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.

[GnRH agonist triggering in IVF and luteal phase support in women at risk of ovarian hyperstimulation syndrome]. / Déclenchement de l'ovulation par agonistes du GnRH en FIV et soutien de la phase lutéale chez les femmes à risque d'hyperstimulation ovarienne.

OBJECTIVE: To evaluate the efficacy and safety of ovulation triggering by agonists in antagonists IVF cycles with fresh embryo transfer in modulating low HCG dose for luteal phase support in patients at risk of ovarian hyperstimulation syndrome (OHSS). PATIENTS AND METHODS: In an observational study from September 2011 to March 2013, we triggered with agonist 107 cycles with OHSS risk, we initially triggered 39 cycles with 2 doses of Triptorelin 0.1 mg. Injection of 1500 IU HCG was performed one hour after the pick up and a second injection of 1500 IU was made 5 days later (group 1) combined with 400 mg of natural progesterone vaginally. In the following 68 cycles we removed the second HCG injection and increased to 600 mg vaginal progesterone associated with E2 4 mg orally (group 2). RESULTS: Group 1: the ongoing pregnancy rate and birth rate in fresh cycle is respectively 37.1% and 34.3% and the cumulative ongoing pregnancy rate and birth rate per patient is 43.6% and 41%. We recorded three late onset OHSS in pregnant women. Group 2: ongoing pregnancy rate in fresh cycle is 39.6%, the current cumulative ongoing pregnancy rate per patient was 45.6%. We observed a case of early onset OHSS. DISCUSSION AND CONCLUSION: Triggering with agonist and administering an injection of 1500 IU of HCG the day of the pick up appears to be effective in women at risk of OHSS. The exclusion of all OHSS is still not reached. The search for the best protocol and its indications should continue.

[Predictive models for ART]. / Les modèles prédictifs de grossesse en AMP.

A predictive model is a mathematical expression estimating the probability of pregnancy, by combining predictive variables, or indicators. Its development requires three successive phases: formulation of the model, its validation--internal then external--and the impact study. Its performance is assessed by its discrimination and its calibration. Numerous models were proposed, for spontaneous pregnancies, IUI and IVF, but with rather poor results, and their external validation was seldom carried out and was mainly inconclusive. The impact study-consisting in ascertaining whether their use improves medical practice--was exceptionally done. The ideal ART predictive model is a "Center specific" model, helping physicians to choose between abstention, IUI and IVF, by providing a reliable cumulative rate of pregnancy for each option. This tool would allow to rationalize the practices, by avoiding premature, late, or hopeless treatments. The model would also allow to compare the performances between ART Centers based on objective criteria. Today the best solution is to adjust the existing models to one's own practice, by considering models validated with variables describing the treated population, whilst adjusting the calculation to the Center's performances.

Simple adaptations to the Templeton model for IVF outcome prediction make it current and clinically useful.

STUDY QUESTION: What is the validity of the Templeton model (TM) in predicting live birth (LB) for a couple starting an IVF/ICSI cycle? SUMMARY ANSWER: A centre-specific model based on the original predictors of the TM may reach a sufficient level of accuracy to be used in every day practice, with a few simple adaptations. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: The TM seems the best predictive model of LB in IVF. However, previous validations of the TM suggest a lack of discrimination and calibration which means that it is not used in regular practice. We confirm this finding, and argue that such results are predictable, and essentially due to a strong centre effect. We provide evidence that the TM constitutes a useful reference reflecting a high proportion of the patient-mix effect since the parameters of the model remain invariant among centres, but also across various cultures, countries and types of hospitals. The only difference was the intercept value, interpreted as the measurement of the global performance of one centre, in particular, for a population of reference. STUDY DESIGN: The validity of the TM was tested by a retrospective analysis all IVF/ICSI cycles (n = 12 901) in our centre since 2000. PARTICIPANTS, SETTING AND METHODS: All IVF/ICSI cycles were included in the analysis. The model discrimination was evaluated by C-statistics, calculated as the area under the curve of an ROC curve. The TM was then adjusted for our data and additional variables were assessed. MAIN RESULTS AND THE ROLE OF CHANCE: Poor calibration and discrimination (C = 0.64) was observed in conformity with previous external validations. Fitting the TM to our centre constituted the first substantial improvement in prediction accuracy of discrimination (C = 0.69) and calibration. We identified an important linear time trend effect and the added value of three other predictors (FSH, smoking habits and BMI) that significantly improved the model (C = 0.71). BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION: Bias due to missing data handling was assessed through sensitivity analyses. GENERALIZABILITY TO OTHER POPULATIONS: Neither the TM nor any other models based on some centres are directly applicable to other centres. However, the TM constitutes a useful basis to build an accurate centre-specific model. STUDY FUNDING/COMPETING INTEREST(S): There were no commercial relationships (i.e. consultancies, patent-licensing agreements) that might pose a conflict of interest in connection with the submitted manuscript. The objective of this research was not directed toward any treatment effects.

