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. 2024 Dec 18;24(1):816.
doi: 10.1186/s12884-024-07023-8.

Evaluating causal associations of chronotype with pregnancy and perinatal outcomes and its interactions with insomnia and sleep duration: a mendelian randomization study

Qian Yang  1   2   3 , Maria C Magnus  4   5   6 , Fanny Kilpi  4   5 , Gillian Santorelli  4   5 , Ana Goncalves Soares  4   5 , Jane West  7 , Per Magnus  6 , Siri E Håberg  6 , Kate Tilling #  4   5   8 , Deborah A Lawlor #  4   5   8 , M Carolina Borges #  4   5 , Eleanor Sanderson #  4   5
Affiliations

Evaluating causal associations of chronotype with pregnancy and perinatal outcomes and its interactions with insomnia and sleep duration: a mendelian randomization study

Qian Yang et al. BMC Pregnancy Childbirth. .

Abstract

Background: Observational studies suggested chronotype was associated with pregnancy and perinatal outcomes. Whether these associations are causal is unclear. Our aims are to use Mendelian randomization (MR) to explore (1) associations of evening preference with stillbirth, miscarriage, gestational diabetes, hypertensive disorders of pregnancy, perinatal depression, preterm birth and offspring birthweight; and (2) differences in associations of insomnia and sleep duration with those outcomes between chronotype preferences.

Methods: We conducted two-sample MR using 105 genetic variants reported in a genome-wide association study (N = 248,100) to instrument for lifelong predisposition to evening- versus morning-preference. We generated variant-outcome associations in European ancestry women from UK Biobank (UKB, N = 176,897), Avon Longitudinal Study of Parents and Children (ALSPAC, N = 6826), Born in Bradford (BiB, N = 2940) and the Norwegian Mother, Father and Child Cohort Study (MoBa, N = 57,430), and extracted equivalent associations from FinnGen (N = 190,879). We used inverse variance weighted (IVW) as main analysis, with weighted median and MR-Egger as sensitivity analyses. Relying on the individual participant data from UKB, ALSPAC, BiB and MoBa, we also conducted IVW analyses of insomnia and sleep duration on the pregnancy and perinatal outcomes, stratified by genetically predicted chronotypes.

Results: In IVW and sensitivity analyses, we did not find robust evidence of associations of chronotype with the outcomes. Insomnia was associated with a higher risk of preterm birth among evening preference women (odds ratio 1.61, 95% confidence interval: 1.17, 2.21), but not among morning preference women (odds ratio 0.87, 95% confidence interval: 0.64, 1.18), with an interaction P-value = 0.01. There was no evidence of interactions between insomnia and chronotype on other outcomes, or between sleep duration and chronotype on any outcomes.

Conclusions: This study raises the possibility of a higher risk of preterm birth among women with insomnia who also have an evening preference. Our findings warrant replications due to imprecise estimates.

Keywords: Chronotype; Mendelian randomization; Pregnancy and perinatal outcomes; Sleep.

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Conflict of interest statement

Ethics approval and consent to participate: Ethical approval for UKB was obtained from the North West Multi-centre Research Ethics Committee. Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. Consent for biological samples has been collected in accordance with the Human Tissue Act (2004). Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendation of the ALSPAC Ethics and Law Committee at the time. Ethical approval for BiB was obtained from the Bradford Research Ethics Committee. The establishment of MoBa and initial data collection was based on a license from the Norwegian Data Protection Agency and approval from The Regional Committees for Medical and Health Research Ethics. The MoBa cohort is now based on regulations related to the Norwegian Health Registry Act. The current study was approved by The Regional Committees for Medical and Health Research Ethics. The Coordinating Ethics Committee of the Helsinki and Uusimaa Hospital District has approved the FinnGen consortium (Nr HUS/990/2017), and this study used its summary level data. Competing interests: KT has acted as a consultant for CHDI Foundation, and Expert Witness to the High Court in England, called by the UK Medicines and Healthcare products Regulatory Agency, defendants in a case on hormonal pregnancy tests and congenital anomalies 2021/22. DAL has received support from Medtronic LTD and Roche Diagnostics for biomarker research that is not related to the study presented in this paper. The other authors report no conflicts.

Figures

Fig. 1
Fig. 1
Summary of methods and data contributing to our two-sample MR analyses. a Two-sample MR methods include IVW, weighted median, MR-Egger and leave-one (SNP)-out analysis. Abbreviations: ALSPAC, Avon Longitudinal Study of Parents and Children; BiB, Born in Bradford; GRS, genetic risk score; IVW, inverse variance weighted; MoBa, Norwegian Mother, Father and Child Cohort Study; MR, Mendelian randomization; SNP, single nucleotide polymorphism; UKB, UK Biobank
Fig. 2
Fig. 2
Two-sample MR estimates for causal effects of chronotype on pregnancy and perinatal outcomes meta-analysing UK Biobank, three birth cohorts and FinnGen. P-value for Cochran’s Q-statistic testing statistical evidence for between-SNP heterogeneity in the two-sample MR estimates. P-value for MR-Egger intercept < 0.05 suggests unbalanced horizontal pleiotropy. Abbreviations: CI, confidence interval; HDP, hypertensive disorders of pregnancy; MR, Mendelian randomization; OR, odds ratio
Fig. 3
Fig. 3
Two-sample MR IVW estimates meta-analysing UK Biobank and three birth cohorts for causal effects of insomnia on pregnancy and perinatal outcomes, stratified on chronotype. Abbreviations: CI, confidence interval; IVW, inverse variance weighted; MD, mean difference; MR, Mendelian randomization; OR, odds ratio
Fig. 4
Fig. 4
Two-sample MR IVW estimates meta-analysing UK Biobank and three birth cohorts for causal effects of sleep duration on pregnancy and perinatal outcomes, stratified on chronotype. Abbreviations: CI, confidence interval; IVW, inverse variance weighted; MD, mean difference; MR, Mendelian randomization; OR, odds ratio
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