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Pediatric Surgery International

, Volume 31, Issue 6, pp 519–527 | Cite as

Genetic and environmental factors in the aetiology of hypospadias

  • Mathew George
  • Francisco J. Schneuer
  • Sarra E. Jamieson
  • Andrew J. A. HollandEmail author
Review Article

Abstract

This article reviews the current evidence and knowledge of the aetiology of hypospadias. Hypospadias remains a fascinating anomaly of the male phallus. It may be an isolated occurrence or part of a syndrome or field defect. The increasing use of assisted reproductive techniques and hormonal manipulation during pregnancy may have been associated with an apparent rise in the incidence of hypospadias. Genetic studies and gene analysis have suggested some defects that could result in hypospadias. New light has also been thrown on environmental factors that could modulate candidate genes, causing altered development of the male external genitalia.

Keywords

Hypospadias Aetiology Genetics Endocrine Gene deletion Gene expression 

Abbreviations

ART

Assisted reproductive technology

ATF3

Activating transcription factor

BMI

Body mass index

BMP7

Bone morphogenic protein

DDE

p p’ Dichloro diphenyl dichloroethane

DDT

p p’Dichloro diphenyl trichloroethane

DES

Diethylstilbestrol

DGKK

Diacylglycerol kinase kappa

DHCR

Dihydrocholesterol reductase

EDC

Endocrine disrupting chemicals

ESR1

Oestrogen receptor 1

ESR2

Oestrogen receptor 2

FGFR2

Fibroblast growth factor

FGF8

Fibroblast growth factor

FGF10

Fibroblast growth factor

GWAS

Genome-wide association study

GXE

Gene environment interactions

HCB

Hexachlorobenzene

HCG

Human chorionic gonadotrophin

HOXA13

Homeobox A 13

ICSI

Intracytoplasmic sperm injection

IUGR

Intrauterine growth retardation

IVF

In vitro fertilisation

LBW

Low birth weight

MAMLD1

Mastermind-like domain containing 1

SF 1

Splicing factor 1

SGA

Small for gestational age

SNP

Single nucleotide polymorphisms

SOX9

SRY box 9

SRD5A2

Steroid 5 alpha reductase

SRY gene

Sex-determining region Y

WT1

Wilms tumour 1

References

  1. 1.
    Van der Zanden LF, van Rooji IA, Feitz WF, Franke B, Knoers NV, Roeleveld N (2012) Aetiology of hypospadias: a systematic review of genes and environment. Hum Reprod Update 18:260–283CrossRefPubMedGoogle Scholar
  2. 2.
    Baskin LS (2006) Hypospadias. In: Stringer MD, Oldham KT, Mouriquand PDE (eds) Pediatric Surgery and Urology: long-term outcomes, 2nd edn. Cambridge University Press, Cambridge, pp 611–620CrossRefGoogle Scholar
  3. 3.
    Gatti JM, Krisch AJ, Troyer WA, Perez-Brayfield MR, Smith EA, Scherz HC (2001) Increased incidence of hypospadias in small-for-gestational age infants in a neonatal intensive-care unit. BJU Int 87:548–550CrossRefPubMedGoogle Scholar
  4. 4.
    Wennerholm UB, Bergh C, Hamberger L, Lundin K, Nilsson L, Wikland M, Källén B (2000) Incidence of congenital malformations in children born after ICSI. Hum Reprod 15:944–948CrossRefPubMedGoogle Scholar
  5. 5.
    Duckett JW (1995) The current hype in hypospadiology. Br J Urol 76(Suppl 3):1–7CrossRefPubMedGoogle Scholar
  6. 6.
    Mureau MA, Slijper FM, Nijman RJ, van der Meulen JC, Verhulst FC, Slob AK (1995) Psychosexual adjustment of children and adolescents after different types of hypospadias surgery: a norm-related study. J Urol 154:1902–1907CrossRefPubMedGoogle Scholar
  7. 7.
