be further explored in carefully designed epidemiological studies. For example, during the 2010-2011 influenza season, a vaccine safety signal for febrile seizures after TIV in young children was identified in VAERS
      • Leroy Z.
      • Broder K.
      • Menschik D.
      • Shimabukuro T.
      • Martin D.
      Febrile seizures after 2010-2011 influenza vaccine in young children, United States: a vaccine safety signal from the Vaccine Adverse Event Reporting System.
      and subsequently confirmed in the Vaccine Safety Datalink,
      • Tse A.
      • Tseng H.F.
      • Greene S.K.
      • Vellozzi C.
      • Lee G.M.
      VSD Rapid Cycle Analysis Influenza Working Group
      Signal identification and evaluation for risk of febrile seizures in children following trivalent inactivated influenza vaccine in the Vaccine Safety Datalink Project, 2010-2011.
      an active surveillance system used to monitor the safety of vaccines in the United States. VAERS has inherent limitations of all passive surveillance systems including underreporting, reporting biases, and inconsistency in quality of reports. Events occurring temporally closer to the time of vaccination are more likely to be reported to VAERS
      US Department of Health and Human Services
      Vaccine Adverse Event Reporting System (VAERS).
      ; 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.
      US Department of Health and Human Services
      Vaccine Adverse Event Reporting System (VAERS).
      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 1 stillbirth report at 37 weeks was coded as serious because the patient was hospitalized, whereas a second stillbirth report at 22 weeks was coded as nonserious because the report did not indicate the patient had been hospitalized.
      Since Tdap was not routinely recommended for use in pregnancy during the period of this review, no national survey was conducted to assessed Tdap coverage in pregnant women. Therefore, because there were no data on the number of Tdap doses administered to pregnant women, reporting rates cannot be calculated and findings are difficult to interpret.
      Prelicensure trials of Tdap did not include pregnant women, and the package inserts for Tdap state that the products should only be used in pregnancy if they are clearly needed.
      Food and Drug Administration
      Vaccines and Related Biological Products Advisory Committee, March 15, 2005: FDA Adacel briefing information.
      Food and Drug Administration
      Vaccines and Related Biological Products Advisory Committee, March 15, 2005: FDA Boostrix briefing information.
      ACIP may sometimes make recommendations for off-label use of vaccines after thorough review of risks and benefits.
      US Department of Health and Human Services
      Charter of Advisory Committee on Immunization Practices, April 1, 2010.
      Our findings are consistent with those of previous observations. Case-control studies of tetanus toxoid have found no association between vaccination with tetanus toxoid during pregnancy and congenital anomalies.
      • Czeizel A.E.
      • Rockenbauer M.
      Tetanus toxoid and congenital abnormalities.
      • Silveria C.M.
      • Caceres V.M.
      • Dutra M.G.
      • Lopes-Camelo J.
      • Castilla E.E.
      Safety of tetanus toxoid in pregnant women: a hospital-based case-control study of congenital anomalies.
      Few studies have been conducted on the safety of Tdap in pregnant women. A recent review from 2005 through 2011 of the Adacel Vaccine Pregnancy Registry reported 539 pregnant women who received Tdap during pregnancy. Among the 480 spontaneous prospective reports in this series, 27 (5.6%) were classified as serious AEs using a similar definition as our review and there were 16 (3.3%) SAB and 8 (1.7%) preterm deliveries.
      • Wang M.
      • Khromava A.
      • Mahmood A.
      • Dickinson N.
      Pregnant women receiving tetanus-diphtheria-acellular pertussis (Tdap) vaccine: 6 years of Adacel vaccine pregnancy registry data.
      In another study of 4524 health care workers who were vaccinated with Tdap during a mass vaccination campaign, 16 women received Tdap during pregnancy, all of whom gave birth to full-term infants who had normal newborn evaluations.
      • Talbot E.A.
      • Brown K.H.
      • Kirkland K.B.
      • Baughman A.L.
      • Halperin S.A.
      • Broder K.R.
      The safety of immunizing with tetanus–diphtheria–acellular pertussis vaccine (Tdap) less than 2 years following previous tetanus vaccination: experience during a mass vaccination campaign of healthcare personnel during a respiratory illness outbreak.
      In June 2011, ACIP recommended that health care personnel should administer Tdap during pregnancy, preferably during the third or late second trimester (>20 weeks' gestation).
      Centers for Disease Control and Prevention (CDC)
      Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) in pregnant women and persons who have or anticipate having close contact with an infant aged <12 months–Advisory Committee on Immunization Practices (ACIP), 2011.
      Although we anticipate that Tdap will continue to have a good safety profile, it is important to continue safety monitoring as more pregnant women are vaccinated.

