Risk of adverse pregnancy outcome in women exposed to livestock: a study within the Danish National Birth Cohort.

Maternal infection in pregnancy is a known risk factor for adverse pregnancy outcome, and a number of zoonotic pathogens may constitute a risk to pregnant women and their fetuses. With animal contact as a proxy for the risk of zoonotic infection, this study aimed to evaluate pregnancy outcome in women with self-reported occupational or domestic contact with livestock compared to pregnant women without such contact. The Danish National Birth Cohort collected information on pregnancy outcome from 100 418 pregnant women (1996-2002) from which three study populations with occupational and/or domestic exposure to livestock and a reference group of women with no animal contact was sampled. Outcome measures were miscarriage, very preterm birth (before gestational week 32), preterm birth (before 37 gestational weeks), small for gestational age (SGA), and perinatal death. Adverse reproductive outcomes were assessed in four different exposure groups of women with occupational or domestic exposure to livestock with no association found between exposure to livestock and miscarriage, preterm birth, SGA or perinatal death. These findings should diminish general occupational health concerns for pregnant women with exposures to a range of different farm animals.

Prevalence of Coxiella burnetii in women exposed to livestock animals, Denmark, 1996 to 2002.

Q fever is a zoonotic infection which can pose a danger to pregnant women. To our knowledge, Denmark has never experienced a clinically verified Q fever outbreak. We aimed to quantify risk of infection in pregnant women occupationally and environmentally exposed to Coxiella burnetii. The Danish National Birth Cohort collected blood samples from 100,418 pregnant women in the period 1996 to 2002. We sampled 195 women with occupational exposure to livestock (veterinarians and female farmers), 202 women with domestic exposure (dairy cattle and/or sheep) and a random sample of 459 unexposed women. Samples were screened for antibodies against C. burnetii by commercial enzyme-linked immunosorbent assay. Positive samples were confirmed by immunofluorescence (cut-off titre ≥1:128). The proportion of seropositive women was higher in the occupationally exposed (47.2% seropositive; relative risk (RR): 9.8; 95% confidence interval (CI): 6.4­15.2) and the domestically exposed population (32.2% seropositive; RR: 6.7; 95% CI: 4.3­10.6) than in unexposed women (4.8% seropositive). We found a high prevalence of antibodies to C. burnetii among pregnant women with occupational or domestic exposure to cattle and/or sheep compared with unexposed pregnant women. Our findings suggest that contact to livestock is a risk factor for C. burnetii infection in Denmark.

Fatigue in out-patients with inflammatory bowel disease is common and multifactorial.

BACKGROUND: Patients with inflammatory bowel disease (IBD) often complain of fatigue. AIM: To investigate the prevalence and characteristics of fatigue among IBD out-patients in Scandinavia and to provide normative values for fatigue in IBD patients. METHODS: A cross-sectional study was conducted on 425 IBD patients from six out-patient centres in Denmark, Norway and Sweden. Fatigue was measured using the Multidimensional Fatigue Inventory. The patients were also screened for anaemia and iron deficiency. Each centre included approximately 5% of their IBD cohort. The patients were enrolled consecutively from the out-patient clinics, regardless of disease activity and whether the visit was scheduled. The fatigue analysis was stratified for age and gender. RESULTS: Using the 95th percentile of the score of the general population as a cut-off, approximately 44% of the patients were fatigued. When comparing the IBD patients with disease activity to the IBD patients in remission, all dimensions of fatigue were statistically significant (P < 0.05). Being anaemic or iron deficient was not associated with increased fatigue. Being a male patient with ulcerative colitis treated with corticosteroids was a strong determinant for increased fatigue. The normative ranges for IBD fatigue were calculated. CONCLUSIONS: Fatigue in IBD is common regardless of anaemia or iron deficiency. Fatigue in IBD is most marked for patients < 60 years of age. Stratifying for gender and age is necessary when analysing fatigue, as fatigue is expressed differently between groups.

Laboratory work and pregnancy outcomes: a study within the National Birth Cohort in Denmark.

