Children’s Health Article Maternal and Paternal Risk Factors for Cryptorchidism and Hypospadias: A Case–Control Study in Newborn Boys Frank H. Pierik,1,2 Alex Burdorf,2 James A. Deddens,3 Rikard E. Juttmann,2,4 and Rob F.A. Weber 1 1Department of Andrology and 2Department of Public Health, Erasmus MC, Rotterdam, the Netherlands; 3Department of Mathematical Sciences, University of Cincinnati, Cincinnati, Ohio, USA; 4Department of Child Health Care, Rotterdam Homecare Foundation, Rotterdam, the Netherlands Little is known on environmental risk factors for cryptorchidism and hypospadias, which are among the most frequent congenital abnormalities. The aim of our study was to identify risk fac- tors for cryptorchidism and hypospadias, with a focus on potential endocrine disruptors in parental diet and occupation. In a case–control study nested within a cohort of 8,698 male births, we compared 78 cryptorchidism cases and 56 hypospadias cases with 313 controls. The participa- tion rate was 85% for cases and 68% for controls. Through interviews, information was collected on pregnancy aspects and personal characteristics, lifestyle, occupation, and dietary phytoestrogen intake of both parents. Occupational exposure to potential endocrine disruptors was classified based on self-reported exposure and ratings of occupational hygienists based on job descriptions. Our ﬁndings indicate that paternal pesticide exposure was associated with cryptorchidism [odds ratio (OR) = 3.8; 95% conﬁdence interval (95% CI), 1.1–13.4]. Smoking of the father was associ- ated with hypospadias (OR = 3.8; 95% CI, 1.8–8.2). Maternal occupational, dietary, and lifestyle exposures were not associated with either abnormality. Both abnormalities were associated with suboptimal maternal health, a lower maternal education, and a Turkish origin of the parents. Being small for gestational age was a risk factor for hypospadias, and preterm birth was a risk fac- tor for cryptorchidism. Because paternal pesticide exposure was signiﬁcantly associated with cryp- torchidism and paternal smoking was associated with hypospadias in male offspring, paternal exposure should be included in further studies on cryptorchidism and hypospadias risk factors. Key words: children, cryptorchidism, endocrine disruptor, environment, epidemiology, hypo- spadias, nutrition, occupational exposure, testis. Environ Health Perspect 112:1570–1576 (2004). doi:10.1289/ehp.7243 available via http://dx.doi.org/ [Online 3 September 2004] Cryptorchidism and hypospadias are among the most frequent congenital abnormalities in male births. Cryptorchidism (maldescent of the testis) is observed in 1–5% of full-term male births (Toppari et al. 1996) and is a risk factor for subfertility and testicular cancer. Hypospadias (abnormal location of the oriﬁce of the urethra) is observed in 0.3–0.7% of male births and requires surgical treatment in most cases (Pierik et al. 2002). In the past two decades, concern has been raised over a possible increase in disorders of the male reproductive tract, including cryp- torchidism, hypospadias, testicular cancer, and impaired semen quality. It has been suggested that these disorders are interrelated and share a common etiology during fetal life, described by Skakkebaek and colleagues as the testicular dysgenesis syndrome (TDS) (Sharpe and Skakkebaek 1993; Skakkebaek et al. 2001). Fetal exposure to endocrine disruptors (EDs) with estrogen-like or antiandrogen-like activ- ity has been suggested as a cause for TDS (Sharpe 2003; Sharpe and Skakkebaek 1993). Various groups of chemicals, including pesti- cides and phthalate esters, have been identiﬁed as being weakly estrogenic or antiandrogenic (Sharpe 2003). These chemicals may occur in working environments, drinking water, and food (Toppari et al. 1996). Humans can also be exposed to natural phytoestrogens, through 1570 consumption of food products derived from plants (Toppari et al. 1996). There is only limited evidence that the suggested increase in male urogenital abnor- malities in humans can be attributed to expo- sure to EDs (Sharpe 2003) or environmental chemicals in general. An excess of hypospadias has been reported among newborns in popu- lations living within 2–3 km of landfill sites (Dolk et al. 1998; Elliott et al. 2001). These findings may indicate an effect of chemical wastes, but exposure classification was too crude to differentiate this exposure from con- founding factors (Dolk et al. 1998; Elliott et al. 2001). In contrast, no association was observed between hypospadias and occupational expo- sure to EDs by the mother during pregnancy (Vrijheid et al. 2003). A maternal vegetarian diet during pregnancy has been associated with hypospadias in the offspring, suggesting a role of a higher intake of phytoestrogens (North and Golding 2000). Although several studies have demonstrated male-mediated develop- mental effects of environmental exposure (Davis et al. 1992; Robaire and Hales 2003), its role in the etiology of cryptorchidism and hypospadias remains unclear. The aim of the present study was to evaluate the role of maternal and paternal occupational and dietary exposures to potential EDs in the occurrence of cryptorchidism and hypospadias. Materials and Methods Design and participants. We conducted a nested case–control study within a large cohort of newborn boys in the city of Rotterdam. This cohort consisted of newborns who were examined at their ﬁrst visit to child health care centers (CHCs). In the Netherlands, CHCs are notiﬁed of live births within 2 days after registration in the municipal birth register. CHCs invite all parents to participate free of charge in the nationwide preventive child health care program, including growth moni- toring and vaccination. From 1 October 1999 to 31 December 2001, 9,146 male births were registered, of which 8,695 boys (95%) were examined by CHC physicians at a median age of 34 days (5th and 95th percentiles, 25 and 105 days, respectively). CHC physicians (n = 30) were trained in a standardized genital examination by a pediatric urologist and a pediatric endocrinologist during a workshop. In addition, all CHC physicians received writ- ten instruction on the genital examination pro- cedure. During the course of the study, new CHC physicians were instructed on the stan- dardized examination, and every 6 months a meeting with the CHC physicians, researchers, and expert pediatricians was organized to refresh the CHC physicians on the procedures. Boys were diagnosed as cryptorchid if one or both testes were nonpalpable or if they could not be manipulated to a stable position at the bottom of the scrotum (de Muinck Keizer- Schrama 1987). Hypospadias was deﬁned as a displacement of the urethral meatus from the tip of the glans penis to the ventral side of the phallus, scrotum, or perineum (Pierik et al. 2002). All 91 cases of cryptorchidism (1.1%) and 67 cases of hypospadias (0.8%) that were identiﬁed by CHC physicians were eligible for the case–control study, of which four cases had Address correspondence to F.H. Pierik, Department of Public Health, Erasmus MC, University Medical Center Rotterdam, Dr Molewaterplein 50, NL-3015 GE Rotterdam, The Netherlands. Telephone: 31- 10-4087448. Fax: 31-10-4089449. E-mail: f.pierik@ erasmusmc.nl The Endocrine Modulators Study Group of the European Chemical Industry Council and the Nutricia Research Foundation are acknowledged for ﬁnancial support. The sponsors of the study had no role in study design, data collection, data interpreta- tion, or reporting. The authors declare they have no competing ﬁnancial interests. Received 10 May 2004; accepted 18 August 2004. VOLUME 112 | NUMBER 15 | November 2004 • Environmental Health Perspectives