Elsevier

The Lancet

Volume 356, Issue 9233, 9 September 2000, Pages 875-880
The Lancet

Articles
Serious life events and congenital malformations: a national study with complete follow-up

https://doi.org/10.1016/S0140-6736(00)02676-3Get rights and content

Summary

Background

Emotional stress during organogenesis could, in theory, cause congenital malformations. We undertook a follow-up study to test the hypothesis that psychosocial stress increases the prevalence of malformations, particularly of the cranial neural crest.

Methods

We defined severe life events as death or first hospital admission for cancer or acute myocardial infarction in partners or children. From 1980 to 1992 all women exposed to severe life events during pregnancy and up to 16 months previously were identified by means of five national registers. We included 3560 exposed pregnancies and 20 299 pregnancies without such exposures randomly selected as a control cohort.

Findings

The frequency of cranial-neural-crest malformations was higher in pregnancies with exposure to severe life events than in those without such exposure (42 [1·18%] vs 131 [0·65%]; adjusted odds ratio 1·54 [95% Cl 1·05–2·27]). For other malformations, the frequencies were 3·04% and 3·26% (1·14 [0·94–1·42]). Women exposed in two consecutive pregnancies had a higher risk of cranial-neural-crest malformations (2·99 [1·06–8·43]). Death of an older child during the first trimester was associated with an adjusted odds ratio of cranial-neural-crest malformations of 4·75 (1·63–13·8). Unexpected death of a child during the first trimester was associated with adjusted odds ratios of 8·36 (2·41–29·0) for cranial-neural-crest malformations and 3·64 (1·29–10·3) for other malformations.

Interpretation

These findings support the hypothesis that severe emotional stress during pregnancy, especially that related to death of a child, may cause congenital malformations, particularly those of the cranial neural crest.

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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