Prenatal Exposure to Severe Stress and Risks of Ischemic Heart Disease and Stroke in Offspring

Key Points Question Is prenatal stress associated with increased risks of ischemic heart disease (IHD) and stroke in the offspring? Findings In this cohort study including 6.8 million participants from Denmark and Sweden, no association between maternal stress during pregnancy, defined as loss of a close relative, and the offspring’s risk of IHD and stroke up to middle-age was observed. However, maternal bereavement in the third trimester was associated with an increased risk of IHD. Meaning The findings of this study suggest that severe maternal stress during pregnancy is not associated with IHD and stroke risk up to middle-age in the offspring.


Swedish Multi-Generation Register
The register was established in 1961 and contains information on family relationships for all Swedish residents born after 1932.

Swedish Register of Education
The register was established in 1985 and contains yearly updated information on educational attainment for all Swedish residents aged 16-74 years.

Swedish Medical Birth Register
The register was established in 1973.We extracted from this register data on individuals' birth date, sex, gestational age, birth weight, singleton status, and their mothers' age at delivery, parity, medical diagnoses, and smoking and bodymass index in early pregnancy (available since 1982).

Swedish Patient Register
The register contains information on inpatient care (since1968, with nationwide coverage since 1987) and outpatient care (established in 2001).We retrieved from this register information on diagnoses and their dates.Abbreviations: HR, hazard ratio; CI, confidence interval.
a Model 1 was unadjusted.
b Model 2 was adjusted for sex, country and calendar year of birth, maternal country of origin, parity, age, education and marital status at the time of birth, hypertensive disease, diabetes, and psychiatric disorders before the index birth, and family history of cardiovascular diseases.Any loss 18 0.12 1.07 (0.67-1.70) 1.05 (0.66-1.68) 1.05 (0.66-1.68)

Hazard ratios and 95% confidence intervals for ischemic heart disease and stroke according to maternal bereavement, stratified by the offspring's sex
Analyses restricted to children whose mother had at least a live parent or a live sibling in the registers at the start of the exposure period (N= 6 749 403).The P-values for the interaction between maternal bereavement and sex on the risk of ischemic heart disease and stroke are 0.19 and 0.43, respectively.
© 2023 Yang F et al.JAMA Network Open. a Model 1 was unadjusted.bcAnalysesrestricted to children whose mother had register links to her partner or at least a live older child at the start of the exposure period (N= 6 755 410).©2023YangF et al.JAMA Network Open.d © 2023 Yang F et al.JAMA Network Open.eTable 5. a Model 1 was unadjusted.bModel 2 was adjusted for country and calendar year of birth, maternal country of origin, parity, age, education and marital status at the time of birth, hypertensive disease, diabetes, and psychiatric disorders before the index birth, and family history of cardiovascular diseases.©2023 Yang F et al.JAMA Network Open.© 2023 Yang F et al.JAMA Network Open.eTable 6.

Hazard ratios and 95% confidence intervals for ischemic heart disease and stroke according to maternal bereavement, stratified by study country
Model 2 was adjusted for sex and calendar year of birth, maternal country of origin, parity, age, education and marital status at the time of birth, hypertensive disease, diabetes, and psychiatric disorders before the index birth, and family history of cardiovascular diseases.The P-values for the interaction between maternal bereavement and study country on the risk of ischemic heart disease and stroke are 0.25 and 0.57, respectively.
a Model 1 was unadjusted.b © 2023 Yang F et al.JAMA Network Open.© 2023 Yang F et al.JAMA Network Open.

eTable 7. Hazard ratios and 95% confidence intervals for ischemic heart disease and stroke according to maternal bereavement, stratified by calendar year of birth
Model 2 was adjusted for country, sex and calendar year of birth, maternal country of origin, parity,The P-values for the interaction between maternal bereavement and calendar year of birth on the risk of ischemic heart disease and stroke are 0.86 and 0.33, respectively.
a Model 1 was unadjusted.b age, education and marital status at the time of birth, hypertensive disease, diabetes, and psychiatric disorders before the index birth, and family history of cardiovascular diseases.© 2023 Yang F et al.JAMA Network Open.© 2023 Yang F et al.JAMA Network Open.