    Kluth D, Lambrecht W, Reich P (1988) Pathogenesis of hypospadias—more questions than answers. J Pediatr Surg 23:1095–1101CrossRefPubMedGoogle Scholar
  8. 8.
    Leung AK, Robson WL (2007) Hypospadias: an update. Asian J Androl 9:16–22CrossRefPubMedGoogle Scholar
  9. 9.
    Moreno-Garcia M, Miranda EB (2002) Chromosomal anomalies in cryptorchidism and hypospadias. J Urol 168:2170–2172 (Discussion 2172)CrossRefPubMedGoogle Scholar
  10. 10.
    Kohler B, Schumacher V, l’Allemand D, Royer-Pokora B, Gruters A (2001) Germline Wilms tumor suppressor gene (WT1) mutation leading to isolated genital malformation without Wilms tumor or nephropathy. J Pediatr 138:421–424CrossRefPubMedGoogle Scholar
  11. 11.
    Wang Y, Li Q, Xu J, Liu Q, Wang W, Lin Y, Ma F, Chen T, Li S, Shen Y (2004) Mutation analysis of five candidate genes in Chinese patients with hypospadias. Eur J Hum Genet 12:706–712CrossRefPubMedGoogle Scholar
  12. 12.
    Beleza-Meireles A, Kockum I, Lundberg F, Soderhall C, Nordenskjold A (2007) Risk factors for hypospadias in the estrogen receptor 2 gene. J Clin Endocrinol Metab 92:3712–3718CrossRefPubMedGoogle Scholar
  13. 13.
    Sutherland RW, Wiener JS, Hicks JP, Marcelli M, Gonzales ET Jr, Roth DR, Lamb DJ (1996) Androgen receptor gene mutations are rarely associated with isolated penile hypospadias. J Urol 156:828–831CrossRefPubMedGoogle Scholar
  14. 14.
    Nordenskjold A, Friedman E, Tapper-Persson M, Soderhall C, Leviav A, Svensson J, Anvret M (1999) Screening for mutations in candidate genes for hypospadias. Urol Res 27:49–55CrossRefPubMedGoogle Scholar
  15. 15.
    Aschim EL, Nordenskjold A, Giwercman A, Lundin KB, Ruhayel Y, Haugen TB, Grotmol T, Giwercman YL (2004) Linkage between cryptorchidism, hypospadias, and GGN repeat length in the androgen receptor gene. J Clin Endocrinol Metab 89:5105–5109CrossRefPubMedGoogle Scholar
  16. 16.
    Vottero A, Minari R, Viani I, Tassi F, Bonatti F, Neri TM, Bertolini L, Bernasconi S, Ghizzoni L (2011) Evidence for epigenetic abnormalities of the androgen receptor gene in foreskin from children with hypospadias. J Clin Endocrinol Metab 96:E1953–E1962CrossRefPubMedGoogle Scholar
  17. 17.
    Thai HT, Kalbasi M, Lagerstedt K, Frisen L, Kockum I, Nordenskjold A (2005) The valine allele of the V89L polymorphism in the 5-alpha-reductase gene confers a reduced risk for hypospadias. J Clin Endocrinol Metab 90:6695–6698CrossRefPubMedGoogle Scholar
  18. 18.
    Lim HN, Chen H, McBride S, Dunning AM, Nixon RM, Hughes IA, Hawkins JR (2000) Longer polyglutamine tracts in the androgen receptor are associated with moderate to severe undermasculinized genitalia in XY males. Hum Mol Genet 9:829–834CrossRefPubMedGoogle Scholar
  19. 19.
    Chamberlain NL, Driver ED, Miesfeld RL (1994) The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res 22:3181–3186CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    Makridakis NM, di Salle E, Reichardt JK (2000) Biochemical and pharmacogenetic dissection of human steroid 5 alpha-reductase type II. Pharmacogenetics 10:407–413CrossRefPubMedGoogle Scholar
  21. 21.
    Kalfa N, Liu B, Klein O, Audran F, Wang MH, Mei C, Sultan C, Baskin LS (2008) Mutations of CXorf6 are associated with a range of severities of hypospadias. Eur J Endocrinol 159:453–458CrossRefPubMedGoogle Scholar
  22. 22.
    Kalfa N, Cassorla F, Audran F, Oulad Abdennabi I, Philibert P, Beroud C, Guys JM, Reynaud R, Alessandrini P, Wagner K et al (2011) Polymorphisms of MAMLD1 gene in hypospadias. J Pediatr Urol 7:585–591CrossRefPubMedGoogle Scholar
