A retrospective population-based cohort study to evaluate the impact of an older sibling with undescended testis and hypospadias on the known maternal and fetal risk factors for undescended testis and hypospadias in Ontario, Canada, 1997–2007. Issue 1 (February 2019) - Dave, S.
Summary: Introduction: There are several reported risk factors for undescended testis (UDT) and hypospadias (HYP). Also, a family history of UDT or HYP has not been accounted for in prior studies, and doing so may influence these independent risk estimates. Study design: A population-based retrospective cohort study was conducted using linked administrative databases in Ontario, Canada, to identify all live male newborns born between 1997 and 2007, and it was determined whether they underwent an orchidopexy or HYP repair within 5 years of birth. Baseline maternal and fetal risk factors were obtained using appropriate ICD codes. A statistical analysis using a generalized estimating equation with a logit link was performed, adjusting for clustering in mothers with a previous child born in the 5 years before the proband with UDT or HYP, to evaluate the adjusted risk factors of UDT and HYP. Results: A total of 709, 968 male infants were followed up from birth for 5 years, of which 5830 underwent an orchidopexy and 2722 had an HYP repair. On multivariable analysis, factors associated with a higher risk of UDT included prematurity, small for gestational age (SGA), associated HYP, gestational hypertension, use of assisted fertility techniques, increased maternal age, Cesarean section, previous sibling with UDT, and disorders of sexual differentiation (DSDs). After adjusting for clustering in mothers with a previous baby with UDT, DSD, associated HYP (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.0–4.1), and a previous sibling with UDT (OR, 3.6; 95% CI, 2.5–5.2) remained significant risk factors. The risk factors on multivariable analysis predicting the risk of HYP included SGA, prematurity, higher income families, and associated anomalies such as UDT. After adjusting for clustering in mothers with a previous sibling with HYP, SGA (OR, 1.8; 95% CI, 1.0–3.1), higher income families (OR, 1.5–1.6), associated UDT (OR, 7.1; 95% CI, 4.9–10.0), and a previous sibling with HYP (OR, 12.8; 95% CI, 9.1–18.1) remained significant risk factors. Discussion: Studies estimating risk factors for UDT and HYP have used variable methodologies to identify index cases and perform statistical analysis. This study suggests that having an older sibling with UDT or HYP is a significant independent risk factor. Performing an analysis adjusting for clustering in mothers with a previous child with UDT or HYP leads to loss of statistical significance for other described risk factors. Conclusion: Underlying genetic or similar environmental exposures may be a key risk factor for UDT and HYP, which confounds known maternal and fetal risk factors for these anomalies.Maternal and fetal risk factors identified on multivariable analyses for infants surgically treated for undescended testis and hypospadias in Ontario, 1997–2007. Risk factors Adjusted OR for UDT (95% confidence interval) Adjusted OR in boys with previous sibling with UDT (95% confidence interval) Adjusted OR for HYP (95% confidence interval) Adjusted OR in boys with previous sibling with HYP (95% confidence interval) Fetal risk factors Small for gestational age 1.86 (1.60–2.15)* 1.54 (0.97–2.54) 2.03 (1.65–2.49)* 1.80 (1.03–3.10)* Prematurity 1.51 (1.38–1.66)* 1.27 (0.98–1.63) 1.40 (1.22–1.61)* 1.11 (0.78–1.59) Disorder of sexual differentiation 56.41 (46.97–67.75)* 82.3 (54.4–124.5)* NA NA Prader–Willi syndrome 32.84 (22.24–48.49)* 29.18 (9.7–87.0)* NA NA Associated HYP 2.68 (2.01–3.55)* 2.04 (1.0–4.1)* NA NA Associated UDT NA NA 7.11 (6.03–8.39)* 7.09 (4.87–10.33)* Maternal risk factors Multiple gestation 0.81 (0.69–0.95) 1.11 (0.76–1.62) 0.64 (0.49–0.85) 0.70 (0.37–1.31) Gestational hypertension 1.12 (1.02–1.24)* 1.02 (0.77–1.37) – – Assisted fertility techniques 1.22 (1.03–1, 45)* 1.25 (0.76–2.04) 1.21 (0.93–1.57) 0.74 (0.33–1.68) Cesarean section 1.13 (1.06–1.19)* 1.06 (0.92–1.23) NA NA Age <20 Ref Ref Ref Ref 20–29 1.21 (1.04–1.40)* 1.32 (0.70–2.49) 1.04 (0.86–1.27) 0.92 (0.46–1.86) 30–39 1.18 (1.02–1.37)* 1.39 (0.74–2.63) 0.97 (0.80–1.19) 0.81 (0.40–1.62) 40+ 1.18 (0.96–1.45) 1.34 (0.65–2.80) 0.71 (0.52–0.97) 0.72 (0.23–1.71) Income quintile 1 Ref Ref Ref Ref 2 1.02 (0.94–1.11) 1.06 (0.88–1.29) 1.01 (0.90–1.14) 1.10 (0.82–1.48) 3 1.03 (0.95–1.12) 1.02 (0.84–1.24) 1.07 (0.95–1.21) 1.53 (1.17–2.01)* 4 1.13 (1.04–1.23)* 1.04 (0.85–1.26) 1.14 (1.01–1.28)* 1.53 (1.17–2.02)* 5 1.04 (0.95–1.13) 0.95 (0.78–1.18) 1.22 (1.08–1.38)* 1.63 (1.23–2.16)* Previous sibling with UDT 3.48 (2.45–4.94)* 3.59 (2.51–5.16)* NA NA Previous sibling with HYP NA NA NA 12.85 (9.12–18.12)* *p value < 0.05. HYP, hypospadias; NA, not assessed; OR, odds ratio; UDT, undescended testis.