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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: environmental health/fertility/population surveillance/pregnancy rate/time factors
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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., 1998) 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TTP with increasing sperm concentration up to ~40x106/ml [this is also studied in an accompanied paper (Slama et al., unpublished data)].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, 1996
). 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 2040 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., 1999; Karmaus et al., 1999
). 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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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., 2000).
![]() |
Questionnaires and semen samples |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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 II. 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., 1999
). 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.
|
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, 1997). 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 II) 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., 1982
; Bracken et al., 1990
; Jensen et al., 1999
). 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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
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 III). 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: 0.501.06), 0.58 (95% CI: 0.410.82), and 0.64 (95% CI: 0.440.91) 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 II
) 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 III
).
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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., 1998). 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, 1985
; Joffe and Li, 1994
). 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., 1982; Bracken et al., 1990
) 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., 1993
) 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., 1999) 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., 1993
). 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., 1999) 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., 1994; Forman and Møller, 1994
) and possibly hypospadias and cryptorchidism (Ansell et al., 1992
) 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, 1993
). 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., 1999; Karmaus et al., 1999
). 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, 1993
; Vierula et al., 1996
; Jensen et al., 2000
; Jørgensen et al., 2000
), 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, 1996
; Jensen et al., 2000
). 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., 1999
). 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., 2000
).
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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Notes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Ansell, P.E., Bennett, V., Bull, D. et al. (1992) Cryptorchidism: a prospective study of 7500 consecutive male births, 19848. Arch. Dis. Child., 67, 892899.[Abstract]
Auger, J. and Jouannet, P. (1997) Evidence for regional differences of semen quality among fertile French men. Federation Francaise des Centres d'Etude et de Conervation des Oeufs et du Sperme Humains. Hum. Reprod., 12, 740745.[Abstract]
Auger, J., Kunstmann, J.M., Czyglik, F. and Jouannet, P. (1995) Decline in semen quality among fertile men in Paris during the past 20 years. N. Engl. J. Med., 332, 281285.
Baird, D.D. and Wilcox, A.J. (1985) Cigarette smoking associated with delayed conception. JAMA, 253, 29792983.[Abstract]
Berling, S. and Wölner-Hanssen, P. (1997) No evidence of deteriorating semen quality among men in infertile relasionships during the past decade: a study of males from Southern Sweden. Hum. Reprod., 12, 10021005.[ISI][Medline]
Bonde, J.P., Ernst, E., Jensen, T.K. et al. (1998) The relation between semen quality and fertility. A population based study of 430 first-pregnancy planners. Lancet, 352, 11721177.[ISI][Medline]
Bostofte, E., Serup, J. and Rebbe, H. (1983) Has the fertility of Danish men declined through the years in terms of semen quality? A comparison of semen qualities between 1952 and 1972. Int. J. Fertil., 28, 9195.[ISI][Medline]
Bracken, M.B., Hellenbrand, K.G. and Holford, T.R. (1990) Conception delay after oral contraceptive use: the effect of estrogen dose. Fertil. Steril. 53, 2127.[ISI][Medline]
Bujan, L., Mansat, A., Pontonnier, F. and Mieusset, R. (1996) Time series analysis of sperm concentration in fertile men in Toulouse, France between 1977 and 1992. Br. Med. J., 312, 471472.
Carlsen, E., Giwercman, A., Keiding N. and Skakkebæk, N.E. (1992) Evidence for decreasing quality of semen during past 50 years. Br Med. J., 305, 609613.[ISI][Medline]
David, G., Bisson, J.P. and Czyglik, F. (1975) Anomalies morphologiques du spermatozoïde humain. 1. Prognitionen pour un système de classification. J. Gynecol. Obstet. Biol. Reprod., 4, 1736.
Fisch, H., Goluboff, E.T., Olson, J.H. et al. (1996) Semen analyses in 1283 men from the United States over a 25-year period: no decline in quality. Fertil. Steril., 65, 10091014.[ISI][Medline]
Forman, D. and Møller, H. (1994) Testicular cancer. Cancer. Surv., 19/20, 323341.
Irvine, S., Cawood, E., Richardson, D. et al. (1996) Evidence of deteriorating semen quality in the United Kingdom: birth cohort study in 577 men in Scotland over 11 years. Br. Med. J., 312, 467471.