[Influence duration of the use of estrogens beyond the menses in estradiol IVF antagonist programming cycles]. / Influence de la durée de prise d'estrogènes au-delà des règles dans les cycles FIV antagonistes programmés par les estrogènes.

OBJECTIVE: To evaluate by the birth rate the impact of the number of days of estrogens continued beyond the menses in a four days estradiol IVF antagonist programming cycles. PATIENTS AND METHODS: Retrospective study from September 2004 to January 2009 among women of age ranging between 25 and 38 years. Four milligrams of provames is prescribed 3 to 5 days before the theorical menses and continued until the beginning day of stimulation, which is distributed equitably between Thursday and Sunday. The birth rate is evaluated according to the number of days of estrogen continued beyond the menses within a limit from 1 to 8. RESULTS: No significant difference appears neither in the duration of stimulation, in the quantity of gonadotrophin, the oocytes pick up, nor in the rate of birth between the groups. CONCLUSION: The programming by estrogens of the antagonist IVF cycles implies a variable number of days of estrogens continued beyond the menses, which does not seem to affect the birth rate.

[Efficiency of antagonist IVF cycle programming by estrogens]. / Efficacité de la programmation des cycles FIV en antagonistes par les estrogènes.

OBJECTIVE: Assess the efficiency of estradiol programming in In Vitro Fertilization (IVF) with antagonists by comparing with classical long luteal agonist protocol. PATIENTS AND METHODS: It is a prospective randomized study, comparing 426 cycles in the arm estradiol antagonist with 412 cycles in the arm long agonist. Estradiol 4 mg/day begins on the 25th day of the previous cycle and continues during the menses until the first day of the stimulation which is from Thursday to Sunday whatever the beginning of the menses. The luteal protocol use Decapeptyl 0,1mg which begins on the 20th day of the previous cycle. RESULTS: Our two populations are similar. No pick-up has been done on Sunday. We have got significantly less oocytes and embryos in estradiol-antagonist (6,8+/-5,3 vs 7,6+/-5,7) and (3,7+/-3,2 vs 4,1+/-3,6) respectively. The ongoing pregnancy rate is comparable in the two groups: 28,6 % for estradiol antagonist 27,9 % for agonist for the whole population and 37 % vs 34,8 % respectively when at least one top embryo was transferred. DISCUSSION AND CONCLUSION: Programming antagonist cycles with estradiol allows the organization of the center; it is easy to implement and seems to give results as good as a long agonist protocol.

[Severe oligospermia with normal FSH. Comparison between radioimmunologically and immunoradiometrically determined levels of LH]. / Oligospermies sévères à FSH normale. Comparaison entre les dosages radio-immunologiques et immuno-radiométriques de la LH.

We have noted in a group of oligospermic patients with normal FSH levels and normal sized testes that there can be a significant drop in the LH levels estimated by IRMA, compared with a control group of fertile men. On the other hand, there is no correlation between IRMA and RIA levels of LH in oligospermic men when there is such a correlation in the control group. As oligospermia is usually testicular in origin preliminary results suggest that there may be a disturbance of gonadotrophin secretion in one type of oligospermia and we intend to continue this preliminary study.

[Acute adrenal gland decompensation in the immediate postpartum]. / Décompensation surrénalienne aiguë dans le post-partum immédiat.

We report the case of acute adrenal gland failure which occurred one hour after cesarian section for the delivery of a child after 31 weeks of amenorrhoea. The clinical picture of the mother was immediately severe and was dominated by neurological features: profound coma with a bilateral Babinski's sign. The laboratory tests however only revealed severe hypoglycaemia among the classical signs of adrenal gland failure. It was extremely difficult to correct the blood glucose level without concomitant administration of corticosteroids.

[Pregnancy in the diabetic woman. Incidence of malformations, of macrosomia, update on obstetrical management]. / La grossesse de la femme diabétique. Incidence des malformations, de la macrosomie, mise à jour sur la conduite obstétricale.

Perinatal mortality for infants born to diabetic mothers has dropped in the years from the 1950's when it was 20% to less than 3% by the end of the 1980's. In spite of this considerable reduction which is due to careful observation and multidisciplinary management in this type of pregnancy, the congenital malformation rate is 4 times greater than with the general population (3%) and the rate of spontaneous abortions is double (13%). The caesarean section rate is 5 times higher (18%). In bringing out a retrospective study we have attempted to analyse the endocrinological and obstetrical features of the cases.