Serum persistent organic pollutants and diminished ovarian reserve: a single-exposure and mixture exposure approach from a French case-control study.

STUDY QUESTION: Are persistent organic pollutants (POPs) associated with a diminished ovarian reserve (DOR) in women of reproductive age? SUMMARY ANSWER: Amongst 17 POPs detected in over 20% of serum samples, only p,p'-DDE was significantly associated with an increased risk of DOR, and ß-hexachlorocyclohexane (ß-HCH) was significantly associated with a decreased risk of DOR whilst mixture analyses yielded non-significant associations and did not detect any interactions between POPs. WHAT IS KNOWN ALREADY: Animal studies have shown that several POPs can alter folliculogenesis and increase follicle depletion. However, only a few studies have been conducted in humans, with small sample sizes and inconsistent results. STUDY DESIGN, SIZE, DURATION: Our study included 138 cases and 151 controls from the AROPE case-control study. Study participants were women between 18 and 40 years of age recruited amongst couples consulting for infertility in four fertility centres in western France between 2016 and 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cases of DOR were defined as women with anti-Müllerian hormone (AMH) levels ≤1.1 ng/ml and/or antral follicle count (AFC) <7, and controls were women with AMH levels between 1.1 and 5 ng/ml and AFC ≥ 7, without genital malformations and with a menstrual cycle length between 26 and 35 days. A total of 43 POPs (including 15 organochlorine pesticides, 17 polychlorinated biphenyls, and 9 polybromodiphenylethers) were measured in the serum at inclusion into the study. We conducted logistic regression adjusted for potential confounders using a directed acyclic graph to study the effect of each POP on DOR as single exposures, and used Bayesian kernel machine regression (BKMR) to measure the mixture effect of POPs on DOR. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 43 POPs, 17 were detected in over 20% of the serum samples. In the single-exposure multivariate logistic regressions, p,p'-DDE (median 165.0 IQR 161.0 ng/l in controls) as a continuous exposure was significantly associated with an increased risk of DOR (odds ratio (OR) 1.39, 95% CI 1.10-1.77) and non-significantly associated with an increased risk of DOR for the second and third terciles (OR 1.46, 95% CI 0.74-2.87, and OR 1.72, 95% CI 0.88-3.37, respectively). ß-HCH (median 24.2 IQR 21.5 ng/l in controls) was significantly associated with a decreased risk of DOR when ß-HCH was treated as a continuous exposure (OR 0.63, 95% CI 0.44-0.89) and for the third tercile of exposure (OR 0.43, 95% CI 0.21-0.84) and non-significantly associated with a decreased risk of DOR for the second tercile (OR 0.77, 95% CI 0.42-1.42). All sensitivity analyses confirmed our results. BKMR showed similar associations for single exposures but found no significant associations for the total mixture effect. In addition, the BKMR results did not suggest any interactions between POPs. LIMITATIONS, REASONS FOR CAUTION: Controls were recruited amongst infertile couples and thus may not be representative of all women of reproductive age. However, their POP concentrations were in the same range as in the general French population. WIDER IMPLICATIONS OF THE FINDINGS: This study is the first to examine the associations between serum POPs and DOR. The well-recognized anti-androgenic properties of p,p'-DDE and estrogenic properties of ß-HCH could explain these associations of opposite direction. If these results are replicated elsewhere, this could have an impact on fertility prevention messages and help in understanding the impact of POPs on the female reproductive system. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Fondation de France (grant numbers 2014-50537 and 00110196) and the French Biomedicine Agency (2016). None of the authors have any conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Association between exposure to persistent organic pollutants and mercury, and glucose metabolism in two Canadian Indigenous populations.

