Risk of Fetal Death after Pandemic Influenza Virus Infection or Vaccination

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1 T h e n e w e ngl a nd j o u r na l o f m e dic i n e original article Risk of Fetal Death after Pandemic Influenza Virus Infection or Vaccination Siri E. Håberg, M.D., Ph.D., Lill Trogstad, M.D., Ph.D., Nina Gunnes, Ph.D., Allen J. Wilcox, M.D., Ph.D., Håkon K. Gjessing, Ph.D., Sven Ove Samuelsen, Ph.D., Anders Skrondal, Ph.D., Inger Cappelen, Ph.D., Anders Engeland, Ph.D., Preben Aavitsland, M.D., Steinar Madsen, M.D., Ingebjørg Buajordet, Ph.D., Kari Furu, Ph.D., Per Nafstad, M.D., Ph.D., Stein Emil Vollset, M.D., Dr.P.H., Berit Feiring, M.Sc.Pharm., Hanne Nøkleby, M.D., Per Magnus, M.D., Ph.D., and Camilla Stoltenberg, M.D., Ph.D. A bs tr ac t Background During the influenza A (H1N1) pandemic, pregnant women were at risk for severe influenza illness. This concern was complicated by questions about vaccine safety in pregnant women that were raised by anecdotal reports of fetal deaths after vaccination. Methods We explored the safety of influenza vaccination of pregnant women by linking Norwegian national registries and medical consultation data to determine influenza diagnosis, vaccination status, birth outcomes, and background information for pregnant women before, during, and after the pandemic. We used Cox regression models to estimate hazard ratios for fetal death, with the gestational day as the time metric and vaccination and pandemic exposure as time-dependent exposure variables. Results There were 117,347 eligible pregnancies in Norway from through Fetal mortality was 4.9 deaths per 1000 births. During the pandemic, 54% of pregnant women in their second or third trimester were vaccinated. Vaccination during pregnancy substantially reduced the risk of an influenza diagnosis (adjusted hazard ratio, 0.30; 95% confidence interval [CI], 0.25 to 0.34). Among pregnant women with a clinical diagnosis of influenza, the risk of fetal death was increased (adjusted hazard ratio, 1.91; 95% CI, 1.07 to 3.41). The risk of fetal death was reduced with vaccination during pregnancy, although this reduction was not significant (adjusted hazard ratio, 0.88; 95% CI, 0.66 to 1.17). From the Norwegian Institute of Public Health (S.E.H., L.T., N.G., H.K.G., S.O.S., A.S., I.C., A.E., P.A., K.F., P.N., S.E.V., B.F., H.N., P.M., C.S.), the University of Oslo (S.O.S., P.N., P.M.), and the Norwegian Medicines Agency (S.M., I.B.), Oslo; the University of Bergen, Bergen (H.K.G., A.E., S.E.V.); and the University of Tromsø, Tromsø (K.F.) all in Norway; the National Institute of Environmental Health Sciences, Durham, NC (A.J.W.); and the London School of Hygiene and Tropical Medicine, London (A.S.). Address reprint requests to Dr. Håberg at the Norwegian Institute of Public Health, P.O. Box 4404, Nydalen, N-0403 Oslo, Norway, or at siri.haberg@fhi.no. This article was published on January 16, 2013, at NEJM.org. N Engl J Med 2013;368: DOI: /NEJMoa Copyright 2013 Massachusetts Medical Society. Conclusions Pandemic influenza virus infection in pregnancy was associated with an increased risk of fetal death. Vaccination during pregnancy reduced the risk of an influenza diagnosis. Vaccination itself was not associated with increased fetal mortality and may have reduced the risk of influenza-related fetal death during the pandemic. (Funded by the Norwegian Institute of Public Health.) n engl j med 368;4 nejm.org january 24,

2 T h e n e w e ngl a nd j o u r na l o f m e dic i n e During the influenza A (H1N1) pandemic, pregnant women were particularly vulnerable to severe influenza illness, with a heightened risk of adverse pregnancy outcomes and maternal death. 1-4 The susceptibility of pregnant women to influenza has also been observed in the past The World Health Organization s recommendation for the administration of seasonal influenza vaccine, which included vaccination of pregnant women, did not change during the H1N1 pandemic. 13 In addition, it was recommended that pregnant women receive a pandemic vaccine. 14 Before, pregnant women in Norway were not routinely advised to be vaccinated against seasonal influenza. During the pandemic, a trivalent seasonal influenza vaccine and an H1N1 vaccine with an AS03 adjuvant were recommended for high-risk groups, although it was recommended that pregnant women receive the pandemic vaccine only, in the second or third trimester. Studies in animals and results provided by the vaccine manufacturer indicated no excess risk of miscarriage or stillbirth after vaccination. 