Associations between synthetic phenols, phthalates, and placental growth/function: a longitudinal cohort with exposure assessment in early pregnancy.

STUDY QUESTION: Is exposure to environmental chemicals associated with modifications of placental morphology and function? SUMMARY ANSWER: Phthalates, a class of ubiquitous chemicals, showed an association with altered placental weight, placental vascular resistance (PVR), and placental efficiency. WHAT IS KNOWN ALREADY: Only a few epidemiological studies have assessed the effects of phenols and phthalates on placental health. Their results were affected by exposure measurement errors linked to the rapid excretion of these compounds and the reliance on a limited number of spot urine samples to assess exposure. STUDY DESIGN SIZE DURATION: A prospective mother-child cohort, with improved exposure assessment for non-persistent chemicals, recruited participants between 2014 and 2017. Sample size ranged between 355 (placental parameters measured at birth: placental weight and placental-to-fetal weight ratio (PFR): a proxy for placental efficiency) and 426 (placental parameters measured during pregnancy: placental thickness and vascular resistance). PARTICIPANTS/MATERIALS SETTING METHODS: Phenols (four parabens, two bisphenols, triclosan, and benzophenone-3), 13 phthalate metabolites, and two non-phthalate plasticizer metabolites were measured in within-subject pools of repeated urine samples collected during the second and third trimesters of pregnancy (median = 21 samples/trimester/woman). Placental thickness and PVR were measured during pregnancy. The placenta was weighed at birth and the PFR was computed. Both adjusted linear regression and Bayesian Kernel Machine Regression were used to evaluate associations between phenols and phthalates (alone or as a mixture) and placental parameters. Effect modification by child sex was also investigated. MAIN RESULTS AND THE ROLE OF CHANCE: Several phthalate metabolites were negatively associated with placental outcomes. Monobenzyl phthalate (MBzP) concentrations, during the second and third trimesters of pregnancy, were associated with a decrease in both placental weight at birth (ß = -20.1 g [95% CI: -37.8; -2.5] and ß = -17.4 g [95% CI: -33.2; -1.6], for second and third trimester, respectively) and PFR (ß = -0.5 [95% CI: -1, -0.1] and ß = -0.5 [95% CI: -0.9, -0.1], for the second and third trimester, respectively). Additionally, MBzP was negatively associated with PVR during the third trimester (ß= -0.9 [95% CI: -1.8; 0.1]). Mono-n-butyl phthalate (MnBP), was negatively associated with PVR in both trimesters (ß = -1.3, 95% CI: [-2.3, -0.2], and ß = -1.2, 95% CI: [-2.4, -0.03], for the second and third trimester, respectively). After stratification for child sex, Σ diisononyl phthalate (DiNP) (either second or third-trimester exposures, depending on the outcomes considered) was associated with decreased PVR in the third trimester, as well as decreased placental weight and PFR in males. No associations were observed for phenol biomarkers. LIMITATIONS REASONS FOR CAUTION: False positives cannot be ruled out. Therefore, chemicals that were associated with multiple outcomes (MnBP and DiNP) or reported in existing literature as associated with placental outcomes (MBzP) should be considered as the main results. WIDER IMPLICATIONS OF THE FINDINGS: Our results are consistent with in vitro studies showing that phthalates target peroxisome proliferator-activated receptor γ, in the family of nuclear receptors involved in key placental development processes such as trophoblast proliferation, migration, and invasion. In addition to placental weight at birth, we studied placental parameters during pregnancy, which could provide a broader view of how environmental chemicals affect maternal-fetal exchanges over the course of pregnancy. Our findings contribute to the increasing evidence indicating adverse impacts of phthalate exposure on placental health. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the French Research Agency-ANR (MEMORI project ANR-21-CE34-0022). The SEPAGES cohort was supported by the European Research Council (N°311765-E-DOHaD), the European Community's Seventh Framework Programme (FP7/2007-206-N°308333-892 HELIX), the European Union's Horizon 2020 research and innovation programme (N° 874583 ATHLETE Project, N°825712 OBERON Project), the French Research Agency-ANR (PAPER project ANR-12-PDOC-0029-01, SHALCOH project ANR-14-CE21-0007, ANR-15-IDEX-02 and ANR-15-IDEX5, GUMME project ANR-18-CE36-005, ETAPE project ANR-18-CE36-0005-EDeN project ANR-19-CE36-0003-01), the French Agency for Food, Environmental and Occupational Health & Safety-ANSES (CNAP project EST-2016-121, PENDORE project EST-2016-121, HyPAxE project EST-2019/1/039, PENDALIRE project EST-2022-169), the Plan Cancer (Canc'Air project), the French Cancer Research Foundation Association de Recherche sur le Cancer-ARC, the French Endowment Fund AGIR for chronic diseases-APMC (projects PRENAPAR, LCI-FOT, DysCard), the French Endowment Fund for Respiratory Health, the French Fund-Fondation de France (CLIMATHES-00081169, SEPAGES 5-00099903, ELEMENTUM-00124527). N.J. was supported by a doctoral fellowship from the University Grenoble Alpes. V.M. was supported by a Sara Borrell postdoctoral research contract (CD22/00176), granted by Instituto de Salud Carlos III (Spain) and NextGenerationEU funds. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02852499.

The Pubic Diastasis Measurement, a Key Element for the Diagnosis, Management, and Prognosis of the Bladder Exstrophy.

