We had sufficient information, primarily from delivery medical records, to assess pregnancy outcomes for 95 (84%) of 113 reports. No maternal deaths, stillbirths, elective terminations, or ectopic pregnancies were identified. Among the 95 reports, there were 84 singleton pregnancies resulting in 84 live births and there were two twin pregnancies resulting in three live births (one twin was a fetal demise [fetus papyraceous] at 12 weeks of gestation). The total number of live births, from singleton (84) and twin (two) pregnancies, was 87. Twenty-one (24.4%) of 86 deliveries were by cesarean. There were 10 spontaneous abortions (including the twin fetal demise) (10 of 95, 10.5%, 95% confidence interval [CI] 5.8–18.3). Nine of the 10 spontaneous abortion reports had information on gestational age at the time of the event: five reports stated the event occurred less than 12 weeks of gestation and four were between 12 and 15 weeks of gestation. The interval from vaccination to onset of symptoms of the spontaneous abortion (onset interval) was known for seven of 10. In two reports, the onset interval was less than 7 days and in five, the interval was between 26 and 54 days. One spontaneous abortion at 6 weeks of gestation was found to have trisomy 16 after chromosomal analysis. There were four preterm births (4.7%, 95% CI 1.8–11.4), three at 35 and one at 36 weeks of gestation. Three were indicated for medical reasons and one was spontaneous. All four women who experienced preterm delivery had at least one risk factor including preeclampsia, gestational hypertension, gestational diabetes, noninsulin-dependent diabetes mellitus, previous preterm births, and oligohydramnios.9 One of the preterm infants was also small for gestational age. No women were hospitalized for reasons other than routine delivery. Three infants (3.4%, 95% CI 1.2–9.7) had one major birth defect each: one each of cleft palate, cleft lip, and microtia (underdeveloped or absent external ear) (Table 2).
The median maternal and gestational age at vaccination for the 95 women with, and the 18 women without, follow-up information was similar (data not shown).
Medical information about the infants born to women who received live H1N1 vaccine during pregnancy and had no adverse event was available for 79 (91.9%) of 86 women at the time of delivery; 58 (67.7%) infants had at least one medical record available for review during the 6-month follow-up. Five infants had temporary serious conditions in the neonatal period, which required prolonged hospitalization or rehospitalization (Table 3). Most conditions present during the neonatal period were self-limited and included jaundice in 21 infants and one case each of macrosomia and abnormal heart rate at birth.
Although there were no deaths in the neonatal period, one male infant died at age 2.5 months as a result of laboratory-confirmed pertussis. In addition, a 4-month-old male infant was hospitalized for 1 day with a diagnosis of respiratory syncytial virus bronchiolitis and acute otitis media. No other infants were hospitalized after the neonatal period. The five most common conditions diagnosed during pediatric outpatient visits were mild and self-limited and included: upper respiratory infection (15), dermatitis (seven), gastroesophageal reflux disease (five), conjunctivitis, and obstruction of the nasolacrimal duct (three each).
The sensitivity analysis included the 116 reports (113 plus three reports with a nonpregnancy-specific adverse event reported); follow-up medical records were available for these three reports. Including these three records, the rates of spontaneous abortion, premature delivery, and major birth defects were 10.2% (5.6–17.8%; 10 of 98), 4.5% (1.8–10.9%; four of 89), and 3.3% (1.1–9.3%; three of 90), respectively.
We assessed pregnancy outcomes in women who received 2009 live H1N1 vaccine during pregnancy and were reported to the Vaccine Adverse Event Reporting System without an associated adverse event at the time of report. Our review did suggest that receipt of live attenuated 2009 pandemic influenza vaccine during pregnancy was not associated with increased risk for adverse health outcomes in pregnant women or their exposed infants. Rates of spontaneous abortion, preterm birth, and overall birth defects in women exposed to live H1N1 vaccine during pregnancy were similar to or lower than published background rates.10 These rates did not differ when the additional three nonpregnancy-specific adverse events were included in the sensitivity analysis. In addition, clinical review of records of pregnant women and their infants up to 6 months of age did not identify any concerning patterns of medical conditions.
