Nitrate in Maternal Drinking Water during Pregnancy and Measures of Male Fecundity in Adult Sons.

Animal studies indicate deleterious effects of nitrate exposure on fecundity, but effects in humans are unknown, both for the prenatal and postnatal periods. We aimed to investigate if exposure to nitrate in maternal drinking water during the sensitive period of fetal life is associated with measures of fecundity in the adult sons. In a sub-analysis, the potential effects of nitrate exposure in adulthood were investigated. This cohort included 985 young adult men enrolled in The Fetal Programming of Semen Quality Cohort (FEPOS). Semen characteristics, testes volume and reproductive hormones were analyzed in relation to nitrate concentration in maternal drinking water, using a negative binomial regression model. The nitrate concentration in drinking water was obtained from monitoring data from Danish waterworks that were linked with the mothers' residential address during pregnancy. The median nitrate concentration in maternal drinking water was 2 mg/L. At these low exposure levels, which are far below the World Health Organization's (WHO) guideline value of 50 mg/L, we did not find indications of harmful effects of nitrate on the investigated measures of male fecundity.

Drinking water nitrate and risk of pregnancy loss: a nationwide cohort study.

BACKGROUND: Nitrate contamination is seen in drinking water worldwide. Nitrate may pass the placental barrier. Despite suggestive evidence of fetal harm, the potential association between nitrate exposure from drinking water and pregnancy loss remains to be studied. We aimed to investigate if nitrate in drinking water was associated with the risk of pregnancy loss. METHODS: We conducted a nationwide cohort study of 100,410 pregnancies (enrolled around gestational week 11) in the Danish National Birth Cohort (DNBC) during 1996-2002. Spontaneous pregnancy losses before gestational week 22 were ascertained from the Danish National Patient Registry and DNBC pregnancy interviews. Using the national drinking water quality-monitoring database Jupiter, we estimated the individual and time-specific nitrate exposure by linking geocoded maternal residential addresses with water supply areas. The nitrate exposure was analyzed in spline models using a log-transformed continuous level or classified into five categories. We used Cox proportional hazards models to estimate associations between nitrate and pregnancy loss and used gestational age (days) as the time scale, adjusting for demographic, health, and lifestyle variables. RESULTS: No consistent associations were found when investigating the exposure as a categorical variable and null findings were also found in trimester specific analyses. In the spline model using the continuous exposure variable, a modestly increased hazard of pregnancy loss was observed for the first trimester at nitrate exposures between 1 and 10 mg/L, with the highest. adjusted hazard ratio at 5 mg/L of nitrate of 1.16 (95% CI: 1.01, 1.34). This trend was attenuated in the higher exposure ranges. CONCLUSION: No association was seen between drinking water nitrate and the risk of pregnancy loss when investigating the exposure as a categorical variable. When we modelled the exposure as a continuous variable, a dose-dependent association was found between drinking water nitrate exposure in the first trimester and the risk of pregnancy loss. Very early pregnancy losses were not considered in this study, and whether survival bias influenced the results should be further explored.

Healthcare Use in the Five Years Before a First Infertility Diagnosis: A Danish Register-Based Case-Control Study in the CROSS-TRACKS Cohort.

Purpose: 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.

Nitrate in Drinking Water and Time to Pregnancy or Medically Assisted Reproduction in Women and Men: A Nationwide Cohort Study in the Danish National Birth Cohort.

Purpose: 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.

Prenatal nitrate exposure from diet and drinking water and timing of puberty in sons and daughters: A nationwide cohort study.

BACKGROUND: In Western countries, age at pubertal development has declined during the last century in girls, and probably also in boys. No studies have investigated whether nitrate, a widespread environmental exposure with teratogenic and hormone disrupting properties, might affect timing of puberty. OBJECTIVES: We investigated if prenatal exposure to nitrate from drinking water and diet was associated with timing of puberty. METHODS: This cohort study included 15,819 children born from 2000 to 2003 within the Danish National Birth Cohort. Self-reported information on current status of various pubertal milestones was provided every six months by a questionnaire from 11 years of age until 18 years or full maturity, whichever came first. Maternal nitrate intake from diet (mg/day) was derived from a mid-pregnancy food frequency questionnaire and individual level nitrate exposure from drinking water (mg/L) was derived using measurements from Danish public waterworks. Adjusted average differences in months in age at attaining several pubertal milestones as well as the average age difference in age at attaining all the milestones were estimated separately for diet and water using a regression model for interval-censored data. C- and E-vitamin, red meat and processed meat intake were explored as potential effect modifiers in sub-analyses. RESULTS: No strong associations were observed between prenatal exposure to nitrate and timing of puberty in children. However, sons born of mothers with a nitrate concentration in drinking water at their residential address of > 25 mg/L (half of the World Health Organisation (WHO) guideline value) compared with ≤ 1 mg/L showed a tendency towards earlier age at pubertal development with an average age difference of -1.2 months (95 % confidence interval,-3.0;0.6) for all the pubertal milestones combined. DISCUSSION: Studies including more highly exposed children are needed before the current WHO drinking water guideline value for nitrate can be considered safe concerning pubertal development.

Prenatal nitrosatable prescription drug intake, drinking water nitrate, and the risk of stillbirth: a register- and population-based cohort of Danish pregnancies, 1997-2017.

