Hypospadias and Vegetarian Diets


Last updated May 2018

Contents

Background on Hypospadias

Hypospadias is a male birth defect in which the opening of the urethra—the tube through which urine passes—isn’t located at the tip of the penis as it should be. It’s believed to be caused by a combination of genetic susceptibility and environmental factors including environmental contaminants (1, 2).

As of 2012, the nationwide rate of hypospadias for the USA was about 64.7 cases per 10,000 male live births, or 1 in 155 male live births (3). Some forms of hypospadias are relatively easy to repair with surgery done on an outpatient basis and surgical repair usually results in a penis with normal, or near-normal, function and appearance (4).

Research on Vegetarians

As of May 2018, there have been six studies comparing hypospadias cases in boys born to vegetarians versus non-vegetarians. Table 1 lists them.

Table 1. Rate of hypospadias cases in boys born to vegetarian mothers
Study Type No. of Boys Cases Vegetarians Vegetarian cases Rate
UK 2000 (5) Prospective 6296 51 321 7 3.53 (1.56, 7.98)
Netherlands 2007 (6) Case-Control 834 583 17 10 0.6 (0.3, 1.6)
Sweden & Denmark 2008 (7) Case-Control 719 291 22 14 4.6 (1.6, 13)
UK 2009 (8) Case-Control 949 467 168 77 0.85 (0.61, 1.2)
India 2011 (9) Case-Control 200 80 123 52 1.28 (0.71, 2.3)
USA 2012 (10) Case-Control 4368 1250 43 10 0.6 (0.3, 1.2)

The first study to examine the link (UK, 2000), found that a vegetarian diet in pregnancy was associated with a 3.5-times higher risk of having a son with hypospadias compared to a non-vegetarian diet in pregnancy (5).

Since 2007, there have been five case-control studies of various sizes. One found a 4.6 times higher risk for sons of vegetarian mothers (7) and the other four found no increased risk (6, 8-10).

Two of these studies deserve more weight—the 2000 UK study which found a link between vegetarian diet and hypospadias, and a 2012 USA study which did not.

The 2000 UK study is a prospective study and prospective studies generally hold more weight than do case-control studies because they involve less risk of mischaracterizing dietary patterns. However, in the case of vegetarians and hypospadias, mischaracterizing dietary patterns in case-control studies is probably not much of an issue because diet recall happened shortly after hypospadias diagnosis.

The 2012 USA study was very large, making random chance findings unlikely. In fact, it contained almost 25 times as many cases of hypospadias than did the 2000 UK study. Additionally, these two studies were designed with the purpose of investigating vegetarian diets while the aims of the other studies were broader.

Thus, the two most important studies have differing findings, though reason to put significant weight on the 2012 USA study.

Possible Connections

It’s important to be aware that the cause of most cases of hypospadias is unknown. There appear to be many genetic and environmental factors (11) so pinpointing a single cause may not be possible. The different results in studies of vegetarian diets and hypospadias risk could be chance or could be due to differences in food choices, supplement use, environmental exposure, or something else.

With that in mind, what are some possible explanations for the higher risk seen in vegetarians in two studies?

Vitamin B12

A first guess would be that vitamin B12 deficiency among vegans and even some lacto-ovo vegetarians could have increased the risk of hypospadias. At least one study has found a link between vitamin B12 deficiency and hypospadias (11).

The UK study examined births between 1991 and 1992 (5). The USA study examined births between 1997 and 2005 (10). And in the years between when these two studies were conducted, there was much education in the vegan community about the need for vitamin B12, which could explain why the risk might have disappeared.

However, there are many documented cases of vegan infants whose mothers had been deficient in vitamin B12 and to none of these boys have been reported to have been born with hypospadias (more info).

Whether or not a lack of vitamin B12 increases the risk of hypospadias, it plays other important roles so all pregnant women should have a reliable daily source of vitamin B12—see Daily Needs.

Folic Acid and Methionine

What about other molecules involved in one-carbon metabolism such as folate (or folic acid), choline, and methionine?

Some studies (6, 12,13) found no effects of folic acid supplementation on preventing hypospadias. Others found a reduced risk with folic acid supplements in the first trimester (8, 14, 15).

There’s a bit of evidence that methionine could play a role (13).

In a report coming from the National Birth Defects Prevention Study (USA, 2009), women taking supplemental folic acid and who ate more than 1,870 mg/day of methionine had a 40% reduced risk of having a baby with hypospadias (0.6, 0.4-0.9). Since no effect of methionine was seen in women who did not take folic acid supplements, it’s possible that the results are mainly due to the folic acid supplements.

Still, methionine is an essential amino acid. The RDA is well under 1,870 mg/day for most pregnant women. Without more evidence, it’s probably unnecessary to strive for 1,870 mg per day. However, it’s a good idea to make sure a pregnant vegan’s diet has plenty of methionine.

