Skip to main content
SpringerLink
Log in

Risk factors for hypospadias

  • Original Paper
  • Published:
European Journal of Pediatrics Aims and scope Submit manuscript

Abstract

Despite being one of the most common congenital defects in boys, the etiology of hypospadias remains largely unknown. In this case-referent study, we evaluated a wide spectrum of potential risk factors for hypospadias. Cases were identified from the hospital information system, and referents were recruited through the parents of the cases. Both parents of cases and referents completed written questionnaires that they received through the mail. Logistic regression analyses were used to assess the independent contribution of different factors to the risk of hypospadias. The final database included 583 cases and 251 referents. Hypospadias more often occurred in children whose father had hypospadias (OR=9.7; 95%CI: 1.3–74.0) and in children with a low birth weight (OR=2.3; 95%CI: 1.2–4.2). Indications for elevated risks were found when mothers were DES-daughters (OR=3.5; 95%CI: 0.8–15.6), fathers were subfertile (OR=1.8; 95%CI: 0.7–4.5), the parents had undergone fertility treatment (OR=2.3; 95%CI: 0.9–5.8), and in twin or triplet pregnancies (OR=2.0; 95%CI: 0.8–5.1). Maternal use of iron supplements (OR=2.2; 95%CI: 0.8–6.0), maternal smoking (OR=1.5; 95%CI: 1.0–2.4), paternal prescriptive drug use (OR=2.6; 95%CI: 1.1–6.6), and paternal exposure to pesticides (OR=2.1; 95%CI: 0.6–7.1) during the 3 months immediately prior to conception or in the first trimester of pregnancy also appeared to increase the risk of hypospadias. The associations found in this study support the hypothesis that genetic predisposition, placental insufficiency, and substances that interfere with natural hormones play a role in the etiology of hypospadias.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

ART:

Assisted reproductive techniques

CI:

Confidence interval

DES:

Diethylstilbestrol

DHT:

Dihydrotestosterone

HCG:

Human chorionic gonadotropin

ICSI:

Intracytoplasmic sperm injection

IDA:

Iron deficiency anemia

IVF:

In vitro fertilization

OR:

Odds ratio

References

  1. Allen LH (2005) Multiple micronutrients in pregnancy and lactation: an overview. Am J Clin Nutr 81:1206S–1212S

    PubMed  CAS  Google Scholar 

  2. Asklund C, Jorgensen N, Kold JT, Skakkebaek NE (2004) Biology and epidemiology of testicular dysgenesis syndrome. Brit J Urol Int 93[Suppl 3]:6–11

    Google Scholar 

  3. Baskin LS, Himes K, Colborn T (2001) Hypospadias and endocrine disruption: is there a connection? Environ Health Perspect 109:1175–1183

    Article  PubMed  CAS  Google Scholar 

  4. Bay K, Asklund C, Skakkebaek NE, Andersson AM (2006) Testicular dysgenesis syndrome: possible role of endocrine disrupters. Best Pract Res Clin Endocrinol Metab 20:77–90

    Article  PubMed  CAS  Google Scholar 

  5. Bianca S, Li VG, Caruso-Nicoletti M, Ettore G, Barone P, Lupo L, Li VS (2003) Elevated incidence of hypospadias in two sicilian towns where exposure to industrial and agricultural pollutants is high. Reprod Toxicol 17:539–545

    Article  PubMed  CAS  Google Scholar 

  6. Brouwers MM, Feitz WF, Roelofs LA, Kiemeney LA, de Gier RP, Roeleveld N (2006) Hypospadias: a transgenerational effect of diethylstilbestrol? Hum Reprod 21:666–669

    Google Scholar 

  7. Carbone P, Giordano F, Nori F, Mantovani A, Taruscio D, Lauria L, Figa-Talamanca I (2006) Cryptorchidism and hypospadias in the Sicilian district of Ragusa and the use of pesticides. Reprod Toxicol 22:8–12

