Regional differences in waiting time to pregnancy among fertile couples from four European cities

T.K. Jensen1,2,9, R. Slama3, B. Ducot3, J. Suominen4, E.H.H. Cawood5, A.G. Andersen1, F. Eustache6, S. Irvine5, S. Auger6, P. Jouannet6, M. Vierula4, N. Jørgensen1, J. Toppari7, N.E. Skakkebaek1, N. Keiding8 and A. Spira3

1 Department of Growth and Reproduction, section GR-5064, Rigshospitalet, The Juliane Marie Centre, Blegdamsvej 9, DK-2100 Copenhagen, Denmark, 2 Department of Epidemiology & Public Health, Imperial College of Medicine at St Mary's, Norfolk Place, London W21PG, UK, 3 INSERM U292, Research in Public Health, Hôpital de Bicêtre, 82 rue du Général Leclerc, Fr-94276 Le Kremlin-Bicêtre Cedex, France, 4 University of Turku, Institute of Biomedicine, Kiinamyllynkatu 10, FIN-20520 Turku, Finland, 5 MRC Reproductive Biology Unit, Centre for Reproductive Biology, 37 Chalmers Street, Edinburgh EH3 9ET, UK, 6 Université Paris V, Groupe Hospitalier Cochin, 123 Boulevard de Port-Royal, FR-75014 Paris, France, 7 University of Turku, Department of Physiology and Department of Paediatrics, Turku, Finland and 8 Department of Biostatistics, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Questionnaires and semen samples
 Results
 Discussion
 Acknowledgements
 References
 
BACKGROUND: A previous European study found a longer time to pregnancy (TTP) among fertile women from Paris compared with women from other Western European countries. A co-ordinated, cross-sectional study of pregnant couples from Denmark (Copenhagen), France (Paris), Scotland (Edinburgh) and Finland (Turku) was therefore undertaken to assess differences in waiting TTP among couples from these cities. METHODS: Pregnant women were invited to participate when they showed up for their first antenatal visit in one of the four centres. Inclusion criteria included that their partner was 20–45 years of age and born in the country in which he was currently living and that the pregnancy was achieved without fertility treatment. Both partners filled in a questionnaire and the man underwent a physical examination and delivered a semen sample (Turku: n = 237, Copenhagen: n = 302, Edinburgh: n = 212, Paris: n = 191). RESULTS: French couples had a decreased probability of conception compared with couples from the other three countries, although only after adjustment for confounders. No significant differences between couples from the three other countries were found. CONCLUSION: The observed geographical differences in TTP remain unexplained and were not due to differences in semen quality, but may be caused by varying exposures to environmental factors or psychological distress. In addition, selection bias due to the low participation rates cannot be ruled out. Future studies examining the causes for geographical differences in TTP are needed.

Key words: environmental health/fertility/population surveillance/pregnancy rate/time factors


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Questionnaires and semen samples
 Results
 Discussion
 Acknowledgements
 References
 
Several studies have shown declining trends in semen quality in different parts of the world, for example in Scotland and France (Bostofte et al., 1983Go; Carlsen et al., 1992Go; Auger et al., 1995Go; Irvine et al., 1996Go), but significant geographical differences may exist. In the USA, a study indicated higher sperm counts in New York compared with California and Minnesota (Fisch et al., 1996Go). In France, a decline in semen quality was detected among Parisian semen donor candidates (Auger et al., 1995Go), whereas no change was observed in the Toulouse area (Bujan et al., 1996Go) where the average semen quality seemed to be worse than in Paris (Auger and Jouannet, 1997Go). In a worldwide meta-analysis (Carlsen et al., 1992Go) the highest sperm count since 1956 was reported in Finland. Finnish studies indicate (Suominen and Vierula, 1993Go; Vierula et al., 1996Go) that sperm counts in Finland have remained unchanged from 1958 to 1992 and are higher than elsewhere in Europe. Previous studies on semen quality have dealt with selected groups of men: volunteers enrolled after advertisement (Irvine et al., 1996Go; Paulsen et al., 1996Go; Lemcke et al., 1997Go), candidates for vasectomy (Sheriff, 1983Go; Fisch et al., 1996Go), semen donor candidates (Leto and Frensilli, 1981Go; Auger et al., 1995Go; Bujan et al., 1996Go; Van Waeleghem et al., 1996Go) or infertility patients (MacLeod and Wang, 1979Go; Bostofte et al., 1983Go; Ombelet et al., 1996Go; Berling and Wölner-Hanssen, 1997Go). Such studies may be flawed by selection bias.