15 Still, anecdotal reports of fetal deaths occurring shortly after vaccination raised public concern about vaccine safety. 15 After the pandemic, we used the national health registries and data regarding reimbursement of primary care physicians in Norway to assess the effectiveness of the pandemic vaccine in pregnant women and the effect of vaccination or influenza on fetal survival. Me thods Data Sources and Study Population We linked information on women of reproductive age in Norway to various national health registries and to national data regarding reimbursement of primary care physicians. We obtained the data from the National Population Register, 16 the Norwegian Immunization Register, 17 the Surveillance System for Communicable Diseases, 18 the Medical Birth Registry of Norway, 19 and the Directorate of Health (for reimbursement data). The Norwegian Patient Registry provided the number of hospitalized pregnant women during the pandemic. Of 1,153,738 girls and women (hereafter referred to as women) living in Norway in who were between the ages of 13 and 49 years, 117,026 gave birth in or We restricted our sample to women who became pregnant 43 weeks before December 31, 2010, so as not to oversample short pregnancies during the latter part of We excluded from the main analysis children who were part of a multiple birth, women with invalid vaccination dates, and the few women who received only a vaccine without adjuvant (Celvapan, Baxter), leaving 113,331 women in the analyses. Details on the numbers and type of information from each data source and a flow chart showing eligibility are provided in the Methods section and Figure S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org. The study was approved by the Regional Committee for Medical and Health Research Ethics and the Norwegian Data Protection Authority. All authors vouch for the integrity of the data and accuracy of the analysis. The makers of the vaccines that were analyzed had no role in the study. Outcome and Exposure Information We defined fetal death as any recorded miscarriage or stillbirth after 12 completed weeks of pregnancy. On the basis of both laboratory-confirmed cases of pandemic influenza and physician visits for influenza that were reported to the Norwegian Institute of Public Health, 20 the main pandemic wave in Norway occurred between October 1,, and December 31,. For women who were already pregnant on October 1, exposure to the pandemic was defined as the period from October 1 to the day of delivery. Women whose first day of pregnancy fell between October 1 and December 31 were considered to have been exposed to the pandemic from the first day of pregnancy until delivery. Exposure to influenza was defined as a contact with a primary care physician that led to a diagnosis of influenza (code R80 in the International Classification of Primary Care; criteria are listed in the Supplementary Appendix). Pregnant women were considered to have been exposed to influenza from the day of diagnosis until delivery. If there were multiple consultation dates during the main pandemic wave, the first visit was used. The immunization registry provided information on two types of pandemic influenza vaccine against the A(H1N1)pdm09 strain: a vaccine with adjuvant (Pandemrix, GlaxoSmithKline) and one without adjuvant (Celvapan). Pregnant women were considered to be unexposed to the vaccine from the first day of pregnancy until the day of vaccination and to be exposed to the vaccine 334 n engl j med 368;4 nejm.org january 24, 2013

3 Fetal Death after Influenza Virus Infection or Vaccination from the day of vaccination until delivery. The Norwegian Institute of Public Health recommended one dose of Pandemrix. For the 266 pregnant women who received two doses, exposure was defined as starting with the first dose. 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. Statistical Analysis The analysis required methods that handle timedependent exposures and data censoring. 