ArticlesSerious life events and congenital malformations: a national study with complete follow-up
Introduction
There has long been debate about whether emotional stress causes congenital malformations. Some studies have suggested that the overall prevalence of congenital malformations, especially cleft palate, is raised in offspring of women with unwanted pregnancies.1, 2, 3, 4 Periconceptional life events, such as job loss, separation, or bereavement, have been associated with conotruncal cardiac defects, cleft lip and palate, and neural-tube defects in offspring.5, 6 In a prospective study, we found that maternal stress was associated with a low head circumference and suboptimal neurological results at birth, indicating an effect on development of the central nervous system.7 Most studies have been small, subject to bias, and without proper control for confounders.
Psychosocial stress affects the autonomic nervous system, the hypothalamic-pituitary-adrenal axis, and the cardiovascular, metabolic, and immune systems.8 If stress is severe or prolonged, it could in theory induce congenital malformations through cortisone, one of the major stress hormones.8 Cortisone given to pregnant mice increases the risk of cleft palate, shortening of the head, shortening of the mandible, and spina bifida.9 Larger human studies have shown an association between cortisone use during the first trimester and cleft lip and palate;10, 11, 12 other studies have not.13 Cranial-neural-crest cells could be more vulnerable to environmental factors because they depend on factors encountered in the environment through which they migrate and also to which they home for survival, proliferation, and differentiation.14
We postulated that psychosocial stress increases the prevalence of malformations, in particular of the cranial neural crest (eg, cleft lip, cleft palate, and congenital heart malformations). We postulated that stress during the period of organogenesis is the most important factor. We also expected multiple exposures to have a larger effect than single exposures and that the size of the effect would be related to the severity of the exposure.
Section snippets
Methods
This historical follow-up study is based on linkage of registers covering the whole population of Denmark. By means of the Medical Birth Registry,15 we identified all 452 625 women who had been pregnant and given birth (livebirth or stillbirth, a total of 698 625 pregnancies) between Jan 1, 1980, and Dec 31, 1992. By use of personal identification numbers, we linked these women to the Fertility Database16, 17 to identify their partners and children born before the index pregnancy. Only about
Results
The exposed cohort consisted of 3560 pregnancies in 3355 women and the control cohort of 20 299 pregnancies in 19948 women. Among the exposed cohort, 196 women had been exposed in two consecutive pregnancies and nine women in three. Among the controls, there were data from two pregnancies in 344 women and from three or more in seven women. Furthermore, data from separate pregnancies in 159 women were included in both cohorts.
Because the exposed women were selected according to past family
Discussion
We found that women exposed to emotional stress from severe life events gave birth to offspring with an increased frequency of cranial-neural-crest congenital malformations. The strongest risk for cranial-neural-crest malformations was seen for exposures during the first trimester to death of an older child, especially if that death was unexpected. Exposures in two consecutive pregnancies doubled the risk; this finding could be due to an increased probability of exposure at the vulnerable
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