In this Canada-wide population-based study, we found that infants conceived in July and August were at a significantly lower rate of gastroschisis than those conceived in any other 2-month intervals of the year. This lower rate in summer months appeared to be associated with decreased maternal depression at least in part mediated by thyroid function, presumably attributable to the circannual endocrine changes driven by increased exposure to sunlight. Substance use and tobacco smoking are also identified to have direct effects on offspring gastroschisis in the associations of maternal factors with infant gastroschisis. Diagnosed maternal depression around conception showed significant independent effects on offspring gastroschisis development, and our mediation analysis indicates that such effects appear to work through the mechanistic pathway of maternal hypothyroidism. Periconception depression appeared to influence the conception seasonal variations in risk, along with several other associated factors (e.g., residential latitude, young maternal age, and gestational diabetes). Our data suggest that these factors play an interactive role in the development of offspring gastroschisis.
Our findings on these associations and their respective strength and seasonal variation of gastroschisis prevalence with identified risk factors suggest that young women with depressive disorder are at significantly elevated risk of offspring gastroschisis. Exposure to summer season appeared to play as an exclusive modifiable factor for the relationship between periconception depression and infant gastroschisis. Our findings provide data supporting the hypothesis that increased periconceptional exposure to summer (i.e., longer daytime, lower latitude and more active lifestyle) could protect against gastroschisis during fetal development, in particular, for young women.
There is a substantial body of evidence that shows maternal perinatal mental disorders are associated with an increase in a range of adverse developmental outcomes in offspring. Prenatal stress and associated epigenetic changes in pregnant women with mental disorders may increase the risk of adverse child outcomes.31 A another example, a recent study from Quebec, Canada reported that maternal depression and stress and anxiety was significantly associated with an increased risk of hypertrophic pyloric stenosis in the newborns.32
Two meta-analyses assessed the association between antenatal depression and fetal and neonatal outcomes.10,33 One reported that studies controlling for women taking antidepressant drugs or smoking generated small (non-significant) odds ratios,33 whereas the other concluded that the summary relative risk was comparable for depressed women treated and not treated with antidepressants. Antidepressants or smoking can be markers for more severe depression, showing stronger association with antidepressants and mental health disorders.10 Selective serotonin reuptake inhibitors are widely used for depression and anxiety and have been associated with birth defects in several studies.34,35 Previous studies reported that use of antidepressants, depression, and stressful pregnancy events were associated with up to 4 times the odds of having a child with gastroschisis.28, 36
Hypothyroidism is considered a cause of or a strong risk factor for depression or depressive disorders.37 Associated with clinical depression, maternal hypothyroidism is relatively common during pregnancy, with an overall prevalence of 0.61% for overt hypothyroidism and 5.1% for subclinical hypothyroidism.38 We observed 0.72% of hypothyroidism in this data (Table 1). Some past studies have identified maternal hypothyroidism as a possible risk factor for birth defects.39,40 Light exposure has been associated with seasonal fluctuation of thyroid function related to circulating hormones, and external stimuli such as light and warm temperature can influence thyroid function.11 Normal maternal thyroid function is essential for optimal pregnancy outcomes, especially during the early gestational period. Firstly, temperature variation is a critical stimulus to the central regulation of hypothalamus-pituitary-thyroid (HPT) axis via changes in secretion of thyroid-stimulating hormone (TSH).41 One systematic review and meta-analysis found that individuals with hypothyroidism had significantly lower vitamin D levels compared to healthy people.42 Secondly, light is associated with seasonal fluctuations in thyroid function. The alteration in thyroid hormone regulation could also be a part of metabolic adaptation to seasonal climate changes.11 Thirdly, hypothyroidism has been causally associated with decreased sex hormone concentrations such as sex hormone binding globulin (SHBG) and free androgen index (FAI) in women.13 In addition, increased sunlight and vitamin D3 exposure in summer was found to be positively associated with steroid hormone production of sex hormones.18 Exposure to winter sunlight in Northern Canada does not promote previtamin D3 synthesis in human skin.43
To our knowledge, this is the first study to report the role of light and presumptive active lifestyle exposure associated with maternal depression, hypothyroidism, and potential mood/mental changes in the causality of fetal gastroschisis development. The strengths of our study include use of data from a vast geography with differential latitude/climate (e.g., far North) along with distinctive seasonal variation. Information on postal codes for maternal residence is complete and accurate and has been used in the past to account for differences in pregnancy-related endpoints such as prenatal screening or pregnancy termination. Our secondary analysis of gestational diabetes by conception season may also elucidate the inverse associations of gastroschisis with gestational diabetes observed in previous studies.9,24,25
However, several limitations must be noted. Firstly, some risk factors that are associated with gastroschisis may be tested after the occurrence of a congenital anomaly or other adverse pregnancy outcome. As antenatal data could not be available for our analysis, subclinical hypothyroidism and depression cases could have been missed in the childbirth hospitalization data. The clinical manifestations may represent a maternal persistent condition. Second, misclassification or lack of diagnosis may occur, though probably not in a differential manner, and thus it is not plausible that the coding of hypothyroidism, clinical depression or other conditions would be different for women who conceived in different months. While this potential misclassification may have underestimated the outcome rates, the rate ratio would still be unchanged. Third, the lack of stillbirths and terminated pregnancies that may have been performed due to very severe gastroschisis could be cases missed in our analysis. In a previous study including stillbirths or more severe or fatal gastroschisis, we reported an increased risk for maternal hypothyroidism but not for depression.9 This difference may indicate that maternal depression is associated with a somewhat less severe spectrum of gastroschisis.
Our study uses data from a vast geography with differential latitudes (i.e., sunlight or active lifestyle exposure), and demonstrates a distinctive seasonal variation. Information on postal codes for maternal residence is complete and accurate and has been successfully used to define residential location (i.e., rural or urban areas) in the past.22,44 Nevertheless, remaining variations in socioeconomic status, education, diet, ethnicity, vitamin D supplementation, etc., could have confounded our analysis when comparing geographic regions of maternal residence.
In conclusion, given the seasonal and geographic variations in gastroschisis occurrence in Canada and many other parts of the world, particularly in the Northern hemisphere, we observed that northern regions with less daylight length and presumably less active lifestyle might be associated with an increased risk of maternal depression that is linked to offspring gastroschisis. Our study has demonstrated that conceptions occurring in shorter photoperiod months or higher latitudes are at increased risk of infant gastroschisis compared to longer light months of summer and/or lower latitudes in which maternal hypothyroidism may play a significant mediating role in depressed women. Our findings that infant gastroschisis is associated with seasonal and regional factors indicative of low light exposure suggest that seasonal changes in other hormones, such as sex hormones, might also play a role in the etiology of fetal gastroschisis development. Further studies are warranted to confirm this suggestion in other areas of the world, and to identify any biological mechanisms that may link variations in sex hormones with maternal mood (e.g., depression) and in turn with offspring gastroschisis development.