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Ninna Hinchely Ebdrup,1– 3 Anders Hammerich Riis,4,5 Cecilia Høst Ramlau-Hansen,2 Bjørn Bay,1,6 Julie Lyngsø,7 Dorte Rytter,2 Marianne Johansson Jørgensen,4 Ulla Breth Knudsen1,3 1Department of Obstetrics and Gynecology, Fertility Clinic, Horsens Regional Hospital, Horsens, Denmark; 2Department of Public Health, Aarhus University, Aarhus, Denmark; 3Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 4Department of Research, Regional Hospital Horsens, Horsens, Denmark; 5Enversion A/S, Aarhus, Denmark; 6Maigaard Fertility Clinic, Aarhus, Denmark; 7Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, DenmarkCorrespondence: Ninna Hinchely Ebdrup, Department of Obstetrics and Gynecology, Fertility Clinic, Horsens Regional Hospital, Sundvej 30, Horsens, 8700, Denmark, Tel +45 28 47 21 11, Email ninebd@clin.au.dkPurpose: Infertility may affect somatic and mental health later in life. Nevertheless, health status before diagnosed infertility is sparsely studied in women. We aimed to describe healthcare use in primary and secondary care before a first infertility diagnosis and compare use between cases and controls.Materials and Methods: The case–control study was based on register data and used incidence density sampling. From the CROSS-TRACKS Cohort, we included women residing in the Horsens area in Denmark in 2012– 2018 (n = 54,175). Eligible women were aged 18– 40 years, nulliparous, and living in heterosexual relationships. Cases were women with a first infertility diagnosis in the Danish National Patient Registry (index date). Five controls were matched on age, birth year, and calendar time. Through linkage to Danish national health registries, we identified general practitioner (GP) attendance, paraclinical examinations, hospital contacts, diagnoses, and redeemed prescriptions. Healthcare use from one year to five years before index date was compared with conditional logistic regression.Results: We identified 711 cases and 3555 controls. At one year before index date, cases consulted their GP (odds ratio (OR) = 5.2, 95% confidence interval (CI): 3.2, 8.3) and visited hospital (OR = 1.2, 95% CI: 1.0, 1.4) and redeemed prescriptions (OR = 2.3 95% CI: 1.9, 2.7) more often compared to controls. Cases more often had blood and hemoglobin tests performed, redeemed more drugs related to genitourinary and hormonal diseases, and were more often diagnosed with endocrine and genitourinary diseases in the year before a first infertility diagnosis compared to controls. Cases and controls had comparable healthcare use from five years to one year before a first infertility diagnosis.Conclusion: Cases and controls had similar healthcare use from five years to one year before a first infertility diagnosis. However, cases had a higher healthcare use in the year preceding a first infertility diagnosis compared to controls.Keywords: behavior, health status, incidence density, fertility, preconception health, medically assisted reproduction

Ninna Hinchely Ebdrup,1– 3 Ulla Breth Knudsen,1,3 Jörg Schullehner,2,4 Linn Håkonsen Arendt,2,5 Zeyan Liew,6,7 Julie Lyngsø,2,5 Bjørn Bay,1,8 Pernille Jul Clemmensen,2 Torben Sigsgaard,2,9,10 Birgitte Hansen,4 Cecilia Høst Ramlau-Hansen2 1Department of Obstetrics and Gynecology, Horsens Regional Hospital, Horsens, Denmark; 2Department of Public Health, Aarhus University, Aarhus, Denmark; 3Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; 4Geological Survey of Denmark and Greenland, Aarhus, Denmark; 5Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, Denmark; 6Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA; 7Yale Center for Perinatal, Pediatric, and Environmental Epidemiology, Yale School of Public Health, New Haven, CT, USA; 8Maigaard Fertility Clinic, Aarhus, Denmark; 9Centre for Integrated Register-based Research at Aarhus University, Aarhus, Denmark; 10Danish Big Data Centre for Environment and Health (BERTHA), Aarhus University, Aarhus, DenmarkCorrespondence: Ninna Hinchely Ebdrup, Department of Obstetrics and Gynecology, Horsens Regional Hospital, Regionshospitalet Horsens, Sundvej 30, Horsens, 8700, Denmark, Tel +4528472111, Email ninebd@rm.dkPurpose: No studies have investigated if drinking water nitrate affects human fecundity. Experimental studies point at detrimental effects on fetal development