Maternal and Gestational Risk Factors for Hypospadias
Maternal and Gestational Risk Factors for Hypospadias
Objectives: Our goal was to assess the association between risk of hypospadias and indicators of placental function and endogenous hormone levels, exposure to exogenous hormones, maternal diet during pregnancy, and other environmental factors.
Methods: We conducted a case–control study in Sweden and Denmark from 2000 through 2005 using self-administered questionnaires completed by mothers of hypospadias cases and matched controls. The response rate was 88% and 81% among mothers of cases and controls, respectively. The analyses included 292 cases and 427 controls.
Results: A diet during pregnancy lacking both fish and meat was associated with a more than 4-fold increased risk of hypospadias [odds ratio (OR) = 4.6; 95% confidence interval (CI), 1.6–13.3]. Boys born to obese [body mass index (BMI) ≥ 30] women had a more than 2-fold increased risk of hypospadias (OR = 2.6; 95% CI, 1.2–5.7) compared with boys born to mothers with a normal weight (BMI = 20–24) . Maternal hypertension during pregnancy and absence of maternal nausea increased a boy's risk of hypospadias 2.0-fold (95% CI, 1.1–3.7) and 1.8-fold (95% CI, 1.2–2.8), respectively. Nausea in late pregnancy also appeared to be positively associated with hypospadias risk (OR = 7.6; 95% CI, 1.1–53).
Conclusions: A pregnancy diet lacking meat and fish appears to increase the risk of hypospadias in the offspring. Other risk associations were compatible with a role for placental insufficiency in the etiology of hypospadias.
Hypospadias is a male birth defect in which the urethral orifice is abnormally located on the ventral side of the penis. In Western countries, the prevalence of hypospadias varies from 2 to 8 cases per 1,000 live births, with increases in prevalence reported over time in several populations (Czeizel et al. 1986; Kallen and Winberg 1982; Nelson et al. 2005; Paulozzi 1999; Paulozzi et al. 1997; Pierik et al. 2002). Although we know that urethral development, occurring during gestational weeks 7–16, is regulated by androgens, the causes of most hypospadias cases are unknown (Baskin and Ebbers 2006). Hypospadias is only rarely a monogenic trait (Fredell et al. 2002). Several gene defects, including defects in genes coding for the androgen receptor, are associated with hypospadias but account for only a small proportion of cases (Nelson et al. 2005).
Reported associations between hypospadias and low birth weight, preterm birth, and signs of preeclampsia (Akre et al. 1999; Aschim et al. 2004; Boisen et al. 2005; Hussain et al. 2002; Main et al. 2006) indicate that placental malfunction and subsequent abnormalities in hormone regulation and/or the provision of nutrients to the fetus may play a role in the maldevelopment of the urethra. Increases in prevalence, as reported by several investigators (Paulozzi 1999; Paulozzi et al. 1997; Pierik et al. 2002; Toppari et al. 2001), also point to the involvement of environmental determinants. To date, only a few studies have reported positive associations between hypospadias and environmental exposures, but reports of links with prenatal exposure to diethylstilbestrol (Brouwers et al. 2006; Klip et al. 2002) and exogenous progestins (Carmichael et al. 2005a), as well as of increased risk associated with maternal vegetarian diet (North and Golding 2000), are of interest. With the results of these previous studies in mind, in the present case–control study we investigated the relationships between hypospadias risk and maternal diet, exposure to exogenous hormones, and exposures thought to reflect placental function.
Objectives: Our goal was to assess the association between risk of hypospadias and indicators of placental function and endogenous hormone levels, exposure to exogenous hormones, maternal diet during pregnancy, and other environmental factors.
Methods: We conducted a case–control study in Sweden and Denmark from 2000 through 2005 using self-administered questionnaires completed by mothers of hypospadias cases and matched controls. The response rate was 88% and 81% among mothers of cases and controls, respectively. The analyses included 292 cases and 427 controls.
Results: A diet during pregnancy lacking both fish and meat was associated with a more than 4-fold increased risk of hypospadias [odds ratio (OR) = 4.6; 95% confidence interval (CI), 1.6–13.3]. Boys born to obese [body mass index (BMI) ≥ 30] women had a more than 2-fold increased risk of hypospadias (OR = 2.6; 95% CI, 1.2–5.7) compared with boys born to mothers with a normal weight (BMI = 20–24) . Maternal hypertension during pregnancy and absence of maternal nausea increased a boy's risk of hypospadias 2.0-fold (95% CI, 1.1–3.7) and 1.8-fold (95% CI, 1.2–2.8), respectively. Nausea in late pregnancy also appeared to be positively associated with hypospadias risk (OR = 7.6; 95% CI, 1.1–53).
Conclusions: A pregnancy diet lacking meat and fish appears to increase the risk of hypospadias in the offspring. Other risk associations were compatible with a role for placental insufficiency in the etiology of hypospadias.
Hypospadias is a male birth defect in which the urethral orifice is abnormally located on the ventral side of the penis. In Western countries, the prevalence of hypospadias varies from 2 to 8 cases per 1,000 live births, with increases in prevalence reported over time in several populations (Czeizel et al. 1986; Kallen and Winberg 1982; Nelson et al. 2005; Paulozzi 1999; Paulozzi et al. 1997; Pierik et al. 2002). Although we know that urethral development, occurring during gestational weeks 7–16, is regulated by androgens, the causes of most hypospadias cases are unknown (Baskin and Ebbers 2006). Hypospadias is only rarely a monogenic trait (Fredell et al. 2002). Several gene defects, including defects in genes coding for the androgen receptor, are associated with hypospadias but account for only a small proportion of cases (Nelson et al. 2005).
Reported associations between hypospadias and low birth weight, preterm birth, and signs of preeclampsia (Akre et al. 1999; Aschim et al. 2004; Boisen et al. 2005; Hussain et al. 2002; Main et al. 2006) indicate that placental malfunction and subsequent abnormalities in hormone regulation and/or the provision of nutrients to the fetus may play a role in the maldevelopment of the urethra. Increases in prevalence, as reported by several investigators (Paulozzi 1999; Paulozzi et al. 1997; Pierik et al. 2002; Toppari et al. 2001), also point to the involvement of environmental determinants. To date, only a few studies have reported positive associations between hypospadias and environmental exposures, but reports of links with prenatal exposure to diethylstilbestrol (Brouwers et al. 2006; Klip et al. 2002) and exogenous progestins (Carmichael et al. 2005a), as well as of increased risk associated with maternal vegetarian diet (North and Golding 2000), are of interest. With the results of these previous studies in mind, in the present case–control study we investigated the relationships between hypospadias risk and maternal diet, exposure to exogenous hormones, and exposures thought to reflect placental function.
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