MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom.
Population Health Sciences, Bristol Medical School, University of Bristol, United Kingdom.
PLoS Med. 2022 Sep 6;19(9):e1004090. doi: 10.1371/journal.pmed.1004090. eCollection 2022 Sep.
Insomnia is common and associated with adverse pregnancy and perinatal outcomes in observational studies. However, those associations could be vulnerable to residual confounding or reverse causality. Our aim was to estimate the association of insomnia with stillbirth, miscarriage, gestational diabetes (GD), hypertensive disorders of pregnancy (HDP), perinatal depression, preterm birth (PTB), and low/high offspring birthweight (LBW/HBW).
We used 2-sample mendelian randomization (MR) with 81 single-nucleotide polymorphisms (SNPs) instrumenting for a lifelong predisposition to insomnia. Our outcomes included ever experiencing stillbirth, ever experiencing miscarriage, GD, HDP, perinatal depression, PTB (gestational age <37 completed weeks), LBW (<2,500 grams), and HBW (>4,500 grams). We used data from women of European descent (N = 356,069, mean ages at delivery 25.5 to 30.0 years) from UK Biobank (UKB), FinnGen, Avon Longitudinal Study of Parents and Children (ALSPAC), Born in Bradford (BiB), and the Norwegian Mother, Father and Child Cohort (MoBa). Main MR analyses used inverse variance weighting (IVW), with weighted median and MR-Egger as sensitivity analyses. We compared MR estimates with multivariable regression of insomnia in pregnancy on outcomes in ALSPAC (N = 11,745). IVW showed evidence of an association of genetic susceptibility to insomnia with miscarriage (odds ratio (OR): 1.60, 95% confidence interval (CI): 1.18, 2.17, p = 0.002), perinatal depression (OR 3.56, 95% CI: 1.49, 8.54, p = 0.004), and LBW (OR 3.17, 95% CI: 1.69, 5.96, p < 0.001). IVW results did not support associations of insomnia with stillbirth, GD, HDP, PTB, and HBW, with wide CIs including the null. Associations of genetic susceptibility to insomnia with miscarriage, perinatal depression, and LBW were not observed in weighted median or MR-Egger analyses. Results from these sensitivity analyses were directionally consistent with IVW results for all outcomes, with the exception of GD, perinatal depression, and PTB in MR-Egger. Multivariable regression showed associations of insomnia at 18 weeks of gestation with perinatal depression (OR 2.96, 95% CI: 2.42, 3.63, p < 0.001), but not with LBW (OR 0.92, 95% CI: 0.69, 1.24, p = 0.60). Multivariable regression with miscarriage and stillbirth was not possible due to small numbers in index pregnancies. Key limitations are potential horizontal pleiotropy (particularly for perinatal depression) and low statistical power in MR, and residual confounding in multivariable regression.
In this study, we observed some evidence in support of a possible causal relationship between genetically predicted insomnia and miscarriage, perinatal depression, and LBW. Our study also found observational evidence in support of an association between insomnia in pregnancy and perinatal depression, with no clear multivariable evidence of an association with LBW. Our findings highlight the importance of healthy sleep in women of reproductive age, though replication in larger studies, including with genetic instruments specific to insomnia in pregnancy are important.
在观察性研究中，失眠很常见，且与不良妊娠和围产期结局相关。然而，这些关联可能容易受到残余混杂或反向因果关系的影响。我们的目的是评估失眠与死胎、流产、妊娠糖尿病（GD）、妊娠高血压疾病（HDP）、围产期抑郁、早产（PTB）以及低体重儿/巨大儿（LBW/HBW）之间的关联。
我们使用两样本孟德尔随机化（MR），使用 81 个单核苷酸多态性（SNP）作为终生易患失眠的工具变量。我们的结局包括经历过死胎、经历过流产、GD、HDP、围产期抑郁、PTB（妊娠年龄<37 周）、LBW（<2500 克）和 HBW（>4500 克）。我们使用了来自英国生物银行（UKB）、芬兰基因、阿冯 longitudinal 研究的父母和孩子（ALSPAC）、布拉德福德出生（BiB）和挪威母亲、父亲和儿童队列（MoBa）的欧洲裔女性（n=356069，分娩时的平均年龄为 25.5 至 30.0 岁）的数据。主要的 MR 分析使用了逆方差加权（IVW），加权中位数和 MR-Egger 作为敏感性分析。我们将 MR 估计与 ALSPAC 中妊娠期间失眠与结局的多变量回归进行了比较（n=11745）。IVW 显示，遗传易感性与失眠与流产（优势比（OR）：1.60，95%置信区间（CI）：1.18，2.17，p=0.002）、围产期抑郁（OR 3.56，95%CI：1.49，8.54，p=0.004）和 LBW（OR 3.17，95%CI：1.69，5.96，p<0.001）相关。IVW 结果不支持失眠与死胎、GD、HDP、PTB 和 HBW 之间的关联，CI 较宽，包括零假设。加权中位数或 MR-Egger 分析也未发现遗传易感性与失眠相关的流产、围产期抑郁和 LBW 之间的关联。这些敏感性分析的结果与 IVW 结果在所有结局上的方向一致，除了在 MR-Egger 中观察到的 GD、围产期抑郁和 PTB。多变量回归显示，18 周妊娠时的失眠与围产期抑郁（OR 2.96，95%CI：2.42，3.63，p<0.001）相关，但与 LBW 无关（OR 0.92，95%CI：0.69，1.24，p=0.60）。由于索引妊娠中病例数较少，多变量回归与流产和死胎无法进行。主要限制因素是潜在的水平遗传多效性（特别是对围产期抑郁）和 MR 的统计能力低，以及多变量回归中的残余混杂。
在这项研究中，我们观察到一些证据支持遗传预测的失眠与流产、围产期抑郁和 LBW 之间可能存在因果关系。我们的研究还发现了与妊娠期间失眠与围产期抑郁相关的观察性证据，而没有明确的多变量证据表明与 LBW 相关。我们的研究结果强调了健康睡眠对育龄妇女的重要性，尽管在更大的研究中进行复制，包括针对妊娠失眠的特定遗传工具非常重要。
