Contents

Understanding the risks for hypospadias

In the previous articles in this issue of TreatmentUpdate, we mentioned that some studies have found a possible link between the use of certain medicines in pregnancy and a risk of male genital birth defects, or hypospadias. In this article, we discuss hypospadias and research findings from pregnant HIV-negative women. This information puts the risk for hypospadias in context.

What is hypospadias?

In males, the opening of the urethra, through which urine leaves the body, is on the tip of the penis. However, with hypospadias, this opening can form on other parts of the shaft of the penis, on the scrotum or even close to the anus. This can be corrected in infancy with surgery.

Points to consider

1. Hypospadias incidence

Hypospadias can occur in about one in every 300 boys born to HIV-negative mothers. Reports from East Asia, Western Europe and the U.S. suggest that in the past two decades hypospadias may have become more common.

The reasons for this trend are not clear but may be due to better monitoring of infants as well as better reporting and collection of data about birth defects. There are also studies that suggest that there are several factors that may affect the potential risk for hypospadias, including the following:

  • certain medicines
  • some chemicals and pesticides
  • certain health issues encountered by pregnant women and the fetus
  • genes

We explore some of these issues next.

2. Pregnancy-related complications and issues

As a result of pregnancy, some women develop temporarily higher-than-normal blood pressure (hypertension) and kidney dysfunction. These are part of a syndrome called preeclampsia and require monitoring and in some cases treatment. Elevated blood pressure during pregnancy can affect the blood supply to the fetus and potentially restrict its growth.

A British study explored the issue of birth defects in 12,821 infants born to HIV-negative women between the years 1998 to 2010. It found that the use of medicines during the first trimester of pregnancy to lower blood pressure in women with hypertension was associated with an increased risk for hypospadias. It also found that women diagnosed with preeclampsia, whether or not they were treated for this condition, were at heightened risk for giving birth to children with birth defects, including hypospadias.

Another study from the U.S. also found an increased risk for hypospadias among infants of HIV-negative women with higher-than-normal blood pressure, regardless of whether they received treatment.

Taken together, the results from these two studies point to the fact that changes in the environment that surrounds the fetus can affect its development.

Research has also found that male babies who are born prematurely and/or who are born underweight are at increased risk for having hypospadias. This may be related to a condition whereby the placenta (the physical connection between the mother and fetus), which supplies oxygen and nutrients to the fetus and helps to remove wastes, is not working properly. Researchers are not certain why this might cause hypospadias.

3. Seizure medication

Researchers in Australia reviewed reports of birth defects collected between 1999 and 2012 among women who took anti-seizure drugs. They found that women who took, on average, higher doses of the drug valproate (valproic acid) during the first trimester of pregnancy were at increased risk for giving birth to infants with birth defects, particularly hypospadias. Women whose physicians decreased their dose of valproate had a reduced risk for infants being born with birth defects. Valproic acid can interfere with male hormones.

4. Obesity

Several studies have found that very overweight women were at increased risk for giving birth to male infants with hypospadias. However, not all researchers agree about the impact of obesity on the risk of hypospadias.

5. Genes and the environment

Hypospadias can occur in infants whose parents have a family history of this condition, suggesting that there is a genetic link.

In some cases, the genes in question have to do with receptors for the hormone estrogen or sensitivity to the hormone testosterone. Some researchers suspect that there are possible interactions between genes in the fetus and chemicals or hormone-like compounds in the environment.

One theory is that certain pollutants in the environment, called endocrine disruptors or hormone disruptors, interact with the fetus. Examples of these pollutants are:

  • PCBs (polychlorinated biphenyls)
  • PCDFs (polychlorinated dibenzofurans)
  • dioxins (polychlorinated dibenzo-p-dioxins, or PCDD)
  • some pesticides

The hormone testosterone is essential for the formation of male genitals. But it is possible that some of these pollutants or other chemicals could mimic the effect of estrogen and affect the development and formation of the penis. This theory about the impact of environmental contaminants is controversial. Indeed, while results of some experiments in animals may support the link between some pollutants and genital malformation, there is no clear proof of this link in humans.

Note well

As mentioned earlier in this issue of TreatmentUpdate, ART is very valuable when it comes to helping HIV-positive women deliver healthy, HIV-negative infants who generally have normal development as children.

Acknowledgement

We thank infectious disease specialist Jason Brophy, MD, for his helpful comments, expert review and research assistance.