AIMS: To examine pregnancy outcomes in women doing laboratory work. METHODS: Using data from the Danish National Birth Cohort (1997-2003), the authors conducted a prospective cohort study of 1025 female laboratory technicians and 8037 female teachers (as reference). The laboratory technicians were asked about laboratory work tasks during pregnancy in an interview (at around 16 weeks of gestation). Pregnancy outcomes were obtained by linking the cohort to the national registers. Hazard ratios (HRs) of late fetal loss and diagnosing of congenital malformations were calculated by using Cox regression, and odds ratios (ORs) of preterm birth and small for gestational age were calculated by using logistic regression. RESULTS: Overall, there were no significant differences in pregnancy outcomes between laboratory technicians and teachers. However, we found that laboratory technicians working with radioimmunoassay or radiolabelling had an increased risk of preterm birth (OR = 2.2, 95% CI 0.8 to 6.2 for radioimmunoassay, and OR = 1.9, 95% CI 0.8 to 4.6 for radiolabelling) and "major" malformations (HR = 2.1, 95% CI 1.0 to 4.7 for radioimmunoassay, and HR = 1.8, 95% CI 0.9 to 3.7 for radiolabelling). The ORs of preterm birth doubled for women working with these tasks every day or several times a week. When an exposure matrix was applied, an increased risk of "major" malformations for exposure to organic solvents was seen. CONCLUSIONS: The results did not indicate any high risk of reproductive failures in laboratory technicians in general. Exposure to radioisotopes may carry a high risk of preterm birth and congenital malformations. This finding deserves further investigation.

Using infertile patients in epidemiologic studies on subfecundity and embryonal loss.

Subfecundity is a frequent and serious problem that may sometimes be preventable, but we need to know more about its determinants. Different epidemiologic designs are available. The best of these use prospectively collected data from the population, but they are time consuming, expensive and often hampered by low-participation rates. Most patients undergoing infertility treatment are closely monitored for clinical reasons, making it feasible to use secondary data to study the period from conception to implantation and pregnancy. In spite that infertility patients are highly selected, there are specific exposure-effect relations that can be studied in cohorts of infertility patients. These patients offer a potentially useful setting for studying exposures that operate late in fertilization, whereas the designs may be inadequate to identify exposures that cause reduced sperm counts, anovulation and total occlusion. The clinical sampling and the treatment set limitations for what can be studied. In certain situations, infertile patients can, however, provide useful epidemiologic evidence for learning about the causes of subfecundity.

Spontaneous abortion in IVF couples--a role of male welding exposure.

BACKGROUND: Fume from welding of stainless steel contains hexavalent chromium, which in animal studies can induce paternally mediated spontaneous abortion. Human studies have shown conflicting results. The best studies include early pregnancy experience, but these are expensive to conduct. In vitro fertilization (IVF) provides new design opportunities. Our aim was to study pregnancy survival in IVF treated women with respect to paternal welding exposure. METHODS: We mailed a questionnaire to 5879 couples from the Danish IVF register that covers all IVF treatments after 1993 (response ratio 68.2%). A subgroup of male metal workers received a second questionnaire on exposure to welding (n = 319 men, response ratio 77%). Information on outcome was collected from national health registers. Survival of the first hCG-positive pregnancy was analysed using Cox regression. RESULTS: The proportion of pregnancies terminated by spontaneous abortion before 28 gestational weeks was 18% (n = 91 pregnancies) and 25% (n = 128) in pregnancies with paternal exposure to stainless steel welding and mild steel welding, respectively. In the reference group of 2925 pregnancies the abortion ratio was 28%. The risk ratio for pregnancies with paternal exposure to stainless steel was 0.6 (95% CI 0.4-1.0). CONCLUSIONS: We found no increased risk of spontaneous abortion in IVF treated women, who became pregnant by a man exposed to welding of any sort. Since the process of fertilization and selection of IVF pregnancies differs from natural pregnancies the negative results need not apply to other pregnancies.

Pesticide exposure in male farmers and survival of in vitro fertilized pregnancies.

