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 2009 who were between the ages of 13 and 49 years, 117,026 gave birth in 2009 or 2010. 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 2010. 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 Fig. 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, 2009, and December 31, 2009. 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 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

Figure 1. Figure 1. Eligible Pregnancies, Observed Pregnancy Days, and Exposure to the Main Pandemic Wave. Births in Norway that occurred in 2009 and 2010 were eligible for the study if women had become pregnant at least 43 weeks before December 31, 2010. Eligible pregnancies were classified as involving maternal exposure to the influenza pandemic if any day of pregnancy occurred between October 1, 2009, and December 31, 2009. For a given pregnancy, days at risk were defined as pregnancy days after week 12 that occurred starting on January 1, 2009, 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.

The analysis required methods that handle time-dependent exposures and data censoring.21 We used a Cox proportional-hazards model22 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, 2009, were included at the gestational age as of that date. Pregnancy days before January 1, 2009, 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 time-dependent 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 time-dependent 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, 2009, to December 31, 2009) 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, 2009, 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).