Night work during pregnancy and small for gestational age: a Danish nationwide register-based cohort study.

OBJECTIVE: The aim was to investigate the association between night work during pregnancy and risk of having a small for gestational age (SGA) child. METHODS: This cohort study had payroll data with detailed information on working hours for employees in all Danish administrative regions (primarily hospital employees) between 2007 and 2015, retrieved from the Danish Working Hour Database. Pregnancies, covariates and outcome were identified from the national birth registry. We used logistic regression to investigate the association between intensity and duration of night work during the first 32 pregnancy weeks and SGA. The adjusted model included age, body mass index, socioeconomic status and smoking. Using quantitative bias analysis and G-estimation, we explored potential healthy worker survivor bias (HWSB). RESULTS: The final cohort comprised 24 548 singleton pregnancies in 19 107 women, primarily nurses and medical doctors. None of the dimensions of night work were associated with an increased risk of SGA. We found a tendency towards higher risk of SGA in pregnancies where the women stopped having night shifts during pregnancy. Using G-estimation we found an OR<1 for the association between night work and SGA if all workers continued having night work during pregnancy compared with daywork only. CONCLUSION: We found no increased risk of SGA in association with night work during pregnancy among healthcare workers. G-estimation was not precise enough to estimate the observed indication of HWSB. We need better data on pregnancy discomforts and complications to be able to safely rule out HWSB.

Vitamin D Supplementation and Vitamin D Status during Pregnancy and the Risk of Congenital Anomalies-A Systematic Review and Meta-Analysis.

Maternal dietary factors have been suggested as possible contributing influences for congenital anomalies (CAs). We aimed to assess the association between vitamin D supplementation or vitamin D status (s-25OHD) during pregnancy and CAs in the offspring. A comprehensive literature search was conducted in the three electronic databases: PubMed, Embase, and Cochrane Library. Included studies were critically appraised using appropriate tools (risk of bias 2, ROBINS-I). A protocol was registered in the International Prospective Register of Systematic Reviews (CRD42019127131). A meta-analysis of four randomised controlled trials (RCTs) including 3931 participants showed no effect of vitamin D supplementation on CAs, a relative risk of 0.76 (95% CI 0.45; 1.30), with moderate certainty in the effect estimates by GRADE assessment. Of the nine identified observational studies, six were excluded due to a critical risk of bias in accordance with ROBINS-I. Among the included observational studies, two studies found no association, whereas one case-control study identified an association between s-25OHD < 20 nmol/L and neural tube defects, with an adjusted odds ratio of 2.34 (95% CI: 1.07; 5.07). Interpretation of the results should be cautious given the low prevalence of CAs, RCTs with onset of supplementation after organogenesis, and low-quality observational studies.

Dietary trans-fatty acid intake in relation to cancer risk: a systematic review and meta-analysis.

CONTEXT: Apart from ruminant fat, trans-fatty acids are produced during the partial hydrogenation of vegetable oils, (eg, in the production of ultraprocessed foods). Harmful cardiovascular effects of trans-fatty acids are already proven, but the link with cancer risk has not yet been summarized. OBJECTIVE: A systematic review (following PRISMA guidelines) - including observational studies on the association of trans-fatty acid intake with any cancer risk - was conducted, with no limitations on population types. DATA SOURCES: The electronic databases PubMed and Embase were searched to identify relevant studies. DATA EXTRACTION: This systematic review included 46 articles. Quality was assessed via the Newcastle-Ottawa scale. Meta-analyses were conducted if at least 4 articles exploring the same transfat-cancer pairings were found. DATA ANALYSIS: Nineteen cancer types have been researched in cohort and case-control studies on trans-fatty acids, with breast cancer (n = 17), prostate cancer (n = 11), and colorectal cancer (n = 9) as the most researched. The meta-analyses on total trans-fat showed a significant positive association for prostate cancer (odds ratio [OR] 1.49; 95%CI, 1.13-1.95) and colorectal cancer (OR 1.26; 95%CI, 1.08-1.46) but not for breast cancer (OR 1.12; 95%CI, 0.99-1.26), ovarian cancer (OR 1.10; 95%CI, 0.94-1.28), or non-Hodgkin lymphoma (OR 1.32; 95%CI, 0.99-1.76). Results were dependent on the fatty acid subtype, with even cancer-protective associations for some partially hydrogenated vegetable oils. Enhancing moderators in the positive transfat-cancer relation were gender (direction was cancer-site specific), European ancestry, menopause, older age, and overweight. CONCLUSION: Despite heterogeneity, higher risk of prostate and colorectal cancer by high consumption of trans-fatty acids was found. Future studies need methodological improvements (eg, using long-term follow-up cancer data and intake biomarkers). Owing to the lack of studies testing trans-fatty acid subtypes in standardized ways, it is not clear which subtypes (eg, ruminant sources) are more carcinogenic. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42018105899.

