Immune thrombocytopenia and pregnancy: an exposed/nonexposed cohort study.

The risk of immune thrombocytopenia (ITP) worsening during pregnancy and neonatal ITP (NITP) have never been prospectively studied. We included 180 pregnant and 168 nonpregnant women with ITP in a prospective, multicenter, observational cohort study. A total of 131 pregnant women with ITP were matched to 131 nonpregnant women with ITP by history of splenectomy, ITP status (no response, response, complete response), and duration. Groups were followed for 15 months. The primary outcome was the first occurrence of ITP worsening defined by a composite end point including bleeding events and/or severe thrombocytopenia (<30 × 109/L) and/or ITP treatment modification. We also studied the recurrence of ITP worsening and the incidence of NITP and risk factors. The first occurrence of ITP worsening did not differ between pregnant and nonpregnant women with ITP (53.4 per 100 person-years [95% confidence interval {CI}, 40.8-69.9] vs 37.1 [95% CI, 27.5-50.0]; hazard ratio {HR}, 1.35 [95% CI, 0.89-2.03], P = .16). Pregnant women with ITP were more likely to have recurrence of severe thrombocytopenia and treatment modification (HR, 2.71 [95% CI, 1.41-5.23], P = .003; HR, 2.01 [95% CI, 1.14-3.57], P = .017, respectively). However, recurrence of severe bleeding events was not different between groups (P = .4). Nineteen (14%) neonates showed NITP <50 × 109/L. By multivariable analysis, NITP was associated with a previous offspring with NITP and maternal platelet count <50 × 109/L within 3 months before delivery (adjusted odds ratio, 5.55 [95% CI, 1.72-17.89], P = .004 and 4.07 [95% CI, 1.41-11.73], P = .009). To conclude, women with ITP do not increase their risk of severe bleeding during pregnancy. NITP is associated with NITP history and the severity of maternal ITP during pregnancy. These results will be useful for counseling women with ITP.

Randomized Trial of Fetal Surgery for Severe Left Diaphragmatic Hernia.

BACKGROUND: Observational studies have shown that fetoscopic endoluminal tracheal occlusion (FETO) has been associated with increased survival among infants with severe pulmonary hypoplasia due to isolated congenital diaphragmatic hernia on the left side, but data from randomized trials are lacking. METHODS: In this open-label trial conducted at centers with experience in FETO and other types of prenatal surgery, we randomly assigned, in a 1:1 ratio, women carrying singleton fetuses with severe isolated congenital diaphragmatic hernia on the left side to FETO at 27 to 29 weeks of gestation or expectant care. Both treatments were followed by standardized postnatal care. The primary outcome was infant survival to discharge from the neonatal intensive care unit. We used a group-sequential design with five prespecified interim analyses for superiority, with a maximum sample size of 116 women. RESULTS: The trial was stopped early for efficacy after the third interim analysis. In an intention-to-treat analysis that included 80 women, 40% of infants (16 of 40) in the FETO group survived to discharge, as compared with 15% (6 of 40) in the expectant care group (relative risk, 2.67; 95% confidence interval [CI], 1.22 to 6.11; two-sided P = 0.009). Survival to 6 months of age was identical to the survival to discharge (relative risk, 2.67; 95% CI, 1.22 to 6.11). The incidence of preterm, prelabor rupture of membranes was higher among women in the FETO group than among those in the expectant care group (47% vs. 11%; relative risk, 4.51; 95% CI, 1.83 to 11.9), as was the incidence of preterm birth (75% vs. 29%; relative risk, 2.59; 95% CI, 1.59 to 4.52). One neonatal death occurred after emergency delivery for placental laceration from fetoscopic balloon removal, and one neonatal death occurred because of failed balloon removal. In an analysis that included 11 additional participants with data that were available after the trial was stopped, survival to discharge was 36% among infants in the FETO group and 14% among those in the expectant care group (relative risk, 2.65; 95% CI, 1.21 to 6.09). CONCLUSIONS: In fetuses with isolated severe congenital diaphragmatic hernia on the left side, FETO performed at 27 to 29 weeks of gestation resulted in a significant benefit over expectant care with respect to survival to discharge, and this benefit was sustained to 6 months of age. FETO increased the risks of preterm, prelabor rupture of membranes and preterm birth. (Funded by the European Commission and others; TOTAL ClinicalTrials.gov number, NCT01240057.).