  23. 23.
    Fukami M, Wada Y, Miyabayashi K, Nishino I, Hasegawa T, Nordenskjold A, Camerino G, Kretz C, Buj-Bello A, Laporte J et al (2006) CXorf6 is a causative gene for hypospadias. Nat Genet 38:1369–1371CrossRefPubMedGoogle Scholar
  24. 24.
    Beleza-Meireles A, Tohonen V, Soderhall C, Schwentner C, Radmayr C, Kockum I, Nordenskjold A (2008) Activating transcription factor 3: a hormone responsive gene in the etiology of hypospadias. Eur 158:729–739Google Scholar
  25. 25.
    Kalfa N, Liu B, Klein O, Wang MH, Cao M, Baskin LS (2008) Genomic variants of ATF3 in patients with hypospadias. J Urol 180:2183–2188CrossRefPubMedGoogle Scholar
  26. 26.
    van der Zanden LF, van Rooij IA, Feitz WF, Vermeulen SH, Kiemeney LA, Knoers NV, Roeleveld N, Franke B (2010) Genetics of hypospadias: are single-nucleotide polymorphisms in SRD5A2, ESR1, ESR2, and ATF3 really associated with the malformation? J Clin Endocrinol Metab 95:2384–2390CrossRefPubMedGoogle Scholar
  27. 27.
    van der Zanden LF, van Rooij IA, Feitz WF, Knight J, Donders AR, Renkema KY, Bongers EM, Vermeulen SH, Kiemeney LA, Veltman JA et al (2011) Common variants in DGKK are strongly associated with risk of hypospadias. Nat Genet 43:48–50CrossRefPubMedGoogle Scholar
  28. 28.
    Geller F, Feenstra B, Carstensen L, Pers TH, van Rooij IA, Korberg IB, Choudhry S, Karjalainen JM, Schnack TH, Hollegaard MV et al (2014) Genome-wide association analyses identify variants in developmental genes associated with hypospadias. Nat Genet 46:957–963CrossRefPubMedGoogle Scholar
  29. 29.
    Carmichael SL, Shaw GM, Laurent C, Croughan MS, Olney RS, Lammer EJ (2005) Maternal progestin intake and risk of hypospadias. Arch Pediatr Adolesc Med 159:957–962CrossRefPubMedGoogle Scholar
  30. 30.
    Kallen BA, Matinez-Frias ML, Castilla EE, Robert E, Lancaster PA, Kringelbach M, Mutchinick OM, Mastroiacovo P (1992) Hormone therapy during pregnancy and isolated hypospadias: an international case-control study. Int J Risk Safety Med 3:183–197Google Scholar
  31. 31.
    Wogelius P, Horváth-Puhó E, Pedersen L, Norgaard M, Czeizel AE, Sorensen HT (2006) Maternal use of oral contraceptives and risk of hypospadias—a population based case—control study. Eur J Epidemiol 21:777–781CrossRefPubMedGoogle Scholar
  32. 32.
    Herbst AL, Ulfelder H, Poskanzer DC (1971) Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. N Eng J Med 284:878–881CrossRefGoogle Scholar
  33. 33.
    Stillman RJ (1982) In utero exposure to diethylstilbestrol: adverse effects on the reproductive tract and reproductive performance and male and female offspring. Am J Obstet Gynecol 142:905–921PubMedGoogle Scholar
  34. 34.
    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 359:1102–1107CrossRefPubMedGoogle Scholar
  35. 35.
    Palmer JR, Wise LA, Robboy SJ, Titus-Ernstoff L, Noller KL, Herbst AL, Troisi R (2005) Hypospadias in sons of women exposed to diethylstilbestrol in utero. Epidemiology 16:583–586CrossRefPubMedGoogle Scholar
  36. 36.
    Pons JC, Papiernik E, Billon A, Hessabi M, Duyme M (2005) Hypospadias in sons of women exposed to diethylstilbestrol in utero. Prenat Diagn 25:418–419CrossRefPubMedGoogle Scholar
  37. 37.
    Brouwers MM, Feitz WF, Roelofs LA, Kiemeney LA, de Gier RP, Roeleveld N (2007) Risk factors for hypospadias. Eur J Pediatr 166:671–678CrossRefPubMedGoogle Scholar
  38. 38.
