Cardiovascular disease (CVD) is among the leading determinants of mortality and morbidity, and causation may begin in the early intrauterine environment. Prenatal exposures to glucocorticoids or stress are potential risk factors of CVD later in life, but empirical evidence from large population studies is lacking. We explored the association between prenatal stress due to maternal bereavement following the death of a relative and CVD in the exposed offspring.
Methods and results
This population-based study included 2,607,851 children born in Denmark (1970–2008). Of these participants, 73,708 (2.8%) had a CVD event during follow-up (up to 40 years). A total of 50,940 (2.0%) subjects born to mothers who lost a relative during pregnancy or the year before were categorized as exposed. Cox Proportional Hazards models were used to analyse the data. The overall hazard ratio (HR) (95% confidence interval) of having a CVD was 1.13 (1.06–1.20); the estimate was 1.24 (1.11–1.38) for heart disease and 1.27 (1.01–1.60) for hypertension. Additional sibling-matched analyses showed an overall attenuated association (1.08 (0.94–1.24)).
Conclusion
Our results suggested a modest association between prenatal stress and CVD, both in childhood and early adulthood, which could be of importance, especially at an older age when the individuals are followed over a long period.
MurrayCJLLopezAD. Measuring the global burden of disease. N Engl J Med2013; 369: 448–457.
2.
FrankelSElwoodPSmithGD. Birthweight, body-mass index in middle age, and incident coronary heart disease. Lancet1996; 348: 1478–1480.
3.
BarkerDJPOsmondCWinterPD. Weight in infancy and death from ischaemic heart disease. Lancet1989; 334: 577–580.
4.
LeonDALithellHOVågeröD. Reduced fetal growth rate and increased risk of death from ischaemic heart disease: cohort study of 15000 Swedish men and women born 1915–29. BMJ1998; 317: 241–245.
5.
Rich-EdwardsJWStampferMJMansonJE. Birth weight and risk of cardiovascular disease in a cohort of women followed up since 1976. BMJ1997; 315: 396–400.
6.
ReynoldsRM. Glucocorticoid excess and the developmental origins of disease: Two decades of testing the hypothesis – 2012 Curt Richter Award Winner. Psychoneuroendocrinology2013; 38: 1–11.
7.
GitauRCameronAFiskNM. Fetal exposure to maternal cortisol. Lancet1998; 352: 707–708.
8.
KapoorADunnEKostakiA. Fetal programming of hypothalamo–pituitary–adrenal function: prenatal stress and glucocorticoids. J Physiol2006; 572: 31–44.
9.
FowdenALSibleyCReikW. Imprinted genes, placental development and fetal growth. Hormone Res2006; 65: 50–58.
10.
HolmesMCAbrahamsenCTFrenchKL. The mother or the fetus? 11β-hydroxysteroid dehydrogenase Type 2 null mice provide evidence for direct fetal programming of behavior by endogenous glucocorticoids. J Neurosci2006; 26: 3840–3844.
11.
SecklJR. Glucocorticoid programming of the fetus; adult phenotypes and molecular mechanisms. Mol Cell Endocrinol2001; 185: 61–71.
12.
WadhwaPD. Psychoneuroendocrine processes in human pregnancy influence fetal development and health. Psychoneuroendocrinology2005; 30: 724–743.
13.
Reynolds RM, Walker BR, Syddall HE, et al. Altered control of cortisol secretion in adult men with low birth weight and cardiovascular risk factors. J Clin Endocrinol Metab 2001; 86: 245–250.
14.
ZhuJLOlsenJSørensenHT. Prenatal maternal bereavement and congenital heart defects in offspring: A registry-based study. Pediatrics2013; 131: e1225–e1230.
15.
DalzielSRWalkerNKParagV. Cardiovascular risk factors after antenatal exposure to betamethasone: 30-year follow-up of a randomised controlled trial. Lancet2005; 365: 1856–1862.
16.
CrowtherCADoyleLWHaslamRR. Outcomes at 2 years of age after repeat doses of antenatal corticosteroids. N Engl J Med2007; 357: 1179–1189.
