Hypospadias: a contemporary epidemiologic assessment

PEDIATRIC UROLOGY

HYPOSPADIAS: A CONTEMPORARY EPIDEMIOLOGIC ASSESSMENT MICHAEL L. GALLENTINE, ALLEN F. MOREY,

AND

IAN M. THOMPSON, JR

ABSTRACT Objectives. To determine whether the incidence of hypospadias is increasing and whether racial differences among patients are significant, we evaluated the current incidence of hypospadias and patient race in an equal-access healthcare system. Methods. We undertook a retrospective review of discharge records between 1990 and 1998 from 15 military treatment facilities to determine the total number of male live births and the number of male live births with hypospadias reported by race (categorized as white, black, Asian, Native American, and unknown). Results. Among 99,210 male live births, 709 cases of hypospadias were identified (0.7%). Of the total male live births, 68,444 were white, 18,984 were black, 1761 were Asian, 175 were Native American, and 9846 were unknown, with an incidence of hypospadias of 0.8%, 0.6%, 0.5%, 0.6%, and 0.6%, respectively. Racial differences were not statistically significant (P ⫽ 0.2). Conclusions. The 0.7% incidence of hypospadias detected is near the upper limit of what has been historically reported. No significant difference between races was found, but the incidence of hypospadias in minorities is higher than previously reported. UROLOGY 57: 788–790, 2001. © 2001, Elsevier Science Inc.

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ypospadias occurs at a reported incidence of 0.3% to 0.8% for white male live births1,2 and 0.05% to 0.4% for minority male live births.3– 6 Multiple reports from England, Norway, Sweden, Denmark, Hungary, and the United States from the 1970s to early 1990s have demonstrated an overall increase in the incidence of hypospadias,7–12 and only two reports could be found that did not.13,14 In addition, Paulozzi et al.12 have suggested a greater increase in nonwhites than in whites. We evaluated the current overall incidence of hypospadias and assessed differences among racial groups in our equal-access healthcare system. MATERIAL AND METHODS The Patient Administration Systems and Biostatistic Activity Analysis Branch of Fort Sam Houston, Texas, performed a The opinions contained herein are those of the authors and are not to be construed as reflecting the views of the Army or the Department of Defense. From the Urology Service, Brooke Army Medical Center, Fort Sam Houston, Texas, and Department of Urology, University of Texas Health Science Center at San Antonio, San Antonio, Texas Reprint requests: Allen F. Morey, M.D., Urology Service, Brooke Army Medical Center, Fort Sam Houston, TX 78234 Submitted: September 1, 2000, accepted (with revisions): November 15, 2000

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© 2001, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED

retrospective computer search of the military’s Standard Inpatient Data Record. Discharge records from 1990 to 1998 from 15 military medical treatment facilities were reviewed (Travis Air Force Base, San Diego Naval Hospital, Andrews Air Force Base, National Naval Medical Center, Keesler Air Force Base, Wright-Patterson Air Force Base, Wilford Hall Medical Center, Portsmouth Naval Medical Center, Tripler Army Medical Center, Womack Army Medical Center, Dwight David Eisenhower Army Medical Center, Brooke Army Medical Center, William Beaumont Army Medical Center, Walter Reed Army Medical Center, and Madigan Army Medical Center). The total number of male live births was determined, and the number with hypospadias was identified with the diagnostic codes from the International Classification of Disease, 9th Revision, Clinical Modification (ICD9-CM). The ICD9-CM includes all cases of hypospadias from glans to the perineum and does not subdivide hypospadias into degrees of severity. The patients were divided by race into white, blacks, Asians, Native Americans, and unknown. Statistical analysis was performed with the chi-square test.

RESULTS Male live births totaled 99,210, of whom 709 had hypospadias for a total incidence of 0.7%. The numbers of male live births, male live births with hypospadias, and incidence of hypospadias for each race are shown in Table I. There was no statistically significant difference in the incidence of hypospadias by race (P ⫽ 0.2). 0090-4295/01/$20.00 PII S0090-4295(00)01105-5

TABLE I. Incidence of hypospadias by racial group Race White Black Asian Native American Unknown Total