It is uncertain whether time trends in semen quality are matched by a corresponding fall in biological fecundity measured as waiting time to pregnancy (TTP) for a couple. A recent study related semen quality to the fecundity of a couple (Bonde et al., 1998Go) and found decreasing TTP with increasing sperm concentration up to ~40x106/ml [this is also studied in an accompanied paper (Slama et al., unpublished data)]. Interestingly in the light of the semen quality studies, Finnish women have been found to have a shorter TTP than English women (Joffe, 1996Go). However, the populations and the TTP questions were not directly comparable, no control for known confounders was performed, and the British women were all <33 years old at the time of interview (the Finnish women were 20–40 years old) and were more often smokers.

In a joint European study among pregnant women, the longest TTP was found in Paris followed by East Germany, Northern Italy, West Germany, Denmark, Sweden and Rome. The highest risk of subfecundity (TTP >12 months) was found in Northern Italy, Germany and Denmark (Juul et al., 1999Go; Karmaus et al., 1999Go). A highly structured and validated questionnaire was developed and used in all of the study areas. However, Finland was not included, and no semen samples were obtained.

Conclusive studies of TTP and semen quality in unselected populations of fertile couples have not previously been conducted. This European study was therefore undertaken to describe possible differences in semen quality and waiting TTP among pregnant couples from Copenhagen (Denmark), Paris (France), Edinburgh (Scotland) and Turku (Finland) by co-ordinated standardized investigation procedures. Pregnant couples were chosen as study subjects because they appeared to constitute well-defined, easily approachable, comparable groups in the participating countries.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Questionnaires and semen samples
 Results
 Discussion
 Acknowledgements
 References
 
Recruitment
Women who were at least 3 months pregnant were recruited. The eligibility criteria for inclusion in the study were: male partner 20–45 years of age at the time of invitation, born in the country in which he was currently living, and couples residing in the local referral area of the hospital to which they were recruited. Furthermore, the current pregnancy had to be achieved without fertility treatment. Diseases in reproductive organs (including cryptorchidism, orchitis, epididymitis, surgery of the genital tract and pelvic inflammatory disease) and previous fertility treatment were not exclusion criteria for men or women. Pregnant women living in the local referral area of the four centres were invited to participate when they showed up for their first antenatal visit or `parent craft' class. At the visit the woman was informed about the study and written information was handed out. If she was interested in participating, she received self-administrated questionnaires for both her and her partner and was asked to book an appointment for her partner to deliver a semen sample and have a physical examination performed. On the day that the man attended, he returned the questionnaires (in Turku, the couples returned the questionnaires by mail and were then contacted to make an appointment for the man). Couples were recruited for at least 1 full calendar year in each country, between October 1996 and June 1998. The study was approved by the local ethics committees in the four countries and was in accordance with the Helsinki Declaration.

In Copenhagen and Paris, the women were attending regular antenatal visits at Rigshospitalet and Hôpital Cochin respectively. The couples from Edinburgh were approached as they were attending `Parent-Craft' classes run at the Royal Infirmary and Eastern general hospitals and outlying city general practitioner's clinics. In Turku, the women were contacted in the special maternity care units, which take care of most pregnant women. Except in Paris, the participants received economic compensation for their travel expenses, and/or lost working hours, according to local traditions within this field. A detailed description of the study is provided elsewhere (Jørgensen et al., 2000Go).


    Questionnaires and semen samples
 Top
 Abstract
 Introduction
 Materials and methods
 Questionnaires and semen samples
 Results
 Discussion
 Acknowledgements
 References
 
Examinations of the semen samples were standardized according to the World Health Organization (WHO) manual from 1992 (World Health Organization, 1992Go) modified by Jørgensen et al. (Jørgensen et al., 1997Go) and inter-laboratory differences in assessment of sperm concentration were controlled by an external quality control study (Jørgensen et al., 2000Go). Sperm concentration, volume, motility and morphology were assessed according to WHO, whereas sperm morphology was assessed using David's criteria (David et al., 1975Go), from which percentage normal and multiple anomalies index (MAI) was calculated (mean number of anomalies per abnormal spermatozoa).

