1 Department of Occupational Medicine, Aarhus University Hospital, DK-8000, Aarhus, 2 Department of Gynaecology and Obstetrics, Aarhus University Hospital, DK-8200, Aarhus, 3 The Fertility Clinic, Copenhagen University Hospital, Herlev, DK-2730, Herlev, 4 The Fertility Clinic, Copenhagen University Hospital, Rigshospitalet, DK-2100, Copenhagen and 5 Danish Epidemiology Science Centre, Aarhus University, DK-8000, Aarhus, Denmark
6 To whom correspondence should be addressed at: Unit of Social Medicine, Department of Public Health, Olof Palmes Allé 17, DK-8200 Aarhus N, Denmark. Email: nhh{at}ag.aaa.dk
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Abstract |
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Key words: IVF/miscarriage/paternal occupational exposure/pregnancy survival/welding
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Introduction |
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In humans 30% of implanted embryos are lost, and
2/3 of them are lost before the woman knows that she is pregnant (Weinberg and Wilcox, 1998
). Even small, but systematic differences, in the time of pregnancy ascertainment among groups that are compared may therefore introduce bias in traditional studies that only include clinically recognised pregnancies. Several population based studies have focused on paternal welding exposure as a possible candidate for paternally mediated spontaneous abortion in humans, but results have been ambiguous (Bonde, 1993
; Hjollund et al., 1995
; Hjollund et al., 2000
). In a study including the early phase of 280 pregnancies, an increased risk of spontaneous abortion was found if the father welded stainless steel [adjusted risk ratio (RR) 3.5; 95%CI 1.39.1]. However, the number of paternally exposed pregnancies was limited (n=23). IVF treatment provides opportunities to follow a large number of pregnancies from the time of conception. The male partner is not medically treated and is less likely to alter occupational activities in the course of treatment. Consequently, IVF pregnancies constitute a possible model for research in paternal risk factors. We compared the survival of pregnancies in the Danish In Vitro Fertilization Registry with respect to paternal exposure to welding.
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Materials and methods |
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Selection of treatment cycles
Treatment with donated eggs, fertilization with donor sperm or thawed eggs were excluded. We also excluded treatment cycles ending with ectopic pregnancies, mola or induced abortion (1.9% of pregnancies). Treatments initiated after 31 December 2000 were excluded to insure complete follow-up in the health registers. Further details are provided elsewhere (Hjollund et al., 2004). The following register information were retrieved from the Danish Central Population Register (CPR): postal address, actual marital status, CPR numbers of any actual and any previous spouses and the date of changes in marital status, and CPR number of any man living at the same address as the IVF treated woman at the day the file was processed (October 2001) as well as at the time of her first hCG positive treatment cycle. The identity of the father is not recorded in the DIVF register, but Danish legislation requires that couples treated with IVF should be living together at the time of treatment. If the woman was married at the date of the first treatment, the spouse was considered to be the father (70.6%). If the woman was unmarried but cohabiting with one man at the time of the first treatment, the cohabiting man was considered to be the father (29.4%), otherwise the woman was excluded. For ethical reasons only couples who were still married or cohabiting in 2001 were selected to receive the questionnaire, except for a few couples who had declined contact from researchers (1.2%). A total of 5879 women who obtained at least one pregnancy fulfilling the criteria and who received the first treatment after January 1, 1996 were included (Table I).
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Based on type of company, trade and job function, each father was assigned a Danish ISCO code. Fathers with ISCO codes as metal workers (7210 to 7233) were selected together with fathers who had marked welding at metals in a list of job functions. On April 22, 2002 these 512 men were mailed a second 18 item questionnaire that focused on current welding exposure with questions about welded material [stainless steel (SS), mild steel (MS), other], welding method (manual metal arch, MIG/MAG, TIG, other), welding time (h/day, years with welding), and safety precautions (exhaust ventilation, airstream helmet). A total of 319 questionnaires were received after one reminder (response ratio 76.5%). Based on actual job situation, each man was classified as SS welder, MS but not SS welder, other welder, or not welder. In other analyses only welders who had had the same working conditions for the last 5 years were included in the exposed group. Also use of safety precautions and cumulated number of years with stainless steel welding was used as exposure indices.