    Brouwers MM, van der Zanden LF, de Gier RP, Barten EJ, Zielhuis GA, Feitz WF, Roeleveld N (2010) Hypospadias: risk factor patterns and different phenotypes. BJU Int 105:254–262CrossRefPubMedGoogle Scholar
  39. 39.
    Ericson A, Källén B (2001) Congenital malformations in infants born after IVF: a population-based study. Hum Reprod 16:504–509CrossRefPubMedGoogle Scholar
  40. 40.
    Källén B, Finnström O, Nygren KG, Olausson PO (2005) In vitro fertilization (IVF) in Sweden: risk for congenital malformations after different IVF methods. Birth Defects Res A Clin Mol Teratol 73:162–169CrossRefPubMedGoogle Scholar
  41. 41.
    Pinborg A, Loft A, Nyboe AA (2004) Neonatal outcome in a Danish national cohort of 8602 children born after in vitro fertilization or intracytoplasmic sperm injection: the role of twin pregnancy. Acta Obstet Gynecol Scand 83:1071–1078CrossRefPubMedGoogle Scholar
  42. 42.
    Fedder JGA, Humaidan P, Erb K, Ernst E, Loft A (2007) Malformation rate and sex ratio in 412 children conceived with epididymal or testicular sperm. Hum Reprod 22:1080–1085CrossRefPubMedGoogle Scholar
  43. 43.
    Funke S, Flach E, Kiss I, Sandor J, Vida G, Bodis J, Ertl T (2010) Male reproductive tract abnormalities: more common after assisted reproduction? Early Hum Dev 86:547–550CrossRefPubMedGoogle Scholar
  44. 44.
    Källén B, Finnström O, Lindam A, Nilsson E, Nygren KG, Otterblad PO (2010) Congenital malformations in infants born after in vitro fertilization in Sweden. Birth Defects Res A Clin Mol Teratol 88:137–143PubMedGoogle Scholar
  45. 45.
    Bonduelle M, Liebaers I, Deketelaere V, Derde MP, Camus M, Devroey P, Van Steirteghem A (2002) Neonatal data on a cohort of 2889 infants born after ICSI (1991–1999) and of 2995 infants born after IVF (1983–1999). Hum Reprod 17:671–694CrossRefPubMedGoogle Scholar
  46. 46.
    Morera AM, Valmalle AF, Asensio MJ, Chossegros L, Chauvin MA, Durand P, Mouriquand PD (2006) A study of risk factors for hypospadias in the Rhoˆne-Alpes region (France). J Pediatr Urol 2:169–177CrossRefPubMedGoogle Scholar
  47. 47.
    Waller DK, Shaw GM, Rasmussen SA, Hobbs CA, Canfield MA, Siega-Riz AM, Gallaway MS, Correa A, National Birth Defects Prevention Study (2007) Prepregnancy obesity as a risk factor for structural birth defects. Arch Pediatr Adolesc Med 161:745–750CrossRefPubMedGoogle Scholar
  48. 48.
    Akre O, Boyd HA, Ahlgren M, Wilbrand K, Westergaard T, Hjalgrim H, Nordenskjöld A, Ekbom A, Melbye M (2008) Maternal and gestational risk factors for hypospadias. Environ Health Perspect 116:1071–1076CrossRefPubMedCentralPubMedGoogle Scholar
  49. 49.
    Blomberg MI, Källén B (2010) Maternal obesity and morbid obesity: the risk for birth defects in the offspring. Birth Defects Res A Clin Mol Teratol 88:35–40PubMedGoogle Scholar
  50. 50.
    Giordano F, Carbone P, Nori F, Mantovani A, Taruscio D, Figà-Talamanca I (2008) Maternal diet and the risk of hypospadias and cryptorchidism in the offspring. Paediatr Perinat Epidemiol 22:249–260CrossRefPubMedGoogle Scholar
  51. 51.
    Rankin J, Tennant PW, Stothard KJ, Bythell M, Summerbell CD, Bell R (2010) Maternal body mass index and congenital anomaly risk: a cohort study. Int J Obes (Lond) 34:1371–1380CrossRefGoogle Scholar
  52. 52.
    Kappel B, Hansen K, Moller J, Faaborg-Andersen J (1985) Human placental lactogen and dU-estrogen levels in normal twin pregnancies. Acta Genet Med Gemellol (Roma) 34:59–65Google Scholar
  53. 53.