The questionnaire was developed in English and translated into Danish, Finnish and French. The translated questionnaires were back translated to control for translation errors. The questionnaires included information on age at the start of the conception attempt, previous or current diseases of the reproductive system, length and regularity of the menstrual cycle, use of oral contraceptives, frequency of sexual intercourse during conception attempt, reproductive history, height and weight before pregnancy, education and working conditions and exposures. The categorization of the answers can be seen in Table IIGo. The TTP questions were phrased similarly to those in the European Studies of Infertility and Subfecundity where a structured questionnaire was designed and validated (Juul et al., 1999Go). The woman was asked: `Were you and your partner doing anything to avoid pregnancy at the time you became pregnant?' If the answer was yes the women stated what contraception they were using to avoid pregnancy. If not, the man and the woman were independently asked, `How many months did it take you/your partner to become pregnant? (From starting time until pregnancy)'. The response was in weeks, months and/or years and transformed into months. TTP was only defined for couples not using contraception when they conceived. Answers 0 and 1 month were grouped. The couples were asked to report on smoking and alcohol intake as average daily or weekly consumption during the time period when they were trying to conceive. Alcohol intake was measured as weekly number of half pints of beers, glasses of wine and measures of spirits. The total weekly alcohol intake (number of drinks) was calculated by summarizing the beer, wine and spirits intake.


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Table II. Differences in the distribution of potential confounding factors among 942 couples with planned pregnancies from four European countries
 
Body mass index (BMI) was calculated as weight in kilograms divided by the squared height in metres. Reported diseases in the female reproductive system associated with TTP (diseases or operations making it difficult to become pregnant, pelvic or Fallopian tube infection, endometriosis, diabetes mellitus, fibroma in the uterus and ruptured appendicitis) were transformed into one variable (present or not present). Self-reported diseases in male reproductive system or those found at the physical examination which were related to semen concentration (varicocele or hydrocele found at physical examination, gonorrhoea, parotitis as an adult affecting the testicles, cryptorchidism, testicular cancer, varicocele or operation for inguinal hernia, varicocele or torsion of the testis) were also transformed into one variable.

Statistical analysis
Differences in TTP (the outcome variable) in the four different cities (explanatory variable) were analysed. TTP was censored after 13 months, which is the time when fertility treatment is normally started. TTP in the four different cities was analysed by survival analysis techniques performed by logistic regression on the total number of observed months with the outcome `pregnant/not pregnant' (Scheike and Jensen, 1997Go). Fecundability is then the probability of obtaining a clinically recognized pregnancy in a month among couples not pregnant in the previous month. The fecundability odds ratio (FR) measures the odds of a conception within a month among couples from one city, divided by the odds among couples from another [fecundability/(1-fecundability)]. First, the unadjusted FR for the four cities was estimated and compared using logistic regression, and then a multiple logistic regression was undertaken, taking into account the different distribution of confounders in the four cities.

Potential confounders were examined in bivariate analyses by comparing TTP distributions among couples with and without the confounder being tested. The following were related to TTP at 10% significance level: male and female age, female alcohol intake, diseases in the reproductive system, parity, sperm concentration, proportion of morphologically normal spermatozoa, MAI of spermatozoa, regularity of the menstrual cycle, ever used oral contraceptives, frequency of sexual intercourse, female education, smoking and male self-reported psychological stress at work. Male education, smoking and alcohol intake and female BMI had no impact on TTP. These confounders were included in the multiple logistic regression analysis (all entered as dummy variables categorized as in Table IIGo) and excluded stepwise if the point estimates of the association between centres and fecundability changed by <10% after exclusion. Ever used oral contraceptives and female BMI were kept in the model, even though they did not affect the point estimate, as they were found to have an effect on fecundability in previous studies (Linn et al., 1982Go; Bracken et al., 1990Go; Jensen et al., 1999Go). FR values are presented with 95% confidence intervals (CI).

