Click here for an Adobe PDF version of this document. (180KB PDF, Viewing Information)
NEW: Please take a moment to evaluate our birth defects risk factor series. Click here to take survey.
Hypospadias is the urethral opening (urethral meatus) being located ventral to the tip of the glans in males. Hypospadias is rare in females and may not truly occur in females (Harris 1990). The condition is often recognized by physical examination shortly after birth, although milder form may be missed in uncircumcised males because the foreskin (may cover the defect) (Dolk 2004). Approximately 30-50% of cases are associated with chordee (ventral curvature of the penis).
Hypospadias is classified by the location of the urethral meatus or the severity of the defect:
• 1st degree: glandular or coronal meatus (60-75% of cases)
• 2nd degree: penile meatus (15-25% of cases)
• 3rd degree: scrotal or perineal meatus (3-6% of cases)
Perineal hypospadias may also be classified as 4th degree hypospadias. Hypospadias is sometimes classified as distal or proximal. Severe hypospadias may be initially classified as ambiguous genitalia.
Hypospadias usually does not occur with autosomal chromosomal abnormalities but some cases have been associated with Down syndrome and with sex chromosome abnormalities (Torfs 1998, Stoll 1990, Calzolari 1986, Aarskog 1979, Svennson 1979, Avellan 1977, Chen1971). The mortality rate of infants with hypospadias is very low (Nazer 1992, Kallen 1982).
Hypospadias occurs due to failure of fusion of the genital folds after approximately eight weeks’ gestation, with the resulting failure of formation of the preputial tissues on the ventral penis (Baskin 2001). At the same time, the production of Müllerian inhibiting substance (MIS) causes the regression of the Müllerian duct system. Production of male androgens (male sex hormones) begins, and the tissues of the genital area fuse to form the urethra and penis around 10 weeks, and the glans is completed by 14 weeks of gestation (Austin 2002).
DEMOGRAPHIC AND REPRODUCTIVE FACTORS
Race/ethnicity has been associated with hypospadias risk, with rates of the defect being highest in whites, followed by blacks, Native Americans, Asians, and Hispanics (Shaw 2002, Leck 1995, Chavez 1988, Lowry 1986, Chung 1968). Lower rates have been found in offsprings of Japanese mothers in Hawaii (Forrester 2006).
Secular trends have been reported for hypospadias, with rates of hypospadias reported to have increased in Australia, Denmark, Great Britain, Hungary, Ireland, Norway, Sweden, Spain, and the United States (Martinez-Frias 2004, Paulozzi 1997, Riley 1998, Giwercman 1993, Czeizel 1990, Kallen 1986, Simpkin 1985, Kallen 1982, Bjerkedal 1975). Nevertheless, other studies failed to find an increase in the defect (Aho 2000, Chambers 1999, Kallen 1986, Baird 1985, Leung 1985, Monteleone 1981). One potential explanation for the secular increases observed in some areas may be that the diagnosis of hypospadias is not well defined. Increased ascertainment of mild cases that previously considered normal variants may result in a perceived increase. Nevertheless, secular increases have been observed when observations are limited to the more severe forms of the defect (Paulozzi 1997). One investigation where all consecutive males were examined for hypospadias reported a higher hypospadias rate than that reported by various birth defects registries (Pierik 2002).
Various investigations have reported seasonal differences in hypospadias rates (Kallen 1986; Angerpointner 1984, Monteleone 1981, Czeizel 1979, Svensson 1979, Avellan 1977, Campbell 1973, Roberts 1973, Wehrung 1970). This seasonal difference may be related to exposure to environmental factors present during a certain time of year. However, there was no consistent pattern in seasonality, and other studies found no effect of seasonality on hypospadias rates (Nazer 1992, Castilla 1990, Stoll 1990, Calzolari 1986, Baird 1985, Leung 1985, Sweet 1974, Record 1973, Chen 1971).
Hypospadias rates have been found to vary by residence, both between countries and within countries (Kallen 1986, Angerpointner 1984, Kallen 1982). One investigation reported hypospadias risk increasing with lower altitude (Castilla 1999).
Neither maternal age nor paternal age appear to affect hypospadias risk (Carbone 2006, Brouwers 2006, Akre 1999, Chambers 1999, Weidner 1999, Nazer 1992, Stoll 1990, Calzolari 1986, Kallen 1982, Monteleone 1981, Czeizel 1979), although one investigation reported increased risk of hypospadias for older mothers (Fisch 2001) and another for mothers under 25 in combination with cryptorchidism (Carbone 2006). Carbone also found that hypospadias with cryptorchidism was higher among mothers who had had gynecological disease. Several investigations have noted an association of hypospadias with parity, with increased risk of the defect among lower birth ranks, particularly firstborns (Meyer 2005, Akre 1999, Weidner 1999, Angerpointner 1984, Czeizel 1979, Hay 1972, Chen 1971). In addition, delayed prenatal care has been associated with higher risk (Meyer 2005).