BACKGROUND: Nitrosatable drugs commonly prescribed during pregnancy can react with nitrite to form N-nitroso compounds which have been associated with an increased risk of stillbirth. Whether maternal residential drinking water nitrate modifies this association is unknown. We investigated, if household drinking water nitrate was associated with stillbirth, and if it modified the association between nitrosatable prescription drug intake and the risk of stillbirth. METHODS: We conducted an individual-level register- and population-based cohort study using 652,810 women with the first recorded singleton pregnancy in the Danish Medical Birth Registry between 1997 and 2017. Nitrosatable drug exposure was recorded by use of the Danish National Patient Registry defined as women with a first redeemed prescription of a nitrosatable drug the first 22 weeks of pregnancy. The reference group was women with no redeemed prescription of a nitrosatable drug in this period. The average individual drinking water nitrate concentration level (mg/L) was calculated in the same period. We categorized nitrosatable drugs as secondary amines, tertiary amines, and amides. Cox hazard regression was used to estimate crude and adjusted hazard ratios with 95% confidence intervals for stillbirth stratified into five categories of nitrate concentrations: ≤1 mg/L, > 1- ≤ 2 mg/L, > 2- ≤ 5 mg/L, > 5- ≤ 25 mg/L, and > 25 mg/L. RESULTS: Drinking water nitrate exposure in the population was not associated with the risk of stillbirth. Among 100,244 women who had a nitrosatable prescription drug redeemed ≤22 weeks of pregnancy of pregnancy, 418 (0.42%) had a stillbirth compared to 1993 stillbirths (0.36%) among 552,566 referent women. Women with any nitrosatable prescription drug intake and > 1- ≤ 2 mg/L nitrate concentration had an increased risk of stillbirth [adjusted hazard ratio 1.55 (95% confidence interval, 1.15-2.09)] compared with referent women. In the stratified analyses, the highest risk of stillbirth was found among women with secondary amine intake and > 25 mg/L nitrate concentrations [adjusted hazard ratio 3.11 (95% CI, 1.08-8.94)]. CONCLUSIONS: The association between nitrosatable prescription drug intake and the risk of stillbirth may depend on the level of nitrate in household drinking water. Evaluations of the effect of nitrosatable drug intake on perinatal outcomes might consider nitrate exposure from drinking water.

Cohort profile: CROSS-TRACKS: a population-based open cohort across healthcare sectors in Denmark.

PURPOSE: This paper describes the open cohort CROSS-TRACKS, which comprises population-based data from primary care, secondary care and national registries to study patient pathways and transitions across sectors while adjusting for sociodemographic characteristics. PARTICIPANTS: A total of 221 283 individuals resided in the four Danish municipalities that constituted the catchment area of Horsens Regional Hospital in 2012-2018. A total of 96% of the population used primary care, 35% received at least one transfer payment and 66% was in contact with a hospital at least once in the period. Additional clinical information is available for hospital contacts (eg, alcohol intake, smoking status, body mass index and blood pressure). A total of 23% (n=8191) of individuals aged ≥65 years had at least one potentially preventable hospital admission, and 73% (n=5941) of these individuals had more than one. FINDINGS TO DATE: The cohort is currently used for research projects in epidemiology and artificial intelligence. These projects comprise a prediction model for potentially preventable hospital admissions, a clinical decision support system based on artificial intelligence, prevention of medication errors in the transition between sectors, health behaviour and sociodemographic characteristics of men and women prior to fertility treatment, and a recently published study applying machine learning methods for early detection of sepsis. FUTURE PLANS: The CROSS-TRACKS cohort will be expanded to comprise the entire Central Denmark Region consisting of 1.3 million residents. The cohort can provide new knowledge on how to best organise interventions across healthcare sectors and prevent potentially preventable hospital admissions. Such knowledge would benefit both the individual citizen and society as a whole.

Psychiatric disorders among women and men in assisted reproductive technology (ART) treatment. The Danish National ART-Couple (DANAC) cohort: protocol for a longitudinal, national register-based cohort study.

INTRODUCTION: There are complex causal associations between mental disorders, fertility treatment, fertility treatment outcome and infertility per se. Eating disorders cause endocrine disturbances, anovulation and thereby infertility, and research has shown that infertility as well as unsuccessful assisted reproductive technology (ART) treatment are potential risk factors for developing a depression on a long-term basis. Despite the fact that worldwide more than 400 000 ART treatment cycles are performed every year, the causal associations between mental disorders, use of medication for mental disorders and ART treatment in both sexes have only been sparsely explored. METHOD AND ANALYSIS: The main objective of this national register-based cohort study is to assess women's and men's mental health before, during, and after ART treatment in comparison with the mental health in an age-matched population-based cohort of couples with no history of ART treatment. Furthermore, the objective is to study the reproductive outcome of ART treatment among women who have a registered diagnosis of a mental disorder or have used medication for mental disorders prior to ART treatment compared with women in ART treatment without a mental disorder. We will establish the Danish National ART-Couple (DANAC) cohort including all women registered with ART treatment in the Danish in vitro fertilisation Register during 1994-2009 (N=42 915) and their partners. An age-matched population-based comparison cohort of women without ART treatment (n=215 290) and their partners will be established. Data will be cross-linked with data from national registers on psychiatric disorders, medical prescriptions for mental disorders, births, causes of deaths and sociodemographic data. Survival analyses and other statistical analyses will be conducted on the development of mental disorders and use of medication for mental disorders for women and men both prior to and after ART treatment.