The multiple logistic regressions were performed and presented both with and without inclusion of semen quality variables (sperm concentration, proportion of normal spermatozoa, MAI index and period of abstinence) to check whether the observed differences could be attributed to differences in semen quality. We also treated length of TTP as a dichotomous variable with 12 months as the threshold and used multiple logistic regressions to calculate odds ratios for subfecundity.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Questionnaires and semen samples
 Results
 Discussion
 Acknowledgements
 References
 
In Paris, among 1368 pregnant women who were invited, 590 (47%) completed the questionnaire, and of these 590 women, 208 (15%) male partners provided a semen sample. The men who delivered a semen sample had a higher socio-economic status than the men who only answered the questionnaire. In Turku and Copenhagen, 1422 and 809 invitations were submitted to the antenatal and parental classes respectively. The number of invitations handed out in Edinburgh was not recorded (Table IGo). Sperm concentration and questionnaire information were finally known for 1081 couples, of which 275 were from Turku, 348 from Copenhagen, 250 from Edinburgh and 208 from Paris. Of these 237, 302, 212 and 191 respectively reported their waiting TTP (Table IGo). The couples in Copenhagen were recruited earlier in pregnancy than couples from the three other cities. The TTP distribution in the four different cities is seen in Figure 1Go. The French couples took longer to conceive than the couples from the three other countries. Respectively 83.1, 82.8, 83.0 and 79.1% of couples from Turku, Copenhagen, Edinburgh and Paris conceived in 6 months, whereas 10.1, 7.9, 7.5 and 9.9% waited >12 months to conceive.


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Table I. Enrolment and participation characteristics among fertile couples from four European centres
 


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Figure 1. Cumulative proportion of couples pregnant according to the number of months of attempt, censored at 13 months, in Turku (Finland), Copenhagen (Denmark), Edinburgh (Scotland) and Paris (France).

 
Large differences were found in the distribution of the different confounders among couples from the four different centres (Table IIGo). Finnish couples were the youngest, but the Scottish women had the lowest parity. Danish women had the highest frequency of diseases in the reproductive system. Danish and Scottish couples had the highest alcohol intake. Danish women were most often smokers, whereas French men smoked the most. French couples had the highest education level and French women the lowest BMI. Finnish men had the highest sperm concentration, and Finnish women most often reported having irregular menstrual periods. The French men most often reported self-experienced psychological stress at work. No differences between cities were found in frequency of sexual intercourse and male diseases in reproductive organs.

Overall comparisons of the four cities showed small and statistically weak differences in the unadjusted FR between cities, but exhibited clear differences in FR after adjustment (Table IIIGo). In particular, adjustment for female education, MAI and frequency of sexual intercourse changed the estimates of fecundability between Paris and the other three cities. After adjustment for confounders, the couples from Paris had a decreased probability of conception (waited longer to become pregnant) compared with couples from the other three cities, although this was only significantly different from couples from Edinburgh and Copenhagen, whereas no differences in probability of conception between couples from the three other cities were found. FR for the couples from Paris was 0.73 (95% CI: 0.50–1.06), 0.58 (95% CI: 0.41–0.82), and 0.64 (95% CI: 0.44–0.91) compared with the couples from Turku, Copenhagen and Edinburgh respectively. This association was adjusted for the number of months elapsed since the beginning of the attempt at pregnancy (entered as a categorical variable), male and female age, female parity and diseases in the reproductive system, regularity of the menstrual cycle, ever used oral contraceptives, frequency of sexual intercourse, female education, BMI, alcohol intake and smoking (all entered as dummy variables categorized as in Table IIGo) and logarithmically transformed sperm concentration and period of abstinence, proportion of normal spermatozoa and MAI (all semen parameters including period of abstinence entered as continuous variables). As the association could be caused by differences in semen quality in the four cities, the analyses were performed without adjusting for semen quality parameters, which did not change the direction of the results (Table IIIGo).