Hypospadias is more common among infants with lower birth weight (Carbone 2006, Fredell 2002, Akre 1999, Weidner 1999, Riley 1998, Mili 1991, Calzolari 1986, Kallen 1986, Angerpointner 1984, Kallen 1982, Monteleone 1981, Czeizel 1979, Avellan 1977, Sweet 1974, Chen 1971), lower placental weight (Stoll 1990), lower gestational age (Meyer 2005, Rasmussen 2001, Weidner 1999, Calzolari 1986, Kallen 1986, Angerpointner 1984, Kallen 1982, Avellan 1977, Sweet 1974), and intrauterine growth retardation (Hassain 2002, Khoury 1988, Kallen 1986). There was no association found between hypospadias and epispadias and macrosomia (Lapunzina 2002, Waller 2001). Hypospadias risk is positively associated with multiple gestation pregnancy (Fredell 2002, Akre 1999, Mastroiacovo 1999, Weidner 1999, Ramos-Arroyo 1991, Kallen 1986, Leung 1985, Monteleone 1981, Czeizel 1979, Roberts 1973), although one study reported no such association (Kallen 1986).
Several studies have found no association between previous abortions and hypospadias risk (Stoll 1990; Calzolari 1986), although another investigation reported an association between the birth defect and previous stillbirths (Weidner 1999).
One investigation found no association between parental consanguinity and hypospadias (Rittler 2001).
Abnormalities of the father’s testes or scrotum have been associated with hypospadias (Brouwers 2006, Sweet 1974), as has abnormalities in the sperm (Fritz 1996) and genital disease in either father or mother (Carbone 2006).
There is a hereditary component to hypospadias with a 4-10% risk of hypospadias among the siblings, children, and other relatives of an individual with the defect (Brouwers 2006, Fredell 2002, Weidner 1999, Calzolari 1986, Kallen 1986, Leung 1985, Angerpointner 1984, Monteleone 1981, Czeizel 1979, Avellan 1977, Sweet 1974, Chen 1971). One study from Sweden indicated that boys with hypospadias had a 6% chance having a brother with hypospadias (Fredell 2002). However, the clustering of hypospadias in families may also be considered as evidence of a shared environmental exposure (Baskin 2001).
Various studies have found associations between specific genetic mutations of CXorf6 and hypospadias (Fukami 2006, Chen 2006, Radpour 2006). Hypospadias also occurs in boys with Klinefelter syndrome (Visootsak 2006).
FACTORS IN LIFESTYLE OR ENVIRONMENT
Findings have been mixed about an association between parental education and hypospadias risk (Brouwers 2006, Carbone 2006, Stoll 1990, Polednak 1983). One study indicated a correlation between socioeconomic status and hypospadias risk; authors indicated that this might be a due to a lower education level and sub-optimal health of the parents (Pierik 2004).
Several investigations have reported no association between hypospadias risk and parental occupation (Carbone 2006, Matte 1993, Kallen 1988, Czeizel 1979). The available literature pertaining to the relationship between hypospadias and parental gardening and farming is contradictory (Weidner 1998; Angerpointner, 1984). An article that reviewed recent studies of paternal occupation and birth defects described increased risk of hypospadias with paternal occupation of forestry and logging worker, firefighter, policeman and guard, and vehicle manufacturer (Chia 2002).
Partly because of the secular increases in hypospadias rates observed in certain areas, a potential association between the defect and chemicals with estrogenic or anti-androgenic effects (polychlorobiphenyls, dioxins, organochlorine pesticides, alkylphenol polyethoxylates, and phthalates) has been suggested, but there has been no strong evidence of this (Brouwers 2006, Dolk, 1998). One study reported not relationship between maternal serum levels of DDE (1,1-Dichloro-2,2-bis(p-chlorophenyl) ethylene), a metabolite of the pesticide DDT that inhibits binding of androgen to the androgen receptor, and risk of hypospadias (Longnecker 2002). Hypospadias rates do not seem to be influenced by residence in proximity to a variety of industries (Castilla 2000) and hazardous waste sites (Dolk 1998), and exposure to pesticides and other contaminants in the water (Chambers and Malone, 1999), although one investigation reported increased risk of hypospadias with parental pesticide exposure (Kristensen 1997), and an Arkansas study found higher rates of hypospadias among boys whose mothers resided in an area treated with diclofop-methyl (Meyer 2006). Another study found a slightly increased risk of hypospadias and epispadias with proximity to landfill sites (Elliott 2001). Hypospadias may be associated with dioxin (TCDD) exposure in a dose-response fashion (Mastroiacovo 1988).
Another potential association has been proposed between sex hormones used as oral contraceptives, pregnancy tests, and to treat threatened miscarriage or because of previous miscarriages. A number of investigations have reported increased risk of hypospadias with sex hormones (Lopez-Camelo 1996, Calzolari 1986, Angerpointner 1984, Monteleone 1981, Aarskog 1979, Czeizel 1979, Sweet 1974). However, other investigations, including a meta-analysis, found no association between hypospadias and sex hormones or oral contraceptives (Wogelius 20006, Chambers 1999, Raman-Wilms 1995, Kallen 1991, Czeizel 1990, Stoll 1990, Czeizel 1988, Kallen 1988, Polednak 1983, Kallen 1982, Mau 1981, Janerich 1980). Since these sex hormones are often used to treat particular conditions, it might be that the underlying condition and not the treatment was associated with increased risk of hypospadias. Threatened miscarriage has been connected with increased risk of hypospadias by some studies (Calzolari 1986, Kallen 1982, Czeizel 1979), but not others (Stoll 1990). No association of the defect was found with subfertility (Akre 1999, Kallen 1988). Additionally, it has been suggested that maternal exposure in utero to diethylstilbestrol (DES), a synthetic estrogen, may increase the risk of this defect (Klip 2002). DES was given to women between 1938 and 1975 to prevent miscarriage, and has been shown to increase the risk of cervical cancer in women who were exposed in utero (i.e., women whose mothers took the drug). Another study found no cases of hypospadias among DES offspring (Gill 1979).