Randomized Trial of Fetal Surgery for Moderate Left Diaphragmatic Hernia.

BACKGROUND: Fetoscopic endoluminal tracheal occlusion (FETO) has been associated with increased postnatal survival among infants with severe pulmonary hypoplasia due to isolated congenital diaphragmatic hernia on the left side, but data are lacking to inform its effects in infants with moderate disease. METHODS: In this open-label trial conducted at many centers with experience in FETO and other types of prenatal surgery, we randomly assigned, in a 1:1 ratio, women carrying singleton fetuses with a moderate isolated congenital diaphragmatic hernia on the left side to FETO at 30 to 32 weeks of gestation or expectant care. Both treatments were followed by standardized postnatal care. The primary outcomes were infant survival to discharge from a neonatal intensive care unit (NICU) and survival without oxygen supplementation at 6 months of age. RESULTS: In an intention-to-treat analysis involving 196 women, 62 of 98 infants in the FETO group (63%) and 49 of 98 infants in the expectant care group (50%) survived to discharge (relative risk , 1.27; 95% confidence interval [CI], 0.99 to 1.63; two-sided P = 0.06). At 6 months of age, 53 of 98 infants (54%) in the FETO group and 43 of 98 infants (44%) in the expectant care group were alive without oxygen supplementation (relative risk, 1.23; 95% CI, 0.93 to 1.65). The incidence of preterm, prelabor rupture of membranes was higher among women in the FETO group than among those in the expectant care group (44% vs. 12%; relative risk, 3.79; 95% CI, 2.13 to 6.91), as was the incidence of preterm birth (64% vs. 22%, respectively; relative risk, 2.86; 95% CI, 1.94 to 4.34), but FETO was not associated with any other serious maternal complications. There were two spontaneous fetal deaths (one in each group) without obvious cause and one neonatal death that was associated with balloon removal. CONCLUSIONS: This trial involving fetuses with moderate congenital diaphragmatic hernia on the left side did not show a significant benefit of FETO performed at 30 to 32 weeks of gestation over expectant care with respect to survival to discharge or the need for oxygen supplementation at 6 months. FETO increased the risks of preterm, prelabor rupture of membranes and preterm birth. (Funded by the European Commission and others; TOTAL ClinicalTrials.gov number, NCT00763737.).

Validity of a Delphi consensus definition of growth restriction in the newborn for identifying neonatal morbidity.