    Bernstein L, Depue RH, Ross RK, Judd HL, Pike MC, Henderson BE (1986) Higher maternal levels of free estradiol in first compared to second pregnancy: early gestational differences. J Natl Cancer Inst 76:1035–1039PubMedGoogle Scholar
  54. 54.
    Jin L, Ye R, Zheng J, Hong S, Ren A (2010) Secular trends of hypospadias prevalence and, 1993–2005. Birth Defects Res A Clin Mol Teratol 88:458–465CrossRefPubMedGoogle Scholar
  55. 55.
    Akre O, Lipworth L, Cnattingius S, Sparén P, Ekbom A (1999) Risk factor patterns for cryptorchidism and hypospadias. Epidemiology 10:364–369CrossRefPubMedGoogle Scholar
  56. 56.
    Carmichael SL, Shaw GM, Laurent C, Olney RS, Lammer EJ, National Birth Defects Prevention S (2007) Maternal reproductive and demographic characteristics as risk factors for hypospadias. Paediatr Perinat Epidemiol 21:210–218CrossRefPubMedGoogle Scholar
  57. 57.
    Carmichael SL, Shaw GM, Nelson V, Selvin S, Torfs CP, Curry CJ (2003) Hypospadias in California: trends and descriptive epidemiology. Epidemiology 14:701–706CrossRefPubMedGoogle Scholar
  58. 58.
    Hussain N, Herndon CD, Herson VC, Rosenkrantz TS, McKenna PH (2002) Hypospadias and early gestation growth restriction in infants. Pediatrics 109:473–478CrossRefPubMedGoogle Scholar
  59. 59.
    Kallen K (2002) Role of maternal smoking and maternal reproductive history in the etiology of hypospadias in the offspring. Teratology 66:185–191CrossRefPubMedGoogle Scholar
  60. 60.
    Meyer KJ, Reif JS, Veeramachaneni DN, Luben TJ, Mosley BS, Nuckols JR (2006) Agricultural pesticide use and hypospadias in eastern Arkansas. Environ Health Perspect 114:1589–1595CrossRefPubMedCentralPubMedGoogle Scholar
  61. 61.
    Nassar N, Abeywardana P, Barker A, Bower C (2010) Parental occupational exposure to potential endocrine disrupting chemicals and risk of hypospadias in infants. Occup Environ Med 67:585–589CrossRefPubMedGoogle Scholar
  62. 62.
    Sorensen HT, Pedersen L, Norgaard M, Wogelius P, Rothman KJ (2005) Maternal asthma, preeclampsia and risk of hypospadias. Epidemiology 16:806–807CrossRefPubMedGoogle Scholar
  63. 63.
    Weidner ISMH, Jensen TK, Skakkebak NE (1999) Risk factors for cryptorchidism and hypospadias. J Urol 161:1606–1609CrossRefPubMedGoogle Scholar
  64. 64.
    Fredell L, Kockum I, Hansson E, Holmner S, Lundquist L, Läckgren G, Pedersen J, Stenberg A, Westbacke G, Nordenskjöld A (2002) Heredity of hypospadias and the significance of low birth weight. J Urol 167:1423–1427CrossRefPubMedGoogle Scholar
  65. 65.
    Sun G, Tang D, Liang J, Wu M (2009) Increasing prevalence of hypospadias associated with various perinatal risk factors in Chinese newborns. Urology 73:1241–1245CrossRefPubMedGoogle Scholar
  66. 66.
    Aschim HT, Haugen TB, Tretli S, Daltveit AK, Grotmol T (2004) Risk factors for hypospadias in Norwegian boys—association with testicular dysgenesis syndrome? Int J Androl 27:213–221CrossRefPubMedGoogle Scholar
  67. 67.
    Ghirri P, Bertelloni S, Pardi D, Celandroni A, Cocchi G, Danieli R, De Santis L, Di Stefano MC, Gerola O et al (2009) Prevalence of hypospadias according to severity, gestational age and birthweight: an epidemiological study. Ital J Pediatr 35:18CrossRefPubMedCentralPubMedGoogle Scholar
  68. 68.
    Hughes IA, Northstone K, Golding J, Team AS (2002) Reduced birth weight in boys with hypospadias: an index of androgen dysfunction? Arch Dis Child Fetal Neonatal Ed 87:F150–F151CrossRefPubMedCentralPubMedGoogle Scholar
  69. 69.