The plant foods highest in methionine are tempeh, peanuts, oatmeal, quinoa, and spaghetti—see Protein and Amino Acid Content of Selected Plant Foods.

Choline

Choline, a nutrient that can be on the low end in vegan diets, was investigated in the National Birth Defects Prevention Study (13). They didn’t find a statistically significant association between high choline intake and risk of hypospadias (0.7, 0.5-1.1), but it’s still a nutrient for pregnant vegans to be aware of—see Choline.

Pesticide Exposure

Parental exposure to pesticides through work or residential lawn care is associated with increased risk of hypospadias in some, but not all studies (1, 16). Dietary exposure to pesticides has been estimated in some studies by examining the use or purchase of organic vegetables. For example,2000 UK study also examined the purchase of organic vegetables.

The authors state:

Unfortunately, only 163 mothers always bought organic vegetables; that none of these mothers had a son with hypospadias is of some interest, but only one case would have been expected. No reduction in risk was evident among those who ‘sometimes’ bought organic vegetables (0.8% had hypospadias, compared with 0.6% who never bought organically grown vegetables) (5).

A study from Denmark found no association between use of organic vegetables and fruits and risk of hypospadias (16).

While there might be something to the pesticide/organic vegetable link, there doesn’t seem to be enough statistical power to draw any conclusions.

Soy

Finally, there is soy, a food no discussion on vegetarianism should ever be without! The concern is that the plant estrogens in soy might interfere with the sexual development of boys.

While there was a trend in the 2000 UK prospective study for a higher risk of hypospadias with drinking soy milk versus not (3.7, 0.87-15.4), and for eating soy meats more than once a week versus never (2.95, 0.90, 9.68), the findings were not statistically significant (5).

Eating beans (not soybeans) was associated with an even higher risk of hypospadias which makes it less likely that plant estrogens are the cause of the increased risk of hypospadias since beans (other than soybeans) contain only very small amounts of plant estrogens. In this study, it might have been hard to separate eating soy milk and meats from simply being vegetarian.

A 2012 study from the USA (18) found reduced risk of hypospadias with higher intakes of some plant estrogens. A 2004 study from the Netherlands (17) measured soy intake and hypospadias and found no link for maternal soy intake. Results are in Table 2.

Table 2. Hypospadias & Soy (2004)4
Soy Protein Intake
None 1.00
0 to 20 g/day 1.1 (.5, 2.5)
20+ g/day 1.0 (.5, 2.2)

Conclusion

Under the worst-case scenario, based on the 2000 UK study, a vegetarian mother would have a 4% chance of having a baby with hypospadias. The trend since that first report has been to find no association between a vegetarian diet and hypospadias and that is punctuated by the most recent 2012 USA study with almost 25 times as many cases of hypospadias than the 2000 UK study. This gives reasonable confidence that a vegetarian diet is not a significant risk.

Making sure pregnant vegans get enough folic acid, vitamin B12, methionine, and choline can help alleviate any potential risks.

References

1. Marrocco G, Grammatico P, Vallasciani S, et al. Environmental, parental and gestational factors that influence the occurrence of hypospadias in male patients. J Pediatr Urol. 2015 Feb;11(1):12-9.

2. Bouty A, Ayers KL, Pask A, Heloury Y, Sinclair AH. The genetic and environmental factors underlying hypospadias. Sex Dev. 2015;9(5):239-259.

3. Mai CT, Isenburg J, Langlois PH, et al. Population-based birth defects data in the United States, 2008 to 2012: Presentation of state-specific data and descriptive brief on variability of prevalence. Birth Defects Res A Clin Mol Teratol. 2015 Nov;103(11):972-93.

4. Hypospadias: Diagnosis and Treatment. Mayo Clinic. Accessed April 19, 2018.

5. North K, Golding J. A maternal vegetarian diet in pregnancy is associated with hypospadias. The ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. BJU Int. 2000 Jan;85(1):107-13.

6. Brouwers MM, Feitz WF, Roelofs LA, Kiemeney LA, de Gier RP, Roeleveld N. Risk factors for hypospadias. Eur J Pediatr. 2007 Jul;166(7):671-8. Epub 2006 Nov 14.

7. Akre O, Boyd HA, Ahlgren M, Wilbrand K, Westergaard T, Hjalgrim H, Nordenskjold A, Ekbom A, Melbye M. Maternal and gestational risk factors for hypospadias. Environ Health Perspect. 2008 Aug;116(8):1071-6.

8. Ormond G, Nieuwenhuijsen MJ, Nelson P, Toledano MB, Iszatt N, Geneletti S, Elliott P. Endocrine disruptors in the workplace, hair spray, folate supplementation, and risk of hypospadias: case-control study. Environ Health Perspect. 2009 Feb;117(2):303-7.

