Maternal Antenatal Bereavement and Hypospadias and Cryptorchidism: A Follow-up Study of 898,961 Boys in Denmark

INTRODUCTION: Normal descent of the testis and function of the penis is essential to the reproductive health of man. Cryptorchidism and hypospadias are common male genital malformations associated with increased risk of low semen quality and testis cancer. Etiology is mostly unknown. Endocrine disruptors have been associated with cryptorchidism and hypospadias. Little is known about prenatal emotional stress possibly affecting prenatal hormones such as cortisol. Our aim was to investigate the associations between maternal bereavement up to one year before and during pregnancy and the development of cryptorchidism and hypospadias in the male offspring. We hypothesized bereavement during first trimester to have the largest effect.

METHODS: We conducted a large population-based cohort study (1978-2008) with data from the Danish national registries on 898,961 boys. Exposure was maternal bereavement due to death of a close relative and outcome was cryptorchidism and hypospadias according to the international classification system of disease. We used cox regression taking delayed diagnosis into consideration adjusting for parental age, birth year, family history of the outcome and stratifying on common risk factors; birth weight, gestational age and size for gestational age.

RESULTS: We found an increased risk for hypospadias when comparing bereaved mothers to non-bereaved mothers, hazard ratio (HR) 1.20 95% CI (1.00;1.44), especially mothers bereaved during the first trimester of pregnancy HR 1.63 95% CI (1.04;2.56). No statistically significant associations were found for cryptorchidism HR 1.01 95% CI (0.92;1.13) or during first trimester HR 1.24 95% CI (0,94;1.64).

CONCLUSION: We had a large sample, validated outcome and adjusted for common risk factors making our results robust. However registration of family history of the outcome and possible lack of registration of testis descended to a low scrotal position should be considered. Severe emotional stress may possibly be added to the risk factors for hypospadias, but not cryptorchidism.