American Journal of Epidemiology Advance Access originally published online on June 4, 2007
American Journal of Epidemiology 2007 166(5):568-570; doi:10.1093/aje/kwm117
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ORIGINAL CONTRIBUTIONS |
Parental Infertility and Semen Quality in Male Offspring: A Follow-up Study
1 Department of Occupational Medicine, Aarhus University Hospital, Aarhus, Denmark
2 Department of Epidemiology, School of Public Health, University of California, Los Angeles, CA
Correspondence to Cecilia Høst Ramlau-Hansen, Department of Occupational Medicine, Aarhus University Hospital, Aarhus Sygehus, Norrebrogade 44, Building 2C, DK-8000 Aarhus C, Denmark (e-mail: craha{at}as.aaa.dk).
Received for publication January 26, 2007. Accepted for publication March 13, 2007.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Jensen et al. (Am J Epidemiol 2007;165:583–90) reported for the first time that men whose mothers had received fertility treatment had poor semen quality. This result could be confounded by the mothers' body mass index. Obesity is a strong predictor of fecundity and could have a programming effect on semen quality through hormonal factors or links to fetal growth. The authors of the current study tried to replicate the finding of Jensen et al. after controlling for maternal body mass index and other covariates using data from a recently conducted, population-based, Danish follow-up study on the association between maternal smoking during pregnancy in 1984–1987 and sons' semen quality, in which the participants were sampled according to levels of maternal smoking during pregnancy. After adjustment, sons of mothers who reported that they had been examined or treated for childlessness (n = 30) had a lower sperm concentration and total sperm count and fewer motile and morphologically normal spermatozoa in comparison with sons of mothers who had not been examined or treated for childlessness (n = 295). None of the differences (except for semen concentration) between the groups reached statistical significance, but the study has limited power. The findings were in the same direction as those reported by Jensen et al. and do not indicate that their results are confounded by maternal body mass index.
body mass index; infertility; obesity; overweight; prenatal exposure delayed effects; semen; spermatozoa; sperm count
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Jensen et al. (1) reported for the first time that men whose mothers had received fertility treatment had poor semen quality. If infertility treatment causes poor semen quality in the offspring, it is important because more and more women receive this treatment. The results may, however, be confounded by the parents' infertility (confounding by indication) or by other confounders, such as the mothers' body mass index. Obesity is a strong predictor of fecundity (2, 3) and may have a programming effect on semen quality, for example, by a higher level of estrogen exposure during fetal life, which may disturb the endocrinologic control of the male fetal urogenital organs (4). Lipophilic persistent organic pollutants, such as polychlorinated biphenyls, accumulate in adipose tissue and are found in the umbilical cord, as well as in pregnant women (5). They have been linked with poor semen quality (6).
We recently conducted a population-based, follow-up study on the association between maternal smoking during pregnancy and semen quality (7). In this cohort, we have data on maternal prepregnant height and weight and can therefore examine if adjustment for body mass index eliminates an association between infertility and semen quality in the offspring.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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The participants in our study were sons of mothers who, during their pregnancies from 1984 to 1987, participated in the "Healthy Habits for Two" cohort (8). The mothers provided information on lifestyle factors during pregnancy and whether they had been examined or treated for childlessness. The information was collected by self-administered questionnaires handed out by the midwives around the 36th week of gestation. Their sons, who were alive and living in Denmark by December 2004, were identified in the Danish Civil Registration System (n = 5,109), and letters of invitation were sent to 716 of these. Since we analyzed data from a study designed to examine the association between prenatal smoking exposure and adult semen quality, the participants were selected according to levels of maternal smoking during pregnancy. A total of 347 (49 percent) men gave consent and participated in the original study. There was no difference in the proportion of men with diseases of the reproductive organs (including cryptorchidism and hypospadias) between participants and nonparticipants.
Information on whether the mother had been examined or treated for childlessness was available for 344 men, and information on maternal prepregnant body mass index was available for 328 men, leaving 325 (94 percent) men available for analysis. (Refer to reference 7 for detailed information on selection and enrollment procedures.)
Each man provided a semen sample, with analysts blinded to information on infertility treatment and any other information obtained during pregnancy. The semen samples were analyzed in accordance with the WHO Laboratory Manual for the Examination of Human Semen-Cervical Mucus Interaction (9). The study was approved by the regional ethics committee (registration number 20040174), and participation was made conditional on written, informed consent.