BACKGROUND: The body burden of metals and persistent organic pollutants (POPs) is particularly high in populations that rely on fish and other marine species for sustenance. This exposure has been associated with an increased risk of type 2 diabetes, but results remain contrasted. OBJECTIVE: We studied this association in two Indigenous populations of northern Québec (Canada) with markedly different prevalences of diabetes and levels of exposure to POPs and mercury. METHODS: As part of health surveys conducted in 2004-2009, diabetes prevalence and glucose metabolism (glucose, insulin, HOMA-IR, HOMA-B) in non-diabetic fasting adults were assessed using similar protocols in two populations: Inuit from Nunavik (n = 877) and Cree from Eeyou Istchee territory (n = 780). Blood mercury, plasma polychlorinated biphenyls (PCBs), organochlorine (OC) pesticides/metabolites and polybrominated diphenylethers (PBDEs) levels were measured in samples collected at the time of examination. Logistic and linear regressions and restricted cubic splines analyses were conducted adjusting for sex, age, waist circumference, smoking and omega-3 fatty acid content in plasma phospholipids. RESULTS: Diabetes prevalence was higher in Cree (20%) than in Inuit (7%), whereas environmental exposure was 2 to 3-fold greater in Inuit than in Cree participants. In the range of exposure common to the two populations, we observed similar linear increases in the risk of diabetes with increasing contaminant exposure. Among Cree participants, fasting glucose was positively associated with plasma PBDE level, and HOMA-B negatively associated with concentrations of ∑PCBs, dichlorodiphenyldichloroethylene, PBDEs and ∑OC pesticides. Among Inuit participants, a trend towards reduced insulin secretion was observed in association with most contaminants, but the relation was nonlinear (greater reduction at intermediate levels of exposure). A significant increase in fasting glucose levels was observed at elevated blood mercury levels (>16 µg/L). CONCLUSION: The observed association between POPs exposure and diabetes risk in the two populations studied should be confirmed using prospective design. Our results suggest the need for additional research on the physiopathological process through which POPs exposure may induce type 2 diabetes in these Indigenous populations.

Impact of maternal body mass index and gestational weight gain on pregnancy complications: an individual participant data meta-analysis of European, North American and Australian cohorts.

OBJECTIVE: To assess the separate and combined associations of maternal pre-pregnancy body mass index (BMI) and gestational weight gain with the risks of pregnancy complications and their population impact. DESIGN: Individual participant data meta-analysis of 39 cohorts. SETTING: Europe, North America, and Oceania. POPULATION: 265 270 births. METHODS: Information on maternal pre-pregnancy BMI, gestational weight gain, and pregnancy complications was obtained. Multilevel binary logistic regression models were used. MAIN OUTCOME MEASURES: Gestational hypertension, pre-eclampsia, gestational diabetes, preterm birth, small and large for gestational age at birth. RESULTS: Higher maternal pre-pregnancy BMI and gestational weight gain were, across their full ranges, associated with higher risks of gestational hypertensive disorders, gestational diabetes, and large for gestational age at birth. Preterm birth risk was higher at lower and higher BMI and weight gain. Compared with normal weight mothers with medium gestational weight gain, obese mothers with high gestational weight gain had the highest risk of any pregnancy complication (odds ratio 2.51, 95% CI 2.31- 2.74). We estimated that 23.9% of any pregnancy complication was attributable to maternal overweight/obesity and 31.6% of large for gestational age infants was attributable to excessive gestational weight gain. CONCLUSIONS: Maternal pre-pregnancy BMI and gestational weight gain are, across their full ranges, associated with risks of pregnancy complications. Obese mothers with high gestational weight gain are at the highest risk of pregnancy complications. Promoting a healthy pre-pregnancy BMI and gestational weight gain may reduce the burden of pregnancy complications and ultimately the risk of maternal and neonatal morbidity. TWEETABLE ABSTRACT: Promoting a healthy body mass index and gestational weight gain might reduce the population burden of pregnancy complications.

Volatile and semi-volatile organic compounds of respiratory health relevance in French dwellings.

Over the last decades, the prevalence of childhood respiratory conditions has dramatically increased worldwide. Considering the time spent in enclosed spaces, indoor air pollutants are of major interest to explain part of this increase. This study aimed to measure the concentrations of pollutants known or suspected to affect respiratory health that are present in dwellings in order to assess children's exposure. Measurements were taken in 150 homes with at least one child, in Brittany (western France), to assess the concentrations of 18 volatile organic compounds (among which four aldehydes and four trihalomethanes) and nine semi-volatile organic compounds (seven phthalates and two synthetic musks). In addition to descriptive statistics, a principal component analysis (PCA) was used to investigate grouping of contaminants. Formaldehyde was highly present and above 30 µg/m(3) in 40% of the homes. Diethyl phthalate, diisobutyl phthalate, and dimethylphthalate were quantified in all dwellings, as well as Galaxolide and Tonalide. For each chemical family, the groups appearing in the PCA could be interpreted in term of sources. The high prevalence and the levels of these compounds, with known or suspected respiratory toxicity, should question regulatory agencies to trigger prevention and mitigation actions.

Water disinfection by-products and bladder cancer: is there a European specificity? A pooled and meta-analysis of European case-control studies.