      Conclusion

      In this comprehensive review encompassing >5 years of reports to VAERS in pregnant women who received Tdap during a time when Tdap was not routinely recommended for pregnant women, we identified no safety concerns. Although our review was subject to limitations of a spontaneous reporting system, our data provide useful baseline information as the new ACIP recommendation for routine use of Tdap in pregnant women is implemented.
      Centers for Disease Control and Prevention (CDC)
      Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) in pregnant women and persons who have or anticipate having close contact with an infant aged <12 months–Advisory Committee on Immunization Practices (ACIP), 2011.

      Acknowledgments

      We thank the CDC Immunization Safety Office staff whose work allowed this activity to be conducted.

      References

        • Gall S.A.
        • Myers J.
        • Pichichero M.
        Maternal immunization with tetanus-diphtheria-pertussis vaccine: effect on maternal and neonatal serum antibody levels.
        Am J Obstet Gynecol. 2011; 204: 334.e1-334.e5
        • Leuridan E.
        • Hens N.
        • Peeters N.
        • de Witte L.
        • Van der Meeren O.
        • Van Damme P.
        Effect of a pre-pregnancy pertussis booster dose on maternal antibody titers in young infants.
        Pediatr Infect Dis J. 2011; 30: 608-610
        • Healy C.M.
        • Rench M.A.
        • Baker C.J.
        Implementation of cocooning against pertussis in a high-risk population.
        Clin Infect Dis. 2011; 52: 157-162
        • Cortese M.M.
        • Baughman A.L.
        • Zhang R.
        • Srivastava P.U.
        • Wallace G.S.
        Pertussis hospitalizations among infants in the United States, 1993 to 2004.
        Pediatrics. 2008; 121: 484-492
        • Food and Drug Administration
        Vaccines and Related Biological Products Advisory Committee, March 15, 2005: FDA Adacel briefing information.
        US Department of Health and Human Services, Food and Drug Administration, Rockville, MD2005 (Accessed Feb. 2, 2012)
        • Food and Drug Administration
        Vaccines and Related Biological Products Advisory Committee, March 15, 2005: FDA Boostrix briefing information.
        US Department of Health and Human Services, Food and Drug Administration, Rockville, MD2005 (Accessed Feb. 2, 2012)
        • Murphy T.V.
        • Slade B.A.
        • Broder K.R.
        • et al.
        Prevention of pertussis, tetanus, and diphtheria among pregnant and postpartum women and their infants: recommendations of the Advisory Committee on Immunization Practices (ACIP).
        MMWR Recomm Rep. 2008; 57: 1-51
        • Centers for Disease Control and Prevention (CDC)
        Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) in pregnant women and persons who have or anticipate having close contact with an infant aged <12 months–Advisory Committee on Immunization Practices (ACIP), 2011.
        MMWR Morb Mortal Wkly Rep. 2011; 60: 1424-1426
        • US Department of Health and Human Services
        Vaccine Adverse Event Reporting System (VAERS).
        (Accessed Feb. 2, 2012)
        • Varricchio F.
        • Iskander J.
        • DeStefano F.
        Understanding vaccine safety information from the Vaccine Adverse Event Reporting System.
        Pediatr Infect Dis J. 2004; 23: 287-294
        • Chen R.T.
        • Rastogi S.C.
        • Mullen J.R.
        • et al.
        The Vaccine Adverse Event Reporting System (VAERS).
        Vaccine. 1994; 12: 542-550
        • US Department of Health and Human Services
        Vaccine Adverse Event Reporting System form.
        (Accessed Feb. 2, 2012)
        • Northrop Grumman Corporation
        Medical Dictionary for Regulatory Activities maintenance and support services organization.
        (Accessed Feb. 2, 2012)
        • US Food and Drug Administration
        21 Code of Federal Regulation Part 600.80.
        Fed Regist. 1997; 62 (Accessed Feb. 2, 2012): 52252-52253
      1. Prenatal care.
        in: Cunningham G. Leveno K.J. Bloom S.L. Hauth J.C. Gilstrap L.C. Wenstrom K.D. Williams obstetrics. McGraw-Hill Companies, Inc, New York2001: 221-247
