Cryptorchidism: Effects of Maternal Diabetes or PBDEs
Environ Health Perspect. doi:10.1289/ehp.11096 available via http://dx.doi.org [Online 22 April 2008]
Referencing: Flame Retardants in Placenta and Breast Milk and Cryptorchidism in Newborn Boys
It was with great interest that we read the article by Main et al. (2007) regarding polybrominated diphenyl ethers (PBDEs) and cryptochordism, and we are impressed with the data in humans. Main et al. stated that the concentration of PBDEs in breast milk was significantly higher in boys with cryptorchidism compared with controls. It is certainly possible that there is a link between fetal PBDE exposure and cryptorchidism; however, we noted that the cohort included children of diabetic mothers. Of the 33 boys with cryptorchidism, 4 in the Finnish group and 1 of 28 in the Danish breast milk–sample group had diabetic mothers. It is widely known that diabetes is a major cause of congenital malformations, and these malformations are dependent on the severity of the diabetes. Therefore, you cannot simply match by diabetes between cases and controls. In a study of 173 mothers with diabetes, we found that 10% of the offspring had congenital malformations related to the severity of the diabetes, classified according to the Priscilla White classification (Koppe et al. 1983). Virtanen et al. (2006), together with Main, published a study reporting an increased risk of cryptorchidism following mild gestational diabetes. In our opinion, the cases of mothers with diabetes should be excluded from analysis of congenital malformations, both in the breast milk group and the placenta group reported by Main et al. (2007).
The group of mothers with diabetes is in itself an interesting group. Are the placenta and breast milk levels of PBDEs or the fat content different between the diabetic cases and the others?
In general, because most PBDEs have phenobarbital-like effects, it seems plausible that they should cause an increase in congenital malformations, such as is seen with phenobarbital (Dessens et al. 1994; Koppe et al. 1973).
G.W.T. is chairman of the board of Health Care Without Harm Europe, a nonprofit, nongovernmental organization promoting sustainable health care. J.G.K. is the chairman of ECOBABY Foundation, a nonprofit, nongovernmental organization promoting research and education in the field of environmental influences in pregnancy and infant outcome.
Gavin W. ten Tusscher
Department of Pediatrics and Neonatology
Westfriesgasthuis, Hoorn, the Netherlands
Janna G. Koppe
ECOBABY Foundation
Loernersloot, the Netherlands
E-mail: Janna.Koppe@inter.nl.net
References
Dessens AB, Boer K, Koppe JG, van de Poll NE, Cohen-Kettenis PT. 1994. Studies on long-lasting consequences of prenatal exposure to anticonvulsant drugs. Acta Paediatr Suppl 404:54–64.
Koppe JG, Bosman W, Oppers VM, Spaans F, Kloosterman GJ. 1973. Epilepsy and congenital anomalies [in Dutch]. Ned Tijdschr Geneeskd 117:220–224.
Koppe JG, Smorenberg-Schoorl ME, van den Berg-Loonen EM, Mills JL. 1983. Diabetes, congenital malformations, and HLA-Type. In: Intensive Care in the Newborn, IV (Stern L, Bard H, Friis-Hansen B, eds). New York:Masson Publishing, 15–18.
Main KM, Kiviranta H, Virtanen HE, Sundqvist E, Tuomisto JT, Tuomisto J, et al. 2007. Flame retardants in placenta and breast milk and cryptorchidism in newborn boys. Environ Health Perspect 115:1519–1526.
Virtanen HE, Tappanainen AE, Kaleva MM, Suomi AM, Main KM, Skakkebaek NE, et al. 2006. Mild gestational diabetes as a risk factor for congenital cryptorchidism. J Clin Endocrinol Metab 91:4862–4865.