21 We used a Cox proportional-hazards model 22 with the gestational day as the underlying time metric. Hazard ratios with 95% confidence intervals were estimated. Pregnancies were included in the risk set on day 84 (after pregnancy week 12) and were followed until delivery; the end point was fetal death, and data were censored at the time of a live birth. Pregnancies longer than 84 days as of January 1,, were included at the gestational age as of that date. Pregnancy days before January 1,, were not included in the risk set. Figure 1 illustrates the study design, eligible pregnancies, observed pregnancy days, and exposure to the pandemic wave. The study had three specific aims: to investigate the risk of fetal death after exposure to the pandemic, the risk after clinical diagnosis of influenza, and the risk after vaccination in pregnancy. In the first model, we used a binary timedependent variable for exposure to the pandemic during pregnancy. In the second model, we treated a clinical diagnosis of influenza during pregnancy as a time-dependent variable, using the following categories: no exposure to the pandemic (reference), exposure without a clinical diagnosis, and exposure with a clinical diagnosis. Exposure to vaccination during pregnancy was a binary timedependent variable. A separate model was used to examine the risk of an influenza diagnosis after vaccination during the pandemic. In this model, only pregnancy days during the main pandemic wave (October 1,, to December 31, ) were included, and the end point was physician consultation for influenza. For this outcome, the vaccine was regarded as effective from 1 week after vaccination. The time metric was the gestational day, and pregnancies were included in the risk set on October 1,, or on the first day of pregnancy if this date was within the pandemic window. Follow-up ended on the day of an influenza diagnosis, the day of delivery, or December 31, whichever occurred first. There were 3208 women who had two pregnancies during the study period. We used a sandwich estimator to obtain confidence intervals that accounted for dependence between the pregnancies. We conducted sensitivity analyses that included multiple births and that excluded women who were vaccinated during the first trimester of pregnancy. We also performed analyses in which women who had been vaccinated before pregnancy were classified as having been vaccinated on the first pregnancy day. The body-mass index was available for only 39% of the women and was therefore analyzed in a separate model. The remaining confounder data were complete for 98% of women and were included in the fully adjusted models. The assumption of proportional hazards was assessed with the use of Schoenfeld residuals and found to be valid. Analyses were performed with the use of SPSS software, version 19 (SPSS), and Stata software, version 11 (StataCorp). R esult s Fetal Death and Vaccination There were 117,347 births in Norway in and 2010 among women who became pregnant during the eligible time window, including 570 fetal deaths (4.9 per 1000 births). There were 113,331 eligible singleton pregnancies, of which 492 ended in fetal death (4.3 deaths per 1000 births). Among the 99,539 women who delivered outside the pandemic window, there were 410 fetal deaths (4.1 deaths per 1000 births). Pandemic influenza vaccinations were offered starting October 19,, and nearly all vaccinations (97%) were administered by December 31,. A total of 25,976 children were born after their mothers were vaccinated during pregnancy, with almost all vaccinations occurring during the second or third trimester. Among the vaccinated women, there were 78 fetal deaths. Among the 87,335 women who were pregnant during the pandemic but unvaccinated, there were 414 fetal deaths. The vaccination status of eligible women and the distribution of gestational age at vaccination are shown in Table S1 and Figure S2 in the Supplementary Appendix. Of the 46,491 women in the second or third trimester during the pandemic wave (October 1, n engl j med 368;4 nejm.org january 24,

4 T h e n e w e ngl a nd j o u r na l o f m e dic i n e The main wave of the pandemic Oct. 1 Dec. 31, Eligible dates of pregnancy onset 43 wk 12 wk Jan. 1, Oct. 1, Jan. 1, 2010 Jan. 1, 2011 Unobserved pregnancy days (not in risk set) Observed pregnancy days as exposed to influenza Observed pregnancy days as unexposed to influenza Figure 1. Eligible Pregnancies, Observed Pregnancy Days, and Exposure to the Main Pandemic Wave. Births in Norway that occurred in and 2010 were eligible for the study if women had become pregnant at least 43 weeks before December 31, Eligible pregnancies were classified as involving maternal exposure to the influenza pandemic if any day of pregnancy occurred between October 1,, and December 31,. For a given pregnancy, days at risk were defined as pregnancy days after week 12 that occurred starting on January 1,, and exposure days were defined as all pregnancy days from the first day of exposure until