    Stoll C, Alembik Y, Roth MP, Dott B (1990) Genetic and environmental factors in hypospadias. J Med Genet 27:559–563CrossRefPubMedCentralPubMedGoogle Scholar
  70. 70.
    Fujimoto T, Suwa T, Kabe K, Adachi T, Nakabayashi M, Amamiya T (2008) Placental insufficiency in early gestation is associated with hypospadias. J Pediatr Surg 43:358–361CrossRefPubMedGoogle Scholar
  71. 71.
    Carlson WH, Kisely SR, MacLellan DL (2009) Maternal and fetal risk factors associated with severity of hypospadias: a comparison of mild and severe cases. J Pediatr Urologia Int 5:283–286CrossRefGoogle Scholar
  72. 72.
    Yinon Y, Kingdom JC, Proctor LK, Kelly EN, Salle JL, Wherrett D, Keating S, Nevo O, Chitayat D (2010) Hypospadias in males with intrauterine growth restriction due to placental insufficiency: the placental role in the embryogenesis of male external genitalia. Am J Med Genet A 152A:75–83CrossRefPubMedGoogle Scholar
  73. 73.
    Furneaux EC, Langley-Evans AJ, Langley-Evans SC (2001) Nausea and vomiting of pregnancy: endocrine basis and contribution to pregnancy outcome. Obstet Gynecol Surv 56:775–782CrossRefPubMedGoogle Scholar
  74. 74.
    Caton AR, Bell EM, Druschel CM, Werler MM, Mitchell AA, Browne ML, McNutt LA, Romitti PA, Olney RS, Correa A (2008) Maternal hypertension, antihypertensive medication use, the risk of severe hypospadias. Birth Defects Res A Clin Mol Teratol 82:34–40CrossRefPubMedGoogle Scholar
  75. 75.
    Mavrogenis S, Urban R, Czeizel AE (2014) Pregnancy complications in the mothers who delivered boys with isolated hypospadias—a population-based case-control study. J Maternal Fet Med 2014:1–5. doi: 10.3109/14767058.2014.921902
  76. 76.
    Nelson DB, Chalak LF, McIntire DD, Leveno KJ (2014) Is preeclampsia associated with fetal malformation? A review and report of original research. J Maternal Fet Med 2014:1–6. doi: 10.3109/14767058.2014.980808
  77. 77.
    Hakonsen LB, Ernst A, Ramlau-Hansen CH (2014) Maternal cigarette smoking during pregnancy and reproductive health in children: a review of epidemiological studies. Asian J Androl 16(1):39–49CrossRefPubMedCentralPubMedGoogle Scholar
  78. 78.
    Pierik FH, Burdorf A, Deddens JA, Juttmann RE, Weber RFA (2004) Maternal and paternal risk factors for cryptorchidism and hypospadias: a case—control study in newborn boys. Environ Health Perspect 112:1570–1576CrossRefPubMedCentralPubMedGoogle Scholar
  79. 79.
    Rocheleau CM, Romitti PA, Dennis LK (2009) Pesticides and hypospadias: a meta-analysis. J Pediatr Urol 5:17–24CrossRefPubMedGoogle Scholar
  80. 80.
    Christensen JS, Asklund C, Skakkebaek NE, Jorgensen N, Andersen HR, Jorgensen TM, Olsen LH, Hoyer AP, Moesgaard J, Thorup J et al (2013) Association between organic dietary choice during pregnancy and hypospadias in offspring: a study of mothers of 306 boys operated on for hypospadias. J Urol 189:1077–1082CrossRefPubMedGoogle Scholar
  81. 81.
    Gilboa SM, Lee KA, Cogswell ME, Traven FK, Botto LD, Riehle-Colarusso T, Correa A, Boyle CA (2014) Maternal intake of vitamin E and birth defects, national birth defects prevention study, 1997–2005. Birth Defects Res A Clin Mol Teratol 100:647–657CrossRefPubMedGoogle Scholar
  82. 82.
    North K, Golding J (2001) A maternal vegetarian diet in pregnancy is associated with hypospadias. The ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. BJU Int 2000(85):107–113Google Scholar
  83. 83.