Several investigations have reported increased risk of hypospadias with assisted reproductive technologies such as in vitro fertilization, gamete intrafallopian transfer (GIFT), and intracytoplasmic sperm injection (ICSI) (Wennerholm 2000, Silver 1999, Macnab 1991), although this association possibly may be due to the underlying fertility problems rather than to the intervention.
One study found that hypospadias with cryptorchidism was associated with the use of condoms (Carbone 2006).
Maternal alcohol consumption and maternal smoking do not appear to influence hypospadias risk (Brouwers 2006, North 2000, Akre 1999, Chambers 1999, Stoll 1990, Van Den Eeden 1990, Kallen 1988, Calzolari 1986, Kallen 1982). However, one study indicated that paternal smoking increased the risk of hypospadias (Pierik 2004).
Hypospadias has been associated with maternal use of various prescription drugs, including anticonvulsants valproic acid and carbamazepine (Arpino 2000, Lindhout 1992), co-trimoxazole (trimethoprim and sulfamethoxazole, an antibacterial agent and folic acid antagonist) (Czeizel 1990), antiemetics (Monteleone 1981), and codeine (North 2000). Hypospadias risk does not appear to be associated with the benzodiazepines nitrazepam, medazepam, tofisopam, alprazolum, and clonazepam (Eros 2002), the antibiotic oxytetracycline (Czeizel 2000), cephalosporin antibiotics (Czeizel 2001a), nalidixic acid (Czeizel 2001b), ampicillin (Czeizel 2001c), cotrimoxazole (trimethoprim-sulfamethoxazo le) (Czeizel 2001d), calcium channel blockers (Sorensen 2001), antineurotic and antidepressant medications (Kallen 1982), thyroid medications (Polednak 1983), and immunizations and radiation (Stoll 1990, Monteleone 1981). The relationship is unclear between aspirin and hypospadias (Correy 1991, Slone 1976) and vaginal spermicides and hypospadias (Louik 1987, Jick 1981). Investigations have reported increased risk of hypospadias with maternal use of oral anti-tuberculosis medications and augmentin; however, when the analyses were limited to exposure during the critical period of hypospadias formation, the results were not significant (Czeizel 2001e, Czeizel 2001f). Although case reports have suggested an association between hypospadias and misoprostol, a synthetic prostaglandin used for elective termination, a case-control study failed to find increased risk of hypospadias with the medication (Orioli 2000). It has been suggested that maternal prenatal cocaine use may increase risk of hypospadias (Battin 1995), although other studies have reported no association between fetal cocaine exposure and birth defects (Behnke 2001). Finally, there has been no link has been found between loratadine (Claritin™) exposure during pregnancy and increased hypospadias risk (Pedersen 2006, MMWR 2004).
One study also found and association between fathers’ use of prescription drugs and hypospadias (Brouwers 2006).
Hypospadias does not appear to be associated with maternal diabetes (Ramos-Arroyo 1992, Becerra 1990, Polednak 1983, Kallen 1988), although one investigation reported increased rates of hypospadias with maternal preexisting diabetes but not gestational diabetes (Aberg 2001). Hypospadias risk is not influenced by epilepsy (Polednak 1983), hypothyroidism or hyperthyroidism (Khoury 1989), cold in the first trimester (Zhang 1993), early pregnancy bleeding (Kallen 1988), vaginal bleeding (Monteleone 1981), abruptio placentae (Kallen 1988, Kallen 1982), or placenta previa (Kallen 1988). One study observed increased risk of hypospadias with maternal influenza in the first trimester (North 2000).
Maternal folic acid or multivitamin use at any time during pregnancy does not affect risk of hypospadias (Goh 2006, Czeizel 1996). However, children of mothers who were vegetarian or took iron supplements had an increased risk for hypospadias (North 2000).
Birth prevalence in the United States for hypospadias or epispadias (a related defect) ranges between 2.01 and 56.17 per 10,000 live births (National Birth Defects Prevention Network 2005). The rate in Texas for 1999-2002 deliveries was 28.25 (Texas Department of State Health Services 2006). Differences in prevalence may be due to differences in case inclusion criteria.
- Aarskog D. Maternal progestins as a possible cause of hypospadias. N Engl J Med 1979;300:75-78.
- Aberg A, Westbom L, Kallen B. Congenital malformations among infants whose mothers had gestational diabetes or preexisting diabetes. Early Hum Dev 2001;61:85-95.
- Aho M, Koivisto AM, Tammela TL, Auvinen A. Is the incidence of hypospadias increasing? Analysis of Finnish hospital discharge data 1970-1994. Environ Health Perspect 2000;108:463-465.
