Hypospadias Rates in New York State are Not Increasing

Harry Fisch, Sarah M. Lambert, Terry W. Hensle and Grace HyunFrom the New York Presbyterian Hospital (HF) and Children’s Hospital of New York (TWH, GH), Columbia University Medical Center,New York, New York, and Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania (SML)

Purpose: The testicular dysgenesis syndrome describes urogenital abnormalitiesassociated with exposure to environmental endocrine disruptors such as phtha-lates, specifically decreased semen quality, and increased rates of testis cancerand hypospadias. Recently there has been concern that these abnormalitiesdescribed in animal studies may also be present in humans. To determine ifhypospadias rates are increasing, we retrospectively reviewed the total preva-lence of hypospadias in New York State from 1992 to 2005, categorized bymaternal age younger than 35 years and 35 years or older.Materials and Methods: Hypospadias rates were obtained from the New YorkState Congenital Malformations Registry from 1992 to 2005. An analysis wasalso performed on the rates of children with hypospadias who had mothersyounger than 35 years and mothers 35 years or older. This investigation wasapproved by the Columbia University internal review board.Results: There was no statistical change in hypospadias rates in New York Statefrom 1992 to 2005 (r � 0.127, p � 0.6). Overall the mean � SE prevalence rate was34.9 � 0.36 per 10,000 live births. However, mean � SE hypospadias rates inchildren of mothers 35 years old or older (38.7 � 0.7) were significantly greater thanthose in children of mothers younger than 35 years (34.1 � 0.386, t test p �0.01).Conclusions: Hypospadias rates have not changed in New York State from 1992to 2005. Additionally advanced maternal age continues to be a risk factor forhypospadias. Combined with previous studies that demonstrate sperm counts arenot declining, these data suggest that the testicular dysgenesis syndrome de-scribed in animal models may not be evident in humans.

Key Words: epidemiology, gonadal dysgenesis, hypospadias, pediatrics,

Abbreviations

and Acronyms

NYS � New York State

Submitted for publication September 13,2009.

Study received Columbia University internalreview board approval.

phthalic acids

RECENTLY there has been considerablediscussion regarding the potentialdeleterious effects of endocrine dis-ruptors such as phthalates on malereproductive health. Phthalate estersare plasticizers currently used in vi-nyl floors, food wraps, cosmetics, med-ical products and toys. Much of theconcern focuses on allegedly signifi-cant in utero exposure to these endo-crine disruptors and the effects on thedeveloping fetus. Some animal stud-

ies have shown increased risks of uro-

0022-5347/09/1815-2291/0THE JOURNAL OF UROLOGY®

Copyright © 2009 by AMERICAN UROLOGICAL ASSOCIATION

genital anomalies including hypospa-dias in the presence of relatively highlevels of in utero exposure to certaincompounds. Considerable controversyexists over claims that similar typesof anomalies can be produced by lev-els of these compounds resulting fromcasual exposure to various plastics inthe environment. As a result, somelegislatures are now considering lawsto ban phthalates and certain otherendocrine disruptors. Thus, it is im-

perative that the scientific basis for

Vol. 181, 2291-2294, May 2009Printed in U.S.A.

DOI:10.1016/j.juro.2009.01.059www.jurology.com 2291

HYPOSPADIAS RATES IN NEW YORK STATE2292

claims of damage from these compounds be firmlyestablished.

Those who support the hypothesis that phtha-lates and other alleged endocrine disruptors are po-tentially harmful have indicated the presence of thetesticular dysgenesis syndrome, a triad of urogenitalabnormalities that includes increased hypospadias,decreased sperm counts and increased testicularcancer. However, the current evidence suggests thathuman sperm counts are not declining, and in iso-lated areas where a decline has been noted no asso-ciation has been found between these declines andany type of endocrine disruptor.1,2

Given the weaknesses in the evidence for declin-ing sperm counts, it is particularly important toassess the strength of the evidence for the allegedincrease in hypospadias rates. This report summa-rizes some of the evidence to date and adds an im-portant inclusion of newer data. Together these datafail to support the alleged increase in hypospadiasrates and, therefore, invalidate 1 of the 3 compo-nents comprising the testicular dysgenesis syn-drome.

To determine if hypospadias rates are increasing,we retrospectively reviewed the New York StateCongenital Malformations Registry from 1992 to2005. In addition to evaluating the rates of hypos-padias, we report the effect of advanced maternalage (35 years or older), since maternal age has beenobserved to be a risk factor for hypospadias.

MATERIALS AND METHODS

The prevalence of hypospadias per 10,000 live births wasobtained from the New York State Congenital Malforma-tions Registry from 1992 to 2005. Birth defects refer tocongenital anomalies, as identified by codes 740 to 759 ofthe International Classification of Diseases, 9th revision.Hypospadias is identified by code 752.6. The registry in-cludes only live births, and 12,764 births were reported.