Fetal exposure to paternal smoking and semen quality in the adult son.

BACKGROUND: The negative impact of maternal smoking during pregnancy on offspring semen quality is well established. Less is known about the impact of paternal smoking. METHODS: We estimated differences in semen parameters and testicle size according to paternal smoking in 772 adult sons of women enrolled in the Danish National Birth Cohort when pregnant. Parents' smoking was reported around gestational week 16, and analyses were adjusted for parents' ages at conception, maternal pre-pregnancy body mass index, maternal alcohol and caffeine intake, family occupational status, ejaculatory abstinence time, clinic of semen analysis, and season. RESULTS: Sons of smoking fathers and non-smoking mothers had a 10% (95% confidence interval: -24%, 7%) lower semen concentration and 11% (95% confidence interval: -27%, 8%) lower sperm count than sons of non-smoking parents. Having two smoking parents was associated with 19% reduction in sperm count (95% confidence interval: -37%, 3%). Paternal smoking was not associated with volume, motility, or morphology. Adjusting for maternal smoking, paternal smoking was associated with a 26% increased risk of small testicular volume (95% confidence interval: 0.89, 1.78). DISCUSSION: Exclusion of sons with a history of testicular cancer, chemotherapy, orchiectomy, and with only one or no testicles may have caused us to underestimate associations if these men's reproductive health including semen quality are in fact more sensitive to paternal smoking. CONCLUSION: The study provides limited support for slightly lower sperm concentration and total sperm concentration in sons of smoking fathers, but findings are also compatible with no association.

Can legal restrictions of prenatal exposure to industrial trans-fatty acids reduce risk of childhood hematopoietic neoplasms? A population-based study.

BACKGROUND: Causes of most childhood hematopoietic neoplasms are unknown. Early age of occurrence suggests prenatal etiology. Positive associations have been reported between industrially produced trans-fatty acids (iTFAs) and risks of some cancers in adults. iTFAs are pro-inflammatory and adversely affect the beneficial effects of essential fatty acids, the latter is diminishing tumor growth. In 2004 Denmark legislated against the use of iTFA in foodstuffs. Using the entire population, we investigated if the changes in the legislation as a proxy to the reduced exposure to iTFA had affected the incidence of childhood hematopoietic neoplasms. METHODS: We used a Cox proportional hazard model to compare the hazard of childhood hematopoietic neoplasms among children born before and after the iTFA ban, as a proxy for fetal iTFA exposure. To take the potential secular trend in hematopoietic neoplasms into account, we modeled the variation in cancer risk across birth cohorts by a piecewise linear spline with a knot in 2004, which allowed a comparison of the hazard of childhood hematopoietic neoplasms between the time before and after the iTFA ban. RESULTS: Among children born in 1988-2008 in Denmark, 720 were diagnosed with hematopoietic neoplasms before the age of 7 years, corresponding to an overall incidence rate of 7.6 per 100 000 person years. The incidence rates increased by 2% per cohort in 1988-2004 (hazard ratio: 1.02 [1.01; 1.04]) and in 2004-2008 (hazard ratio: 1.02 [0.95; 1.11]). CONCLUSIONS: No apparent benefit of the iTFA legislation in reducing childhood hematopoietic neoplasms was observed on population basis. Individual-level data are needed to investigate any possible associations between biomarkers of iTFA intake and risk of childhood hematopoietic neoplasms.