9. Shekharyadav C, Bajpai M, Kumar V, Ahmed RS, Gupta P, Banerjee BD. Polymorphism in CYP1A1, GSTMI, GSTT1 genes and organochlorine pesticides in the etiology of hypospadias. Hum Exp Toxicol. 2011 Oct;30(10):1464-74. Epub 2011 Feb 7.

10. Carmichael SL, Ma C, Feldkamp ML, Munger RG, Olney RS, Botto LD, Shaw GM, Correa A. Nutritional factors and hypospadias risks. Paediatr Perinat Epidemiol. 2012 Jul;26(4):353-60.

11. Kowal A, Mydlak D, Ołtarzewski M, Bauer A, Sawicka E, Hozyasz KK. Propionylcarnitine and methionine concentrations in newborns with hypospadias. Cent European J Urol. 2013;66(3):377-80.

12. Goh YI, Bollano E, Einarson TR, Koren G. Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis. J Obstet Gynaecol Can. 2006 Aug;28(8):680-9. Review.

13. Carmichael SL, Yang W, Correa A, Olney RS, Shaw GM; National Birth Defects Prevention Study. Hypospadias and intake of nutrients related to one-carbon metabolism. J Urol. 2009 Jan;181(1):315-21; discussion 321.

14. de Kort CA, Nieuwenhuijsen MJ, Mendez MA. Relationship between maternal dietary patterns and hypospadias. Paediatr Perinat Epidemiol. 2011 May;25(3):255-64.

15. Mavrogenis S, Urban R, Czeizel AE, Ács N. Possible preventive effect of high doses of folic acid for isolated hypospadias: a national population-based case-control study. Am J Med Genet A. 2014 Dec;164A(12):3108-14.

16. Christensen JS, Asklund C, Skakkebæk NE, et al. Association between organic dietary choice during pregnancy and hypospadias in offspring: a study of mothers of 306 boys operated on for hypospadias. J Urol. 2013 Mar;189(3):1077-82.

17. Pierik FH, Burdorf A, Deddens JA, Juttmann RE, Weber RF. Maternal and paternal risk factors for cryptorchidism and hypospadias: a case-control study in newborn boys. Environ Health Perspect. 2004 Nov;112(15):1570-6.

18. Carmichael SL, Cogswell ME, Ma C, et al. Hypospadias and maternal intake of phytoestrogens. Am J Epidemiol. 2013 Aug 1;178(3):434-40.

Reviewed

Czeizel AE. The primary prevention of birth defects: Multivitamins or folic acid? Int J Med Sci. 2004;1(1):50-61. Epub 2004 Mar 20.

Botto LD, Mulinare J, Erickson JD. Occurrence of omphalocele in relation to maternal multivitamin use: a population-based study. Pediatrics. 2002 May;109(5):904-8.

Dokter EM, van Rooij IA, Wijers CH, Groothuismink JM, van der Biezen JJ, Feitz WF, Roeleveld N, van der Zanden LF. Interaction between MTHFR 677C>T and periconceptional folic acid supplementation in the risk of hypospadias. Birth Defects Res A Clin Mol Teratol. 2016 Apr;106(4):275-84.

García J, Ventura MI, Requena M, Hernández AF, Parrón T, Alarcón R. Association of reproductive disorders and male congenital anomalies with environmental exposure to endocrine active pesticides. Reprod Toxicol. 2017 Aug;71:95-100.

Giordano F, Carbone P, Nori F, Mantovani A, Taruscio D, Figa-Talamanca I. Maternal diet and the risk of hypospadias and cryptorchidism in the offspring. Paediatr Perinat Epidemiol. 2008 May;22(3):249-60.

Giordano F, Abballe A, De Felip E, di Domenico A, Ferro F, Grammatico P, Ingelido AM, Marra V, Marrocco G, Vallasciani S, Figa-Talamanca I. Maternal exposures to endocrine disrupting chemicals and hypospadias in offspring. Birth Defects Res A Clin Mol Teratol. 2010 Apr;88(4):241-50.

Goh YI, Bollano E, Einarson TR, Koren G. Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis. J Obstet Gynaecol Can. 2006 Aug;28(8):680-9. Review.

Springer A, van den Heijkant M, Baumann S. Worldwide prevalence of hypospadias. J Pediatr Urol. 2016 Jun;12(3):152.e1-7.

Strom BL, Schinnar R, Ziegler EE, Barnhart KT, Sammel MD, Macones GA, Stallings VA, Drulis JM, Nelson SE, Hanson SA. Exposure to soy-based formula in infancy and endocrinological and reproductive outcomes in young adulthood. JAMA. 2001 Aug 15;286(7):807-14.

van der Horst HJ, de Wall LL. Hypospadias, all there is to know. Eur J Pediatr. 2017 Apr;176(4):435-441.

Vilela ML, Willingham E, Buckley J, Liu BC, Agras K, Shiroyanagi Y, Baskin LS. Endocrine disruptors and hypospadias: role of genistein and the fungicide vinclozolin. Urology. 2007 Sep;70(3):618-21. (Abstract)

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