BACKGROUND: Male-mediated spontaneous abortion is well described among animals, but less well documented in humans. Studies that include early pregnancy experience are expensive to conduct, but IVF provides new opportunities. MATERIALS AND METHODS: The Danish IVF register covers all IVF treatments performed after 1993. We mailed a questionnaire to 5879 women (response rate 68.2%). A subgroup of exposed male partners received a questionnaire on specific exposure to pesticides and growth retardants (n = 128 men, response rate 81.3%). Information on outcome was collected from national health registers. Survival of the first HCG-positive pregnancy was analysed using Cox regression. RESULTS: The proportion of pregnancies terminated by spontaneous abortion before 28 gestational weeks was 19.7% (n = 66 pregnancies), 19.7% (n = 61), 21.3% (n = 47) and 22.2% (n = 18) in pregnancies with paternal exposure to herbicides, fungicides, pesticides and growth retardants. respectively. In the reference group of 2925 pregnancies, the abortion rate was 28.4%. The differences in survival were not statistically significant. CONCLUSIONS: We found no increased risk of spontaneous abortion in IVF-treated women attributable to paternal agricultural application of pesticides and growth retardants. Exposure to potentially harmful pesticides in Denmark is relatively low, and the findings are restricted to countries with similar standards of protection.

Shift work and subfecundity: a causal link or an artefact?

AIMS: The Danish National Birth Cohort (DNBC) was used to examine whether shift work is associated with reduced fecundity as estimated by time to pregnancy (TTP). METHODS: From 1 March 1998 to 1 May 2000, 39 913 pregnant women were enrolled in the DNBC. Data on job characteristics and TTP (0-2, 3-5, 6-12, and >12 months) were used for 17 531 daytime workers and 3907 shift workers who had planned the pregnancy. Fecundity odds ratios (ORs) were calculated with 95% confidence intervals using the discrete time survival analysis techniques performed by logistic regression. An OR above 1 expresses a shorter TTP and then a higher fecundity. Potential confounders, such as age at conception, gravidity, prepregnant body mass index, smoking, and alcohol consumption, as well as occupational characteristics, were also included in the model. RESULTS: Fixed evening workers and fixed night workers had a longer TTP. Compared with daytime workers, the adjusted ORs were 0.80 (95% CI 0.70 to 0.92) for fixed evening workers, 0.80 (95% CI 0.63 to 1.00) for fixed night workers, 0.99 (95% CI 0.91 to 1.07) for rotating shift (without night) workers, and 1.05 (95% CI 0.97 to 1.14) for rotating shift (with night) workers. When analysis was restricted to nulliparous women, the estimates remained unchanged. The proportions of unplanned pregnancies and contraceptive failures were higher among fixed evening and fixed night workers. CONCLUSIONS: There was no unequivocal evidence of a causal association between shift work and subfecundity. The slightly reduced fecundity among fixed evening workers and fixed night workers may be mediated by pregnancy planning bias or differential options for sexual contacts.

[Stress and fertility. A follow-up study among couples planning the first pregnancy]. / Stress og frugtbarhed. En forløbsundersøgelse blandt par, som forsøger at blive gravide for første gang.

Mental distress has often been suggested as a cause of unexplained infertility. However, the causal direction may well be from infertility to distress, and prospective data are needed. We therefore followed 393 couples, who were planning their first pregnancy, with prospective collection of information on distress from termination of birth control until pregnancy for a maximum of six menstrual cycles. The analyses included 1,475 menstrual cycles, and mental distress was measured in each cycle by the General Health Questionnaire (GHQ). Urine samples from each period of vaginal bleeding were analyzed for human chorionic gonadotrophic hormone, indicating early embryonal loss. We found that for cycles with the highest distress score (GHQ score above the 80 percentile) the probability of conception per cycle was 12.8% compared to 16.5% in other cycles (adjusted OR 0.6; 95% CI 0.4-1.0). The effect of distress was almost exclusively found among women with long menstrual cycles (OR 0.1; 95% CI 0.01-0.4 and OR 0.9; 0.5-1.4 for women with cycles > or = 35 and < 35 days, respectively). An increased incidence of early embryonal loss was also found among highly distressed women with long cycles, but was based on a small number of observations. It is concluded that psychological distress may be a risk factor for reduced fertility in women with long menstrual cycles.

Diurnal scrotal skin temperature and semen quality. The Danish First Pregnancy Planner Study Team.