The spontaneous abortion rate of 10.5% among pregnant women who received 2009 live H1N1 vaccines is comparable to background rates of spontaneous abortion, which can vary from 10.4% in women aged younger than 25 years to 22.4% in women aged 34 years or older.10 The available evidence has not shown an association between spontaneous abortion and trivalent inactivated influenza vaccine, although few studies have assessed this association. A case–control study of trivalent inactivated influenza vaccine and early pregnancy loss in the U.S. and cohort studies of 2009 H1N1 inactivated influenza vaccines in Europe did not identify an increased risk for spontaneous abortion or stillbirth after vaccination with either vaccine.11–14 The rate of preterm birth among pregnant women who received 2009 live H1N1 vaccines in this study (4.7%) is below observed background rates of 10.4–11.5% in the general population of pregnant women in the United States.10,13 Similarly, the proportion of small-for-gestational-age newborns (1.1%) was below the background rate for this condition (8–16%).15 Although these data do not suggest an association between 2009 live H1N1 vaccines and preterm birth or small for gestational age, it is not clear how to interpret our finding of lower rates compared with the U.S. population. It is possible the pregnant women in this study were a select population that would be expected to have a lower rate of preterm birth. For example, only 6.2% were African American, and the women were receiving either prenatal or primary care.9,16 However, because in our study 19% of reports represented adolescent pregnancies (15–19 years), in contrast to 7% in the general population, and adolescents are at higher risk for preterm births,17 we might have expected a higher rate of preterm births. Women receiving 2009 live H1N1 may have been healthier than the general population because live H1N1 was not recommended for persons with certain chronic conditions (eg, diabetes)3 that may be associated with preterm birth.7 Some studies have found an association between inactivated influenza vaccine and lower risk for preterm birth and small for gestational age possibly as a result of prevention of maternal influenza.18–21 A similar association between live attenuated influenza vaccine and these pregnancy outcomes is plausible but has not been studied.
The overall rate of major birth defects after live H1N1 vaccine identified in this study was 3.4%, which is similar to the overall background rate of 3%.22 The small number of major birth defects observed does not allow us to make any conclusions about an association of live H1N1 vaccines and birth defects; however, it is reassuring that no increase in birth defects was observed. Many of the temporary serious conditions found among some infants were medical conditions often encountered in pediatric practice (eg, urinary tract infection, upper respiratory infection, respiratory distress), which may require hospitalization.23
Reporting exposure to live H1N1 vaccine during pregnancy before knowledge of the pregnancy outcome reduces reporting bias and permits estimation of the risk of certain pregnancy outcomes.24,25 Traditionally spontaneous reporting systems like the Vaccine Adverse Event Reporting System are not able to yield reliable information about incidence of pregnancy outcomes in exposed women for two main reasons: reporting bias and lack of denominator data.6 Our study provided a denominator by including pregnant women before adverse events were recognized, when the only motivating factor to report to the Vaccine Adverse Event Reporting System was exposure to the live vaccine, most likely inadvertently. We found a sizable number of reports, which only reported exposure to live H1N1 vaccine during pregnancy. We were able to prospectively assess maternal and infant outcomes in most of the women vaccinated during pregnancy through comprehensive medical record review. This approach allowed us to directly calculate rates for certain outcomes of interest with less reporting bias. It also minimized underreporting; relying on spontaneous reporting system surveillance alone, we would have only identified one spontaneous abortion report after live H1N1 vaccine; however, through active surveillance by obtaining medical records, we were able to identify 10 cases of spontaneous abortion after exposure to live vaccine. Our primary analysis excluded reports of any adverse event, including nonpregnancy-specific adverse events, and likely resulted in more conservative rate calculations because the three reports that included a nonpregnancy-specific adverse event did not result in an adverse pregnancy outcome. If, however, our review revealed that these three pregnancies resulted in an adverse pregnancy outcome, our primary results could have been biased. The sensitivity analysis demonstrated that inclusion of these reports did not change our results.
There are some limitations that should be noted. First, our sample size was small, and this limits precise estimation of risks for the main outcomes of interest. Pregnant women who received live H1N1 vaccines and whose health care providers reported to the Vaccine Adverse Event Reporting System may not be representative of the general population of pregnant women or pregnant women who received the live H1N1 vaccine in the United States.
Although our study was a convenience sample from a passive reporting database and was not adequately powered to detect rare events with precision, it is reassuring that no concerning pattern of adverse events was observed in pregnant women or their infants who received the live H1N1 vaccines. However, those instances when live influenza vaccine was administered to a woman known to be pregnant emphasizes the need to provide continued education to vaccine administrators to ensure they are familiar with influenza vaccine recommendations.29,30 This method of enhanced surveillance may be useful to complement traditional pregnancy registries when a large number of pregnant women may be exposed to a vaccine such as during an epidemic, and may also be useful in situations when inadvertent administration of a vaccine not recommended during pregnancy is more likely to occur such as with adolescent vaccines to evaluate safety and provide additional evidence to inform policy.
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