ESPE Abstracts

Background: The anogenital distance (AGD) is defined as the distance from the anus to genital tubercle. AGD is an established method for sex determination of pups in rodents, and in animal studies, AGD is strongly affected by androgen exposure during fetal life. In accordance, human studies have reported reduced postnatal AGD following prenatal exposure to anti-androgenic agents, suggesting AGD to be a sensitive postnatal read out of in utero exposure to androgens. Little is known on AGD in humans during fetal life.

Aim: The aim of this sub-study is to evaluate fetal AGD in healthy males and females.

Methods: The Copenhagen Analgesic Study (COPANA) (ClinicalTrials.gov NCT04369222) is an ongoing prospective cohort study, designed to evaluate prenatal exposure of mild analgesics on reproductive function in offspring (currently ongoing inclusion aim 600 families). Fetal AGD was measured by transabdominal ultrasound at gestational week (GW) 29-34 in healthy, singleton fetuses who are subsequently born AGA. Measurements were performed in the axial plane from the center of the anus to the posterior converge of the fourchette (females), and to the posterior base of the scrotum (males). All scans were performed by a single sonographer with a minimum of three repeated measurements. The reproducibility of the AGD measurements were assessed by Intraclass Correlation Coefficients (ICCs).

Results: Fetal AGD measurements were available for this sub-analysis in 183 fetuses (98 males), with no difference in GW or estimated fetal weight (EFW) between males and females (median 31.2 GW vs. 31.1 GW, P = 0.683 and 1809g vs. 1680g, P = 0.134). Male AGD; median (IQR) 21.9 mm (19.1-23.9) was significantly longer than female AGD; 13.6 mm (12.2-14.7), P = 0.001 (Mann Whitney U (MWU)). AGD showed near complete separation of AGD between sexes. Male and female AGD levels were moderately correlated with GW (Spearman r²=0.39 and r²=0.41 (both P = 0.001), respectively. Adjusting AGD for weight (AGD/EFW) did not alter the above findings concerning sex-specific AGD levels (P = 0.001 MWU). AGD measurements were strongly reproduceable; ICC 0.95 and 0.81 for males and females, respectively.

Conclusions: Fetal AGD determination by ultrasonography is sexually dimorphic as early as GW 29. Thus, fetal AGD candidates as a key endpoint in clinical research evaluating compounds affecting androgen exposure during early fetal life.