An ongoing genetic epidemiological study in Finland afforded us the unique possibility to test the association of prenatal exposure to a naturally occurring stressor with behavior outcomes in early adolescence. Large groups of 14-year-old adolescents that were exposed from early or mid pregnancy onwards, or during the third trimester of pregnancy, were compared with reference groups. Our results show that adolescents who were exposed from second trimester in pregnancy onwards had more than a two-fold risk of exhibiting lifetime depression symptoms and ADHD symptoms in structured interviews. This effect was found only among those exposed from the second trimester onwards and not after exposure from first trimester onwards or during third trimester; that contrast may suggest that this period in fetal brain development is sensitive to perturbations. We also showed that exposure during pregnancy resulted in a more than 2-fold risk of fulfilling DSM-III-R criteria for Major Depressive Disorder. The twins’ mothers had been interviewed with the adult SSAGA on average two years before the twin’s own interview; using those data, we performed an additional adjustment for maternal depressive symptoms and found that adjustment did not change these findings (data not shown).
Similar results have been found in several other studies. A relatively high incidence of psychiatric disorders, including depressive and neurotic symptoms was found in children up to age 15 born to mothers who faced the death of their spouse during pregnancy (12
). Watson et al. (15
) reported more depressive symptoms and more signs of severe depression in 18-year-old students that were prenatally exposed to a severe earthquake in China when compared with non-exposed peers. The latter study found that males exposed in the second trimester differed most from controls on rates of severe depression (19.0% versus 6.8%). No such timing effect was found for prenatally exposed females.
Our findings with regard to ADHD symptoms are also consistent with other studies. Most previous studies that focused on ADHD symptoms after exposure to prenatal stress, were conducted with younger children up to the age of 9 (4
). Van den Bergh and Marcoen (5
) found that high antenatal maternal anxiety, especially in the second trimester, was related to ADHD symptoms and anxiety in 8-to-9-year-olds: this report used a prospective design with its methodological strengths, but the study sample was relatively small (n=52). Nonetheless, it is interesting that the strongest effects in this study were also found for second trimester exposure.
The fetal central nervous system is undergoing development, including rapid proliferation, migration and differentiation, of many critical areas (21
) during the second trimester of pregnancy and many neurons are still immature (22
). Of interest, the limbic system, including the hippocampus and the amygdala, starts differentiating from the third month of gestation onwards (23
). The limbic system is involved in affective disorders. Moreover, the fetal hippocampus exhibits a prenatal peak from week 16–22 in the density of serotonin receptors (24
). Thus, perturbations in this period of fetal brain development may affect serotonin receptor functioning, which may explain the increased prevalence of depressive symptoms after prenatal stress exposure from the second trimester onwards in our study and the study of Watson et al. (15
In contrast, we found no differences in anxiety, CD or ODD symptoms between prenatally exposed and non-exposed adolescents. Apparently, the prenatal exposure may have resulted in more specific behavioral outcomes, i.e. depression and ADHD, rather than resulting in a general increased risk of internalizing or externalizing psychopathology.
We emphasize that the differences in outcome observed here appear to be related to maternal stress associated with the threat of being exposed to radiation, and the overall effects of the Chernobyl disaster in a nearby environment, rather than being due to prenatal fetal exposure to radiation. Auvinen et al. (16
) examined the relationship between the Chernobyl fallout and birth outcomes, such as rate of live births and stillbirths, pregnancy loss, and induced abortions in Finland and found no association. In the present study, no adverse effects on birth outcome of in utero exposure to Chernobyl was found. Rather, twins born after in utero exposure had marginally increased gestational ages and higher birth weights than those not exposed. Thus, if present, exposure to radiation in utero has not resulted in adverse birth outcomes. Moreover, the mothers of the twins in the present study lived in all areas throughout Finland, so that the exposure to actual and perceived radiation levels likely show high variability within our sample. However, because the highest momentary dose rate measured in Finland was only 5 μSv/h it is highly unlikely that exposure to radiation in utero has directly influenced the development of the twins in this study. Fetuses may be exposed to excess glucocorticoids when the mother is stressed (e.g. 25–28). Unfortunately we did not, even retrospectively, have individual-level assessments of perceived stress in the mothers of the present study.
Despite this limitation, the results of our study provide evidence for the fetal programming hypothesis, which reflects the action of a disturbing factor during sensitive developmental periods to affect the development and organization of specific tissues, producing effects that persist throughout life (29
). More specifically, the present study of a large sample of adolescents shows that prenatal exposure to stress or anxiety may be related to increased risk of depressive symptoms and ADHD symptoms in adolescence. We do not know whether these are transient effects manifesting themselves during puberty or are more permanent and persist into adulthood. These results warrant future studies into the mechanisms related to prenatal perturbations in fetal brain development.