Investigating causal relations between sleep duration and risks of adverse pregnancy and perinatal outcomes: linear and nonlinear Mendelian randomization analyses

Qian Yang*, Maria C Magnus, Fanny C Kilpi, Gillian Santorelli, Ana Luiza Goncalves Soares, Jane West, Per Magnus, John Wright, Siri Haberg, Eleanor C M Sanderson, Debbie A Lawlor, Kate M Tilling, Maria C Borges

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Abstract

Background
Observational studies have reported maternal short/long sleep duration to be associated with adverse pregnancy and perinatal outcomes. However, it remains unclear whether there are nonlinear causal effects. Our aim was to use Mendelian randomization (MR) and multivariable regression to examine nonlinear effects of sleep duration on stillbirth (MR only), miscarriage (MR only), gestational diabetes, hypertensive disorders of pregnancy, perinatal depression, preterm birth and low/high offspring birthweight.

Methods
We used data from European women in UK Biobank (N=176,897), FinnGen (N=~123,579), Avon Longitudinal Study of Parents and Children (N=6826), Born in Bradford (N=2940) and Norwegian Mother, Father and Child Cohort Study (MoBa, N=14,584). We used 78 previously identified genetic variants as instruments for sleep duration and investigated its effects using two-sample, and one-sample nonlinear (UK Biobank only), MR. We compared MR findings with multivariable regression in MoBa (N=76,669), where maternal sleep duration was measured at 30 weeks.

Results
In UK Biobank, MR provided evidence of nonlinear effects of sleep duration on stillbirth, perinatal depression and low offspring birthweight. Shorter and longer duration increased stillbirth and low offspring birthweight; shorter duration increased perinatal depression. For example, longer sleep duration was related to lower risk of low offspring birthweight (odds ratio 0.79 per 1 h/day (95% confidence interval: 0.67, 0.93)) in the shortest duration group and higher risk (odds ratio 1.40 (95% confidence interval: 1.06, 1.84)) in the longest duration group, suggesting shorter and longer duration increased the risk. These were supported by the lack of evidence of a linear effect of sleep duration on any outcome using two-sample MR. In multivariable regression, risks of all outcomes were higher in the women reporting <5 and ≥10 h/day sleep compared with the reference category of 8–9 h/day, despite some wide confidence intervals. Nonlinear models fitted the data better than linear models for most outcomes (likelihood ratio P-value=0.02 to 3.2×10−52), except for gestational diabetes.

Conclusions
Our results show shorter and longer sleep duration potentially causing higher risks of stillbirth, perinatal depression and low offspring birthweight. Larger studies with more cases are needed to detect potential nonlinear effects on hypertensive disorders of pregnancy, preterm birth and high offspring birthweight.
Original languageEnglish
Article number295
Pages (from-to)1-16
Number of pages16
JournalBMC Medicine
Volume20
Issue number1
DOIs
Publication statusPublished - 12 Sept 2022

Bibliographical note

Funding Information:
This research has been conducted using the UKB Resources under application number 23938. The authors would like to thank the participants and researchers from UKB who contributed or collected data. We are extremely grateful to all the families who took part in ALSPAC, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. BiB is only possible because of the enthusiasm and commitment of the children and parents in BiB. We are grateful to all the participants, teachers, school staff, health professionals and researchers who have made BiB happen. This research has been conducted using MoBa data using application number 2552. MoBa is supported by the Norwegian Ministry of Health and Care services and the Ministry of Education and Research. We are grateful to all the participating families in Norway who take part in this on-going cohort study. We thank the Norwegian Institute of Public Health (NIPH) for generating high-quality genomic data. This research is part of the HARVEST collaboration, supported by the Research Council of Norway (#229624). We also thank the NORMENT Centre for providing genotype data, funded by the Research Council of Norway (#223273), South East Norway Health Authority and KG Jebsen Stiftelsen. We further thank the Center for Diabetes Research, the University of Bergen, for providing genotype data and performing quality control and imputation of the data funded by the ERC AdG project SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, Trond Mohn Foundation, the Research Council of Norway, the Novo Nordisk Foundation, the University of Bergen and the Western Norway health Authorities (Helse Vest). The authors thank FinnGen investigators for sharing their summary-level data.

Funding Information:
The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and DAL will serve as guarantor for the contents of this paper. A comprehensive list of grant funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ). ALSPAC was specifically funded by Wellcome Trust (WT088806), and child’s GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. BiB is supported by a Wellcome programme grant (WT223601/Z/21/Z: Age of Wonder), an infrastructure grant (WT101597MA), a UK Medical and Economic and Social Science Research Councils programme grant (MR/N024397/1), a British Heart Foundation Clinical Study grant (CS/16/4/32482) and the National Institute of Health Research under its Applied Research Collaboration for Yorkshire and Humber (NIHR200166). Further support for genome-wide and multiple ‘omics measurements in BiB is from the UK Medical Research Council (G0600705), National Institute of Health Research (NF-SI-0611-10196), US National Institute of Health (R01DK10324) and the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007–2013) / ERC grant agreement no 669545. The funders had no role in the design of the study; the collection, analysis or interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. The views expressed in this paper are those of the authors and not necessarily those of any funder.

Funding Information:
This research has been conducted using the UKB Resources under application number 23938. The authors would like to thank the participants and researchers from UKB who contributed or collected data. We are extremely grateful to all the families who took part in ALSPAC, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. BiB is only possible because of the enthusiasm and commitment of the children and parents in BiB. We are grateful to all the participants, teachers, school staff, health professionals and researchers who have made BiB happen. This research has been conducted using MoBa data using application number 2552. MoBa is supported by the Norwegian Ministry of Health and Care services and the Ministry of Education and Research. We are grateful to all the participating families in Norway who take part in this on-going cohort study. We thank the Norwegian Institute of Public Health (NIPH) for generating high-quality genomic data. This research is part of the HARVEST collaboration, supported by the Research Council of Norway (#229624). We also thank the NORMENT Centre for providing genotype data, funded by the Research Council of Norway (#223273), South East Norway Health Authority and KG Jebsen Stiftelsen. We further thank the Center for Diabetes Research, the University of Bergen, for providing genotype data and performing quality control and imputation of the data funded by the ERC AdG project SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, Trond Mohn Foundation, the Research Council of Norway, the Novo Nordisk Foundation, the University of Bergen and the Western Norway health Authorities (Helse Vest). The authors thank FinnGen investigators for sharing their summary-level data.

Funding Information:
This work was supported by the University of Bristol and UK Medical Research Council (MM_UU_00011/1, MM_UU_00011/3 and MM_UU_00011/6), the US National Institute for Health (R01 DK10324), the European Research Council via Advanced Grant 669545, the British Heart Foundation (AA/18/7/34219 and CS/16/4/32482) and the National Institute of Health Research Bristol Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. QY is funded by a China Scholarship Council PhD Scholarship (CSC201808060273). MCB was funded by a UK Medical Research Council Skills Development Fellowship (MR/P014054/1) and a University of Bristol Vice Chancellor Fellowship during her contribution to this research. MCM has received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 947684). MCM and SEH are partly funded by the Research Council of Norway (project No 320656) through its Centres of Excellence funding scheme (project No 262700). AGS is supported by the study of Dynamic longitudinal exposome trajectories in cardiovascular and metabolic non-communicable diseases (H2020-SC1-2019-Single-Stage-RTD, project ID 874739). DAL is a British Heart Foundation Chair (CH/F/20/90003) and a National Institute of Health Research Senior Investigator (NF-0616-10102).

Publisher Copyright:
© 2022, The Author(s).

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