BACKGROUND: Small for gestational age is defined as a birthweight below a birthweight percentile threshold, usually the 10th percentile, with the third or fifth percentile used to identify severe small for gestational age. Small for gestational age is used as a proxy for growth restriction in the newborn, but small-for-gestational-age newborns can be physiologically small and healthy. In addition, this definition excludes growth-restricted newborns who have weights more than the 10th percentile. To address these limits, a Delphi study developed a new consensus definition of growth restriction in newborns on the basis of neonatal anthropometric and clinical parameters, but it has not been evaluated. OBJECTIVE: To assess the prevalence of growth restriction in the newborn according to the Delphi consensus definition and to investigate associated morbidity risks compared with definitions of Small for gestational age using birthweight percentile thresholds. STUDY DESIGN: Data come from the 2016 and 2021 French National Perinatal Surveys, which include all births ≥22 weeks and/or with birthweights ≥500 g in all maternity units in France over 1 week. Data are collected from medical records and interviews with mothers after the delivery. The study population included 23,897 liveborn singleton births. The Delphi consensus definition of growth restriction was birthweight less than third percentile or at least 3 of the following criteria: birthweight, head circumference or length <10th percentile, antenatal diagnosis of growth restriction, or maternal hypertension. A composite of neonatal morbidity at birth, defined as 5-minute Apgar score <7, cord arterial pH <7.10, resuscitation and/or neonatal admission, was compared using the Delphi definition and usual birthweight percentile thresholds for defining small for gestational age using the following birthweight percentile groups: less than a third, third to fourth, and fifth to ninth percentiles. Relative risks were adjusted for maternal characteristics (age, parity, body mass index, smoking, educational level, preexisting hypertension and diabetes, and study year) and then for the consensus definition and birthweight percentile groups. Multiple imputation by chained equations was used to impute missing data. Analyses were carried out in the overall sample and among term and preterm newborns separately. RESULTS: We identified that 4.9% (95% confidence intervals, 4.6-5.2) of newborns had growth restriction. Of these infants, 29.7% experienced morbidity, yielding an adjusted relative risk of 2.5 (95% confidence intervals, 2.2-2.7) compared with newborns without growth restriction. Compared with birthweight ≥10th percentile, morbidity risks were higher for low birthweight percentiles (less than third percentile: adjusted relative risk, 3.3 [95% confidence intervals, 3.0-3.7]; third to fourth percentile: relative risk, 1.4 [95% confidence intervals, 1.1-1.7]; fifth to ninth percentile: relative risk, 1.4 [95% confidence intervals, 1.2-1.6]). In adjusted models including the definition of growth restriction and birthweight percentile groups and excluding birthweights less than third percentile, which are included in both definitions, morbidity risks remained higher for birthweights at the third to fourth percentile (adjusted relative risk, 1.4 [95% confidence intervals, 1.1-1.7]) and fifth to ninth percentile (adjusted relative risk, 1.4 [95% confidence intervals, 1.2-1.6]), but not for the Delphi definition of growth restriction (adjusted relative risk, 0.9 [95% confidence intervals, 0.7-1.2]). Similar patterns were found for term and preterm newborns. CONCLUSION: The Delphi consensus definition of growth restriction did not identify more newborns with morbidity than definitions of small for gestational age on the basis of birthweight percentiles. These findings illustrate the importance of evaluating the results of Delphi consensus studies before their adoption in clinical practice.

A multidisciplinary and structured investigation of three suspected clusters of transverse upper limb reduction defects in France.

INTRODUCTION: Between 2019-2021, facing public concern, a scientific expert committee (SEC) reanalysed suspected clusters of transverse upper limb reduction defects (TULRD) in three administrative areas in France, where initial investigations had not identified any risk exposure. We share here the national approach we developed for managing suspicious clusters of the same group of congenital anomalies occurring in several areas. METHODS: The SEC analysed the medical records of TURLD suspected cases and performed spatiotemporal analyses on confirmed cases. If the cluster was statistically significant and included at least three cases, the SEC reviewed exposures obtained from questionnaires, environmental databases, and a survey among farmers living near to cases' homes concerning their plant product use. RESULTS: After case re-ascertainment, no statistically significant cluster was observed in the first administrative areas. In the second area, a cluster of four children born in two nearby towns over two years was confirmed, but as with the initial investigations, no exposure to a known risk factor explaining the number of cases in excess was identified. In the third area, a cluster including just two cases born the same year in the same town was confirmed. DISCUSSION: Our experience highlights that in the event of suspicious clusters occurring in different areas of a country, a coordinated and standardised approach should be preferred.

Very elevated hCGß (≥10 multiple of the median) in maternal marker screening for Down syndrome: Frequency, etiologies, outcomes, and guidelines.

AIM: This aim of this study was to detail maternal and fetal anomalies observed on a national scale in a large French cohort of patients presenting high hCG values (≥10 multiple of the median [MoM]) at Down syndrome screening in order to define clear and optimal guidelines. METHODS: This is a retrospective multicenter study based on a French annual database of all trisomy 21 screenings. Our study targeted and studied cases with hCG or hCGß values ≥10 MoM. Complementary exams and outcomes were analyzed. RESULTS: The calculated frequency was 0.05% for hCGß ≥10 MoM in unselected patients. For this series of 289 cases, a complication of the pregnancy or a poor outcome was observed in 145 cases (51%) as follows: 96 (66%) cases of fetal disease, 23 (16%) of maternal disease, 5 (3.5%) of placental anomalies and 21 (14.5%) of systemic disease concerning mother, fetus and placenta. CONCLUSION: This study establishes the frequency of hCG or hCGß values ≥10 MoM, presents a flow chart that optimizes follow-up, and gives clear information for patients presenting with such abnormal values at trisomy 21 screening.

