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Epidemiology:
doi: 10.1097/EDE.0000000000000014
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Gestational Diabetes and the Risk of Cryptorchidism and Hypospadias

Trabert, Britton; Chodick, Gabriel; Shalev, Varda; Sella, Tal; Longnecker, Matthew P.; McGlynn, Katherine A.

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Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, britton.trabert@nih.gov

Medical Division, Maccabi Healthcare Services, Tel Aviv, Israel, Sackler Faculty of Tel-Aviv University, Tel Aviv, Israel

Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD

Support for this research was provided, in part, by the Intramural Research Programs of the National Cancer Institute and the National Institute of Environmental Health Sciences of the National Institutes of Health (NIH).

The authors report no conflicts of interest.

Supplemental digital content is available through direct URL citations in the HTML and PDF versions of this article (www.epidem.com). This content is not peer-reviewed or copy-edited; it is the sole responsibility of the author.

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To the Editor:

Gestational diabetes mellitus is the onset of glucose intolerance during pregnancy. Pregnancies complicated with diabetes are at increased risk for many maternal and fetal complications, including cesarean delivery, macrosomia, neonatal hypoglycemia, stillbirth, shoulder dystocia, and congenital malformations.1 However, few epidemiologic studies have evaluated associations between gestational diabetes and the risk of cryptorchidism (failure of one or both testicles to descend into the scrotum) or hypospadias (urethral opening on the ventral side of the penis). Shared risk factors for cryptorchidism and hypospadias include intrauterine growth restriction (small for gestational age), low birth weight, preterm delivery, and concomitant genital abnormalities. These two defects are commonly associated with testicular cancer risk in adult life2; thus, gaining a better understanding of their etiology that may provide new means of identifying men at risk of developing testicular cancer.

In Israel, universal gestational diabetes screening is conducted in accordance with American Diabetes Association guidelines, and approximately 90% of the pregnancies in the Maccabi Healthcare Services healthcare maintenance organization (HMO) between 2000 and 2010 were screened.3 Using administrative and clinical data, we conducted a population-based retrospective cohort study in this HMO to evaluate the association between gestational diabetes and two common male congenital anomalies, cryptorchidism and hypospadias, in male offspring.

Details on the study methods and characteristics of the study cohort are provided in the eAppendix (http://links.lww.com/EDE/A737) and the eTable (http://links.lww.com/EDE/A737). Associations between gestational diabetes and the risk of cryptorchidism and hypospadias were estimated separately, using unconditional logistic regression analyses adjusting for year of birth, maternal age at oral glucose tolerance test, maternal birthplace, socioeconomic status, history of infertility, use of in vitro fertilization, and history of polycystic ovarian syndrome.

The study included 150,144 mother-infant pairs. The frequency of diabetes was 40.3 per 1000 pregnancies; 3649 cases of cryptorchidism (24.2 per 1000 male births) and 2342 cases of hypospadias (15.6 per 1000 male births) were identified. Maternal diabetes was not associated with cryptorchidism (odds ratio = 0.93 [95% confidence interval = 0.77–1.10]) or hypospadias (0.83 [0.66–1.04]) (Table). Furthermore, among male children of mothers with gestational diabetes (n = 5,497), neither of the indices of diabetes severity (number of abnormal glucose tolerance test values and the use of insulin during pregnancy) was associated with the risk of either anomaly (Table).

TABLE. Risk of Crypt...
TABLE. Risk of Crypt...
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The current retrospective cohort study does not support an association of gestational diabetes with cryptorchidism or hypospadias. Consistent with our study, a Swedish registry-based study (1973–1982) reported no association between gestational diabetes and cryptorchidism.4 In contrast, one case-control study reported a positive association between gestational diabetes, diagnosed based on medical record reports of diet-controlled diabetes or abnormal glucose tolerance test, and cryptorchidism.5 However, that study was based on relatively small numbers (125 cases), and only 30% of cases and 22% of controls had a glucose tolerance test during pregnancy. In the current study, all pregnancies included in the analysis were screened for gestational diabetes mellitus and approximately 90% of pregnancies in the MHS HMO during the study time period were screened.3 We are aware of three previous studies that evaluated the association of gestational diabetes with hypospadias and, consistent with our results, all reported a null association.6–8

An important strength of the current study is the direct ascertainment of gestational diabetes based on laboratory glucose tolerance tests, avoiding issues concerning self-report and inconsistent diagnostic criteria. Additional strengths of the study include its large size, retrospective cohort design, and the systematic and comprehensive collection of personal data. The study adds persuasive evidence that gestational diabetes is not associated with the risk of cryptorchidism or hypospadias.

Britton Trabert

Division of Cancer Epidemiology and Genetics

National Cancer Institute

National Institutes of Health

Bethesda, MD

britton.trabert@nih.gov

Gabriel Chodick

Varda Shalev

Tal Sella

Medical Division

Maccabi Healthcare Services

Tel Aviv, Israel

Sackler Faculty of Tel-Aviv University

Tel Aviv, Israel

Matthew P. Longnecker

Epidemiology Branch

National Institute of Environmental Health Sciences

National Institutes of Health

Research Triangle Park, NC

Katherine A. McGlynn

Division of Cancer Epidemiology and Genetics

National Cancer Institute

National Institutes of Health

Bethesda, MD

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REFERENCES

1. Jiwani A, Marseille E, Lohse N, Damm P, Hod M, Kahn JG. Gestational diabetes mellitus: results from a survey of country prevalence and practices. J Matern Fetal Neonatal Med. 2012;25:600–610

2. Trabert B, Zugna D, Richiardi L, McGlynn KA, Akre O. Congenital malformations and testicular germ cell tumors. Int J Cancer. 2013;133:1900–1904

3. Sella T, Shalev V, Elchalal U, Chovel-Sella A, Chodick G. Screening for gestational diabetes in the 21st century: a population-based cohort study in Israel. J Matern Fetal Neonatal Med. 2013;26:412–416

4. Hjertkvist M, Damber JE, Bergh A. Cryptorchidism: a registry based study in Sweden on some factors of possible aetiological importance. J Epidemiol Community Health. 1989;43:324–329

5. Virtanen HE, Tapanainen AE, Kaleva MM, et al. Mild gestational diabetes as a risk factor for congenital cryptorchidism. J Clin Endocrinol Metab. 2006;91:4862–4865

6. Hussain N, Chaghtai A, Herndon CD, Herson VC, Rosenkrantz TS, McKenna PH. Hypospadias and early gestation growth restriction in infants. Pediatrics. 2002;109:473–478

7. Aberg A, Westbom L, Källén B. Congenital malformations among infants whose mothers had gestational diabetes or preexisting diabetes. Early Hum Dev. 2001;61:85–95

8. Porter MP, Faizan MK, Grady RW, Mueller BA. Hypospadias in Washington State: maternal risk factors and prevalence trends. Pediatrics. 2005;115:e495–e499

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