delivery. For simplicity, the figure shows all pregnancies as lasting 9 months. The study included all registered pregnancies lasting at least 12 weeks. The period of the main wave of the influenza pandemic is shaded., to December 31, ), 54% were vaccinated. Characteristics of these pregnancies are provided in Table 1, with an extended list in Table S2 in the Supplementary Appendix. Vaccination coverage of pregnant women was higher in those with chronic diseases and lower in daily smokers and younger women. A clinical diagnosis of influenza during the pandemic wave was recorded for 2278 eligible pregnant women, among whom there were 16 fetal deaths. There were 516 women with positive laboratory results for the A(H1N1)pdm09 strain; among these women, there were 5 fetal deaths (too few to estimate risk). The temporal distribution of vaccinations and positive laboratory tests in pregnant women is shown in Figure 2. Vaccination during pregnancy reduced the risk of receiving a clinical diagnosis of influenza (adjusted hazard ratio, 0.30; 95% confidence interval [CI], 0.25 to 0.34). In an analysis in which women who were pregnant outside the pandemic window were the reference group, women who were exposed to the pandemic had an increased risk of fetal death (adjusted hazard ratio, 1.26; 95% CI, 1.02 to 1.55) (Table 2). The risk of fetal death was increased among women with a clinical diagnosis of influenza (adjusted hazard ratio, 1.91; 95% CI, 1.07 to 3.41). Pregnant women who were vaccinated had a slightly lower risk of fetal death, as compared with unvaccinated women, a difference that was not significant (hazard ratio, 0.88; 95% CI, 0.66 to 1.17). Since nearly all vaccinations occurred during the main pandemic wave, the estimated hazard ratio in effect compares vaccinated and unvaccinated women who were pregnant during the pandemic period. Unvaccinated women had a higher risk of fetal death during the pandemic (hazard ratio, 1.25; 95% CI, 1.02 to 1.55) (Table 3). Adjustment for covariates did not substantially influence the estimates, which were likewise similar in models in which multiple births were included, women who received first-trimester vaccinations were excluded, adjustment was made for 336 n engl j med 368;4 nejm.org january 24, 2013

5 Fetal Death after Influenza Virus Infection or Vaccination Table 1. Vaccination Coverage and Characteristics of Women Who Were Pregnant during the Influenza Pandemic.* Characteristic No. of Women Vaccinated percent All women 46, Age <20 yr 1, yr 6, yr 14, yr 15, yr 7, yr 1, No. of previous pregnancies 0 19, , , , Smoking during pregnancy No 32, Occasionally 1, Daily 6, Declined to give information 6, Missing data Chronic illness No 41, Yes 5, * Listed are data for women with at least 1 day in the second or third trimester that occurred between October 1,, and December 31, (the main wave of the influenza pandemic). Listed are the proportions of women who received the pandemic influenza vaccine at any time during pregnancy. body-mass index, or women who were vaccinated before pregnancy were reclassified as having been exposed to the vaccine on the first pregnancy day. The Norwegian Patient Registry reported that 40 pregnant women were hospitalized with influenza during the pandemic wave; of these hospitalizations, only one was associated with a fetal death. We also considered nonfatal birth outcomes (preterm delivery, low birth weight at term, and low Apgar score at term) and found no evidence of an association between vaccination and these outcomes (Table S3 in the Supplementary Appendix). Confirmed H1N1 (no.) July Confirmed H1N1 Aug. Sept. Oct. Discussion Nov. Vaccinations Dec. Jan Although safety data for use of the Pandemrix vaccine in pregnant women were lacking at the time of the pandemic, studies in animals showed no reproductive toxicity, and it was considered safe for use during pregnancy. 