Idiopathic polyhydramnios and postnatal outcomes of children: The role of exome sequencing.

OBJECTIVES: The objective of our study was to evaluate the long-term outcome of children born from a pregnancy complicated by idiopathic polyhydramnios. The secondary objective was to investigate factors associated with adverse outcomes. METHODS: We conducted a retrospective study in two prenatal diagnosis centers between January 1, 2009 and December 31, 2020. Inclusion criteria were pregnancies with a diagnosis of idiopathic polyhydramnios, defined by a deepest pocket greater than 8 cm, no detectable abnormality at ultrasound and a negative amniotic fluid assessment including karyotype, chromosomal microarray, biochemical assays (electrolytes and digestive enzymes), and viruses (parvovirus B19 and cytomegalovirus). One-year outcomes of these children were collected. The primary endpoint was adverse postnatal outcome, defined by at least one of the following criteria: stillbirth, neonatal death, or serious and incurable condition diagnosed in the first year of life. RESULTS: Of the 245 women referred for isolated polyhydramnios, 73 were diagnosed with idiopathic polyhydramnios after prenatal investigations. The mean age at follow-up of children was 28 months (95% CI 20-36). An adverse outcome occurred in 25% of cases (18/73), with one stillbirth, two neonatal deaths, and 15 severe conditions diagnosed postnatally, including a rate of monogenic disorders of 8.2% (6/73). Pediatric follow-up was normal for 75% of the children (55/73), including a rate of 9% (5/55) of curable conditions. Repeated amnioreduction was independently associated with an adverse outcome. CONCLUSION: Pregnant women with polyhydramnios should be informed of the increased risk of 25% of perinatal mortality and serious conditions diagnosed after birth.

Cell-free DNA screening for common autosomal trisomies using rolling-circle replication in twin pregnancies.

OBJECTIVE: To evaluate the performance of prenatal screening for common autosomal trisomies in twin pregnancies through the use of rolling-circle replication (RCR)-cfDNA as a first-tier test. METHOD: Prospective multicenter study. Women who underwent prenatal screening for trisomy (T) 21, 18 and 13 between January 2019 and March 2022 in twin pregnancies were included. Patients were included in two centers. The primary endpoint was the rate of no-call results in women who received prenatal screening for common autosomal trisomies by RCR-cfDNA at the first attempt, compared to that in prospectively collected samples from 16,382 singleton pregnancies. The secondary endpoints were the performance indices of the RCR-cfDNA. RESULTS: 862 twin pregnancies underwent screening for T21, T18 and T13 by RCR-cfDNA testing at 10-33 weeks' gestation. The RCR-cfDNA tests provided a no-call result from the first sample obtained from the patients in 107 (0.7%) singleton and 17 (2.0%) twin pregnancies. Multivariable regression analysis demonstrated that significant independent predictors of test failure were twin pregnancy and in vitro fertilization conception. All cases of T21 (n = 20/862; 2.3%), T18 (n = 4/862; 0.5%) and T13 (n = 1/862; 0.1%) were correctly detected by RCR-cfDNA (respectively, 20, 4 and 1 cases). Sensitivity was 100% (95% CI, 83.1%-100%), 100% (95% CI 39.8%-100%) and 100% (95% CI 2.5%-100%) for T21, T18 and T13, respectively, in twin pregnancies. CONCLUSION: The RCR-cfDNA test appears to have good accuracy with a low rate of no-call results in a cohort of twin pregnancies for the detection of the most frequent autosomal trisomies.

Performance of cell-free DNA testing for common fetal trisomies in triplet pregnancies.