17.
HuhSYAndrewRRich-EdwardsJW. Association between umbilical cord glucocorticoids and blood pressure at age 3 years. BMC Med2008; 6: 25–25.
18.
van DijkAEvan EijsdenMStronksK. The association between prenatal psychosocial stress and blood pressure in the child at age 5–7 years (Jaddoe VW, ed.). PLoS ONE2012; 7: e43548–e43548.
19.
van DijkAEDaweKDeanfieldJ. The association of maternal prenatal psychosocial stress with vascular function in the child at age 10–11 years: findings from the Avon longitudinal study of parents and children. Eur J Prev Cardiol2014; 21: 1097–1108.
20.
RoseboomTJvan der MeulenJHPOsmondC. Coronary heart disease after prenatal exposure to the Dutch famine, 1944–45. Heart2000; 84: 595–598.
21.
PainterRCde RooijSRBossuytPM. Blood pressure response to psychological stressors in adults after prenatal exposure to the Dutch famine. J Hypertension2006; 24: 1771–1778.
22.
LumeyLHMartiniLHMyersonM. No relation between coronary artery disease or electrocardiographic markers of disease in middle age and prenatal exposure to the Dutch famine of 1944–5. Heart2012; 98: 1653–1659.
23.
StannerSABulmerKAndrèsC. Does malnutrition in utero determine diabetes and coronary heart disease in adulthood? Results from the Leningrad siege study, a cross sectional study. BMJ1997; 315: 1342–1348.
24.
SchreierNKMoltchanovaEVBlomstedtPA. Prenatal exposure to wartime stress – long-term effect on coronary heart disease in later life. Ann Med2011; 43: 555–561.
25.
SkodolAEShroutPE. Use of DSM-III axis IV in clinical practice: rating etiologically significant stressors. Am J Psychiatry1989; 146: 61–66.
26.
LiJVestergaardMObelC. Cohort profile: The Nordic perinatal bereavement cohort. Int J Epidemiol2011; 40: 1161–1167.
27.
AndersenTFMadsenMJørgensenJ. The Danish National Hospital Register. A valuable source of data for modern health sciences. Dan Med Bull1999; 46: 263–268.
28.
Helweg-LarsenK. The Danish Register of Causes of Death. Scand J Public Hlth2011; 39: 26–29.
29.
KnudsenLBOlsenJ. The Danish Medical Birth Registry. Dan Med Bull1998; 45: 320–323.
30.
PeterssonFBaadsgaardMThygesenLC. Danish registers on personal labour market affiliation. Scand J Public Hlth2011; 39: 95–98.
31.
CovielloVBoggessM. Cumulative incidence estimation in the presence of competing risks. STATA J2004; 4: 103–112.
32.
ParnerETAndersenPK. Regression analysis of censored data using pseudo-observations. Stata J2010; 10: 408–422.
33.
ReynoldsRM. Programming effects of glucocorticoids. Clin Obstet Gynecol2013; 56: 602–609.
34.
DoyleLWFordGWDavisNM. Antenatal corticosteroid therapy and blood pressure at 14 years of age in preterm children. Clin Sci2000; 98: 137–142.
35.
GoodkinKBaldewiczTTBlaneyNTPhysiological effects of bereavement and bereavement support group interventions. In: StroebeMSHanssonROStroebeWSchutH (eds). Handbook of Bereavement Research: Consequences, Coping, and Care, Washington, DC: American Psychological Association, 2001, pp. 671–703.
36.
RostilaMSaarelaJKawachiI. Fatal stroke after the death of a sibling: A nationwide follow-up study from Sweden. PLoS One2013; 8(2): e56994–e56994.
37.
RostilaMSaarelaJKawachiI. Mortality from myocardial infarction after the death of a sibling: A nationwide follow-up sudy from Sweden. J Am Heart Assoc2013; 2: e000046–e000046.
38.
LiJHansenDMortensenPB. Myocardial infarction in parents who lost a child. A nationwide prospective cohort study in Denmark. Circulation2002; 106: 1634–1639.