    Google Scholar 

  8. Carmichael SL, Shaw GM, Nelson V, Selvin S, Torfs CP, Curry CJ (2003) Hypospadias in California: trends and descriptive epidemiology. Epidemiology 14:701–706

    Article  PubMed  Google Scholar 

  9. Carmichael SL, Shaw GM, Laurent C, Croughan MS, Olney RS, Lammer EJ (2005) Maternal progestin intake and risk of hypospadias. Arch Pediatr Adolesc Med 159:957–962

    Article  PubMed  Google Scholar 

  10. Dolk H, Vrijheid M, Scott JE, Addor MC, Botting B, de Vigan C, de Walle H, Garne E, Loane M, Pierini A, Garcia-Minaur S, Physick N, Tenconi R, Wiesel A, Calzolari E, Stone D (2004) Toward the effective surveillance of hypospadias. Environ Health Perspect 112:398–402

    Article  PubMed  Google Scholar 

  11. Fisch H, Golden RJ, Libersen GL, Hyun GS, Madsen P, New MI, Hensle TW (2001) Maternal age as a risk factor for hypospadias. J Urol 165:934–936

    Article  PubMed  CAS  Google Scholar 

  12. Fredell L, Iselius L, Collins A, Hansson E, Holmner S, Lundquist L, Lackgren G, Pedersen J, Stenberg A, Westbacke G, Nordenskjold A (2002) Complex segregation analysis of hypospadias. Hum Genet 111:231–234

    Article  PubMed  Google Scholar 

  13. Fredell L, Lichtenstein P, Pedersen NL, Svensson J, Nordenskjold A (1998) Hypospadias is related to birth weight in discordant monozygotic twins. J Urol 160:2197–2199

    Article  PubMed  CAS  Google Scholar 

  14. Fredell L, Kockum I, Hansson E, Holmner S, Lundquist L, Lackgren G, Pedersen J, Stenberg A, Westbacke G, Nordenskjold A (2002) Heredity of hypospadias and the significance of low birth weight. J Urol 167:1423–1427

    Article  PubMed  Google Scholar 

  15. Fritz G, Czeizel AE (1996) Abnormal sperm morphology and function in the fathers of hypospadiacs. J Reprod Fertil 106:63–66

    Article  PubMed  CAS  Google Scholar 

  16. Gallentine ML, Morey AF, Thompson IM Jr (2001) Hypospadias: a contemporary epidemiologic assessment. Urology 57:788–790

    Article  PubMed  CAS  Google Scholar 

  17. Hussain N, Chaghtai A, Herndon CD, Herson VC, Rosenkrantz TS, McKenna PH (2002) Hypospadias and early gestation growth restriction in infants. Pediatrics 109:473–478

    Article  PubMed  Google Scholar 

  18. Klip H, Verloop J, van Gool JD, Koster ME, Burger CW, van Leeuwen FE (2002) Hypospadias in sons of women exposed to diethylstilbestrol in utero: a cohort study. Lancet 359:1102–1107

    Article  PubMed  CAS  Google Scholar 

  19. Manson JM, Carr MC (2003) Molecular epidemiology of hypospadias: Review of genetic and environmental risk factors. Birth Defects Res Part A-Clin Mol Teratol 67:825–836

    Article  PubMed  CAS  Google Scholar 

  20. Meijer WM, de Jong-Van den Berg LT, van dB, Verheij JB, de Walle HE (2006) Clomiphene and hypospadias on a detailed level: Signal or chance? Birth Defects Res A Clin Mol Teratol 76:249–252

    Article  PubMed  CAS  Google Scholar 

  21. North K, Golding J (2000) A maternal vegetarian diet in pregnancy is associated with hypospadias. The ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. Brit J Urol Int 85:107–113

    CAS  Google Scholar 

  22. Paulozzi LJ (1999) International trends in rates of hypospadias and cryptorchidism. Environ Health Perspect 107:297–302

    Article  PubMed  CAS  Google Scholar 

  23. Paulozzi LJ, Erickson JD, Jackson RJ (1997) Hypospadias trends in two US surveillance systems. Pediatrics 100:831–834