Male Incidence Live Births Hypospadias (%) 68,444 18,984 1,761 175 9,846 99,210

520 120 9 1 59 709

0.8 0.6 0.5 0.6 0.6 0.7

COMMENT Is the incidence of hypospadias increasing? With the use of two United States surveillance systems, Paulozzi et al.12 reported that the incidence of hypospadias increased from 20.2 to 39.7 per 10,000 from 1970 to 1993. Of note, their annual percentage increase was much higher for minority patients (5.7%) than for whites (1.4%). We found a 0.6% incidence of hypospadias in minorities, which is higher than the previously reported 0.05% to 0.4% incidence.3– 6 What factors would account for an increase in the incidence of hypospadias among minority patients? One explanation would be better access to medical care now than 30 years ago. Our analysis of births from military facilities, in which all members of the military have equal access to healthcare, may explain this increased incidence. A second explanation would be better recognition and reporting of less severe forms of hypospadias. There are no known risk factors specifically found on military bases that might account for an increase of hypospadias in military babies. In our review, the trend was for hypospadias to occur more frequently in whites (0.8%) than in minorities (0.6%), but we found no statistically significant difference between races. This is likely secondary to the low incidence of hypospadias and the consequently small sample size. Other studies have also shown a trend toward greater frequency in whites than in other races,3,4,6 and one larger study (n ⫽ 4,617,613 total births) has shown a statistically significant difference.5 Why might a racial difference exist? The increased incidence of hypospadias in whites could be a result of lower testosterone levels in utero. For example, Henderson et al.15 studied the hormone levels in maternal blood of black and white women during early pregnancy and found that serum testosterone values were 48% greater among black women. Another possible explanation may be that the level of circulating fetal testosterone varies between races. Ross et al.16 reported a difference in the testosterone level between young healthy black and white men, with blacks having higher testosUROLOGY 57 (4), 2001

terone and free testosterone levels of 15% and 13%, respectively. The difference in testosterone levels has been linked to sociocultural factors rather than to genetics.17 The above questions could be better answered if the etiology of hypospadias was known. Hypospadias is polygenic, as there is a high familial incidence.18 At the cellular and molecular levels, the epithelial–mesenchymal interaction appears to be important for penile growth and differentiation.19 Hypospadias may result from endogenous or exogenous dysfunction of the male endocrine system, although the majority of hypospadias cases occur in isolation.10 Exogenous influence may occur from environmental exposure to progestins or estrogens during gestation. It is thought that progestins inhibit testosterone biosynthesis or act as a competitive inhibitor to 5-alpha-reductase activity.10 Support for the significance of exogenous exposure comes from in vitro fertilization (IVF) studies that reveal a fivefold increased risk for hypospadias in IVF babies.10 Other possible risk factors have been proposed, such as advanced maternal age,12,14 and paternal risk factors, such as increased testicular anomalies, including cryptorchidism and varicoceles.2 In addition, hypospadias may occur more frequently in premature births,2,13 in those with low birth weight,13 and in monozygotic twins.19 We acknowledge that our report is a retrospective study of records from multiple institutions and contains bias inherent in this type of investigation. Also, we did not stratify for any of the above-mentioned risk factors associated with hypospadias, nor was hypospadias subdivided by degree of severity. With two exceptions, prior studies do not specify which variants of hypospadias are included in their analysis.2,5 No prior study has directly compared differences in the degree of hypospadias between races. CONCLUSIONS Our contemporary epidemiologic assessment of hypospadias suggests no increase in the overall incidence or significant difference between races. However, the incidence in minority patients is higher than previously reported. REFERENCES 1. Myrianthopoulos NC, and Chung CS: Congenital malformations in singletons: epidemiologic survey. Birth Defects Orig Artic Ser 10: 1–58, 1974. 2. Sweet RA, Schrott HG, Kurland R, et al: Study of the incidence of hypospadias in Rochester, Minnesota, 1940 –1970, and a case– control comparison of possible etiologic factors. Mayo Clin Proc 49: 52–57, 1974. 3. Altemus LA, and Ferguson AD: Comparative incidence of birth defects in negro and white children. Pediatrics 36: 56 – 61, 1965. 4. Wallace HM, Baumgartner L, and Rich H: Congenital 789