Hypospadias prevalence in NYS from

Most of the reported data for incidence include childrendiagnosed after age 2 weeks and before age 2 months.

Pearson’s correlation coefficient was used to determinethe direction and magnitude of change. A Poisson modelwas fitted to the data using maternal age and year ofbirth, from which relative rates were calculated. A t testwas used to compare mean hypospadias rates by maternalage. A p value of �0.05 was used to determine signifi-cance.

RESULTS

There was no statistical change in hypospadiasrates in NYS from 1992 to 2005 (r � 0.127, p � 0.6).Overall the mean � SE prevalence rate was 34.9 �0.36 per 10,000 live births. However, mean � SEhypospadias rates among children of mothers 35years old or older were significantly greater (38.7 �0.7) compared to those in children of mothersyounger than 35 years (34.1 � 0.386, t test p �0.01,see figure).

DISCUSSION

Prior data obtained from the NYS Congenital Mal-formations Registry from 1983 to 1995 revealed astandardized prevalence of hypospadias of 36.34 per10,000 live births in 1983 and no significant changein prevalence throughout the study period. In com-bination with our current data demonstrating a sta-ble mean � SE hypospadias prevalence of 34.9 �0.36 per 10,000 live births from 1992 to 2005 thesenew data now confirm a stable rate of hypospadiasspanning a period of 22 years.3 Similarly data fromWashington State evaluating the prevalence of hy-pospadias documented that the rate in 2002 (5.0cases per 1,000 male births) was not significantlydifferent from that in 1987.4 Furthermore, Car-michael et al, who studied the rates of hypospadiasin California from 1984 to 1997, determined thatrates did not increase during the 13-year period.5

1992 to 2005 by maternal age

HYPOSPADIAS RATES IN NEW YORK STATE 2293

This stable trend in hypospadias rates has alsobeen documented in the United Kingdom. A linkedregister of congenital urogenital anomalies in Scot-land documented that from 1988 to 1997 the rateremained unchanged.6 In this registry hypospadiasconstituted 73% of the genital anomalies evaluated.Although the prevalence of hypospadias did notchange significantly, the authors noted an associa-tion between hypospadias and small size for gesta-tional age (OR 1.43, p �0.001), higher socioeconomicstatus (OR 0.73, p �0.01 for low socioeconomic sta-tus) and increased maternal age (OR 1.2, p �0.05).Finally Dolk et al studied the prevalence of hypos-padias from 1980 to 1999 in 20 regions of Europewith European Surveillance of Congenital Anoma-lies population based registers, as well as from theEngland and Wales National Congenital AnomalySystem.7 Their results did not suggest a continua-tion of trends of increasing hypospadias prevalencein Europe.

Advanced maternal age has consistently been rec-ognized as a risk factor for hypospadias and othercongenital anomalies. A review of the MetropolitanAtlanta Congenital Defects Program by the Centersfor Disease Control and Prevention included1,050,616 singleton infants born at 20 weeks of ges-tation or later in the 5 counties of metropolitanAtlanta from 1968 through 2000, who did not have achromosomal abnormality and whose mother was 14to 40 years old.8 This evaluation showed an in-creased risk of all heart defects, tricuspid atresia,right outflow tract defects, hypospadias second de-gree or higher, male genital defects excluding hypo-spadias and craniosynostosis in women 35 to 40years old. Interestingly among the congenital anom-alies evaluated male offspring born to women ofadvanced maternal age were at greatest risk forhypospadias.

This association between advanced maternal ageand increased risk of hypospadias is also docu-mented in data from New York State based on thecurrent study and an investigation of the New YorkState Department of Health and California BirthDefects Monitoring Program (1983 to 1996).9 Eval-uation during the earlier period correlates with cur-rent data revealing a significant association betweenadvanced maternal age and hypospadias, especiallyin cases of severe hypospadias. While the associationbetween advanced maternal age and congenital de-fects, especially hypospadias, is consistent throughtime and for a variety of geographic locations, theunderlying causes for this association remain un-clear.

The weight of available evidence strongly refutesclaims for region wide increases in hypospadiasrates. The hypothesis for a link between hypospa-

dias and endocrine disruptors is based primarily on

animal studies, which have documented an in-creased risk of hypospadias in concert with exposureto high levels of endocrine disruptors. Gray et aldemonstrated that in utero exposure to antiandro-gens or phthalate esters in Sprague-Dawley ratsresulted in reduced anogenital distance, retainednipples, hypospadias, undescended testes, a vaginalpouch, epididymal agenesis and small to absent sexaccessory glands in male offspring in comparison tounexposed controls.10 Vilela et al examined hypo-spadias rates in pregnant mice exposed to genistein(a phytoestrogen) and vinclozolin (a fungicide) incomparison to controls.11 They identified no hypo-spadias in the control group, although the rates ofhypospadias in exposed mice were 25% withgenistein alone, 42% with vinclozolin alone, and 41%with genistein and vinclozolin together.

