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  1. Research
  2. Infertility, recurrent...
  3. Infertility, recurrent pregnancy loss, and risk of stroke: pooled analysis of individual patient data of 618 851 women
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Research

Infertility, recurrent pregnancy loss, and risk of stroke: pooled analysis of individual patient data of 618 851 women

BMJ 2022; 377 doi: https://doi.org/10.1136/bmj-2022-070603 (Published 22 June 2022) Cite this as: BMJ 2022;377:e070603
  1. Chen Liang, PhD candidate1,
  2. Hsin-Fang Chung, research fellow1,
  3. Annette J Dobson, professor1,
  4. Kunihiko Hayashi, professor2,
  5. Yvonne T van der Schouw, professor3,
  6. Diana Kuh, professor4,
  7. Rebecca Hardy, professor5,
  8. Carol A Derby, professor6 7,
  9. Samar R El Khoudary, associate professor8,
  10. Imke Janssen, associate professor9,
  11. Sven Sandin, statistician10,
  12. Elisabete Weiderpass, director11,
  13. Gita D Mishra, professor12
  1. 1University of Queensland, School of Public Health, Queensland, Australia
  2. 2School of Health Sciences, Gunma University, Gunma, Japan
  3. 3Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, University Utrecht, Utrecht, Netherlands
  4. 4Medical Research Council Unit for Lifelong Health and Ageing at UCL, London, UK
  5. 5UCL Social Research Institute, London, UK
  6. 6Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA
  7. 7Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA
  8. 8Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, PA, USA
  9. 9Department of Preventive Medicine, Rush University Medical Center, Chicago, IL, USA
  10. 10Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  11. 11International Agency for Research on Cancer, World Health Organization, Lyon, France
  12. 12University of Queensland, School of Public Health, Queensland, Australia
  1. Correspondence to: G D Mishra g.mishra{at}uq.edu.au
  • Accepted 4 May 2022

Abstract

Objective To examine the associations of infertility, recurrent miscarriage, and stillbirth with the risk of first non-fatal and fatal stroke, further stratified by stroke subtypes.

Design Individual participant pooled analysis of eight prospective cohort studies.

Setting Cohort studies across seven countries (Australia, China, Japan, Netherlands, Sweden, the United Kingdom, and the United States) participating in the InterLACE (International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events) consortium, which was established in June 2012.

Participants 618 851 women aged 32.0-73.0 years at baseline with data on infertility, miscarriage, or stillbirth, at least one outcome event (non-fatal or fatal stroke), and information on covariates were included; 93 119 women were excluded. Of the participants, 275 863 had data on non-fatal and fatal stroke, 54 716 only had data on non-fatal stroke, and 288 272 only had data on fatal stroke.

Main outcome and measures Non-fatal strokes were identified through self-reported questionnaires, linked hospital data, or national patient registers. Fatal strokes were identified through death registry data.

Results The median follow-up for non-fatal stroke and fatal stroke was 13.0 years (interquartile range 12.0-14.0) and 9.4 years (7.6-13.0), respectively. A first non-fatal stroke was experienced by 9265 (2.8%) women and 4003 (0.7%) experienced a fatal stroke. Hazard ratios for non-fatal or fatal stroke were stratified by hypertension and adjusted for race or ethnicity, body mass index, smoking status, education level, and study. Infertility was associated with an increased risk of non-fatal stroke (hazard ratio 1.14, 95% confidence interval 1.08 to 1.20). Recurrent miscarriage (at least three) was associated with higher risk of non-fatal and fatal stroke (1.35, 1.27 to 1.44, and 1.82, 1.58 to 2.10, respectively). Women with stillbirth were at 31% higher risk of non-fatal stroke (1.31, 1.10 to 1.57) and women with recurrent stillbirth were at 26% higher risk of fatal stroke (1.26, 1.15 to 1.39). The increased risk of stroke (non-fatal or fatal) associated with infertility or recurrent stillbirths was mainly driven by a single stroke subtype (non-fatal ischaemic stroke and fatal haemorrhagic stroke), while the increased risk of stroke (non-fatal or fatal) associated with recurrent miscarriages was driven by both subtypes.

Conclusion A history of recurrent miscarriages and death or loss of a baby before or during birth could be considered a female specific risk factor for stroke, with differences in risk according to stroke subtypes. These findings could contribute to improved monitoring and stroke prevention for women with such a history.

Footnotes

  • Contributors: CL, H-FC, AJD, and GDM contributed to the conception, study design, and statistical methods. CL performed statistical analyses and drafted the manuscript. AJD, KH, YTvdS, DK, RH, CAD, SREK, IJ, SS, and EW contributed data and provided critical revision of the manuscript for important intellectual content. GDM is the guarantor. The corresponding author attests that all listed authors meet authorship criteria and no others meeting the criteria have been omitted.

  • Funding: This study is funded by the Australian National Health and Medical Research Council Centres of Research Excellence (APP1153420). GDM is supported by an Australian National Health and Medical Research Council Investigator grant (APP2009577). The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: support from the Australian National Health and Medical Research Council Centres of Research Excellence for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • The lead author (GDM) affirms that the 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.

  • Dissemination to participants and related patient and public communities: The dissemination plan targets a wide rangeing audience, including patients, public communities, health professionals, and experts in related fields through social media, websites, conferences, and scientific events. The results will be presented at conferences and disseminated through press releases and social media.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

Data availability statement

No additional data available.

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