The influence of prenatal exposure to trans-fatty acids for development of childhood haematopoietic neoplasms (EnTrance): a natural societal experiment and a case-control study.

BACKGROUND: Little is known about the causes of childhood cancer, partly as not many children develop cancer, although childhood cancer is a leading cause of death by disease in the young. The young age of the children suggests that risk factors for childhood cancer may be present during pregnancy. Previous studies have shown that exposure to trans-fat, a type of unsaturated fat common in industrially produced foods (iTFA), has adverse health effects in adults, including the risk of developing cancer. Haematopoietic neoplasms are the most common cancer types among European children under the age of 15 years. This study will bring new knowledge as to whether trans-fat and other fatty acids may also increase the risk of developing haematopoietic neoplasms during childhood. METHODS: We will investigate if the Danish iTFA legislation ban, which radically reduced the use of iTFA in foodstuffs, influenced the risk of childhood haematopoietic neoplasms in children born either before or after the change in legislation, adjusting for relevant secular trends. Further, in a case-control study, we will examine if levels of fatty acids in dried blood spots from newborns can predict the risk of developing childhood haematopoietic neoplasms. Permission from the Danish Data Protection Agency and the Ethical Committee has been granted. DISCUSSION: The results from this study will provide important information about fatty acids in the mother's diet as a contributor to development of haematopoietic neoplasms during childhood, which may result in relevant preventive action. TRIAL REGISTRATION: Not relevant.

The epidemiologic evidence linking prenatal and postnatal exposure to endocrine disrupting chemicals with male reproductive disorders: a systematic review and meta-analysis.

BACKGROUND: More than 20 years ago, it was hypothesized that exposure to prenatal and early postnatal environmental xenobiotics with the potential to disrupt endogenous hormone signaling might be on the causal path to cryptorchidism, hypospadias, low sperm count and testicular cancer. Several consensus statements and narrative reviews in recent years have divided the scientific community and have elicited a call for systematic transparent reviews. We aimed to fill this gap in knowledge in the field of male reproductive disorders. OBJECTIVE AND RATIONALE: The aim of this study was to systematically synthesize published data on the risk of cryptorchidism, hypospadias, low sperm counts and testicular cancer following in utero or infant exposure to chemicals that have been included on the European Commission's list of Category 1 endocrine disrupting chemicals defined as having documented adverse effects due to endocrine disruption in at least one intact organism. SEARCH METHODS: A systematic literature search for original peer reviewed papers was performed in the databases PubMed and Embase to identify epidemiological studies reporting associations between the outcomes of interest and exposures documented by biochemical analyses of biospecimens including maternal blood or urine, placenta or fat tissue as well as amnion fluid, cord blood or breast milk; this was followed by meta-analysis of quantitative data. OUTCOMES: The literature search resulted in 1314 references among which we identified 33 papers(28 study populations) fulfilling the eligibility criteria. These provided 85 risk estimates of links between persistent organic pollutants and rapidly metabolized compounds (phthalates and Bisphenol A) and male reproductive disorders. The overall odds ratio (OR) across all exposures and outcomes was 1.11 (95% CI 0.91-1.35). When assessing four specific chemical subgroups with sufficient data for meta-analysis for all outcomes, we found that exposure to one of the four compounds, p,p'-DDE, was related to an elevated risk: OR 1.35 (95% CI 1.04-1.74). The data did not indicate that this increased risk was driven by any specific disorder. WIDER IMPLICATIONS: The current epidemiological evidence is compatible with a small increased risk of male reproductive disorders following prenatal and postnatal exposure to some persistent environmental chemicals classified as endocrine disruptors but the evidence is limited. Future epidemiological studies may change the weight of the evidence in either direction. No evidence of distortion due to publication bias was found, but exposure-response relationships are not evident. There are insufficient data on rapidly metabolized endocrine disruptors and on specific exposure-outcome relations. A particular data gap is evident with respect to delayed effects on semen quality and testicular cancer. Although high quality epidemiological studies are still sparse, future systematic and transparent reviews may provide pieces of evidence contributing to the narrative and weight of the evidence assessments in the field.