It is well established that heat is associated with reduced sperm production, but the role of physiological variation in temperature has never been scrutinized in humans. We studied diurnal scrotal temperature and markers of male fertility in a population of couples planning their first pregnancy. Sixty men from a cohort of couples who were planning their first pregnancy were included and scrotal skin temperature was monitored during 3 days using a portable data recorder. Working hours and working postures were recorded daily in a questionnaire. Each man provided a fresh semen sample and the couples were followed for six menstrual cycles or until a clinical pregnancy was recognized. The median value of scrotal skin temperature was 33.3 degrees C in the daytime and 34.8 degrees C at night. In periods of sedentary work, the median temperature was on average 0.7 degrees C higher (SE=0.2 degrees C). In addition, scrotal temperature was higher in the daytime, in summer, and in leisure time compared with working hours. Median sperm concentration among men with more than 75% of their daytime readings above 35 degrees C was 33.4 x 10(6)/mL, compared with 91.8 x 10(6)/mL for men with less than half of their readings above 35 degrees C (difference 58.4; 95% CI: 25.9-77.8 x 10(6)/mL). It is concluded that a sedentary position is a significant source of increased scrotal skin temperature, and even moderate and physiological elevation in scrotal skin temperature is associated with a substantially reduced sperm concentration. Sedentary work should be considered as an important potential confounder for reduced sperm count in epidemiological research.

Male-mediated spontaneous abortion among spouses of stainless steel welders.

OBJECTIVES: Male-mediated spontaneous abortion has never been documented for humans. The welding of stainless steel is associated with the pulmonary absorption of hexavalent chromium, which has genotoxic effects on germ cells in rodents. Clinical and early subclinical spontaneous abortions were examined among spouses of stainless-steel welders. METHODS: A cohort of first-pregnancy planners was recruited from members of the union of metal workers and 3 other trade unions. The cohort was followed for 6 menstrual cycles from the cessation of contraceptive use. Altogether, 280 pregnancies were conceived, of which 35 were detected by human chorionic gonadotrophic hormone analysis and did not survive to a clinically recognized pregnancy. Information on exposure was collected prospectively in relation to the outcome and was available for all cycles resulting in a pregnancy. Information on pregnancy outcome was collected for all 245 clinically recognized pregnancies. RESULTS: Increased risk of spontaneous abortion was found for pregnancies with exposure to paternal stainless-steel welding (adjusted relative risk 3.5, 95% confidence interval 1.3-9.1). The results were consistent in analyses of both biochemically and clinically recognized abortions. There was no increased risk for spontaneous abortion in pregnancies with paternal exposure to the welding of metals other than stainless steel. CONCLUSIONS: Male welding of stainless steel was associated with an increased risk of spontaneous abortion in spouses. A mutagenic effect of hexavalent chromium has been found previously in both somatic and germ cells, and the findings could be due to mutations in the male genome.

Birthweight and semen characteristics.

A correlation between birthweight and sperm counts in adult life was anticipated because impaired fetal growth could impair replication of Sertoli cells produced in fetal life. Furthermore, it was expected that males born with a high birthweight might have impaired sperm production as they are expected to have been exposed to higher levels of oestrogen in fetal life. We examined these predictions by including midwives records for 296 Danish males that had taken part in studies on male fecundity for other reasons. The study provided no support for these expectations. If anything, males born with a birthweight of 3000-3999 g had slightly lower sperm counts and more abnormal spermatozoa.

Computer-assisted semen analysis parameters as predictors for fertility of men from the general population. The Danish First Pregnancy Planner Study Team.

