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Olof Akre,¹ Heather A. Boyd,² Martin Ahlgren,² Kerstin Wilbrand,^1,3 Tine Westergaard,² Henrik Hjalgrim,² Agneta Nordenskjöld,^4,5 Anders Ekbom,¹ and Mads Melbye²

¹Clinical Epidemiology Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden; ²Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark; ³Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden; ⁴Department of Molecular Medicine and Surgery, and ⁵Division of Pediatric Surgery, Department of Women and Child Health, Karolinska Institutet, Stockholm, Sweden

Abstract
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.

Key words: birth weight, body mass index, diet, hypertension, hypospadias, pregnancy, risk. Environ Health Perspect 116:1071–1076 (2008) . doi:10.1289/ehp.10791 available via http://dx.doi.org/ [Online 9 April 2008]

Address correspondence to O. Akre, Karolinska Institutet, Clinical Epidemiology Unit, Karolinska University Hospital, Solna M9:01, SE-171 76 Stockholm. Telephone: 46-8-5177-9324. Fax: 46-8-5177-9304. E-mail: olof.akre@ki.se.

We thank G. Läckgren and A. Stenberg for their valuable contributions in identifying case patients.

This study was funded by a grant from the European Chemical Industry Council. The European Chemical Industry Council had no role in the design or conduct of the study ; in the collection, management, analysis, or interpretation of the data ; or in the preparation, review, or approval of the manuscript.

The authors declare they have no competing financial interests.

Received 22 August 2007 ; accepted 8 April 2008.