- Akre O, Lipworth L, Cnattingius S, Sparen P, Ekbom A. Risk factor patterns for cryptorchidism and hypospadias. Epidemiology 1999;10:364-369.
- Ahmed S, Dobbie R, Finlayson A, Gilbert J, Youngston G, Chalmers J, Sotene D. Prevalence of hypospadias and other genital anomalies among singleton births, 1988—1997, in Scotland. Arch. Dis, Child, Fetal Neonatology, Ed. 2004; 89; 149-151.
- Angerpointner TA. Hypospadias - genetics, epidemiology and other possible aetiological influences. Z Kinderchir 1984;39:112-118.
- 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. Teratogenic effects of antiepileptic drugs: use of an international database on malformations and drug exposure. Epilepsia 2000;41:1436-1443.
- Aschim E, Haugen T, Tretli S, Dalveit A, Grotomol T. Risk factors for hypspadias in Norwegian boys—an association with testicular dysgenesis syndrome. International Journal of Andrology, 27: 213-221 (2004).
- Austin P, Siow Y, Fallat M, Cain M, Rinks R, Casale A. The relationship between mullerian inhibiting substance and androgens in boys with hypospadias. Journal of Urology, Vol. 168, 1784-1788, 2002.
- Avellan L. The incidence of hypospadias in Sweden. Scand J Plast Reconstr Surg 1975;9:129-139.
- Avellan L. On aetiological factors in hypospadias. Scand J Plast Reconstr Surg 1977;11:115-123.
- Baird PA. Incidence of hypospadias. Lancet 1985;1:1162.
- Baskin LS, Himes K, Colborn T. Hypospadias and endocrine disruption: is there a connection? Environ Health Perspect 2001;109:1175-1183.
- Battin M, Albersheim S, Newman D. Congenital genitourinary tract abnormalities following cocaine exposure in utero. Am J Perinatol 1995;12:425-428.
- Becerra JE, Khoury MJ, Cordero JF, Erickson JD. Diabetes mellitus during pregnancy and the risks for specific birth defects: a population-based case-control study. Pediatrics 1990;85:1-9.
- Behnke M, Eyler FD, Garvan CW, Wobie K. The search for congenital malformations in newborns with fetal cocaine exposure. Pediatrics 2001;107:e74.
- Bjerkedal T, Bakketeig LS. Surveillance of congenital malformations and other conditions of the newborn. Int J Epidemiol 1975;4:31-36.
- Bhatia, R, Shiau, R, Petreas, M, Weintraub, J, Farhang, L, Eskenzai, B. Organochloride pesticides and male genital anomalies in the child health development studies. Environmental health Perspectives, Vol. 113, No. 2, 2005.
- Brouwers MM, Feitz WF, Roelofs LA, Kiemeney LA, de Gier RP, Roeleveld N. Risk factors for hypospadias.
- Eur J Pediatr. 2006 Nov 14; [Epub ahead of print]
- Calzolari E, Cavazzuti GB, Cocchi G, Contrino C, Magnani C, Moretti M, Roncarati E, Salvioli GP, Volpato S. Congenital malformations in 100,000 consecutive births in Emilia Romagna region, northern Italy: comparison with the EUROCAT data. Eur J Epidemiol 1987;3:423-430.
- Calzolari E, Contiero MR, Roncarati E, Mattiuz PL, Volpato S. Aetiological factors in hypospadias. J Med Genet 1986;23:333-337.
- Campbell H, Newcombe RG, Weatherall JA. Epidemiology of simple hypospadias. BMJ 1973;2:52-53.
- Carbone P, Giordano F, Nori F, Mantovani A, Taruscio D, Lauria L, Figa-Talamanca I. The possible role of endocrine disrupting chemicals in the aetiology of cryptorchidism and hypospadias: a population-based case-control study in rural Sicily. Int J Androl. 2006 Jul 4; [Epub ahead of print]
- Carmichael, S, Shaw G, Nelson V, Selvin S, Torfs C, Curry C. Hypospadias in Calfornia: trends and descriptive epidemiology. Epidemiology, Vol. 14, No. 6, 2003.
- Castilla EE, Campana H, Camelo JS. Economic activity and congenital anomalies: an ecologic study in Argentina. Environ Health Perspect 2000;108:193-197.
- Castilla EE, Lopez-Camelo JS, Campana H. Altitude as a risk factor for congenital anomalies. Am J Med Genet 1999;86:9-14.
- Castilla EE, Orioli IM, Lugarinho R, Dutra GP, Lopez-Camelo JS, Campana HE, Spagnolo A, Mastroiacovo P. Monthly and seasonal variations in the frequency of congenital anomalies. Int J Epidemiol 1990;19:399-404.
- Castilla EE, Lopez-Camelo JS. The surveillance of birth defects in South America. In: Advances in Mutagenesis Research. Springer-Verlag, New York. 1990b pp. 191-210.
- Chambers EL, Malone PS. The incidence of hypospadias in two English cities: a case-control comparison of possible causal factors. BJU Int 1999;84:95-98.
- Chavez GF, Cordero JF, Becerra JE. Leading major congenital malformations among minority groups in the United States, 1981-1986. Mor Mortal Wkly Rep CDC Surveill Summ 1988;37:17-24.