    Article  PubMed  CAS  Google Scholar 

  24. Pierik FH, Burdorf A, Deddens JA, Juttmann RE, Weber RF (2004) Maternal and paternal risk factors for cryptorchidism and hypospadias: a case-control study in newborn boys. Environ Health Perspect 112:1570–1576

    Article  PubMed  Google Scholar 

  25. Pierik FH, Burdorf A, Nijman JM, de Muinck Keizer-Schrama SM, Juttmann RE, Weber RF (2002) A high hypospadias rate in The Netherlands. Hum Reprod 17:1112–1115

    Article  PubMed  Google Scholar 

  26. Pons JC, Papiernik E, Billon A, Hessabi M, Duyme M (2005) Hypospadias in sons of women exposed to diethylstilbestrol in utero. Prenatal Diagn 25:418–419

    Article  CAS  Google Scholar 

  27. Porter MP, Faizan MK, Grady RW, Mueller BA (2005) Hypospadias in Washington State: maternal risk factors and prevalence trends. Pediatrics 115:e495–e499

    Article  PubMed  Google Scholar 

  28. Scholl TO (2005) Iron status during pregnancy: setting the stage for mother and infant. Am J Clin Nutr 81:1218S–1222S

    PubMed  CAS  Google Scholar 

  29. Sharpe RM, Irvine DS (2004) How strong is the evidence of a link between environmental chemicals and adverse effects on human reproductive health? BMJ 328:447–451

    Article  PubMed  CAS  Google Scholar 

  30. Silver RI, Rodriguez R, Chang TS, Gearhart JP (1999) In vitro fertilization is associated with an increased risk of hypospadias. J Urol 161:1954–1957

    Article  PubMed  CAS  Google Scholar 

  31. Skakkebaek NE, Rajpert-De Meyts E, Main KM (2001) Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod 16:972–978

    Article  PubMed  CAS  Google Scholar 

  32. Vrijheid M, Armstrong B, Dolk H, van Tongeren M, Botting B (2003) Risk of hypospadias in relation to maternal occupational exposure to potential endocrine disrupting chemicals. Occup Environ Med 60:543–550

    Article  PubMed  CAS  Google Scholar 

  33. Weidner IS, Moller H, Jensen TK, Skakkebaek NE (1998) Cryptorchidism and hypospadias in sons of gardeners and farmers. Environ Health Perspect 106:793–796

    Article  PubMed  CAS  Google Scholar 

  34. Weidner IS, Moller H, Jensen TK, Skakkebaek NE (1999) Risk factors for cryptorchidism and hypospadias. J Urol 161:1606–1609

    Article  PubMed  CAS  Google Scholar 

  35. Wennerholm UB, Bergh C, Hamberger L, Lundin K, Nilsson L, Wikland M, Kallen B (2000) Incidence of congenital malformations in children born after ICSI. Hum Reprod 15:944–948

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Professor Gerhard Zielhuis for his advice on methodology and all of the parents for their participation in the study.

Author information

Authors and Affiliations

  1. Department of Epidemiology and Biostatistics (133), Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

    Marijn M. Brouwers, Lambertus A. L. M. Kiemeney & Nel Roeleveld

  2. Department of Urology (648), Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

    Wouter F. J. Feitz, Luc A. J. Roelofs, Lambertus A. L. M. Kiemeney & Robert P. E. de Gier

Authors
  1. Marijn M. Brouwers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wouter F. J. Feitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Luc A. J. Roelofs
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lambertus A. L. M. Kiemeney
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robert P. E. de Gier
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nel Roeleveld
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marijn M. Brouwers.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brouwers, M.M., Feitz, W.F.J., Roelofs, L.A.J. et al. Risk factors for hypospadias. Eur J Pediatr 166, 671–678 (2007). https://doi.org/10.1007/s00431-006-0304-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00431-006-0304-z

Keywords

Search

Navigation