Cryptorchidism: Main et al. Respond
Environ Health Perspect. doi:10.1289/ehp.11096R available via http://dx.doi.org [Online 22 April 2008]
ten Tusscher and Koppe point out that maternal diabetes increases the risk of malformations in newborns and suggest that we should have excluded diabetic mothers from the data set. We agree with them that maternal diabetes increases the risk of congenital malformations, although there is only limited evidence for this in the case of cryptorchidism. In our large mother–child cohort from which this data set was derived, we found a significant association between gestational diabetes and congenital cryptorchidism (Virtanen et al. 2006).
We did not initially carry out an analysis corrected for diabetes because the biological samples were not selected with regard to diabetes; therefore data were potentially skewed for this outcome. For the same reason, the total number of mothers with diabetes in each country was low in this data set.
We have now reanalyzed the data, omitting the mothers with diabetes (2 Danish and 4 Finnish mothers for breast milk samples, and 2 Danish and 10 Finnish mothers for placentas). In a binary logistic regression analysis including all relevant confounders (maternal age, maternal prepregnancy body mass index, gestational age, weight for gestational age, parity, and country of origin), the association between the level of the seven most prevalent polybrominated biphenyl ethers (PBDEs) in breast milk (BDEs 28, 47, 66, 99, 100, 153, and 154) and congenital cryptorchidism remained significant (p < 0.032), with a median level (2.5th–97.5th percentiles) of 3.16 ng/g fat (1.08–21.73) in controls and 4.19 ng/g fat (1.42–52.64) in cryptorchid boys. The same analysis for the five most prevalent BDEs in placenta (BDEs 47, 153, 99, 100, and 28) remained nonsignificant (p = 0.173), with 1.23 ng/g fat (0.56–5.46) in controls and 1.12 ng/g fat (0.37–4.24) in cryptorchid boys.
ten Tusscher and Koppe also suggest the investigation of potential differences between mothers with and without diabetes with respect to fat content in the samples and the concentrations of PBDEs. We previously reported that the lipid content in breast milk and placenta was higher in Finnish than in Danish samples (Shen et al. 2007). Country of origin was therefore included as a covariate in a binary logistic regression. We found no significant difference between mothers with and without diabetes for fat content in breast milk or placenta (p = 0.975 and 0.107, respectively) or the sum of the most prevalent BDE congeners (p = 0.233 and 0.317, respectively). However, the number of diabetic mothers in our data set is too small to draw any firm conclusions from these results.
In conclusion, the association between perinatal exposure to PBDEs and congenital cryptorchidism was significant after exclusion of diabetic mothers. Exposure to environmental chemicals is, however, one of many adverse factors that alone, or in combination with each other, may cause testicular maldescent (Main et al. 2007). These additional factors include gestational complications, lifestyle, and genetic factors (Virtanen et al. 2007).
The authors declare they have no competing financial interests.
Katharina M. Main
University Department of Growth and Reproduction,
Copenhagen, Denmark
E-mail: katharina.main@rh.regionh.dk
Jorma Toppari
Departments of Physiology and Paediatrics
University of Turku
Turku, Finland
References
Main KM, Kiviranta H, Virtanen HE, Sundqvist E, Tuomisto JT, Tuomisto J, et al. 2007. Flame retardants in placenta and breast milk and cryptorchidism in newborn boys. Environ Health Perspect 115:1519–1526.
Shen H, Main KM, Andersson A-M, Damgaard IN, Virtanen HE, Skakkebæk NE, et al. 2008. Concentrations of persistent organochlorine compounds in human milk and placenta are higher in Denmark than in Finland. Hum Reprod 23:201–210.
Virtanen HE, Bjerknes R, Cortes D, Jørgensen N, Rajpert-De Meyts E, Thorsson AV, et al. 2007. Cryptorchidism: classification, prevalence and long term consequences. Acta Paediatr 96:611–616.
Virtanen HE, Tapanainen AE, Kaleva MM, Suomi AM, Main KM, Skakkebæk NE, et al. 2006. Mild gestational diabetes as a risk factor for congenital cryptorchidism. J Clin Endocrinol Metab 91:4862–4865.