These data have led some investigators to suggestthat exposure to even low levels of phthalates andother alleged endocrine disruptors could have anadverse effect on male fetal development. An evalu-ation of women participating in the Avon Longitu-dinal Study of Pregnancy and Childhood identified51 cases of hypospadias in a total of 7,928 boys bornduring the study period. Interestingly significantdifferences were detected in women who consumed avegetarian diet or supplemented their diet with ironduring the first half of pregnancy. Specificallywomen who consumed a vegetarian diet in preg-nancy had an adjusted OR of 4.99 (95% CI, 2.10–11.88) of giving birth to a boy with hypospadias incomparison to omnivores who did not supplementtheir diet with iron.12 These results raise the possi-bility that endocrine disruptors such as phytoestro-gens or pesticides, which can be increased in quan-tity in the vegetarian diet, may adversely affect thedeveloping male reproductive system.

CONCLUSIONS

Hypospadias rates have not changed in New YorkState from 1992 to 2005. When combined with hy-pospadias rates in NYS from 1983 to 1995 there isno evidence of any overall change in rates during the22-year period. Additionally advanced maternal agecontinues to be a risk factor for hypospadias. Al-though effects of endocrine disruptors in the devel-opment of hypospadias in mouse models have beendocumented, these epidemiological data refute claimsof an increasing prevalence of hypospadias in hu-mans. The effects of endocrine disruptors such asphthalates on human development have yet to beelucidated fully and require further investigation.The stable prevalence of hypospadias suggests thatalleged deleterious effects of endocrine disruptors onthe rate of hypospadias described in animal models

may not be evident in humans.

HYPOSPADIAS RATES IN NEW YORK STATE2294

REFERENCES

1. Saidi JA, Chang DT, Goluboff ET, Bagiella E,Olsen G and Fisch H: Declining sperm counts inthe United States? A critical review. J Urol 1999;161: 460.

2. Fisch H: Declining worldwide sperm counts: dis-proving a myth. Urol Clin North Am 2008; 35: 137.

3. Choi J, Cooper KL, Hensle TW and Fisch H:Incidence and surgical repair rates of hypospa-dias in New York State. Urology 2001; 57: 151.

4. Porter MP, Faizan MK, Grady RW and MuellerBA: Hypospadias in Washington State: maternalrisk factors and prevalence trends. Pediatrics2005; 115: e495.

5. Carmichael SL, Shaw GM, Nelson V, Selvin S, Torfs

CP and Curry CJ: Hypospadias in California: trends

and descriptive epidemiology. Epidemiology 2003;14: 701.

6. Ahmed SF, Dobbie R, Finlayson AR, Gilbert J,Youngson G, Chalmers J et al: Prevalence ofhypospadias and other genital anomalies amongsingleton births, 1988 –1997, in Scotland. ArchDis Child Fetal Neonatal Ed 2004; 89: F149.

7. Dolk H, Vrijheid M, Scott JE, Addor MC, BottingB, de Vigan C et al: Toward the effective surveil-lance of hypospadias. Environ Health Perspect2004; 112: 398.

8. Reefhuis J and Honein MA: Maternal age andnon-chromosomal birth defects, Atlanta—1968 –2000: teenager or thirty-something, who is atrisk? Birth Defects Res A Clin Mol Teratol 2004;

70: 572.

9. Fisch H, Golden RJ, Libersen GL, Hyun GS, Mad-sen P, New MI et al: Maternal age as a riskfactor for hypospadias. J Urol 2001; 165: 934.

10. Gray LE Jr, Ostby J, Furr J, Price M, Veera-machaneni DN and Parks L: Perinatal exposure tothe phthalates DEHP, BBP, and DINP, but notDEP, DMP, or DOTP, alters sexual differentiationof the male rat. Toxicol Sci 2000; 58: 350.

11. Vilela ML, Wilingham E, Buckley J, Liu BC, AgrasK, Shiroyanagi Y et al: Endocrine disruptors andhypospadias: role of genistein and the fungicidevinclozolin. Urology 2007; 70: 618.

12. North K and Golding J: A maternal vegetariandiet in pregnancy is associated with hypospadias.The ALSPAC Study Team. Avon LongitudinalStudy of Pregnancy and Childhood. BJU Int 2000;

85: 107.