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Table III. Unadjusted and adjusted fecundability odds ratios (FR) and 95% confidence intervals (95% CI) among conceiving couples from four different European countries
 
No differences in the unadjusted and adjusted odds ratio centres were found (data not shown). We repeated the analyses among subgroups of women with regular menstrual cycles or with no diseases of the reproductive system, which did not change the results. We also analysed primi- and multiparous for subfecundity among the couples from the four different centres were found (data not shown). We repeated the analyses among subgroups of women with regular menstrual cycles or with no diseases of the reproductive system, which did not change the results. We also analysed primi- and multiparous women separately. Among primiparous women, no significant difference in FR was found after control for confounders, whereas among multiparous women the difference between the four centres was even more pronounced than among all women.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Questionnaires and semen samples
 Results
 Discussion
 Acknowledgements
 References
 
In this joint European study with a standardized protocol and external quality control of the semen analysis, we found that couples from Paris had a longer TTP than couples from Turku, Copenhagen and Edinburgh. Large differences in age, sexually transmitted diseases, reproductive history and semen quality existed between couples from the four centres and it was only after adjustment for these characteristics that the differences were observed. The adjustment procedure implies that the findings cannot be explained by differences in the factors adjusted for, and therefore differences in semen quality between centres are not likely to explain our results.

Although our results indicate that the reduced fecundability in Paris cannot be attributed to differences in semen quality and socio-economic factors between centres, we cannot offer any explanation for our findings. We can speculate that it could be caused by differences in environmental factors, selection due to low participation rates or psychological stress, which could not be properly assessed in our study.

Participation rates varied considerably between centres and were low, which is expected when men are requested to deliver a semen sample. In Edinburgh the participation rate could not be assessed, as the number of invitations handed out was unfortunately not recorded. This may have introduced a bias of unknown direction and magnitude that may explain our findings, as the couples are unlikely to represent the underlying general population attending the antenatal clinics in the four cities and thereby not the fertile part of the general population of each (Larsen et al., 1998Go). The couples from Paris were recruited in a hospital from the 14th Arrondissement, which is a part of Paris attracting academics (middle or upper class people). Seventy-five percent of the men from Paris had a university degree. Higher socio-economic status has, however, been related to shorter TTP (Baird and Wilcox, 1985Go; Joffe and Li, 1994Go). We controlled for differences in education but our information about education was not very detailed. Also, the mean TTP and the percentage not pregnant in 6 and 12 months among the couples from Paris who completed the questionnaire, but did not deliver a semen sample, was 3.7 months, 17.0 and 5.0%, respectively compared with 4.1 months, 21.1 and 10.0% among couples who delivered a semen sample. Those percentages are more like the observed values for Copenhagen, Turku and Edinburgh, which suggest that the findings may be explained by selection bias.

Our study focused on male reproductive health and female factors associated with fecundity (e.g. diseases in reproductive system or regularity of the menstrual cycle) that were retrospectively assessed by questionnaire. For example, use of oral contraceptives as last contraceptive method has been found to prolong TTP in the first three cycles (Linn et al., 1982Go; Bracken et al., 1990Go) and we only obtained information on `ever used oral contraceptives'. Therefore, the observed differences may be explained by differences in female factors not adequately controlled for. Also, differences in the way the couples responded to the TTP question may explain our findings. However, TTP is easily obtained by self-administered standardized questionnaires or by interview in retrospective surveys. A recall time of up to several years (Joffe et al., 1993Go) appears feasible at population level, and as the women were questioned in pregnancy, we find no reason to believe that the quality of recall is different in the four cities. Furthermore, TTP studies rely upon the assumption that exposures affecting fecundability have an impact on the entire distribution and not only affect the risk of sterility. Sterility cannot be measured in retrospective TTP surveys, as only women who achieved a pregnancy are included. So, if differences in the proportion of sterile couples without a corresponding increase in TTP between the four cities exist, it cannot be studied using this design. The reason for choosing a pregnant population was that it is an easy target population to assess with good compliance.