Environmental hexachlorobenzene exposure and human male reproductive function.

Hexachlorobenzene (HCB) is a persistent environmental fungicide that may disrupt androgen regulation. The aim of this study was to investigate associations between HCB levels and biomarkers of male reproductive function. 589 Spouses of pregnant women from Greenland, Poland and Ukraine were enrolled between 2002 and 2004. The men provided semen and blood samples and were interviewed. HCB was measured in serum by gas chromatography. The mean serum concentrations of HCB were higher in Ukraine (182.3ng/g lipid) and Greenland (79.0ng/g lipid) compared to Poland (14.2ng/g lipid). Sex hormone binding globulin (SHBG) and free androgen index (FAI) were associated with HCB in men from Ukraine and Poland. This study spanning large differences in environmental HCB exposure levels shows a positive association for SHBG and negative association for FAI with high serum levels of HCB in fertile men, but without major consequences for semen quality and the Inuit study population.

Cadmium may impair prostate function as measured by prostate specific antigen in semen: A cross-sectional study among European and Inuit men.

We investigated the association between cadmium in blood and the concentration of the prostate specific antigen (PSA) in semen, including the modifying effects of zinc or the CAG polymorphism in the androgen receptor (AR). Blood and semen samples were collected from 504 partners of pregnant women in Greenland, Poland and Ukraine. We found an inverse trend between cadmium and PSA (log(ß) = -0.121, 95% confidence interval (CI): -0.213; -0.029, P = 0.0103) in Greenlandic men. Similar results were observed in men with a high number of CAG repeats (CAG 24) (log(ß) = -0.231, 95% CI: -0.363; -0.098, P = 0.0009). Inverse trends between cadmium and PSA were found when semen zinc concentrations were below the median value for men from Ukraine and Greenland. These outcomes suggest that cadmium may impair prostate function, as measured by PSA in semen, while high zinc levels and a low number of CAG repeats protects against this action.

Dietary relevant mixtures of phytoestrogens inhibit adipocyte differentiation in vitro.

Phytoestrogens (PEs) are naturally occurring plant components, with the ability to induce biological responses in vertebrates by mimicking or modulating the action of endogenous hormones. Single isoflavones have been shown to affect adipocyte differentiation, but knowledge on the effect of dietary relevant mixtures of PEs, including for instance lignans, is lacking. In the current study dietary relevant mixtures of isoflavones and their metabolites, lignans and their metabolites, coumestrol, and a mixture containing all of them, were examined for effects on adipogenesis in 3T3-L1 adipocytes, as well as tested for their PPARγ activating abilities. The results showed that mixtures of isoflavonoid parent compounds and metabolites, respectively, a mixture of lignan metabolites, as well as coumestrol concentration-dependently inhibited adipocyte differentiation. Furthermore, a mixture of isoflavonoid parent compounds, and a mixture of isoflavonoid metabolites were found to have PPARγ activating abilities. These results suggest that PEs can affect pathways known to play a role in obesity development, and indicate that the inhibitory effect on adipocyte differentiation does not appear to be strictly associated with PPARγ activation/inhibition. The current study support the hypothesis that compounds with endocrine activity can affect pathways playing a role in the development obesity and obesity related diseases.