- Chen T, Li Q, Xu J, Ding K, Wang Y, Wang W, Li S, Shen Y. Mutation screening of BMP4, BMP7, HOXA4 and HOXB6 genes in Chinese patients with hypospadias. Eur J Hum Genet. 2006 Sep 27; [Epub ahead of print]
- Chen YC, Woolley PV. Genetic studies on hypospadias in males. J Med Genet 1971;8:153-159.
- Chia SE, Shi LM. Review of recent epidemiological studies on paternal occupations and birth defects. Occup Environ Med. 2002;59:149-155.
- Chung CS, Myrianthopoulos NC. Racial and prenatal factors in major congenital malformations. Am J Hum Genet 1968;20:44-60.
- Correy JF, Newman NM, Collins JA, Burrows EA, Burrows RF, Curran JT. Use of prescription drugs in the first trimester and congenital malformations. Aust N Z J Obstet Gynaecol 1991;31:340-344.
- Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. Use of cephalosporins during pregnancy and in the presence of congenital abnormalities: a population-based, case-control study. Am J Obstet Gynecol 2001a;184:1289-1296.
- Czeizel AE, Sorensen HT, Rockenbauer M, Olsen J. A population-based case-control teratologic study of nalidixic acid. Int J Gynaecol Obstet 2001b;73:221-228.
- Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. A population-based case-control teratologic study of ampicillin treatment during pregnancy. Am J Obstet Gynecol 2001c;185:140-147.
- Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. The teratogenic risk of trimethoprim-sulfonamides: a population based case-control study. Reprod Toxicol 2001d;15:637-646.
- Czeizel AE, Rockenbauer M, Olsen J, Sorensen HT. A population-based case-control study of the safety of oral anti-tuberculosis drug treatment during pregnancy. Int J Tuberc Lung Dis 2001e;5:564-568.
- Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. Augmentin treatment during pregnancy and the prevalence of congenital abnormalities. A population-based case-control teratologic study. Eur J Obstet Gynecol Reprod Biol 2001f;97:188-192.
- Czeizel AE, Rockenbauer M. A population-based case-control teratologic study of oral oxytetracycline treatment during pregnancy. Eur J Obstet Gynecol Reprod Biol 2000;88:27-33.
- Czeizel AE, Toth M, Rockenbauer M. Population-based case control study of folic acid supplementation during pregnancy. Teratology 1996;53:345-351.
- Czeizel A, Toth J. Correlation between the birth prevalence of isolated hypospadias and parental subfertility. Teratology 1990;41:167-172.
- Czeizel A. A case-control analysis of the teratogenic effects of co-trimoxazole. Reprod Toxicol 1990;4:305-313.
- Czeizel A, Huiskes N. A case-control study to evaluate the risk of congenital anomalies as a result of allylestrenol therapy during pregnancy. Clin Ther 1988;10:725-739.
- Czeizel A, Toth J, Czvenits E. Increased birth prevalence of isolated hypospadias in Hungary. Acta Paediatr Hung 1986;27:329-337.
- Czeizel A, Vitez M. Birth prevalence of five congenital abnormalities of medium frequency in Budapest. Acta Paediatr Acad Sci Hung 1981;22:299-308.
- Czeizel A, Toth J, Erodi E. Aetiological studies of hypospadias in Hungary. Hum Hered 1979;29:166-71.
- Dolk H. Rise in prevalence of hypospadias. Lancet 1998;351:770.
- Dolk H, Vrijheid M, Armstrong B, Abramsky L, Bianchi F, Garne E, Nelen V, Robert E, Scott JE, Stone D, Tenconi R. Risk of congenital anomalies near hazardous-waste landfill sites in Europe: the EUROHAZCON study. Lancet 1998;352:423-427.
- Dolk H, Vrijheid M, Scott JES, Addor M, Botting B, dr Vigan C, de Walle H, Garne E, Loane M, Pierini M, Pierini A, Garcia-Minaur S, Physick N, Tenconi R, Wiesel A, Calzolari E, Stone D. Toward the effextive surveillance of Hypospadias. Environmental Health Perspectives, Vol. 112, No. 3, 2004.
- Elliott P, Briggs D, Morris S, de Hoogh C, Hurt C, Jensen TK, Maitland I, Richardson S, Wakefield J, Jarup L. Risk of adverse birth outcomes in populations living near landfill sites. BMJ 2001;323:363-368.
- Eros E, Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. A population-based case-control teratologic study of nitrazepam, medazepam, tofisopam, alprazolum and clonazepam treatment during pregnancy. Eur J Obstet Gynecol Reprod Biol 2002;101:147-154.
- Finley WH, Gustavson KH, Hall TM, Hurst DC, Barganier CM, Wiedmeyer JA. Birth defects surveillance: Jefferson County, Alabama, and Uppsala County, Sweden. South Med J 1994;87:440-445.
- Fisch H, Golden RJ, Libersen GL, Hyun GS, Madsen P, New MI, Hensle TW. Maternal age as a risk factor for hypospadias. J Urol 2001;165:934-936.
- Forrester MB, Merz RD. Rates for specific birth defects among offspring of Japanese mothers, Hawaii, 1986-2002. Congenit Anom ( Kyoto). 2006 Jun;46(2):76-80.
