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      Risk Factors for Congenital Cryptorchidism in a Prospective Birth Cohort Study

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          Abstract

          Background

          Risk factors for congenital cryptorchidism were investigated in a prospective birth cohort study in Denmark and Finland from 1997 to 2001.

          Methodology and Principal Findings

          In total, 2,496 boys were examined for cryptorchidism at birth (cryptorchid/healthy: 128/2,368) and three months old (33/2,215). Information on risk factors was obtained antenatally (questionnaire/interview) or at birth from birth records. Use of nicotine substitutes during pregnancy ( n = 40) and infertility treatment by intrauterine insemination ( n = 49) were associated with an increased risk for cryptorchidism, adjusted odds ratio (95% confidence interval) (OR (95%CI)) 3.04 (95%CI 1.00–9.27) and 3.01 (95%CI 1.27–7.15), respectively. No association was seen for mothers ( n = 79) who had infertility treatment in form of intracytoplasmic sperm injection (ICSI) or in vitro fertilization (IVF) treatment (OR 0.71 95%CI 0.21–2.38). In total, 728 (29%) reported to have smoked during pregnancy, however, no increased risk among maternal smokers was found. Furthermore, we found statistically significant associations between cryptorchidism and low birth weight, prematurity, being small for gestational age, substantial vaginal bleeding, and breech presentation, which are in accordance with other studies.

          Conclusions and Significance

          Our study revealed two novel risk factors for cryptorchidism: intrauterine insemination and the use of nicotine substitutes in pregnancy. This suggests that cryptorchidism may not only be associated to genetic factors, but also to maternal lifestyle and exposure.

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          Most cited references51

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          The Danish National Birth Cohort--its background, structure and aim.

          J. Olsen, M Melbye, S. F. Olsen … (2001)
          It is well known that the time from conception to early childhood has importance for health conditions that reach into later stages of life. Recent research supports this view, and diseases such as cardiovascular morbidity, cancer, mental illnesses, asthma, and allergy may all have component causes that act early in life. Exposures in this period, which influence fetal growth, cell divisions, and organ functioning, may have long-lasting impact on health and disease susceptibility. To investigate these issues the Danish National Birth Cohort (Better health for mother and child) was established. A large cohort of pregnant women with long-term follow-up of the offspring was the obvious choice because many of the exposures of interest cannot be reconstructed with sufficient validity back in time. The study needs to be large, and it is aimed to recruit 100,000 women early in pregnancy, and to continue follow-up for decades. The Nordic countries are better suited for this kind of research than most other countries because of their population-based registers on diseases, demography and social conditions, linkable at the individual level by means of the unique ID-number given to all citizens. Exposure information is mainly collected by computer-assisted telephone interviews with the women twice during pregnancy and when their children are six and 18 months old. Participants are also asked to fill in a self-administered food frequency questionnaire in mid-pregnancy. Furthermore, a biological bank has been set up with blood taken from the mother twice during pregnancy and blood from the umbilical cord taken shortly after birth. Data collection started in 1996 and the project covered all regions in Denmark in 1999. By August 2000. a total of 60,000 pregnant women had been recruited to the study. It is expected that a large number of gene-environmental hypotheses need to be based on case-control analyses within a cohort like this.
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            Intrauterine growth curves based on ultrasonically estimated foetal weights.

            H Lilja, Louise J. P. Persson, A Selbing … (1996)
            Available standard intrauterine growth curves based on birthweights underestimate foetal growth in preterm period. New growth curves are presented based on data from four Scandinavian centres for 759 ultrasonically estimated foetal weights in 86 uncomplicated pregnancies. Mean weight of boys exceeded that of girls by 2-3%. A uniform SD value of 12% of the mean weight was adopted for the standard curves as the true SD varied non-systematically between 9.1 and 12.4%. Applied to an unselected population of 8663 singleton births, before 210 days of gestation, 32% of birthweights were classified as small-for-gestational age (SGA; i.e. below mean - 2 SD); the corresponding figures were 11.1% for gestational ages between 210 and 258 days, and 2.6% for ages of 259 days or longer. The new growth curves reveal better the true distribution of SGA foetuses and neonates, and are suggested for use in perinatological practice.
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              Difference in prevalence of congenital cryptorchidism in infants between two Nordic countries.

              M Reunanen, I Damgaard, J Toppari … (2004)
              Several investigators have shown striking differences in semen quality and testicular cancer rate between Denmark and Finland. Since maldescent of the testis is a shared risk factor for these conditions we undertook a joint prospective study for the prevalence of congenital cryptorchidism. 1068 Danish (1997-2001) and 1494 Finnish boys (1997-99) were consecutively recruited prenatally. We also established prevalence data for all newborns at Turku University Central Hospital, Finland (1997-99, n=5798). Testicular position was assessed by a standardised technique. All subtypes of congenital cryptorchidism were included, but retractile testes were considered normal. Prevalence of cryptorchidism at birth was 9.0% (95% CI 7.3-10.8) in Denmark and 2.4% (1.7-3.3) in Finland. At 3 months of age, prevalence rates were 1.9% (1.2-3.0) and 1.0% (0.5-1.7), respectively. Significant geographic differences were still present after adjustment for confounding factors (birthweight, gestational age, being small for gestational age, maternal age, parity, mode of delivery); odds ratio (Denmark vs Finland) was 4.4 (2.9-6.7, p<0.0001) at birth and 2.2 (1.0-4.5, p=0.039) at three months. The rate in Denmark was significantly higher than that reported 40 years ago. Our findings of increasing and much higher prevalence of congenital cryptorchidism in Denmark than in Finland contribute evidence to the pattern of high frequency of reproductive problems such as testicular cancer and impaired semen quality in Danish men. Although genetic factors could account for the geographic difference, the increase in reproductive health problems in Denmark is more likely explained by environmental factors, including endocrine disrupters and lifestyle.
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2008
                Publication date (Electronic): 25 August 2008
                Volume: 3
                Issue: 8
                Electronic Location Identifier: e3051
                Affiliations
                [1 ]University Department of Growth and Reproduction, GR-5064 Rigshospitalet, Copenhagen, Denmark
                [2 ]Department of Physiology and Pediatrics, University of Turku, Turku, Finland
                [3 ]Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark
                JARING, Malaysia
                Author notes

                Conceived and designed the experiments: TKJ The Nordic Cryptorchidism Study Group JHP NES JT KMM. Performed the experiments: IND The Nordic Cryptorchidism Study Group. Analyzed the data: IND TKJ JHP NES JT KMM. Contributed reagents/materials/analysis tools: IND TKJ The Nordic Cryptorchidism Study Group JHP NES JT KMM. Wrote the paper: IND TKJ JHP NES KMM.

                Article
                Publisher ID: 08-PONE-RA-04616R1
                DOI: 10.1371/journal.pone.0003051
                PMC ID: 2516600
                PubMed ID: 18725961
                SO-VID: f43d091e-4178-4454-a92c-2c36c87a3e4d
                Copyright © Damgaard et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 9 May 2008
                Date accepted : 4 August 2008
                Page count
                Pages: 8
                Categories
                Subject: Research Article
                Subject: Pediatrics and Child Health
                Subject: Public Health and Epidemiology
                Subject: Pediatrics and Child Health/Child Development

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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