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BIRTH DEFECT RISK FACTOR SERIES: Hypospadias

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DEFINITION

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).

EMBRYOLOGY

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).

GENETIC FACTORS

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).

PREVALENCE

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.

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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.

For more information:

Birth Defects Epidemiology and Surveillance
Texas Department of State Health Services
1100 W. 49th Street, Austin, Texas 78756
512-776-7232 Fax 512-776-7330

Document E58-10957  Revised November 2006

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Last updated February 10, 2012