Risk of Fetal Death After Pandemic Influenza Virus Infection or Vaccination

Abstract

During the 2009 influenza A (H1N1) pandemic, pregnant women were vulnerable to severe influenza, with increased risks of adverse fetal outcomes and maternal death. Pregnant women were advised to be vaccinated in the second or third trimester. After this pandemic, national health data were used to assess the effectiveness of pandemic vaccine in pregnant women and the effect of vaccination or influenza on fetal survival. Information on women of reproductive age in Norway was linked to national health registries. Of 1,153,738 females, aged 13 to 49 years, 117,026 gave birth in 2009 or 2010. The analyses included 113,331 women. The main pandemic wave in Norway occurred between October 1 and December 31, 2009. Exposure to influenza was defined as a contact with a primary care physician that led to a diagnosis of influenza with the gestational day as the time metric and vaccination and pandemic exposure as time-dependent exposure variables. Fetuses of mothers who were unvaccinated, vaccinated before pregnancy, or vaccinated on the day of delivery or thereafter were classified as unexposed to the vaccine. Hazard ratios (HRs) were estimated. The primary end point was fetal death. In 2009 and 2010, 117,347 births were recorded among women who became pregnant during the eligible time window, including 570 fetal deaths (4.9/1000 births). Of 113,331 eligible singleton pregnancies, 492 ended in fetal death (4.3 deaths/1000 births). Among 99,539 women who delivered outside the pandemic window, 410 fetal deaths occurred (4.1 deaths/1000 births). Pandemic vaccinations began in October 2009, and 97% of vaccinations were given by December 31, 2009. A total of 25,976 children were born after their mothers were vaccinated during pregnancy; 78 fetal deaths occurred. Among 87,335 women pregnant during the pandemic but unvaccinated, 414 fetal deaths were reported. Of 46,491 women in the second or third trimester during the pandemic wave, 54% were vaccinated. A clinical diagnosis of influenza during the pandemic was made for 2278 eligible pregnant women, among whom 16 fetal deaths occurred. Of 516 women with positive laboratory results for the A(H1N1)pdm09 strain, 5 fetal deaths occurred. Vaccination during pregnancy reduced the risk of receiving a clinical diagnosis of influenza (adjusted HR, 0.30). Women who were exposed to the pandemic had an increased risk of fetal death (adjusted HR, 1.26) as did women with a clinical diagnosis of influenza (adjusted HR, 1.91). Unvaccinated women had a higher risk of fetal death during the pandemic (HR, 1.25). One fetal death occurred among 40 pregnant women hospitalized with influenza during the pandemic. No association was found between vaccination and preterm delivery, low birth weight at term, and low Apgar score at term. This study found no evidence that influenza vaccination of pregnant women increased the risk of fetal death. For pregnant women who had a clinical diagnosis of influenza, the risk of fetal death nearly doubled. Given the danger posed by maternal influenza virus infection for fetal survival, these results provide additional evidence that vaccination of pregnant women during an influenza pandemic does not harm, and may benefit, the fetus. Withholding influenza vaccination from pregnant women in their second or third trimester has no basis, given that these women can be vulnerable to the severe effects of influenza.