The predictive value of sperm motility parameters obtained by computer-assisted semen analysis (CASA) was evaluated for the fertility of men from general population. In a prospective study with couples stopping use of contraception in order to try to conceive, CASA was performed on semen samples from 358 men. A recently developed CASA system, Copenhagen Rigshospitalet Image house sperm Motility Analysis System (CRISMAS) was used for assessment of motility parameters. This system has an editing function which allows correction of tracks made by the computer. Probably due to this function, the concentration assessment made by CRISMAS was very close to that made by the technician (median difference <5%) in all concentration ranges. Correlation between CASA parameters and fertility of normal couples (measured as probability of achieving pregnancy) was examined by the Cox regression model. In univariate models ln(sperm concentration) [beta = 0.331, risk ratio (RR) = 1.392, P = 0.0001], ln(total sperm count) (beta = 0.252, RR = 1.286, P = 0.0007) and percentage motile spermatozoa (beta = 0.014, RR = 1.014, P = 0.0004) were most significant predictors for fertility. In a multivariate analysis ln(sperm concentration) (beta = 0.268, RR = 1.307, P = 0.0016) and percentage motile spermatozoa (beta = 0.010, RR = 1.010, P = 0.011) but even more significantly the combined parameter, ln(concentration of motile spermatozoa) (beta = 0.329, RR = 1.389, P = 0.0001), were the only parameters of predictive value for fertility of men in the general population. In conclusion, these parameters obtained by CASA measurements can be used for prediction of fertility potential in normal men. This appears to be the first study showing the value of CASA in prediction of fertility in the general male population.

Spontaneous abortion and physical strain around implantation: a follow-up study of first-pregnancy planners.

Existing studies of physical strain and spontaneous abortion are mainly retrospective or based only on pregnancies that have survived the first trimester. Furthermore, almost all studies have relied on averaged measures of physical strain, which tend to blur an effect if peak values during short time periods are the relevant measure. We followed a cohort of first pregnancy planners from termination of birth control until pregnancy for a maximum of six menstrual cycles. The analyses include 181 pregnancies, of which 32 were subclinical pregnancies detected by hCG analysis only. During early pregnancy the women recorded physical strain prospectively in a structured diary. Physical strain around the time of implantation was associated with later spontaneous abortion. The adjusted risk ratio for women who reported physical strain higher than average at day 6 to 9 after the estimated date of ovulation was 2.5 (95% CI = 1.3-4.6).

Semen quality among Danish and Finnish men attempting to conceive. The Danish First Pregnancy Planner Study Team.

OBJECTIVE: To assess differences in semen quality between similar populations from Denmark and Finland. DESIGN: Comparison of semen quality between 221 Finnish men (of whom 115 had no proven fertility) and 411 Danish men with no proven fertility in two follow-up studies among normal couples trying to conceive. METHODS: In Finland male partners of couples without experienced infertility attempting to conceive were recruited through advertisements in local newspapers from 1984 to 1986. From 1992 to 1995 Danish men who lived with a partner and who had not attempted to achieve a pregnancy previously were recruited through their union when they discontinued birth control. All semen analyses were performed in accordance with the World Health Organization guidelines. RESULTS: Median sperm concentration, total sperm count and the percentage of morphologically normal spermatozoa were significantly higher among the Finnish men without proven fertility (104.0 million/ml, 304.0 million and 58% respectively) compared with the Danish men (53.0 million/ml, 140.8 million, and 41% respectively). Sperm concentration was 105.7% (95% confidence interval (CI) 58.1%-167.6%) and total sperm count was 127.4% (95% CI 71.4%-201.6%) higher among Finnish men without proven fertility than among Danish men after control for confounders. CONCLUSIONS: Some, but hardly all, of the observed difference in semen quality may be explained by differences in recruitment procedures, selection of the men and by methodological differences in semen analysis between the two countries. Also a birth cohort effect may explain some of the differences between countries as the Finnish men were recruited 11 years before the Danish men. Therefore, follow-up studies with identical recruitment and selection of men from the two countries are needed.

Extremely low frequency magnetic fields and fertility: a follow up study of couples planning first pregnancies. The Danish First Pregnancy Planner Study Team.