Several epidemiological studies suggested an association between the risk of bladder cancer and the exposure to trihalomethanes (THMs), the main disinfection by-products (DBPs) of chlorinated water. A previous pooled analysis of case-control studies from North America and Europe estimated a summarized dose-response relation. For policy guidance of drinking water disinfection in Europe and because major differences exist in water disinfection practices and DBPs occurrence between both continents, specific risk estimates for bladder cancer in relation to DBPs exposure for European populations were needed. We conducted a pooled and a two-stage random-effect meta-analyses of three European case-control studies from France, Finland, and Spain (5467 individuals: 2381 cases and 3086 controls). Individual exposure to THMs was calculated combining information on residential history, estimates of the average total THMs (TTHM) level in tap water at the successive residences and personal water consumption. A significant odds-ratio was observed for men exposed to an average residential TTHM level > 50 µg/l (OR = 1.47 (1.05; 2.05)) when compared to men exposed to levels ≤ 5 µg/l. The linear trend of the exposure-risk association was significant (p = 0.01). Risks increased significantly for exposure levels above 25 µg/l and with more than 30 years of exposure to chlorinated water, but were mainly driven by the level rather than the duration of exposure. No significant association was found among women or with cumulative exposure through ingestion. There was no evidence of a differential exposure-response relation for TTHM and bladder cancer in Europe and North America. Consequently, a global exposure-risk relation based on 4351 cases and 7055 controls is now available.

[Diagnostic management of patients with rare genetic diseases: example of five pathologies]. / Prise en charge diagnostique des patients atteints de maladies génétiques rares: exemple de cinq pathologies.

BACKGROUND: Orphan diseases are serious and unknown chronic diseases, for which a rapid diagnosis may provide a better access to healthcare. The aim of this study was to describe the procedures of diagnosis for patients with such ailments. METHODS: Self-administered questionnaires describing patient's behavior, medical examinations until the final diagnosis, as well as received medical care and financial support, were directly sent to the patients through patient associations and special examinations dedicated to rare diseases. RESULTS: 532 patients were included, suffering from 5 different diseases. Although the average delay between the appearance of symptoms and diagnosis is 2 years and 8 months, this hides great disparities (from 0 to 40 years) and half of the patients were diagnosed within 4 months. The study shows that the diagnosis management is influenced by the illness and its symptoms as well as by the characteristics of the first medical examination. CONCLUSIONS: The diagnosis management of patients with rare diseases is strongly determined by personnel initiatives or exceptional opportunities, rather than by a real organisational strategy of the healthcare system.

Participation in maternal marker screening for Down syndrome: contribution of the information delivered to the decision-making process.

OBJECTIVE: In France, health care providers now have to fulfill two requirements before serum marker screening for Down syndrome can be carried out: provide a written statement confirming that they informed the pregnant woman about the test and obtain the woman's written consent. A survey was designed to assess: (1) women's opinion on the explanations they received when the screening test was offered and when test results were given, and (2) the decisions women planned to make in light of the test results (i.e. to carry out amniocentesis or not). METHODS: The survey was intended for all French pregnant women who underwent the serum marker screening test during the first week of October 1998. The questionnaire was sent to women via clinical laboratories (3,825 questionnaires were sent to the 54 laboratories authorized for Down syndrome screening in France). Besides chi(2) tests and tests of comparisons of paired proportions, we conducted a hierarchical clustering analysis and qualitatively analyzed the free comments provided by women. RESULTS: The response rate was 39% (n = 1,473). Explanations given by the provider at the time the test was offered were not clear and ample enough for 38.8% of women. Furthermore, 45.9% of women stated the same opinion about the explanations provided with the test results. Based on the test results, amniocentesis was recommended to 125 high-risk women; 20.8% of them were going to decline the offer or had not yet decided. Among low-risk women, 13% requested amniocentesis or had not yet decided. The opinion of these high- or low-risk women on the clarity and ampleness of the explanations provided with the test results was similar to that of high-risk women who wished to carry out amniocentesis. The hierarchical clustering analysis led us to identify clusters of women who mainly differed according to their opinion (anxious or reassured) on the explanations provided, regardless of their risk (high or low). CONCLUSION: Women's decision regarding screening for Down syndrome requires them to promptly integrate complex information on what the test is and entails. The question is then raised as to the type of information that is actually disclosed or that could be disclosed, based on how women value its contribution to decision-making.

[Prenatal screening for trisomy 21 with maternal serum markers: information for decision-making in pregnant women]. / Dépistage prénatal de la trisomie 21 par marqueurs sériques maternels: de l'information à la prise de décision des femmes enceintes.