- Fredell L, Kockum I, Hansson E, Holmner S, Lundquist L, Lackgren G, Pedersen J, Stenberg A, Westbacke G, Nordenskjold A. Heredity of hypospadias and the significance of low birth weight. J Urol 2002;167:1423-1427.
- Fritz G, Czeizel AE. Abnormal sperm morphology and function in the fathers of hypospadiacs. J Reprod Fertil 1996;106:63-66.
- Fukami M, Wada Y, Miyabayashi K, Nishino I, Hasegawa T, Camerino G, Kretz C, Buj-Bello A, Laporte J, Yamada G, Morohashi KI, Ogata T. CXorf6 is a causative gene for hypospadias. Nat Genet. 2006 Nov 5; [Epub ahead of print]
- Gallentine M, Morey A, Thopson I. Hypospadias: a contemporary epidemiological assessment. Pediatric Urology, 2001.
- Gill WB, Schumacher GF, Bibbo M, Straus FH 2nd, Schoenberg HW. Association of diethylstilbestrol exposure in utero with cryptorchidism, testicular hypoplasia and semen abnormalities. J Urol 1979;122:36-39.
- Giwercman A, Carlsen E, Keiding N, Skakkebaek NE. Evidence for increasing incidence of abnormalities of the human testis: a review. Environ Health Perspect 1993;101 Suppl 2:65-71.
- Goh YI, Bollano E, Einarson TR, Koren G. Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis. J Obstet Gynaecol Can. 2006 Aug;28(8):680-9.
- Harris EL. Genetic epidemiology of hypospadias. Epidemiol Rev 1990;12:29-40.
- Hay S, Barbano H. Independent effects of maternal age and birth order on the incidence of selected congenital malformations. Teratology 1972;6:271-279.
- Hussain N, Chaghtai A, Herndon A, Herson VC, Rosenkrantz TS, McKenna PH. Hypospadias and early gestation growth restriction in infants. Pediatrics 2002;109:473-478.
- Janerich DT, Piper JM, Glebatis DM. Oral contraceptives and birth defects. Am J Epidemiol 1980;112:73-79.
- Jick H, Walker AM, Rothman KJ, Hunter JR, Holmes LB, Watkins RN, D'Ewart DC, Danford A, Madsen S. Vaginal spermicides and congenital disorders. JAMA 1981;245:1329-1332.
- Kallen B, Mastroiacovo P, Lancaster PA, Mutchinick O, Kringelbach M, Martinez-Frias ML, Robert E, Castilla EE. Oral contraceptives in the etiology of isolated hypospadias. Contraception 1991;44:173-182.
- Kallen B. Case control study of hypospadias, based on registry information. Teratology 1988;38:45-50.
- Kallen B. Congenital malformations in twins: a population study. Acta Genet Med Gemellol (Roma) 1986;35:167-178.
- Kallen B, Bertollini R, Castilla E, Czeizel A, Knudsen LB, Martinez-Frias ML, Mastroiacovo P, Mutchinick O. A joint international study on the epidemiology of hypospadias. Acta Paediatr Scand Suppl 1986;324:1-52.
- Kallen B, Winberg J. An epidemiological study of hypospadias in Sweden. Acta Paediatr Scand Suppl 1982;293:1-21.
- Khoury MJ, Becerra JE, d'Almada PJ. Maternal thyroid disease and risk of birth defects in offspring: a population-based case-control study. Paediatr Perinat Epidemiol 1989;3:402-420.
- Khoury MJ, Erickson JD, Cordero JF, McCarthy BJ. Congenital malformations and intrauterine growth retardation: a population study. Pediatrics 1988;82:83-90.
- Klip H, Verloop J, van Gool JD, Koster ME, Burger CW, van Leeuwen FE. Hypospadias in sons of women exposed to diethylstilbestrol in utero: a cohort study. Lancet 2002;359:1102-1107.
- Kristensen P, Irgens LM, Andersen A, Bye AS, Sundheim L. Birth defects among offspring of Norwegian farmers, 1967-1991. Epidemiology 1997;8:537-544.
- Lapunzina P, Lopez Camelo JS, Rittler M, Castilla EE. Risks of congenital anomalies in large for gestational age infants. J Pediatr 2002;140:200-204.
- Leck I, Lancashire RJ. Birth prevalence of malformations in members of different ethnic groups and in the offspring of matings between them, in Birmingham, England. J Epidemiol Community Health 1995;49:171-179.
- Leung TJ, Baird PA, McGillivray B. Hypospadias in British Columbia. Am J Med Genet 1985;21:39-50.
- Lindhout D, Meinardi H, Meijer JW, Nau H. Antiepileptic drugs and teratogenesis in two consecutive cohorts: changes in prescription policy paralleled by changes in pattern of malformations. Neurology 1992;42:94-110.
- Longnecker MP, Klebanoff MA, Brock JW, Zhou H, Gray KA, Needham LL, Wilcox AJ. Maternal Serum Level of 1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene and Risk of Cryptorchidism, Hypospadias, and Polythelia among Male Offspring. Am J Epidemiol 2002;155:313-322.
- Lopez-Camelo JS, Orioli IM. Heterogeneous rates for birth defects in Latin America: hints on causality. Genet Epidemiol 1996;13:469-481.