OBJECTIVE: In singleton pregnancies, the use of cell-free DNA (cfDNA) analysis as a screening test for common fetal trisomies has spread worldwide though we still lack sufficient data for its use in triplet pregnancies. The objective of this study is to assess the performance of cfDNA testing in detecting fetal aneuploidies in triplet pregnancies as a first-tier test. METHOD: We performed a retrospective cohort study including data from pregnant women with a triplet pregnancy who underwent cfDNA testing between May 1, 2017, and January 15, 2020. cfDNA was obtained by massive parallel sequencing (VeriSeq NIPT solution; Illumina®). The objectives of the study were to assess the diagnostic performance of cfDNA testing for trisomy 21 (T21) (primary outcome), trisomy 18 (T18) and 13 (secondary outcomes). RESULTS: During the study period, cfDNA testing was performed in 255 women with triplet pregnancy, of which 165 (64.7%) had a neonatal outcome available. Three tests were positive for T21, one of which was confirmed by an antenatal karyotype, and the other was confirmed at birth. The third case did not undergo an invasive procedure and was not confirmed at birth (false positive). In one case, cfDNA testing was positive for T18 and was confirmed by an antenatal karyotype. There were no cases of trisomy 13 in the cohort. The no-call rate was 2.4% at first sampling. Fifty-eight (22.7%) women had embryo reduction, which in 40 (69%) of whom was performed after the cfDNA test result. CONCLUSION: cfDNA testing could be offered as primary screening for main fetal aneuploidies in triplet pregnancies after provision of appropriate patient information.

Prenatal diagnosis of isolated bilateral clubfoot: Is amniocentesis indicated?

INTRODUCTION: The aim of this study is to evaluate the benefit of cytogenetic testing by amniocentesis after an ultrasound diagnosis of isolated bilateral talipes equinovarus. MATERIAL AND METHODS: This multicenter observational retrospective study includes all prenatally diagnosed cases of isolated bilateral talipes equinovarus in five fetal medicine centers from 2012 through 2021. Ultrasound data, amniocentesis results, biochemical analyses of amniotic fluid and parental blood samples to test neuromuscular diseases, pregnancy outcomes, and postnatal outcomes were collected for each patient. RESULTS: In all, 214 fetuses with isolated bilateral talipes equinovarus were analyzed. A first-degree family history of talipes equinovarus existed in 9.8% (21/214) of our cohort. Amniocentesis was proposed to 86.0% (184/214) and performed in 70.1% (129/184) of cases. Of the 184 karyotypes performed, two (1.6%) were abnormal (one trisomy 21 and one triple X syndrome). Of the 103 microarrays performed, two (1.9%) revealed a pathogenic copy number variation (one with a de novo 18p deletion and one with a de novo 22q11.2 deletion) (DiGeorge syndrome). Neuromuscular diseases (spinal muscular amyotrophy, myasthenia gravis, and Steinert disease) were tested for in 56 fetuses (27.6%); all were negative. Overall, 97.6% (165/169) of fetuses were live-born, and the diagnosis of isolated bilateral talipes equinovarus was confirmed for 98.6% (139/141). Three medical terminations of pregnancy were performed (for the fetuses diagnosed with Down syndrome, DiGeorge syndrome, and the 18p deletion). Telephone calls (at a mean follow-up age of 4.5 years) were made to all parents to collect medium-term and long-term follow-up information, and 70 (33.0%) families were successfully contacted. Two reported a rare genetic disease diagnosed postnatally (one primary microcephaly and one infantile glycine encephalopathy). Parents did not report any noticeably abnormal psychomotor development among the other children during this data collection. CONCLUSIONS: Despite the low rate of pathogenic chromosomal abnormalities diagnosed prenatally after this ultrasound diagnosis, the risk of chromosomal aberration exceeds the risks of amniocentesis. These data may be helpful in prenatal counseling situations.

Management of copy number variants associated with incomplete penetrance and variable expressivity-Results of a French survey.

