Association of Maternal First Trimester Serum Levels of Free Beta Human Chorionic Gonadotropin and Hypospadias: A Population Based Study
This article is commented on by the following:
Human chorionic gonadotropin stimulates fetal testosterone production and contributes to normal development of male genitalia. Using population based data we hypothesized that differences in maternal free beta human chorionic gonadotropin may be associated with hypospadias.
Materials and Methods:
Data were obtained from the Paris Registry of Congenital Malformations (REMAPAR) (2011 to 2016). The initial study population included 3,172 pregnant women who gave birth to a singleton live born male infant with a congenital malformation. After exclusion of cases with unknown beta human chorionic gonadotropin and those with chromosomal or genetic abnormalities, the study population included 194 boys with isolated hypospadias and 1,075 controls. For cases with operative notes (125) we obtained data on type (proximal/distal) of hypospadias. Using quantile regression we compared median values of multiple of median beta human chorionic gonadotropin measured for first trimester Down syndrome screening (10th to 13th gestational weeks) for overall as well as by type of hypospadias vs controls. We also considered possible effects of placental dysfunction (maternal age, intrauterine growth retardation and preterm births) as potential confounding factors.
Overall the median beta human chorionic gonadotropin multiple of median was comparable for women who had an infant with hypospadias vs controls (0.99 vs 0.95, p=0.3). However, proximal hypospadias was associated with a statistically significant higher median multiple of median than distal hypospadias or unspecified (1.49 vs 0.92 vs 1.05, p=0.02). The estimates were comparable after adjustment for placental dysfunction.
Our findings support the hypothesis that an alteration in maternal beta human chorionic gonadotropin levels is associated with hypospadias. However, this association appears to be limited to proximal hypospadias.
- 1. : Hypospadias prevalence and trends in International Birth Defect Surveillance Systems, 1980-2010. Eur Urol 2019; 76: 482. Google Scholar
- 2. : Genetic and environmental factors in the aetiology of hypospadias. Pediatr Surg Int 2015; 31: 519. Google Scholar
- 3. : Is hypospadias a genetic, endocrine or environmental disease, or still an unexplained malformation?Int J Androl 2009; 32: 187. Google Scholar
- 4. : Testis development. Endocr Rev 2019; 40: 857. Google Scholar
- 5. : A critical role for estrogen signaling in penis development. FASEB J 2019: 33: 10383. Google Scholar
- 6. : Assessing the impact of in-utero exposures: potential effects of paracetamol on male reproductive development. Arch Dis Child 2017; 102: 1169. Google Scholar
- 7. : Androgen insensitivity syndrome. Lancet 2012; 380: 1419. Google Scholar
- 8. : Experimentally induced testicular dysgenesis syndrome originates in the masculinization programming window. JCI Insight 2017; 2: e91204. Google Scholar
- 9. : Is hypospadias associated with prenatal exposure to endocrine disruptors? A French collaborative controlled study of a cohort of 300 consecutive children without genetic defect. Eur Urol 2015; 68: 1023. Google Scholar
- 10. : Maternal exposure to domestic hair cosmetics and occupational endocrine disruptors is associated with a higher risk of hypospadias in the offspring. Int J Environ Res Public Health 2016; 14: 27. Google Scholar
- 11. : Review: hCGs: different sources of production, different glycoforms and functions. Placenta, suppl., 2015; 36: S60. Google Scholar
- 12. : Placental insufficiency in early gestation is associated with hypospadias. J Pediatr Surg 2008; 43: 358. Google Scholar
- 13. : Maternal serum human chorionic gonadotrophin during early pregnancy resulting in boys with hypospadias or cryptorchidism. Br J Urol 1995; 76: 389. Google Scholar
- 14. : Maternal first trimester serum levels of free-beta human chorionic gonadotrophin and male genital anomalies. Hum Reprod 2016; 31: 1895. Google Scholar
- 15. : A risk prediction model for fetal hypospadias by testing maternal serum AFP and free beta-HCG. Clin Biochem 2019; 69: 21. Google Scholar
- 16. : Hypospadias: risk factor patterns and different phenotypes. BJU Int 2010; 105: 254. Google Scholar
- 17. : Placental weight and risk of cryptorchidism and hypospadias in the collaborative perinatal project. Am J Epidemiol 2018; 187: 1354. Google Scholar
- 18. : Placental weight and male genital anomalies: a nationwide Danish cohort study. Am J Epidemiol 2016; 183: 1122. Google Scholar
- 19. : Fetal growth restriction but not preterm birth is a risk factor for severe hypospadias. Pediatr Int 2016; 58: 573. Google Scholar
- 20. : Hypospadias, intrauterine growth restriction, and abnormalities of the placenta. Birth Defects Res 2018; 110: 122. Google Scholar
- 21. : Hypospadias in sons of women exposed to diethylstilbestrol in utero: a cohort study. Lancet 2002; 359: 1102. Google Scholar
- 22. : Maternal smoking and developmental changes in luteinizing hormone (LH) and the LH receptor in the fetal testis. J Clin Endocrinol Metab 2009; 94: 4688. Google Scholar
- 23. : Alternative (backdoor) androgen production and masculinization in the human fetus. PLoS Biol 2019; 17: e3000002. Google Scholar
- 24. : Minor hypospadias: the “tip of the iceberg” of the partial androgen insensitivity syndrome. PLoS One 2013; 8: e61824. Google Scholar
- 25. : “Idiopathic” partial androgen insensitivity syndrome in 28 newborn and infant males: impact of prenatal exposure to environmental endocrine-disruptor chemicals?Eur J Endocrinol 2011; 165: 579. Google Scholar
- 26. : Nuchal translucency measurement, free β-hCG and PAPP-A concentrations in IVF/ICSI pregnancies: systematic review and meta-analysis. Prenat Diagn 2017; 37: 540. Google Scholar
- 27. : A standardized classification of hypospadias. J Pediatr Urol 2012; 8: 410. Google Scholar
- 28. : Single-nucleotide and copy-number variance related to severity of hypospadias. Pediatr Surg Int 2018; 34: 991. Google Scholar
- 29. : Family history is underestimated in children with isolated hypospadias: a French multicenter report of 88 families. J Urol 2018; 200: 890. Link, Google Scholar
- 30. : Maternal overweight and obesity and genital anomalies in male offspring: a population-based Swedish cohort study. Paediatr Perinat Epidemiol 2017; 31: 317. Google Scholar
Supported by INSERM (Paris, France) and Santé Publique France (Saint-Maurice, France).
No direct or indirect commercial, personal, academic, political religious or ethical incentive is associated with publishing this article.