Jensen, T.K., Scheike, T., Keiding, N. et al. (1999) Fecundability in relation to body mass and menstrual cycle patterns. Epidemiology, 10, 422428.[ISI][Medline]
Jensen, T.K., Vierula, M., Hjollund, N.H. et al. and The Danish First Pregnancy Planner Study Team (2000) Semen quality Danish and Finnish men attempting to conceive. Eur. J. Endocrinol., 142, 4752.[ISI][Medline]
Joffe, M. (1996) Decreased fertility in Britain compared with Finland. Lancet, 347, 15191522.[ISI][Medline]
Joffe, M. and Li, Z. (1994) Male and female factors in fertility. Am. J. Epidemiol., 140, 921929.[Abstract]
Joffe, M., Villard, L., Li, Z. et al. (1993) Long-term recall of time-to-pregnancy. Fertil. Steril., 60, 99104.[ISI][Medline]
Jørgensen, N., Auger, J., Giwercman, A. et al. (1997) Semen analysis performed by different laboratory teams: an intervariation study. Int. J. Androl., 20, 201208.[ISI][Medline]
Jørgensen, N., Andersen, A.G., Eustache, F. et al. (2000) Regional differences in semen quality in Europe. Hum. Reprod., 16, 10121029.
Juul, S., Karmaus, W., Olsen, J. and The European Infertility and Subfecundity Study Group (1999) Regional differences in waiting time to pregnancy: pregnancy-based surveys from Denmark, France, Germany, Italy and Sweden. Fertil. Steril., 14, 12501254.
Karmaus, W., Juul, S. and The European Infertility and Subfecundity Group (1999) Infertility and subfecundity in population-based samples from Denmark, Germany, Italy, Poland and Spain. Eur. J. Public Health., 9, 229235.[Abstract]
Larsen, S.B., Abell, A. and Bonde, J.P. (1998) Selection bias in occupational sperm studies. Am. J. Epidemiol., 147, 681685.[Abstract]
Lemcke, B., Behre, H.M. and Nieschlag, E. (1997) Frequently subnormal semen profiles of normal volunteers recruited over 17 years. Int. J. Androl., 20, 144152.[ISI][Medline]
Leto, S. and Frensilli, F.J. (1981) Changing parameters of donor semen. Fertil. Steril., 36, 766770.[ISI][Medline]
Linn, S., Schoenbaum, S.C., Monson, R.R. et al. (1982) Delay in conception for former `Pill' users. JAMA, 247, 629632.[Abstract]
MacLeod, J. and Wang, Y. (1979) Male fertility potential in terms of semen quality: a review of the past, a study of the present. Fertil. Steril., 31, 103116.[ISI][Medline]
Ombelet, W., Maes, M., Vandeput, H. et al. (1996) Chronobiological fluctuations in semen parameters with a constant abstinence period. Arch. Androl., 37, 9196.[ISI][Medline]
Paulsen, C.A., Berman, N.G. and Wang, C. (1996) Data from men in greater Seattle area reveals no downward trend in semen quality: further evidence that deterioration of semen quality is not geographically uniform. Fertil. Steril., 65, 10151020.[ISI][Medline]
Scheike, T. and Jensen, T.K. (1997) A discrete survival model with random effects: an application to time to pregnancy. Biometrics, 53, 318329.[ISI][Medline]
Sharpe, R.M. and Skakkebæk, N.E. (1993) Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract? Lancet, 341, 13921395.[ISI][Medline]
Sheriff, D.S. (1983) Setting standards of male fertility I. Semen analyses in 1500 patientsa report. Andrologia, 15, 687692.[ISI][Medline]
Suominen, J. and Vierula, M. (1993) Semen quality of Finnish men. Br. Med. J., 306, 1579.[ISI][Medline]
Van Waeleghem, K., De Clercq, N., Vermeulen, L. et al. (1996) Deterioration of sperm quality in young healthy Belgian men. Hum. Reprod., 11, 325329.[Abstract]
Weinberg, C.R., Baird, D.D. and Rowland, A.S. (1993) Pitfalls inherent in retrospective time-to-event studies: the example of time to pregnancy. Stat. Med., 12, 867879.[ISI][Medline]
Vierula, M., Niemi, M., Keiski, A. et al. (1996) High and unchanged sperm counts of Finnish men. Int. J. Androl., 19, 1117.[ISI][Medline]
World Health Organization (1992) WHO Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction. Cambridge University Press, Cambridge.
Submitted on March 8, 2001; accepted on August 13, 2001.