title: Hypospadias: risk factor patterns and different phenotypes.
abstract: OBJECTIVE
  To obtain more insight into the origin of hypospadias by exploring a wide range of potential risk factors in a case-referent study in which a distinction was made between different phenotypes.
  
  
  METHODS
  Cases and referents were 305 boys with hypospadias and 629 boys with middle ear effusion whose parents completed postal questionnaires. Hypospadias phenotype was classified as distal (195 boys), middle (67), and proximal (43). Adjusted odds ratios (OR) with 95% confidence intervals (CI) were estimated using logistic regression.
  
  
  RESULTS
  Low birth weight, being a twin or triplet, mother being a diethylstilbestrol-daughter, fertility treatments, paternal subfertility, obesity, prescriptive drug use, and familial occurrence of hypospadias or testicular cancer were associated with hypospadias in general. For familial occurrence of hypospadias, there were high risk estimates for the distal and middle phenotypes with an OR (95%CI) of 10.4 (4.5-24.1) and 9.0 (3.1-26.0), but not for the proximal type at 1.8 (0.2-14.9). By contrast, the association with low birth weight (a proxy for placental dysfunction) seemed much stronger for proximal hypospadias with an OR (95%CI) of 9.1 (3.4-24.2) compared with distal and middle hypospadias at 2.6 (1.4-5.0) and 2.3 (0.8-6.5). There were similar estimates for pre-eclampsia.
  
  
  CONCLUSIONS
  These findings indicate aetiological heterogeneity of hypospadias and provide indications for the possible mechanisms through which specific risk factors may interfere with penile development.
authors.affiliation: Department of Epidemiology, Biostatistics, and HTA, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. m.brouwers@medzaken.umcn.nl
authors.forename: Marijn M
authors.initials: MM
authors.lastname: Brouwers
authors.forename: Loes F M
authors.initials: LF
authors.lastname: van der Zanden
authors.forename: Robert P E
authors.initials: RP
authors.lastname: de Gier
authors.forename: Evert J
authors.initials: EJ
authors.lastname: Barten
authors.forename: Gerhard A
authors.initials: GA
authors.lastname: Zielhuis
authors.forename: Wouter F J
authors.initials: WF
authors.lastname: Feitz
authors.forename: Nel
authors.initials: N
authors.lastname: Roeleveld
mesh_terms: D016022:Case-Control Studies; D002675:Child, Preschool; D004054:Diethylstilbestrol / Q000009:adverse effects; D020022:Genetic Predisposition to Disease; D006801:Humans; D007021:Hypospadias / Q000209:etiology*; D007223:Infant; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D007248:Infertility, Male / Q000150:complications; D008297:Male; D009765:Obesity / Q000150:complications; D010641:Phenotype; D012307:Risk Factors; D011795:Surveys and Questionnaires; D014310:Triplets; D014427:Twins
chemical_list: D004054:Diethylstilbestrol