and on female and male reproduction. This cohort study aimed to explore if female and male preconception and long-term exposure to nitrate in drinking water was associated with fecundability measured as time to pregnancy (TTP) or use of medically assisted reproduction (MAR) treatment.Methods: The study population consisted of pregnant women recruited in their first trimester in 1996– 2002 to the Danish National Birth Cohort. Preconception drinking-water nitrate exposure was estimated for the pregnant women (89,109 pregnancies), and long-term drinking water nitrate exposure was estimated from adolescence to conception for the pregnant women (77,474 pregnancies) and their male partners (62,000 pregnancies) by linkage to the national drinking water quality-monitoring database Jupiter. Difference in risk of TTP > 12 months or use of MAR treatment between five exposure categories and log-transformed continuous models of preconception and long-term nitrate in drinking water were estimated. Binominal regression models for risk ratios (RR) were adjusted for age, occupation, education, population density, and lifestyle factors.Results: Nitrate in drinking water (median preconception exposure: 1.9 mg/L; median long-term exposure: 3.3 mg/L) was not associated with TTP > 12 months or use of MAR treatment, neither in the categorical nor in the continuous models.Conclusion: We found no association between preconception or long-term exposure to drinking water nitrate and fecundability.Keywords: environmental pollutant, subfecundity, time to pregnancy, public health, groundwater

Julie Lyngsø,1 Cecilia Høst Ramlau-Hansen,1 Bjørn Bay,2 Hans Jakob Ingerslev,3 Adam Hulman,1,4 Ulrik Schiøler Kesmodel5 1Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, 2The Fertility Clinic, Regional Horsens Hospital, Horsens, 3Department of Obstetrics and Gynaecology, Aarhus University Hospital, Aarhus, 4Danish Diabetes Academy, Odense, 5Department of Obstetrics and Gynaecology, Herlev and Gentofte Hospital, Herlev, Denmark Objective: The aim was to investigate whether coffee or caffeine consumption is associated with reproductive endpoints among women with natural fertility (ie, time to pregnancy [TTP] and spontaneous abortion [SAB]) and among women in fertility treatment (ie, clinical pregnancy rate or live birth rate). Design: This study was a systematic review and dose–response meta-analysis including data from case–control and cohort studies. Methods: An extensive literature search was conducted in MEDLINE and Embase, with no time and language restrictions. Also, reference lists were searched manually. Two independent reviewers assessed the manuscript quality using the Newcastle–Ottawa Scale (NOS). A two-stage dose–response meta-analysis was applied to assess a potential association between coffee/caffeine consumption and the outcomes: TTP, SAB, clinical pregnancy, and live birth. Heterogeneity between studies was assessed using Cochrane Q-test and I2 statistics. Publication bias was assessed using Egger’s regression test. Results: The pooled results showed that coffee/caffeine consumption is associated with a significantly increased risk of SAB for 300 mg caffeine/day (relative risk [RR]: 1.37, 95% confidence interval [95% CI]: 1.19; 1.57) and for 600 mg caffeine/day (RR: 2.32, 95% CI: 1.62; 3.31). No association was found between coffee/caffeine consumption and outcomes of fertility treatment (based on two studies). No clear association was found between exposure to coffee/caffeine and natural fertility as measured by fecundability odds ratio (based on three studies) or waiting TTP (based on two studies). Conclusion: Results from this meta-analysis support the growing evidence of an association between coffee/caffeine intake and the risk of SAB. However, viewing the reproductive capacity in a broader perspective, there seems to be little, if any, association between coffee/caffeine consumption and fecundity. In general, results from this study are supportive of a precautionary principle advised by health organizations such as European Food Safety Authority (EFSA) and World Health Organization (WHO), although the advised limit of a maximum of two to three cups of coffee/200–300 mg caffeine per day may be too high. Keywords: coffee, caffeine, fecundity, fertility, spontaneous abortion, assisted reproduction