OBJECTIVE: To demonstrate the feasibility of measuring the fetal pubic diastasis (PD) distance on antenatal ultrasound in normal fetuses and to compare it to fetuses with bladder exstrophy. METHODS: Firstly, a prospective multicentric study was conducted to determine the feasibility of the PD ultrasound measurement during the second half of pregnancy. Secondly, data from a single center were used to develop a nomogram for PD values in normal fetuses. Thirdly, retrospective PD measurements were collected from fetuses with bladder exstrophy, diagnosed in seven French Multidisciplinary Centers for Prenatal Diagnosis (MCPDs). RESULTS: Operators from several MCPDs examined 868 fetuses and found that overall PD ultrasound measurement was feasible in 71% of cases and that the ossification of pubic points increased to be always visible from 27 weeks of gestation onward. Performed in a single center by a referring operator on 1,539 fetuses, the feasibility reached 94.74%. Both set of measurements were concordant (mean PD distance value of 5.42 ± 1.8 mm). Interestingly, all 23 fetuses with bladder exstrophy showed a significantly larger PD distance (mean 15.74 ± 3.9 mm). CONCLUSION: PD measurement in the fetus is feasible and reliable in the second half of gestation and can be used to support the antenatal diagnosis of bladder exstrophy with PD values exceeding 10 mm.

Formative assessment based on an audit and feedback improves nuchal translucency ultrasound image quality.

OBJECTIVES: The purpose of this work was to study the impact of an audit and feedback on the quality of routine first-trimester nuchal transparency ultrasound images. METHODS: Eighty-eight sonographers were each sent 2 different series of 30 consecutive nuchal translucency images at a mean interval of 3 months to a dedicated, protected server for remote double-blind independent analysis based on the new Collège Français d'Echographie Foetale/Centre National de la Recherche Scientifique image-scoring method (https://www.cfef.org/evaluation/ISMCFEFCNRS.pdf). The sonographers were classified as low (score below the median) or high (score above the median) scorers for each series. Before their second evaluation, 73 of the 88 sonographers received a feedback report on their first series of images, whereas the other 15 participants received no feedback. The baseline characteristics of the participants who did and did not receive feedback were comparable. RESULTS: Participants who received feedback increased their average score significantly, from a mean ± SD of 11.1 ± 1.3 to 13.4 ± 1.4 among low scorers (P < .00001) and from 15.1 ± 1.2 to 16.0 ± 1.4 among high scorers (P < .001), whereas no significant change was seen among participants who received no feedback (low scorers, 10.9 ± 1.5 to 12.1 ± 2.0; P = .11; high scorers, 14.7 ± 1.3 to 14.6 ± 1.3; P = .99). The proportion of satisfactory images increased by 48% among low scorers who received feedback. CONCLUSIONS: Formative assessment based on a moderately intensive audit and feedback is feasible and effective for improving the quality of routine first-trimester nuchal transparency ultrasound images.

Prenatal diagnosis of achondroplasia: new specific signs.

BACKGROUND: Achondroplasia is one of the most common forms of short limb dwarfism. It is usually suspected on third trimester routine ultrasound because of very shortened long bones. We have described two new prenatal sonographic signs of achondroplasia visible at the proximal femoral metaphysis. METHODS: Over 5 years, five fetuses were diagnosed with achondroplasia at the Grenoble Prenatal Diagnosis Centre. Ultrasound and tomographic examinations were performed by specialists. To study the proximal metaphysis, the ultrasound transducer was positioned at a 45 degree angle to the diaphyseal axis. Postnatal diagnosis was confirmed. RESULTS: On computed tomography and postnatal X-ray, proximal femoral metaphysis appeared rounded, with poor, uneven ossification. Connexion to diaphysis was abnormal, with relative overgrowth of the periosteum, creating a new diagnostic sign that we called the 'collar hoop' sign. On ultrasound, all fetuses had a very rounded metaphyseal-epiphyseal interface, with an angle connexion to diaphysis wider than expected. The 'collar hoop' sign was obvious on four of the fetuses. During the same period, proximal femoral metaphyses appeared normal in 653 healthy fetuses, suggesting high specificity of those two new signs. CONCLUSION: Metaphysis examination is recommended if fetal femur length measures below the fifth percentile, as normal aspect may rule out achondroplasia.

Quality control of an image-scoring method for nuchal translucency ultrasonography.

OBJECTIVE: The objective of the study was to describe a new image-scoring method (NISM) for the measurement of nuchal translucency and crown-rump length on ultrasound scans and to establish interreviewer reliability. STUDY DESIGN: This NISM was based on 8 criteria on a scale of 4 levels (1-4) established on clearly defined ultrasound reference marks. Ten reviewers assessed the same images of 30 fetuses. After a short training period, the same images and those of 30 new fetuses were scored by these 10 reviewers. RESULTS: The differences in scores among the 10 reviewers were significant for 4 of 45 pairwise comparisons before training, but no pairwise comparison was significant after training. Interreviewer variance was significantly lower after training (P = .045). The intraclass correlations before and after training were 0.75 and 0.82. For each criterion, the scores were dichotomized into 2 categories (1-2 vs 3-4). Kappa values for each criterion were substantial (0.61 to 0.80) or even almost perfect (0.81 to 1.00). CONCLUSION: This NISM was highly reliable for the total scores and for each criterion evaluating the image of nuchal translucency and crown-rump length and provides a relevant quality control tool for ultrasound operators.