Lund Ingunn Olea, Hannigan Laurie J, Ask Helga, Askelund Adrian D, Hegemann Laura, Corfield Elizabeth C, Wootton Robyn E, Ahmadzadeh Yasmin I, Davey Smith George, McAdams Tom A, Ystrom Eivind, Havdahl Alexandra
PsychGen Center for Genetic Epidemiology and Mental Health, Norwegian Institute of Public Health, Oslo, Norway.
Department of Child Health and Development, Norwegian Institute of Public Health, Oslo, Norway.
BMC Med. 2025 Jan 21;23(1):18. doi: 10.1186/s12916-024-03834-w.
Maternal stress during pregnancy may impact offspring development via changes in the intrauterine environment. However, genetic and environmental factors shared between mothers and children might skew our understanding of this pathway. This study assesses whether prenatal maternal stress has causal links to offspring outcomes: birthweight, gestational age, or emotional and behavioral difficulties, triangulating across methods that account for various measured and unmeasured confounders.
We used data from the Norwegian Mother, Father, and Child Cohort Study (MoBa), including maternal reports on prenatal stress at work, at home, and via stressful life events as exposures. Outcomes were children's birthweight and gestational age, from the Medical Birth Registry of Norway, and maternal reports on early offspring emotional and behavioral difficulties. We assessed associations using four approaches: sibling control analyses, gene-environment interaction analyses, intergenerational Mendelian randomization (MR), and negative control (i.e., postnatal stress) analyses.
Maternal prenatal stress was observationally associated with offspring lower birthweight (e.g., β = - 0.01 [95%CI: - 0.02, - 0.01]), earlier birth (e.g., β = - 0.04 [95%CI: - 0.04, - 0.03])), and more emotional (e.g., β = 0.08 [95%CI: 0.07, 0.09]) and behavioral difficulties (e.g., β = 0.08 [95%CI: 0.07, 0.09]) in the full sample (N = 112,784). However, sibling control analyses (N = 36,511) revealed substantial attenuation of all associations after accounting for familial factors. Gene-environment interaction models (N = 76,288) showed no clear evidence of moderation of associations by mothers' polygenic scores for traits linked to stress sensitivity. Intergenerational MR analyses (N = 29,288) showed no clear evidence of causal effects of maternal plasma cortisol on any offspring outcomes. Negative control exposure analyses revealed similar effect sizes whether exposures were measured prenatally or postnatally.
Our results indicate that links between prenatal maternal stress and variation in early offspring outcomes are more likely to be confounded than causal. While no observational study can rule out causality, the consistency of our findings across different approaches is striking. Other sources of prenatal stress or more extreme levels may represent intrauterine causal risk factors for offspring development. Nonetheless, our research contributes to identifying boundary conditions of the fetal programming and developmental origins of health and disease hypotheses, which may not be as universal as sometimes assumed.
孕期母亲压力可能通过子宫内环境的变化影响后代发育。然而，母亲和孩子之间共享的遗传和环境因素可能会影响我们对这一途径的理解。本研究评估产前母亲压力与后代结局（出生体重、孕周或情绪和行为问题）之间是否存在因果关系，通过多种方法综合考量各种已测量和未测量的混杂因素。
我们使用了挪威母亲、父亲和儿童队列研究（MoBa）的数据，将母亲报告的工作、家庭中的产前压力以及应激性生活事件作为暴露因素。结局指标包括挪威医疗出生登记处提供的孩子出生体重和孕周，以及母亲报告的后代早期情绪和行为问题。我们采用四种方法评估关联：同胞对照分析、基因-环境交互分析、代际孟德尔随机化（MR）分析和阴性对照（即产后压力）分析。
在全样本（N = 112,784）中，观察到母亲产前压力与后代较低出生体重（例如，β = -0.01 [95%CI：-0.02，-0.01]）、早产（例如，β = -0.04 [95%CI：-0.04，-0.03]）以及更多情绪问题（例如，β = 0.08 [95%CI：0.07，0.09]）和行为问题（例如，β = 0.08 [95%CI：0.07，0.09]）相关。然而，同胞对照分析（N = 36,511）显示，在考虑家族因素后，所有关联均大幅减弱。基因-环境交互模型（N = 76,288）未显示出与应激敏感性相关性状的母亲多基因评分对关联有明显的调节作用。代际MR分析（N = 29,288）未显示母亲血浆皮质醇对任何后代结局有明显因果效应的证据。阴性对照暴露分析显示，无论暴露因素是在产前还是产后测量，效应大小相似。
我们的结果表明，产前母亲压力与后代早期结局变化之间的联系更可能是混杂因素导致的而非因果关系。虽然没有观察性研究能够排除因果关系，但我们不同方法的研究结果一致性显著。产前压力的其他来源或更极端水平可能代表后代发育的子宫内因果风险因素。尽管如此，我们的研究有助于确定胎儿编程以及健康与疾病发育起源假说的边界条件，这些条件可能并不像有时假设的那样普遍。