INTRODUCTION: French health professionals are now required to provide relevant information on the test screening for Down syndrome and its possible implications when making the test available to pregnant women. A questionnaire was designed to assess prescription modalities, explanation of results, opinion on the information received when test was offered and test results were given, and likely decision after screening. RESULTS: The response rate was 39% (1473 questionnaires analyzed). In 90.5% of the answers, women declared that an interview had preceded test prescription. 61.2% of women were satisfied with both the clarity and quantity of explanations provided and 57.6% considered that the information had helped them decide to undergo or refuse screening. 54.1% were satisfied with the explanations of test results. Amniocentesis was proposed to 125 women, 79.2% of which decided to undergo the procedure. Their opinion concerning explanations of test results was similar to that of women who refused amniocentesis or had not yet made up their minds. CONCLUSION: Such results demonstrate the necessity to improve and adapt the information delivered by health professionals, keeping in mind that in this type of situation, decision making requires the rapid integration of complex information.

Cross-cultural adaptation of a health status classification system in children with cancer. First results of the French adaptation of the Health Utilities Index Marks 2 and 3.

Our objective was to adapt and validate the Health Utilities Index Mark 2 (HUI 2) and HUI 3 health status classification systems self-report questionnaire in a population of children with cancer, a group of 42 children already included in a multi-centre database designed by the Group on Brain Tumors in Children of the French Society for Pediatric Oncology. Children were recruited during a routine consultation. Most of them had completed treatment. The version of the questionnaire for French adults was adapted linguistically for children. Open-ended queries by children about the comprehensiveness of the questions and very low non-response rates showed a good acceptability of the questionnaire. The main psychometric properties of the HUI 2 and HUI 3 classification systems were assessed in 3 groups of raters (child, parent, physician): construct validity was tested against the rating of the child's health state on a Likert scale and through comparison with clinical data, and internal consistency was determined through multi-trait analysis. Weighted and unweighted kappa values were used to measure the inter-rater agreement between the child's, parent's and physician's assessment of the child's health state. The convergent validity was satisfactory, with better results when the physician's assessment was used. The most affected attributes were the expected ones (i.e., cognition, pain and emotion). Disagreement was observed between the 3 raters, more often in the same direction: taking the child's assessment as the reference, the parents tended to under-estimate the health status while physicians tended to over-estimate it.

French cross-cultural adaptation of the Health Utilities Indexes Mark 2 (HUI2) and 3 (HUI3) classification systems. Clinical and Economic Working Groups.

The McMaster Health Utilities Indexes Mark 2 (HUI2) and 3 (HUI3) are multiattribute health classification systems, for which multiattribute preference functions have been developed in Canada. They provide a comprehensive instrument for use in economic evaluations and population health survey studies. This paper reports on the first results on the adaptation of the HUI2 and HUI3 systems cross-culturally and the assessment of the validity and reliability of the French self-report questionnaire in different patient populations. The cross-cultural adaptation included translation, backtranslations, an expert consensus meeting and pre-test with a few patients and healthy subjects in order to produce a conceptually equivalent French version of the 15 question self-report questionnaire and the HUI2 and HUI3 classification systems. Different groups of patients attending specialized clinics (n = 709) completed the questionnaire and another generic questionnaire (the Sickness Impact Profile (SIP)) for validity assessment. Physicians and patients were also asked for a global subjective assessment of the patient's health status. The French questionnaire was well received by the patients. The criterion and convergent validities of both classification systems (correlations with the patients' and physicians' assessments and with the responses to the SIP questionnaire) were satisfactory. The internal consistency was acceptable too (Cronbach's alpha = 0.81), as was the 3 day test-retest reproducibility. These first results authorize careful use of the 15 question self-report questionnaire in French. An assessment of the multiattribute preference function for the HUI3 system in France will be the study's next objective.

Down syndrome serum marker screening: decision criteria and implicit values.

Maternal serum markers assess the individual risk of giving birth to a fetus with Down syndrome. Because this information is a probability, and because of the infinite number of cut-off risks that can be adopted, a decision criterion is needed to define a population screening program. While a decision criterion for cut-off risks may refer to arbitrations between risks, another criterion must be considered. This criterion focuses on a societal perspective by comparing the costs of the program to the expected benefits. We will first discuss the questions that are raised when assessing, in terms of cost-effectiveness, the consequences of having adopted the policy maker's preferences for prenatal diagnosis referral. Subsequently, we will discuss the implicit values attributed to the outcomes of the program when the societal point of view is reduced to societal profitability. This is accomplished by means of a cost-benefit analysis using the 'avoided costs' approach. The consequences of screening with 'double' and 'triple' tests were assessed using a database made of 10,108 observations, including 63 Down syndrome cases. For a cut-off risk of 1:250 (resulting in a 7% amniocentesis referral rate, regardless of the technique), conclusions in terms of decision making differ according to the effectiveness indicator. Although a criterion based on resource allocation would promote the triple test, cost-benefit analysis points out the impact on results of factors such as the amniocentesis related fetal losses or the introduction of equity principles.