We propose to conduct a prospective cohort study of risk factors for delayed time to pregnancy (TTP) among Danish couples. About 10-15 per cent of couples suffer from infertility, and the prevalence may be increasing. Use of infertility services constitutes a major economic burden, and success rates of treatment are relatively low. Thus, identifying risk factors for delayed TTP, especially modifiable factors, is an important public health goal. Most previous studies of delayed TTP have used retrospective designs, which may be particularly subject to selection bias. This prospective cohort study in Denmark will expand a highly successful R21-funded pilot study, using the internet to recruit and follow 10,000 women and their male partners who are planning a pregnancy. Based on results from the pilot study, internet-based methods appear to be an efficient and cost- effective means of recruitment and follow-up in a prospective cohort study, especially for couples planning a pregnancy who are not readily identifiable by other means. The combination of internet-based prospective recruitment and linkage to registry data is a powerful research design that can mitigate biases due to loss to follow-up, recall, and misclassification of exposures and outcomes. Owing to unique registry resources in Denmark, establishment of this cohort will allow, with extended follow-up, the long-term evaluation of other endpoints such as childhood obesity and asthma. In the expanded study, both female and male participants will complete a baseline questionnaire and bi-monthly follow-up questionnaires that collect data on a wide range of factors including alcohol consumption, caffeine intake, body mass index, physical activity and sedentary behavior. In addition, guided by recent research, we will collect exposure data on dietary factors, such as fatty acids, folic acid, dairy foods, and iron intake, using a validated food frequency questionnaire. Other objectives will focus on several common and increasingly used medications, including glucocorticoids, serotonin re-uptake inhibitors, and non-steroidal anti-inflammatory drugs. For these exposures, miscarriage as well as TTP will be evaluated as endpoints. We have given priority to these risk factors because they are common and existing studies of their relation to TTP and miscarriage are inconclusive. Couples will be followed until a pregnancy is reported or for up to twelve months, the standard clinical definition of infertility and the time when fertility treatment is typically sought. We will conduct miscarriage analyses among the majority subset of couples that conceive during the follow-up. We will collect potential confounder data on frequency of intercourse, smoking, parity, cycle regularity, cycle length, last method of contraception, occupation, education, stress and depressive symptoms, among other factors. Registry data will be used to validate self-reported data on prescription medications, medical history, and reproductive history and to ascertain pregnancies and birth outcomes among participants who are lost to follow-up.

Public Health Relevance

Nearly 15 per cent of all couples have difficulty becoming pregnant and approximately 20 per cent of all pregnancies end in miscarriage. Despite their frequent occurrence, few factors have been firmly linked to an increased risk of infertility and miscarriage. Identifying modifiable risk factors for infertility and miscarriage is an important public health goal, especially because the effectiveness of treatments for these conditions is relatively poor.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
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Davis, Maurice
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Boston University
Public Health & Prev Medicine
Schools of Public Health
United States
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Rothman, Kenneth J; Gallacher, John E J; Hatch, Elizabeth E (2013) Rebuttal: When it comes to scientific inference, sometimes a cigar is just a cigar. Int J Epidemiol 42:1026-8

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