Statistical methods
For each couple only the first pregnancy was selected for analysis (n=4007 pregnancies). The unexposed group were respondents who had answered no to all specific occupational exposures in the basic questionnaire (n=2925). We also used an alternative reference group of respondents to three other trade-specific questionnaires, who had thus been subjected to the same selection mechanisms as the metal workers (farmers, green house workers, and workers in the reinforced plastic industry, n=285 pregnancies). Pregnancy survival curves were constructed by the KaplanMeier method (Allison, 1995). Pregnancies were right-censored at completion of the 28th week, and 27.9% of all hCG-detected pregnancies were terminated before that time and considered a spontaneous abortion. We used this definition of spontaneous abortion to allow comparison with previous studies, but in additional analyses we also used the current definition based upon a cut-off at 20 gestational weeks. A positive hCG test with no clinical recognised pregnancy was encountered in 14.7% of pregnancies and was assigned a survival time of 29 days (Hjollund et al., 2004
). Another 5.5% became clinically pregnant but had no registered abortion or birth. A survival time of 50 days was assigned to these abortions (Hjollund et al., 2004
). Abortion rate ratios were calculated by Cox regression (SAS PROC PHREG) (Allison, 1995
) after taking a priori selected potential confounding factors into consideration: male and female age, smoking, coffee consumption, alcohol consumption, and number of embryos transferred (Table I). Difference between clinics, e.g. cut-off level in hCG analyses and timing of ultrasonography, was adjusted for by including clinic id number in the STRATA statement. The proportional risk assumption was evaluated by including time dependent covariates in the model (Allison, 1995
).
The study was approved by the Research Ethics Committee and the Danish Data Protection Agency.
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Results |
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Discussion |
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The studies differ, however, substantially with respect to the process of fertilization. In normal pregnancies only one ovum is fertilized, except in case of twinning, while in IVF pregnancies the typically two transferred embryos are usually selected from a number of candidate embryos. A Dutch study of paternal exposure to pesticides found decreased fertilization rate, but increased implantation rate in two partly overlapping groups of IVF patients (Tielemans et al., 1999; Tielemans et al., 2000
). The authors suggested that ability of fertilization and successful implantation may share mechanisms. In that case an exposure (e.g. paternal exposure to pesticides or hexavalent chromium) that compromises the first step (fertilization) will result in a population of survived embryos, which may be more viable (Selevan and Lemasters, 1987
). We have previously reported a borderline statistically significant protective effect of paternal exposure to pesticides and growth retardants in the same IVF material (Hjollund et al., 2004
). The tendency in our data towards increased pregnancy survival in exposed pregnancies could be explained by such a biological mechanism, which may be augmented by the active selection of the (normally two) most promising embryos for transfer by the laboratory technician. Information on fertilization is not recorded in the DIVF register.
Validity of the IVF model
The external validity of our results depends on comparability of IVF pregnancies and normal pregnancies with respect to causes leading to spontaneous abortion. Spontaneous abortion occurred in 30% of reference pregnancies, similar to what has been reported in other IVF studies (Liu and Rosenwaks, 1991
) as well as in non-IVF pregnancies, when early pregnancy losses are included (Weinberg and Wilcox, 1998
). On the other hand, in IVF pregnancies two or more embryos are usually transferred (Danish National Board of Health, 2002
). If more than one embryo is successfully implanted and results in a hCG positive pregnancy, a spontaneous abortion is only registered in case of death of all fetuses. Thus, we will overestimate the survival of the individual fetus, and although we obtained similar findings when stratified on the number of transferred embryos, it should be acknowledged that in >80% of cases more than one embryo was transferred. Little is known about physiological processes involved in human gestation in the period from implantation of the blastocyst until a pregnancy is detectable, and the initial adhesion of the blastocyst has never been observed (Robertson et al., 1985
; Norwitz et al., 2001
). Moreover, mechanisms responsible for early embryonal loss may be different in IVF pregnancies and natural pregnancies, and findings based upon IVF data need not be generalized to pregnant women at large. In future studies of causes for spontaneous abortion based on IVF pregnancies, information on fertilization should be included.
In conclusion, we could not corroborate our previous finding of increased risk for spontaneous abortion attributable to paternal stainless steel welding. The welding intermittence was relatively low and most participants used the prescripted protective measures. The findings are in all circumstances restricted to countries with similar standards of protection.
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Acknowledgements |
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References |
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Submitted on June 25, 2004; accepted on November 25, 2004.