- Louik C, Mitchell AA, Werler MM, Hanson JW, Shapiro S. Maternal exposure to spermicides in relation to certain birth defects. N Engl J Med 1987;317:474-478.
- Lowry RB, Thunem NY, Silver M. Congenital anomalies in American Indians of British Columbia. Genet Epidemiol 1986;3:455-467.
- Macnab AJ, Zouves C. Hypospadias after assisted reproduction incorporating in vitro fertilization and gamete intrafallopian transfer. Fertil Steril 1991;56:918-922.
- Manson J, Carr M. Molecular epidemiology of hypospadias: a review of genetic and environmental risk factors. Birth Defects Research (Part A) 67:825-836 (2003).
- Martinez-Frias M, Prieto D, Preto L, Bermejo E, Rodriguez-Pineilla E, Cuevas L. Secular decreasing trend of the frequency of hypospadias among newborn male infants in Spain. Birth -Defects Research (Part A) 67: (2003).
- Mastroiacovo P, Castilla EE, Arpino C, Botting B, Cocchi G, Goujard J, Marinacci C, Merlob P, Metneki J, Mutchinick O, Ritvanen A, Rosano A. Congenital malformations in twins: an international study. Am J Med Genet 1999;83:117-124.
- Mastroiacovo P, Spagnolo A, Marni E, Meazza L, Bertollini R, Segni G, Borgna-Pignatti C. Birth defects in the Seveso area after TCDD contamination. JAMA 1988;259:1668-1672.
- Matte TD, Mulinare J, Erickson JD. Case-control study of congenital defects and parental employment in health care. Am J Ind Med 1993;24:11-23.
- Mau G. Progestins during pregnancy and hypospadias. Teratology 1981;24:285-7.
- Meyer KJ, Reif JS, Veeramachaneni DN, Luben TJ, Mosley BS, Nuckols JR. Agricultural pesticide use and hypospadias in eastern Arkansas. Environ Health Perspect. 2006 Oct;114(10):1589-95.
- Mili F, Edmonds LD, Khoury MJ, McClearn AB. Prevalence of birth defects among low-birth-weight infants. A population study. Am J Dis Child 1991;145:1313-1318.
- Monteleone Neto R, Castilla EE, Paz JE. Hypospadias: an epidemiological study in Latin America. Am J Med Genet 1981;10:5-19.
- Nazer J, Cifuentes L, Hubner ME, Ramirez R, Ruiz G, Pizarro MT, Nazer C, Morales I. [Epidemiologic study of factors associated with hypospadias]. Rev Med Chil 1992;120:244-249.
- National Birth Defects Prevention Network (NBDPN). Birth Defects Surveillance Data from Selected States, 1998-2002. Birth Defects Research Part A 2005; 73:759-852.
- North K, Golding J. A maternal vegetarian diet in pregnancy is associated with hypospadias. The ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. BJU Int 2000;85:107-113.
- Orioli IM, Castilla EE. Epidemiological assessment of misoprostol teratogenicity. BJOG 2000;107:519-523.
- Papp Z, Toth-Pal E, Papp C, Toth Z, Szabo M, Veress L, Torok O. Impact of prenatal mid-trimester screening on the prevalence of fetal structural anomalies: a prospective epidemiological study. Ultrasound Obstet Gynecol 1995;6:320-326.
- Paulozzi LJ, Erickson JD, Jackson RJ. Hypospadias trends in two US surveillance systems. Pediatrics 1997;100:831-834.
- Pedersen L, Norgaard M, Skriver MV, Olsen J, Sorensen HT. Prenatal exposure to loratadine in children with hypospadias: a nested case-control study within the Danish National Birth Cohort. Am J Ther. 2006 Jul-Aug;13(4):320-4.
- Pierik FH, Burdorf A, Nijman JM, de Muinck Keizer-Schrama SM, Juttmann RE, Weber RF. A high hypospadias rate in The Netherlands. Hum Reprod 2002;17:1112-1115.
- Pierik F, Budorf A, Deddens J, Juttmann R, Weber R. Maternal and paternal risk factors for cryptorchidism and hypospadias: a case control study in newborn boys. Environmental Health Perspectives, Vol. 112, No. 15, 2004.
- Polednak AP, Janerich DT. Maternal characteristics and hypospadias: a case-control study. Teratology 1983;28:67-73.
- Radpour R, Rezaee M, Tavasoly A, Solati S, Saleki A. Association of Long Polyglycine Tracts (GGN repeats) in Exon 1 of the Androgen Receptor Gene with Cryptorchidism and Penile Hypospadias in Iranian Patients. J Androl. 2006 Sep 6; [Epub ahead of print]
- Raman-Wilms L, Tseng AL, Wighardt S, Einarson TR, Koren G. Fetal genital effects of first-trimester sex hormone exposure: a meta-analysis. Obstet Gynecol 1995;85:141-149.
- Ramos-Arroyo MA. Birth defects in twins: study in a Spanish population. Acta Genet Med Gemellol (Roma) 1991;40:337-344.
- Ramos-Arroyo MA, Rodriguez-Pinilla E, Cordero JF. Maternal diabetes: the risk for specific birth defects. Eur J Epidemiol 1992;8:503-508.