15 Nevertheless, early reports of fetal losses after vaccination, including 30 reports in Norway, 23 raised public concern about the safety of vaccination during pregnancy. Using national registries and records of health care reimbursement in Norway, we found no evidence that influenza vaccination of pregnant women increased the risk of fetal death. However, influenza virus infection itself posed a major risk; among pregnant women who received a clinical diagnosis of influenza, the risk of fetal death nearly doubled. Vaccination appeared to provide some protection against excess fetal mortality during the pandemic. A strength of this study was the use of nationwide registries with mandatory reporting of dates of events, combined with relatively high vaccination coverage. Because of the organization of health care in Norway, nearly all consultations for influenza symptoms are in primary care or emergency outpatient settings, for which physicians are reimbursed by the government. Pregnant women in Norway receive free prenatal care and give birth free of charge in hospitals. During the Figure 2. Temporal Distribution of Vaccination and Laboratory-Confirmed Pandemic Influenza. Shown are the number of pregnant women in Norway with a laboratoryconfirmed diagnosis of pandemic influenza and the number of vaccinations that were administered from October 19,, through February The numbers were smoothed by kernel estimation Vaccinations during Pregnancy (no.) n engl j med 368;4 nejm.org january 24,

6 T h e n e w e ngl a nd j o u r na l o f m e dic i n e Table 2. Hazard Ratios for Fetal Death, According to Status Regarding Vaccination, Pregnancy during the Pandemic Wave, and a Clinical Diagnosis of Influenza.* Variable No. of Pregnancy- Days at Risk Hazard Ratio (95% CI) Total no. of days 18,970,404 Vaccinated during pregnancy Without Adjustment With Initial Adjustment No 15,942, With Further Adjustment Yes 3,028, ( ) 0.84 ( ) 0.88 ( ) Pregnant during the pandemic No 10,422, Yes 8,548, ( ) 1.21 ( ) 1.26 ( ) Without an influenza diagnosis 8,221, ( ) 1.18 ( ) 1.23 ( ) With an influenza diagnosis 326, ( ) 2.10 ( ) 1.91 ( ) * Shown are hazard ratios based on the 492 fetal deaths among 113,331 women who gave birth to or miscarried a singleton in Norway in or Hazard ratios were estimated with the gestational day as the time metric. Fetal death was defined as a recorded miscarriage or stillbirth after 12 completed weeks of pregnancy. A pregnancy during the pandemic included at least 1 day between October 1,, and December 31,. Each woman could have contributed both exposed and unexposed days at risk. Vaccination status was adjusted for pregnancy during the main pandemic wave (yes or no) but not for other covariates. Influenza exposure was adjusted for vaccination status but not for other covariates. In addition to adjustment for influenza exposure and vaccination status, hazard ratios were also adjusted for age, parity, marital status, and status with respect to use of nutritional supplements during pregnancy, smoking during pregnancy, previous fetal death, and eight chronic medical conditions (asthma, hypertension, heart disease, kidney disease, rheumatoid arthritis, epilepsy, thyroid disease, and diabetes). pandemic, vaccines were offered to all Norwegian residents either free of charge or with a small administration fee. It is therefore unlikely that cost or availability influenced vaccination status in pregnant women. The birth-registry data have been found to have adequate validity, 24,25 and it is unlikely that they would be influenced by vaccination status. However, if awareness of potential risks after vaccination triggered more reporting of early losses in vaccinated women than in unvaccinated women, the adverse effects of the vaccine might have been overestimated, and the potential protective effects underestimated. Registration of vaccination was mandatory, although around 10% of the 2.43 million doses distributed in Norway were not registered. If some women who were classified in our analysis as unvaccinated had been vaccinated without registration, the benefits of vaccination might be greater than we estimate. Our estimates could be confounded if women with known risk factors for fetal death (e.g., diabetes or a history of previous fetal death) were either more or less likely to accept vaccination. The vaccination coverage was higher among women with chronic conditions and those who were obese (high-risk groups for influenza) and lower among women who were smokers, indicating that lifestyle factors may have confounded associations. However, adjustment for known potential confounding factors had little effect on the associations. The main pandemic wave and the vaccination period had substantial overlap (Fig. 2), and women could have been exposed to influenza before being vaccinated (or before the vaccine became effective), which could have attenuated the protective effects of the vaccine. We used three approaches to assess exposure to influenza virus. First, we accessed all reported cases of laboratory-confirmed pandemic influenza. The Norwegian Institute of Public Health issued recommendations for laboratory testing during the pandemic. Until July 20,, physicians were encouraged to sample widely. After this date, for reasons of limited capacity, the recommendations were revised to restrict testing to prioritized groups, including pregnant women. However, too 338 n engl j med 368;4 nejm.org january 24, 2013