—Sean R. Hosein

REFERENCES:

  1. Williams PL, Crain MJ, Yildirim C, et al. Congenital anomalies and in utero antiretroviral exposure in human immunodeficiency virus-exposed uninfected infants. JAMA Pediatrics. 2014; in press.
  2. Watts DH, Williams PL, Kacanek D, et al. Combination antiretroviral use and preterm birth. Journal of Infectious Diseases. 2013 Feb 15;207(4):612-21.
  3. Siberry GK, Williams PL, Mendez H, et al. Safety of tenofovir use during pregnancy: early growth outcomes in HIV-exposed uninfected infants. AIDS. 2012 Jun 1;26(9):1151-9.
  4. Chou R, Cantor AG, Zakher B, et al. Screening for HIV in pregnant women: systematic review to update the 2005 U.S. Preventive Services Task Force recommendation.  Annals of Internal Medicine. 2012 Nov 20;157(10):719-28.
  5. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989 through 31 January 2014. Wilmington, NC: Registry Coordinating Center; 2014. Available at: www.APRegistry.com [accessed 19 November 2014]
  6. Nelson CP, Park JM, Wan J, et al. The increasing incidence of congenital penile anomalies in the United States. Journal of Urology. 2005 Oct;174(4 Pt 2):1573-6.
  7. Foster PM. Disruption of reproductive development in male rate offspring following in utero exposure to phthalate esters. International Journal of Andrology. 2006 Feb;29(1):140-7.
  8. Sharpe PM. Pathways of endocrine disruption during male sexual differentiation and masculinization. Best practice & research. Clinical Endocrinology & Metabolism. 2006 Mar;20(1):91-110.
  9. Agras K, Willingham E, Liu B, et al. Ontogeny of androgen receptor and disruption of its mRNA expression by exogenous estrogens during morphogenesis of the genital tubercle. Journal of Urology. 2006 Oct;176(4 Pt 2):1883-8.
  10. Giwercman YL, ,Kleist KE, Giwercman A, et al. Remarkably low incidence of hypospadias in Greenland despite high exposure to endocrine disrupters; possible protective effect of androgen receptor genotype. Pharmacogenetics and Genomics. 2006 May;15(5):375-7.
  11. Townsend CL, Tookey PA, Cortina-Borja M, et al. Antiretroviral therapy and congenital abnormalities in infants born to HIV-1-infected women in the United Kingdom and Ireland, 1990 to 2003. Journal of Acquired Immune Deficiency Syndromes. 2006 May;42(1):91-4.
  12. van Gelder M, Van Bennekom C, Louik C, et al. Maternal hypertensive disorders, antihypertensive medication use, and the risk of birth defects: a case-control study. BJOG. 2014; in press.
  13. Jensen MS, Anand-Ivell R, Nørgaard-Pedersen B, et al. Amniotic fluid phthalate levels and male fetal gonad function. Epidemiology. 2014; in press.
  14. Rignell-Hydbom A, Lindh CH, Dillner J, et al. A nested case-control study of intrauterine exposure to persistent organochlorine pollutants and the risk of hypospadias. PLoS One. 2012;7(9):e44767.
  15. Nelson DB, Chalak LF, McIntire DD, et al. Is preeclampsia associated with fetal malformation? A review and report of original research. Journal of Maternal-Fetal & Neonatal Medicine. 2014; in press.
  16. Geller F, Feenstra B, Carstensen L, et al. Genome-wide association analyses identify variants in developmental genes associated with hypospadias. Nature Genetics. 2014 Sep;46(9):957-63.
  17. Shih EM, Graham JM Jr. Review of genetic and environmental factors leading to hypospadias. European Journal of Medical Genetics. 2014 Aug;57(8):453-63.
  18. van Rooij IA, van der Zanden LF, Brouwers MM, et al. Risk factors for different phenotypes of hypospadias: results from a Dutch case-control study. BJU International. 2013 Jul;112(1):121-8.
  19. Marengo L, Farag NH, Canfield M. Body mass index and birth defects: Texas, 2005-2008. Maternal and Child Health Journal. 2013 Dec;17(10):1898-907.
  20. Carmichael SL, Witte JS, Ma C, et al. Hypospadias and variants in genes related to sex hormone biosynthesis and metabolism. Andrology. 2014 Jan;2(1):130-7.
  21. Van Zutphen AR, Werler MM, Browne MM, et al. Maternal hypertension, medication use, and hypospadias in the National Birth Defects Prevention Study. Obstetrics and Gynecology. 2014 Feb;123(2 Pt 1):309-17.
  22. Vajda FJ, O’Brien TJ, Graham JE, et al. Dose dependence of fetal malformations associated with valproate. Neurology. 2013 Sep 10;81(11):999-1003.
  23. Agopian AJ, Lupo PJ, Canfield MA, et al. Case-control study of maternal residential atrazine exposure and male genital malformations. American Journal of Medical Genetics. Part A. 2013 May;161A(5):977-82.
  24. van der Zanden LF, Galesloot TE, Feitz WF, et al. Exploration of gene-environment interactions, maternal effects and parent of origin effects in the etiology of hypospadias. Journal of Urology. 2012 Dec;188(6):2354-60.