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Maternal vaccination against H1N1 influenza and offspring mortality: population based cohort study and sibling design

BMJ 2015; 351 doi: (Published 16 November 2015) Cite this as: BMJ 2015;351:h5585
  1. Jonas F Ludvigsson, professor of clinical epidemiology1, paediatrician2,
  2. Peter Ström, statistician1,
  3. Cecilia Lundholm, statistician1,
  4. Sven Cnattingius, professor of reproductive epidemiology3,
  5. Anders Ekbom, professor of epidemiology3,
  6. Åke Örtqvist, associate professor4, county medical officer5,
  7. Nils Feltelius, associate professor6,
  8. Fredrik Granath, statistician3,
  9. Olof Stephansson, associate professor3, gynaecologist7
  1. 1Department of Medical Epidemiology, Karolinska Institutet, Sweden
  2. 2Department of Paediatrics, Örebro University Hospital, Sweden
  3. 3Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Sweden
  4. 4Unit of Infectious Diseases, Department of Medicine, Karolinska Institutet, Sweden
  5. 5Department of Communicable Disease Control and Prevention, Stockholm County Council, Sweden
  6. 6Medical Product Agency, Uppsala, Sweden
  7. 7Department of Women’s and Children’s Health, Karolinska Institutet and Hospital, Sweden
  1. Correspondence to: J F Ludvigsson jonasludvigsson{at}
  • Accepted 9 October 2015


Study question What is the mortality in offspring of mothers who had influenza A(H1N1)pdm09 vaccination during pregnancy?

Methods This was a prospective population based cohort study in seven healthcare regions in Sweden based on vaccinations taking place between 2 October 2009 and 26 November 2010. H1N1 vaccination data were linked with pregnancy and birth characteristics and offspring mortality data in 275 500 births (of which 1203 were stillbirths) from 137 886 mothers. Of these offspring, 41 183 had been exposed to vaccination with Pandemrix, a monovalent AS03 adjuvanted H1N1 influenza vaccine, during fetal life. A primary comparison group consisted of pregnancies of women who were not vaccinated during the same calendar period. In a second comparison, non-exposed siblings of infants prenatally exposed to vaccination were used as controls. Cox regression was used to estimate hazard ratios for stillbirth, early neonatal mortality (days 0-6 after birth), and subsequent mortality (beginning on day 7) in vaccinated versus non-vaccinated women, adjusting for mother’s age at delivery, body mass index, parity, smoking, country of birth, and disposable income and for sex of offspring.

Study answer and limitations The results of this study suggest that AS03 adjuvanted H1N1 vaccination during pregnancy does not affect the risk of stillbirth, early neonatal death, or later mortality in the offspring. During follow-up, 1172 stillbirths, 380 early neonatal deaths, and 706 deaths thereafter occurred. Compared with general population controls, this corresponded to adjusted hazard ratios of 0.83 (95% confidence interval 0.65 to 1.04) for stillbirth, 0.71 (0.44 to 1.14) for early neonatal death, and 0.97 (0.69 to 1.36) for later death. When siblings were used as controls, adjusted hazard ratios were 0.88 (0.59 to 1.30) for stillbirth, 0.82 (0.46 to 1.49) for early neonatal death, and 0.78 (0.52 to 1.19) for later death. Limitations of the study include lack of data on miscarriage before gestational week 22, inability to ascertain which mothers had pandemic flu during pregnancy, and lack of data on factors influencing the decision to vaccinate during pregnancy.

What this study adds H1N1 vaccination during pregnancy is not associated with adverse fetal outcome or offspring mortality, including when familial factors are taken into account.

Funding, competing interests, data sharing This project was supported by grants from the Swedish Research Council and the Swedish Council for Working Life and Social Research. NF was employed at the Swedish Medical Product Agency at the time of the study.


  • We thank Ingemar Persson for his previous work with the H1N1 cohort.

  • Contributors: JFL conceived and designed the study, with input from the other authors. JFL wrote the first draft of the paper and supervised the project. JFL and SC obtained funding for the study. PS analysed the data, with support from CL and FG. All authors interpreted the data and contributed to the writing of the paper. All authors revised and approved the final version. JFL is the guarantor.

  • Funding: This project was supported by grants from the Swedish Research Council (Medicine, 2010-4202) and the Swedish Council for Working Life and Social Research (FAS: 2010-0923).

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at (available on request from the corresponding author) and declare: support for the submitted work as described above; NF was employed at the Swedish Medical Product Agency at the time of the study; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: The study was approved by the Research Ethics Committee of Karolinska Institutet (2009/1952-31/4), which deemed that no individual informed consent was required.

  • Data sharing: Other researchers can apply for our data through the Swedish National Board of Health and Welfare.

  • Transparency: The lead author (the manuscript’s guarantor) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

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