- Rasmussen SA, Moore CA, Paulozzi LJ, Rhodenhiser EP. Risk for birth defects among premature infants: A population-based study. J Pediatr 2001;138:668-673.
- Record RG, Armstrong E. Epidemiology of simple hypospadias. BMJ 1973;3:233.
- Richards ID, Bentley HB, Glenny AM. A local congenital anomalies register: monitoring preventive interventions. J Public Health Med 1999;21:37-40.
- Riley MM, Halliday JL, Lumley JM. Congenital malformations in Victoria, Australia, 1983-95: an overview of infant characteristics. J Paediatr Child Health 1998;34:233-240.
- Rittler M, Liascovich R, Lopez-Camelo J, Castilla EE. Parental consanguinity in specific types of congenital anomalies. Am J Med Genet 2001;102:36-43.
- Roberts CJ, Lloyd S. Observations on the epidemiology of simple hypospadias. BMJ 1973;1:768-770.
- Sekhobo JP, Druschel CM. An evaluation of congenital malformations surveillance in New York State: an application of Centers for Disease Control and Prevention (CDC) guidelines for evaluating surveillance systems. Public Health Rep 2001;116:296-305.
- Shaw GM, Carmichael SL, Nelson V. Congenital malformations in offspring of Vietnamese women in California, 1985-97. Teratology 2002;65:121-124.
- Silver RI, Rodriguez R, Chang TS, Gearhart JP. In vitro fertilization is associated with an increased risk of hypospadias. J Urol 1999;161:1954-1957.
- Simpkin JM, Owens JR, Harris F. Incidence of hypospadias. Lancet 1985;2:384.
- Slone D, Siskind V, Heinonen OP, Monson RR, Kaufman DW, Shapiro S. Aspirin and congenital malformations. Lancet 1976;1:1373-1375.
- Sorensen HT, Czeizel AE, Rockenbauer M, Steffensen FH, Olsen J. The risk of limb deficiencies and other congenital abnormalities in children exposed in utero to calcium channel blockers. Acta Obstet Gynecol Scand 2001;80:397-401.
- Stoll C, Alembik Y, Roth MP, Dott B. Genetic and environmental factors in hypospadias. J Med Genet 1990;27:559-563.
- Svensson J. Male hypospadias, 625 cases, associated malformations and possible etiological factors. Acta Paediatr Scand 1979;68:587-592.
- Sweet RA, Schrott HG, Kurland R, Culp OS. Study of the incidence of hypospadias in Rochester, Minnesota, 1940-1970, and a case-control comparison of possible etiologic factors. Mayo Clin Proc 1974;49:52-58.
- Texas Department of State Health Services. Texas birth defects registry report of birth defects among 1999-2002 deliveries. 2005.
- Torfs CP, Christianson RE. Anomalies in Down syndrome individuals in a large population-based registry. Am J Med Genet 1998;77:431-438.
- Van Den Eeden SK, Karagas MR, Daling JR, Vaughan TL. A case-control study of maternal smoking and congenital malformations. Paediatr Perinat Epidemiol 1990;4:147-155.
- Visootsak J, Graham JM Jr. Klinefelter syndrome and other sex chromosomal aneuploidies. Orphanet J Rare Dis. 2006 Oct 24;1:42.
- Waller DK, Keddie AM, Canfield MA, Scheuerle AE. Do infants with major congenital anomalies have an excess of macrosomia? Teratology 2001;64:311-317.
- Wehrung DA, Hay S. A study of seasonal incidence of congenital malformations in the United States. Br J Prev Soc Med 1970;24:24-32.
- Weidner IS, Moller H, Jensen TK, Skakkebaek NE. Risk factors for cryptorchidism and hypospadias. J Urol 1999;161:1606-1609.
- Weidner IS, Moller H, Jensen TK, Skakkebaek NE. Cryptorchidism and hypospadias in sons of gardeners and farmers. Environ Health Perspect 1998;106:793-796.
- Wennerholm UB, Bergh C, Hamberger L, Lundin K, Nilsson L, Wikland M, Kallen B. Incidence of congenital malformations in children born after ICSI. Hum Reprod 2000;15:944-948.
- Werler M, McCloskey C, Edmonds L, Olney R, Honein M, Reefhuis J. Evaluation of an association between loratadine and hypospadias—United States1997—2001. MMWR, Vol. 53, No. 10, 2004.
- Wogelius P, Horvath-Puho E, Pedersen L, Norgaard M, Czeizel AE, Sorensen HT. Maternal use of oral contraceptives and risk of hypospadias - a population-based case-control study. Eur J Epidemiol. 2006 Nov 1; [Epub ahead of print]
- Zhang J, Cai WW. Association of the common cold in the first trimester of pregnancy with birth defects. Pediatrics 1993;92:559-563.
Please Note: The primary purpose of this report is to provide background necessary for conducting cluster investigations. It summarizes literature about risk factors associated with this defect. The strengths and limitations of each reference were not critically examined prior to inclusion in this report. Consumers and professionals using this information are advised to consult the references given for more in-depth information. This report is for information purposes only and is not intended to diagnose, cure, mitigate, treat, or prevent disease or other conditions and is not intended to provide a determination or assessment of the state of health. Individuals affected by this condition should consult their physician and when appropriate, seek genetic counseling.