malformations and birth injuries in New York City. Pediatrics 12: 525–535, 1953. 5. Chavez GF, Cordero JF, and Becerra JE: Leading major congenital malformations among minority groups in the United States, 1981–1986. MMWR 37: 17–24, 1988. 6. Chung CS, and Myrianthopoulos NC: Racial and prenatal factors in major congenital malformations. Am J Hum Genet 20: 44 – 60, 1968. 7. Matlai P, and Beral V: Trends in congenital malformations of external genitalia. Lancet 1: 108, 1985. 8. Bjerkedal T, and Bakketeig LS: Surveillance of congenital malformations and other conditions of the newborn. Int J Epidemiol 4: 31–36, 1975. 9. Kallen B, and Winberg J: An epidemiologic study of hypospadias in Sweden. Acta Paediatr Scand Suppl 293: 1–52, 1982. 10. Silver RI, Rodriguez R, Chang TSK, et al: In vitro fertilization is associated with an increased risk of hypospadias. J Urol 161: 1954 –1957, 1999. 11. Czeizel A: Increasing trends in congenital malformations of male external genitalia. Lancet 1: 462– 463, 1985. 12. Paulozzi LJ, Erickson D, and Jackson RJ: Hypospadias trends in two US surveillance systems. Pediatrics 100: 831– 834, 1997. 13. Leung TJ, Baird PA, and McGillivray B: Hypospadias in British Columbia. Am J Med Genet 21: 39 – 48, 1985. 14. Fisch H, Liberson G, Cooper KL, et al: Maternal age and hypospadias rates (abstract). J Urol 163(suppl): A606, 2000. 15. Henderson BE, Bernstein L, Ross RK, et al: The early in utero oestrogen and testosterone environment of blacks and whites: potential effects on male offspring. Br J Cancer 57: 216 –218, 1988. 16. Ross R, Bernstein L, Judd H, et al: Serum testosterone levels in healthy young black and white men. J Natl Cancer Inst 70: 45– 48, 1986. 17. James WH: Causes of racial differences in testosterone levels of men. J Natl Cancer Inst 85: 506 –507, 1993. 18. Levitt SB, and Reda EF: Hypospadias. Pediatr Ann 17: 48 –57, 1988. 19. Baskin LS: Hypospadias and urethral development. J Urol 163: 951–956, 2000. EDITORIAL COMMENT Modern textbooks on urology indicate that the incidence of hypospadias is approximately 0.3%, or about 1 in 335 boys.1 Recent literature, however, indicates that the incidence of hypospadias may be increasing,2 and this report adds evidence to support that possibility. Although there was no significant difference in the incidence of hypospadias between races, the authors believe that they found an increased incidence of hypospadias in minority groups who seek care in military base hospitals. The incidence of hypospadias in all subgroups, 0.6% to 0.8%, is roughly two to three times that historically reported and approaches the incidence for cryptorchidism (0.8% at age 1 year), which is considered (at least for now) the most common birth defect of the male genitalia. Although this report is based on a large population, there are some inherent limitations to a retrospective review using birth defect registry data. Diagnostic accuracy, phenotypic variation, risk factor exposure, and family history pedigrees are difficult to assess. Despite the lack of any evidence at this time, it is also possible that some unrecognized risk factor in military families, or on military bases, might account for a small, but real, increased risk of hypospadias. Therefore, it will be interesting to see if other groups will confirm the trend observed in this report. Despite our ability to surgically repair hypospadias, the majority of cases are identified without an obvious etiology, al790

though maternal or fetal endocrine derangements are generally considered to be responsible. Multiple risk factors related to the development of isolated hypospadias have been identified. Such risk factors include impaired testosterone biosynthesis,3 5-alpha-reductase type 2 gene mutations,4 progestin exposure and/or in vitro fertilization,5 and on rare occasions even androgen receptor mutations.6 Early menarche, advanced maternal age, and subfertility also seem to be risk factors,6 perhaps because of subtle endocrine imbalances in the mother. Increasing attention is also being paid to elements in our environment, such as chemical pesticides with estrogenic activity, which may have an adverse effect on male genital embryology, fertility, and even sexual function.7 What should we learn from this study? Well, it adds to the growing body of evidence that the incidence of hypospadias is increasing in the general population or, as indicated here, certain population subgroups. This should be alarming information not only for pediatric urologists but also for potential parents. It is especially alarming to note that this change has occurred in just the past few decades. Because there seems to be no biologic advantage to being born with hypospadias, disciples of Charles Darwin might suggest that we have done something to our environment, or ourselves, to alter natural selection. Our responsibility for treating hypospadias includes more than surgical repair in the operating room. Our mission should also include a search to determine why the incidence of hypospadias is increasing so that we will have a chance to limit or reverse this trend. A combination of both clinical and basic science investigation will serve well in this regard. New developments in the laboratory, including genetic knock-outs of 5-alpha-reductase types 1 and 2 in mice, are exciting avenues for such research. It is hoped that further study will reveal more about the factors that lead to hypospadias and why this birth defect is becoming more common. If we meet that challenge, then perhaps future epidemiologic studies will report better news regarding the changing incidence of hypospadias. REFERENCES 1. Duckett JW: Hypospadias, in Walsh PC, Retik AB, Vaughan ED Jr, et al (Eds): Campbell’s Urology. Philadelphia, WB Saunders, 1998, pp 2093–2119. 2. Paulozzi LJ, Erickson D, and Jackson RJ: Hypospadias trends in two US surveillance systems. Pediatrics 100: 831– 834, 1997. 3. Aaronson IA, Cakmak MA, and Key LL: Defects of the testosterone biosynthetic pathway in boys with hypospadias. J Urol 157: 1884 –1888, 1997. 4. Silver RI, and Russell DW: 5-alpha-reductase type 2 mutations are present in some boys with isolated hypospadias. J Urol 162: 1142–1145, 1999. 5. Silver RI, Rodriguez R, Chang TSK, et al: In vitro fertilization is associated with an increased risk of hypospadias. J Urol 161: 1954 –1957, 1999. 6. Silver RI: What is the etiology of hypospadias? A review of recent research. Del Med J 72: 343–347, 2000. 7. Colborn T, Dumanoski D, and Myers JP: Our Stolen Future: Are We Threatening Our Fertility, Intelligence, and Survival? A Scientific Detective Story. New York, Penguin, 1997. Richard I. Silver, M.D. Pediatric Urology Associates Great Neck, New York PII S0090-4295(00)01106-7 © 2001, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED

UROLOGY 57 (4), 2001