    Vilela ML, Willingham E, Buckley J, Liu BC, Agras K, Shiroyanagi Y, Baskin LS (2007) Endocrine disruptors and hypospadias: role of genistein and the fungicide vinclozolin. Urology 70:618–621CrossRefPubMedGoogle Scholar
  84. 84.
    Arpino C, Brescianini S, Robert E, Castilla EE, Cocchi G, Cornel MC, de Vigan C, Lancaster PA, Merlob P, Sumiyoshi Y, Zampino G, Renzi C, Rosano A, Mastroiacovo P (2000) Teratogenic effects of antiepileptic drugs: use of an International Database on Malformations and Drug Exposure (MADRE). Epilepsia 41:1436–1443CrossRefPubMedGoogle Scholar
  85. 85.
    Rodríguez-Pinilla E, Mejías C, Prieto-Merino D, Fernández P, Martínez-Frías ML, ECEMC Working Group (2008) Risk of hypospadias in newborn infants exposed to valproic acid during the first trimester of pregnancy: a case—control study in Spain. Drug Saf 31:537–543CrossRefPubMedGoogle Scholar
  86. 86.
    Ajayi GO, Fadiran EO (1999) The effect of combined iron therapy (Chemiron) and single iron therapy on the dexamethasone-estriol reaction test for placenta insufficiency during normal pregnancy. Clin Exp Obstet Gynecol 26:27–30PubMedGoogle Scholar
  87. 87.
    Lipworth BJ (1999) Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med 159:941–955CrossRefPubMedGoogle Scholar
  88. 88.
    Negulescu RI, Strecker JR, Lauritzen C, Pal S (1977) The influence of betamethasone on the feto-placental unit: a preliminary report. J Perinat Med 5:120–132CrossRefPubMedGoogle Scholar
  89. 89.
    Reinisch JM, Simon NG, Karow WG, Gandelman R (1978) Prenatal exposure to prednisone in humans and animals retards intrauterine growth. Science 202(4366):436–438CrossRefPubMedGoogle Scholar
  90. 90.
    Willingham E, Agras K, Vilela M, Baskin LS (2006) Loratadine exerts estrogen-like effects and disrupts penile development in the mouse. J Urol 175:723–726CrossRefPubMedGoogle Scholar
  91. 91.
    Yucel S, Desouza A, Baskin LS (2004) In utero prednisone exposure affects genital development. J Urol 172(4 Pt 2):1725–1730CrossRefPubMedGoogle Scholar
  92. 92.
    Källén B, Nilsson E, Otterblad Olausson P (2008) Maternal use of loperamide in early pregnancy and delivery outcome. Acta Paediatr 97:541–545CrossRefPubMedGoogle Scholar
  93. 93.
    Watts DH, Li D, Handelsman E, Tilson H, Paul M, Foca M, Vajaranant M, Diaz C, Tuomala R, Thompson B (2007) Assessment of birth defects according to maternal therapy among infants in the Women and Infants Transmission Study. J Acquir Immune Defic Syndr 44:299–305CrossRefPubMedGoogle Scholar
  94. 94.
    Czeizel AE, Kazy Z, Puho E (2003) A population-based case—control teratological study of oral nystatin treatment during pregnancy. Scand J Infect Dis 35:830–835CrossRefPubMedGoogle Scholar
  95. 95.
    Reis M, Källén B (2010) Delivery outcome after maternal use of antidepressant drugs in pregnancy: an update using Swedish data. Psychol Med 40:1723–1733CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Mathew George
    • 1
  • Francisco J. Schneuer
    • 2
  • Sarra E. Jamieson
    • 3
  • Andrew J. A. Holland
    • 1
    Email author
  1. 1.Douglas Cohen Department of Paediatric Surgery, The Children’s Hospital at Westmead, Discipline of Paediatrics and Child Health, Sydney Medical SchoolThe University of SydneyWestmeadAustralia
  2. 2.Northern Clinical School, Kolling Institute of Medical ResearchThe University of SydneySt LeonardsAustralia
  3. 3.Telethon Kids InstituteUniversity of Western AustraliaPerthAustralia

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