For each of the outcome variables, we performed multiple regression using the two groups (mother examined or treated for childlessness or not) as a categorically coded explanatory variable. Data on semen volume, sperm concentration, total sperm count, and percentage of morphologically normal sperm were cubic-root transformed, and data on the percentage of motile sperm were logit transformed to normalize the distribution of the residuals. We evaluated the fit of the regression models by inspecting the residual and leverage plots. Back-transformed means were adjusted for abstinence time (<2 days, 
2 days), history of diseases of the reproductive organs excluding cryptorchidism and hypospadias (varicocele, hydrocele, orchitis, or chlamydia—yes or no), maternal smoking during pregnancy (yes or no), and maternal prepregnant body mass index (<18.50 kg/m2, 18.50–24.99 kg/m2, 25.00 kg/m2), with 95 percent confidence intervals presented.
Participants who reported spillage during sampling (n = 78) were excluded from all statistical analysis on sperm volume and on total sperm count.
All statistical analyses were performed by using Intercooled STATA, version 8.2, software (StataCorp LP, College Station, Texas). A two-tailed probability level of less than 0.05 was considered statistically significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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The 325 participants were from 18 to 21 (median: 20) years of age.
When we compared sons of mothers who reported that they had been examined or treated for childlessness (n = 30) with sons of mothers who reported that they had not been examined or treated for childlessness (n = 295), "exposed" men had a lower sperm concentration and total sperm count and fewer motile and morphologically normal spermatozoa (table 1). The differences between the groups were statistically significant only for sperm concentration. We repeated the analysis after additional adjustment for cryptorchidism and hypospadias and found results similar to those reported in table 1.
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Stratification on maternal prepregnant body mass index showed tendencies toward lower sperm concentration and percentage of motile sperm among the exposed men in comparison with the "unexposed" men in all three body mass index levels (<18.50 kg/m2, 18.50–24.99 kg/m2,
25.00 kg/m2), but the association appeared to be strongest for sons of mothers who had a body mass index of 25.00 kg/m2 or greater (numbers too small for statistical analysis). |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Our data do not indicate that the results found by Jensen et al. were confounded by maternal body mass index. It is unknown whether the poor semen quality is related to infertility treatment or is caused by male or female infertility itself, for instance, through hereditary factors. It is important to get data that can address this issue, since it is plausible that some infertility treatments may impact organogenesis and function of the testis.
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ACKNOWLEDGMENTS |
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The study was supported by the Health Insurance Foundation (grants 2004B137, 2005B081, and 2006B107), the Danish Medical Research Council (grants 22-03-0200, 22-04-0271, and 271-05-0760), the Augustinus Foundation (grant 05-2620), the Knud Højgaard Foundation (grant 37.065), the Fulbright Commission, the Simon Fougner Hartmanns Family Foundation, the Aase and Ejnar Danielsens Foundation, the University of Aarhus Research Foundation, and the Biomedical Laboratory Scientist Education and Research Fund.
The authors thank Joan Dideriksen for her important work with collecting the samples and performing the initial semen analysis.
Conflict of interest: none declared.
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References |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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- Jensen TK, Jorgensen N, Asklund C, et al. Fertility treatment and reproductive health of male offspring: a study of 1,925 young men from the general population. Am J Epidemiol (2007) 165:583–90.
[Abstract/Free Full Text] - Gosman GG, Katcher HI, Legro RS. Obesity and the role of gut and adipose hormones in female reproduction. Hum Reprod Update (2006) 12:585–601.
[Abstract/Free Full Text] - Diamanti-Kandarakis E, Bergiele A. The influence of obesity on hyperandrogenism and infertility in the female. Obes Rev (2001) 2:231–8.[CrossRef][Medline]
- Sharpe RM, Skakkebaek NE. Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract? Lancet (1993) 341:1392–5.[CrossRef][ISI][Medline]
- Jimenez TM, Campoy FC, Canabate RF, et al. Organochlorine pesticides in serum and adipose tissue of pregnant women in southern Spain giving birth by cesarean section. Sci Total Environ (2006) 372:32–8.[CrossRef][Medline]
- Hauser R. The environment and male fertility: recent research on emerging chemicals and semen quality. Semin Reprod Med (2006) 24:156–67.[ISI][Medline]
- Ramlau-Hansen CH, Thulstrup AM, Storgaard L, et al. Is prenatal exposure to tobacco smoking a cause of poor semen quality? A follow-up study. In: Am J Epidemiol. (DOI 10.1093/aje/kwm032).
- Olsen J, Frische G, Poulsen AO, et al. Changing smoking, drinking, and eating behaviour among pregnant women in Denmark. Evaluation of a health campaign in a local region. Scand J Soc Med (1989) 17:277–80.[ISI][Medline]
- World Health Organization. WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction. (1999) 4th ed. Cambridge, United Kingdom: Cambridge University Press.
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