In addition, TTP is only reported among couples with a planned pregnancy and if there are differences in the percentage of planned pregnancy between countries, this may affect our results. In the previous European TTP study (Juul et al., 1999Go) no differences in the percentage of planners were found between Denmark and Paris. However, the percentages of couples with a TTP of 0 months varied considerably between cities in this study (from 8% in Paris to 18% in Copenhagen), which suggests that more couples in Paris were `planners'. Planners are also more likely to be of higher socio-economic status and to remember their TTP, as demonstrated by the couples from Paris (all provided information about TTP). Weinberg et al. have suggested the analysis of TTP data after exclusion of couples who reported a TTP of 0 months, as these are more likely not to be planners (Weinberg et al., 1993Go). We repeated the analyses without these couples, which made the differences between Paris and the other three cities less marked, suggesting that differences in planning habits between countries may exist.

The TTP questions used in this study have previously been used and validated in the European Studies of Infertility and Subfecundity (Juul et al., 1999Go) and were translated from and back to English. Therefore, language differences are unlikely to have caused comparability problems. However, cultural differences, i.e. use of contraceptive methods, lifestyle habits etc., might lead to differences in reporting. For example, 67% of French women compared with 16% of women from the other three countries reported no alcohol intake.

The incidences of testicular cancer (Adami et al., 1994Go; Forman and Møller, 1994Go) and possibly hypospadias and cryptorchidism (Ansell et al., 1992Go) have recently increased, whilst semen quality may have declined. It has been speculated that the adverse changes in male reproductive health are attributable to altered exposures to endocrine disrupting agents during fetal development and childhood (Sharpe and Skakkebæk, 1993Go). In the search for environmental factors of importance for fecundity, including endocrine disrupters, geographical variation may give important clues and future studies on differences in exposures are needed.

It is interesting that our results correspond to the findings of a previous European study of Infertility and Subfecundity, using the same TTP question, which found longer TTP but not a higher risk for subfecundity among couples from Paris (Juul et al., 1999Go; Karmaus et al., 1999Go). The participation rates in that study were much higher than in the present, but no semen samples were collected, so variations could be due to differences in semen quality. Our study found reduced fecundity in Paris both with and without control for semen quality, indicating that the differences cannot be explained by differences in semen quality. We found no difference in the proportion of subfecund couples between cities, but this analysis had less statistical power as it is derived from TTP by dichotomizing the information obtained (waiting more or less than 12 months) and thereby disregarding valuable and more detailed information. Also, no couples from Finland, where semen quality was found to be higher than anywhere else in Europe (Suominen and Vierula, 1993Go; Vierula et al., 1996Go; Jensen et al., 2000Go; Jørgensen et al., 2000Go), were included in the previous EU study. Studies comparing TTP and semen quality among Finnish and English or Danish couples found higher fecundity among Finnish than English women and a better semen quality among Finnish than Danish men (Joffe, 1996Go; Jensen et al., 2000Go). However, the studies compared data from previously published studies and therefore different recruitment methods and questionnaires were used; TTP measures have been found to depend strongly upon how the key questions are phrased (Juul et al., 1999Go). In our study, the Finnish couples did not have a better fecundity than couples from Copenhagen or Edinburgh, even though sperm concentration among men from Turku was significantly better than among the men from the three other areas (Jørgensen et al., 2000Go).

In conclusion, we found lower fecundability, measured as time to pregnancy, in the Paris area compared with Turku, Copenhagen and Edinburgh after control for differences in confounders. A previous EU study also found that couples living in Paris waited longer to conceive. As differences in participation rates and distribution of confounders, including parity between countries, existed selection bias may be a likely explanation and future studies examining geographical differences in fecundability and causes for these differences are urgently needed.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Questionnaires and semen samples
 Results
 Discussion
 Acknowledgements
 References
 
All the volunteers participating in the study are thanked. Without their participation the study would not have been possible. Aleksander Giwercman is acknowledged for co-ordinating the sperm quality control study of the sperm concentrations. This study was supported by contract BMH4-CT96-0314 from the European Union, the Danish Medical Research Council, grant no. 9700833, and the Finnish Research Programme on Environmental Health, Academy of Finland.


    Notes
 
9 To whom correspondence should be addressed. E-mail: tkjensen{at}health.sdu.uk Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Questionnaires and semen samples
 Results
 Discussion
 Acknowledgements
 References
 
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Submitted on March 8, 2001; accepted on August 13, 2001.