Background: There are sex differences in the risk of development of cardiovascular disease (CVD). According to the developmental origins of health and disease paradigm (DOHaD), CVD originates in fetal life. This study examines fetal sex differences in cardiovascular development in utero. Methods: In 1028 pregnant women, we assessed fetal circulation using pulsed wave Doppler examinations between 28 and 34 weeks gestation. To test associations between fetal sex and fetal circulation measurements, linear regression models were used adjusting for fetal size, gestational age, and fetal heart rate. Results: A higher pulsatility index in the ductus venosus was observed in male fetuses compared to female fetuses (difference 0.02, 95 % CI 0.01; 0.05) with a lower E/A ratio of the tricuspid (difference -0.01, 95 % CI -0.03; -0.00) and mitral (difference -0.02, 95 % CI -0.03; -0.01) valves. This was mainly determined by differences in the E wave of the tricuspid and mitral valves (differences -1.02, 95 % CI -1.81; -0.24 and -1.28, 95 % CI -2.11; -0.46, respectively). Also in males, a lower peak systolic velocity was seen in the pulmonary artery (difference -1.33, 95 % CI -2.63; -0.03) with a similar lower trend regarding peak systolic velocity in the ascending aorta. Conclusions: Male fetuses exhibit an increased preload and reduced afterload conditions compared to females. While it is difficult to relate these measurements to exact cardiac function, our findings strongly suggest that the known differences in cardiovascular performance between the sexes already start in utero.

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Biology of Sex Differences
Department of Gynaecology & Obstetrics

Schalekamp-Timmermans, S., Cornette, J., Hofman, A., Helbing, W., Jaddoe, V., Steegers, E., & Verburg, B. O. (2016). In utero origin of sex-related differences in future cardiovascular disease. Biology of Sex Differences, 7(1). doi:10.1186/s13293-016-0108-4