        • Evans S.J.W.
        • Waller P.C.
        • Davis S.
        Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports.
        Pharmacoepidemiol Drug Saf. 2001; 10: 483-486
        • Banks D.
        • Woo E.J.
        • Burwen D.R.
        • Perucci P.
        • Braun M.M.
        • Ball R.
        Comparing data mining methods on the VAERS database.
        Pharmacoepidemiol Drug Saf. 2005; 14: 601-609
        • Moro P.L.
        • 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: 146.e1-146.e7
        • Moro P.L.
        • 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: 473.e1-473.e9
        • Kroger A.T.
        • Atkinson W.L.
        • Marcuse E.K.
        • Pickering L.K.
        • Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC)
        General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP).
        MMWR Recomm Rep. 2006; 55: 1-48
        • Wright J.G.
        • Quinn C.P.
        • Shadomy S.
        • Messonnier N.
        • Centers for Disease Control and Prevention (CDC)
        Use of anthrax vaccine in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009.
        MMWR Recomm Rep. 2010; 59: 1-30
        • Moore T.R.
        • Cayle J.E.
        The amniotic fluid index in normal human pregnancy.
        Am J Obstet Gynecol. 1990; 162: 1168-1173
        • Wang M.
        • Khromava A.
        • Mahmood A.
        • Dickinson N.
        Pregnant women receiving tetanus-diphtheria-acellular pertussis (Tdap) vaccine: 6 years of Adacel vaccine pregnancy registry data.
        Pharmacoepidemiol Drug Saf. 2011; 20 (Presented at the 27th International Conference on Pharmacoepidemiology and Therapeutic Management, Chicago, IL): S1-S364
        • Black S.
        • Eskola J.
        • Siegrist C.A.
        • et al.
        Importance of background rates of disease in assessment of vaccine safety during mass immunization with pandemic H1N1 influenza vaccines.
        Lancet. 2009; 374: 2115-2122
        • Canfield M.A.
        • Honein M.A.
        • Yuskiv N.
        • et al.
        National estimates and race/ethnic-specific variation of selected birth defects in the United States, 1999-2001.
        Birth Defects Res A Clin Mol Teratol. 2006; 76: 747-756
        • Rasmussen S.A.
        • Frias J.L.
        Non-genetic risk factors for gastroschisis.
        Am J Med Genet C Semin Med Genet. 2008; 148C: 199-212
        • Leroy Z.
        • Broder K.
        • Menschik D.
        • Shimabukuro T.
        • Martin D.
        Febrile seizures after 2010-2011 influenza vaccine in young children, United States: a vaccine safety signal from the Vaccine Adverse Event Reporting System.
        Vaccine. 2012; 30: 2020-2023
        • Tse A.
        • Tseng H.F.
        • Greene S.K.
        • Vellozzi C.
        • Lee G.M.
        • VSD Rapid Cycle Analysis Influenza Working Group
        Signal identification and evaluation for risk of febrile seizures in children following trivalent inactivated influenza vaccine in the Vaccine Safety Datalink Project, 2010-2011.
        Vaccine. 2012; 30: 2024-2031
        • US Department of Health and Human Services
        Charter of Advisory Committee on Immunization Practices, April 1, 2010.
        (Accessed Feb. 2, 2012)
        • Czeizel A.E.
        • Rockenbauer M.
        Tetanus toxoid and congenital abnormalities.
        Int J Gynecol Obstet. 1999; 64: 253-258
        • Silveria C.M.
        • Caceres V.M.
        • Dutra M.G.
        • Lopes-Camelo J.
        • Castilla E.E.
        Safety of tetanus toxoid in pregnant women: a hospital-based case-control study of congenital anomalies.
        Bull World Health Organ. 1995; 73: 605-608
        • Talbot E.A.
        • Brown K.H.
        • Kirkland K.B.
        • Baughman A.L.
        • Halperin S.A.
        • Broder K.R.
        The safety of immunizing with tetanus–diphtheria–acellular pertussis vaccine (Tdap) less than 2 years following previous tetanus vaccination: experience during a mass vaccination campaign of healthcare personnel during a respiratory illness outbreak.
        Vaccine. 2010; 20: 8001-8007