7 Fetal Death after Influenza Virus Infection or Vaccination Table 3. Hazard Ratios for Fetal Death, According to Pregnancy during the Pandemic Wave and Vaccination Status.* Pregnancy and Vaccination Status during Pandemic No. of Pregnancy- Days at Risk Hazard Ratio (95% CI) Unadjusted Adjusted Not pregnant during the pandemic Not vaccinated during pregnancy 10,414, Vaccinated during pregnancy 7,402 NA NA Pregnant during the pandemic Not vaccinated during pregnancy 5,527, ( ) 1.25 ( ) Vaccinated during pregnancy 3,020, ( ) 1.10 ( ) * Shown are hazard ratios for the 492 fetal deaths among 113,331 women who gave birth to or miscarried a singleton in Norway in or Hazard ratios were estimated with the gestational day as the time metric. Fetal death was defined as a recorded miscarriage or stillbirth after 12 completed weeks of pregnancy. A pregnancy during the pandemic included at least 1 day between October 1,, and December 31,. NA denotes not available because there were too few days at risk to estimate the hazard ratio. Each woman could have contributed both exposed and unexposed days at risk. In addition to adjustment for influenza exposure and vaccination status, hazard ratios were adjusted for age, parity, marital status, and status with respect to use of nutritional supplements during pregnancy, smoking during pregnancy, previous fetal death, and eight chronic medical conditions (asthma, hypertension, heart disease, kidney disease, rheumatoid arthritis, epilepsy, thyroid disease, and diabetes). few women were tested during pregnancy to make analyses of fetal death meaningful. Second, we obtained data on physician contacts leading to a diagnosis of influenza. Approximately 20 to 30% of the Norwegian population had clinical influenza during the pandemic. 26 In our study of women who gave birth in or 2010, a total of 8.9% received a diagnosis of influenza by a physician. It is likely that a greater proportion of women with more severe symptoms contacted a physician than did those with mild symptoms, so our results may reflect risks related to infection with more severe clinical symptoms. However, only one woman who was hospitalized with influenza had a fetal death during the pandemic, so our fetal-loss data represent almost entirely nonhospitalized women. Among women with a clinical diagnosis of influenza, the risk of subsequent fetal death was nearly doubled. Third, we used the time period of the main pandemic wave as a proxy for exposure to the pandemic influenza virus. Pregnant women who were exposed to the main pandemic wave had an elevated risk of fetal death (Table 2). The risk of fetal death was slightly lower among vaccinated women than among those who were not vaccinated (Table 3). Taken together, these results are consistent in suggesting a harmful effect of pandemic influenza virus on fetal survival. Recent, smaller studies in Denmark and Canada have likewise shown no evidence that influenza vaccination during the pandemic increased the risk of stillbirth 27,28 or other adverse birth outcomes. 29 Unlike these earlier studies, our study showed an increased risk of fetal death after maternal infection with influenza virus, especially among women with a clinical diagnosis of influenza. This consequence of infection was suggested by data from the influenza pandemic of ,7,8 and was reported in women hospitalized during the pandemic. 4 However, maternal infection with influenza virus had not generally been recognized as a risk to fetal survival in the absence of hospitalized maternal illness. Given the danger posed by maternal influenza virus infection for fetal survival, our study adds to growing evidence that vaccination of pregnant women during an influenza pandemic does not harm and may benefit the fetus. We found no basis for withholding influenza vaccination from pregnant women in their second or third trimester an important group, given that these women can be particularly vulnerable to the severe effects of influenza virus infection. Supported by the Norwegian Institute of Public Health. Dr. Wilcox was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. n engl j med 368;4 nejm.org january 24,

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