OBJECTIVES: To evaluate the impact of extremely low frequency (ELF) magnetic fields on markers of human fertility. METHODS: A follow up study of time to pregnancy, semen quality, and reproductive hormones was conducted among couples planning first pregnancies (36 males were welders and 21 were non-welders). The male and the female partner were monitored for exposure to ELF magnetic field by personal exposure meters. As summary measures of exposure the median value was calculated together with the 75 percentile value and the proportion of measurements exceeding 0.2 and 1.0 microT, respectively. Each summary measure was divided in three categories: low, medium, and high. RESULTS: Couples in which the man had a medium or a high proportion of measurements > 1.0 microT had a reduced probability of conception per menstrual cycle compared with the men with low exposure, but the result was only significant for the men with medium exposure. This finding was partly attributable to a high probability of conception per menstrual cycle among the men with low exposure compared with non-welders in the original cohort of 430 couples. Other summary measures were not related to probability of conception or other markers of fertility. A possible negative association was found between high probability of conception and female exposure measures based on the median, the 75 percentile, and the proportion of measurements > 0.2 microT, but no association was found with the proportion of measurements > 1.0 microT. CONCLUSIONS: The findings provide no consistent support for a hypothesis of a deleterious effect of low level ELF magnetic fields on markers of human fertility. However, due to the relatively small size of the studied population only large associations would be detected.

Distress and reduced fertility: a follow-up study of first-pregnancy planners.

OBJECTIVE: To assess the effect of psychological distress on time to first pregnancy. DESIGN: A follow-up study of time to pregnancy with prospective data on distress, with controlling for potential confounding variables. SETTING: Two university hospitals. PATIENT(S): Danish couples (n = 430) who were planning their first pregnancy and had no previous reproductive experience were followed for six menstrual cycles. Psychological distress was measured in each menstrual cycle by the General Health Questionnaire. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): A clinically recognized pregnancy or a biochemical pregnancy detected in urine samples from each period of vaginal bleeding. RESULT(S): For cycles with the highest distress score (General Health Questionnaire score >80th percentile), the probability of conception per cycle was 12.8%, compared with 16.5% in other cycles (adjusted odds ratio [OR] 0.6; 95% confidence interval [CI] 0.4-1.0). The effect of distress was found almost exclusively among women with long menstrual cycles (OR 0.1; 95% CI 0.01-0.4 and OR 0.9; 95% CI 0.5-1.4 for women with cycles of > or =35 and <35 days, respectively). An increased incidence of early embryonal loss was also found among highly distressed women with long cycles, but was based on a small number of observations. CONCLUSION(S): Psychological distress may be a risk factor for reduced fertility in women with long menstrual cycles.

Is glycosylated haemoglobin a marker of fertility? A follow-up study of first-pregnancy planners.

We performed a follow-up study of time to pregnancy in a population of first-time pregnancy planners without previous reproductive experience. The objective of this paper is to report and discuss a finding of a strong relationship between glycosylated haemoglobin (HbA1C) and fertility. A total of 165 Danish couples without previous reproductive experience was followed from termination of birth control until pregnancy for a maximum of six menstrual cycles. HbA1C and reproductive hormones were measured at entry. Questionnaire data were collected at entry and once in each cycle during follow-up. The odds ratio (OR) for pregnancy per cycle decreased with increasing concentration of HbA1C (OR per percent HbA1C 0.4, 95% CI 0.2-0.9 for all six cycles and 0.2, 95% CI 0.1-0.5 in the first three cycles). A high concentration of HbA1C was associated with a high concentration of testosterone and a low concentration of inhibin A. No association was found between HbA1C and psychosocial distress. The reduced fertility among women with high HbA1C may be due to an association with subclinical polycystic ovaries as indicated by the hormonal profile.

Environmental semen studies--is infertility increased by a decline in sperm count?

The objective of the studies was to evaluate infertility according to sperm count shifts. The distribution of the sperm count of 1024 Danish men (median 56 million/ml) served as reference. The data were transformed with multiplicative or additive models to create alternative distributions with median sperm count values changed by 25-100%. Sperm-count-specific fecundabilities were provided from a follow-up of first-pregnancy planners in a Danish population. The estimated average fecundability of the 1024 Danish men was 16.9% [95% confidence interval (95% CI) 16.7-17.2], and the proportion of cohabiting men with spouses pregnant within 1 year was 86.0% (95% CI 84.1-87.8). Simulations of alternative sperm count distributions indicated that the relationship between sperm count shift and fertility strongly depends on the median level of the sperm count at onset and the type of shift, a dramatic decline from a high level in a multiplicative model indicating a marginal change and a minor decline from a low level in an additive model representing a strong decrease in fertility. In some cases sperm count, therefore, may be an early warning of changes in fertility.