Infertility affects approximately 15% of couples in North America. As couples increasingly postpone childbearing to the later reproductive years, many seek infertility treatment, which costs an estimated $5 billion per year, has relatively low success rates, and is associated with adverse pregnancy outcomes. Identifying modifiable risk factors for subfertility is an important public health goal. The present application proposes to investigate the influence of cervical dysplasia, surgical treatments for cervical dysplasia, and HPV vaccination on female fertility in an analysis of over 15,000 female pregnancy planners from three interrelated NICHD-funded prospective cohort studies. The cervix plays an important role in fertility by keeping pathogens out of the upper reproductive tract while also facilitating transport of sperm. Cervical dysplasia and surgical treatments can disrupt the cervical ecosystem by altering mucus production and immunological factors, which in turn may affect female fertility. Previous studies on this topic have been inconclusive and have had several methodologic limitations. The proposed study will use registry-based data on cervical pathology and cervical surgeries from more than 10,000 Danish women and self-reported data with medical record validation from 5,500 women in the United States and Canada. We will prospectively assess the relation of cervical dysplasia and treatments for cervical dysplasia? loop electrosurgical excision procedure (LEEP) conization (knife cone or laser), cryosurgery, and laser ablation? in relation to time-to-pregnancy (TTP). We will also assess the extent to which the recency of cervical dysplasia diagnosis and treatment affects delayed conception. The role of human papillomavirus (HPV) vaccination on female fertility will also be assessed. We will stratify analyses by smoking status, history of sexually transmitted infections, and other potential effect modifiers. The prospective design of the proposed study will minimize misclassification of exposure, outcome, and covariates, reduce selection bias, and clarify temporality. The inclusion of women from the entire fertility spectrum, and from three countries (Demark, United States, and Canada), will enhance generalizability of the results. HPV vaccination, cervical dysplasia, and treatment for cervical dysplasia are understudied risk factors for subfertility and infertility. This prospective study will be the largest and most informative investigation of these associations to date. By leveraging existing web-based methods and infrastructure supported by the NICHD, the proposed study will be extremely cost-effective relative to a study designed de novo. The results will allow clinicians to more accurately counsel women about the associations of HPV infection, cervical dysplasia, and dysplasia treatment with fertility to maximize successful childbearing. Findings from the proposed research are likely to have a large and sustained impact on the field of reproductive medicine.

Public Health Relevance

Infertility is a common public health problem that leads to increased medical costs and potential adverse outcomes for both mother and child. The proposed study combines participants from three prospective cohorts of women to evaluate the relations of 1) cervical dysplasia, 2) surgeries for cervical dysplasia, and 3) HPV vaccination with time-to-pregnancy, a sensitive measure of a couple?s fertility. Findings from this study will enable us to guide health care recommendations for women who plan to conceive in the future.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Small Research Grants (R03)
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National Institute of Child Health and Human Development Initial Review Group (CHHD)
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Eisenberg, Esther
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Boston University
Public Health & Prev Medicine
Schools of Public Health
United States
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McInerney, Kathryn A; Hatch, Elizabeth E; Wesselink, Amelia K et al. (2017) The Effect of Vaccination Against Human Papillomavirus on Fecundability. Paediatr Perinat Epidemiol 31:531-536