Increasing interest regarding neurodevelopmental disorders and democratization of chromosomal microarray analysis have led to growing identification of neuro-susceptibility copy number variations (CNVs). These CNVs have incomplete penetrance and variable expressivity (PIEV), which makes phenotypic features hard to predict. The French Consortium "AchroPuce" has provided a list of 17 CNVs that should be considered as PIEV CNVs. This list led to consensual French practices of healthcare professionals in postnatal diagnosis. However, no consensus was established in prenatal diagnosis and fetal pathology. 121 French health professionals were surveyed their opinions and practices regarding reporting of PIEV CNVs to patients, in order to identify key points so as to establish French recommendations. The survey showed that professionals in favor of reporting PIEV CNVs to patients in prenatal diagnosis and fetal pathology (respectively, 76% and 84% of respondents) considered highlighted that multidisciplinary consultation is the main point-of-care management before family survey. This statement is close to recommendations published worldwide. As a consequence, multidisciplinary expertise should be the basis of French recommendations concerning the reporting of PIEV CNVs and genetic counseling in prenatal diagnosis and fetal pathology.

Systematic review and synthesis of stillbirths and late miscarriages following SARS-CoV-2 infections.

OBJECTIVE: This study aimed to describe the characteristics of fetal demise after SARS-CoV-2 infections and clarify whether it is associated with clinical severity, placental lesions, or malformations or due to actual fetal infections. DATA SOURCES: PubMed and Web of Science databases were searched between December 1, 2019, and April 30, 2022. STUDY ELIGIBILITY CRITERIA: Cohort, cross-sectional, and case-control studies and case series or case reports describing stillbirths or late miscarriages (ie, pregnancy loss occurring between 14 and 22 weeks of gestation, before and after the onset of labor) from mothers with SARS-CoV-2 infection during pregnancy (demonstrated by at least 1 positive real-time reverse transcription-polymerase chain reaction from nasopharyngeal swabs and/or SARS-CoV-2 placental infection). No language restriction was applied; cases with other causes possibly explaining the fetal demise were excluded. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-analysis Of Observational Studies in Epidemiology guidelines were followed. The quality of the case series and case reports was evaluated using the specific Mayo Clinic Evidence-Based Practice Center tool. Maternal and clinical fetal data and placental and fetal virology and histology findings were collected. Data were summarized with descriptive statistics using the World Health Organization criteria to classify disease severity and fetal-neonatal infections. RESULTS: Data from 184 mothers and 190 fetuses were analyzed. No clear link to maternal clinical severity or fetal malformation was evident. Approximately 78% of fetal demise cases occurred during the second and third trimesters of pregnancy, approximately 6 to 13 days after the diagnosis of SARS-CoV-2 infection or the onset of symptoms. Most placentas (88%) were positive for SARS-CoV-2 or presented the histologic features of placentitis (massive fibrin deposition and chronic intervillositis) previously observed in transplacentally transmitted infections (85%-91%). Of note, 11 fetuses (5.8%) had a confirmed in utero transmitted SARS-CoV-2 infection, and 114 fetuses (60%) had a possible in utero transmitted SARS-CoV-2 infection. CONCLUSION: The synthesis of available data showed that fetal demise generally occurs a few days after the infection with histologic placental inflammatory lesions associated with transplacental SARS-CoV-2 transmission and eventually causing placental insufficiency.

Survival in very preterm infants with congenital diaphragmatic hernia and association with prenatal imaging markers: A retrospective cohort study.

OBJECTIVES: To describe the outcomes of preterm born infants with congenital diaphragmatic hernia (CDH; ≤32.0 weeks of gestation) and the associations between prenatal imaging markers and survival. DESIGN: Retrospective cohort study. SETTING: Multicentre study in large referral centres. POPULATION: Infants with an isolated unilateral CDH, live born at 32.0 weeks or less of gestation, between January 2009 and January 2020. METHODS: Neonatal outcomes were evaluated for infants that were expectantly managed during pregnancy and infants that underwent fetoscopic endoluminal tracheal occlusion (FETO) therapy, separately. We evaluated the association between prenatal imaging markers and survival to discharge. Prenatal imaging markers included observed to expected lung-to-head ratio (o/e LHR), side of the defect, liver position, stomach position grade, and observed to expected total fetal lung volume (o/e TFLV). MAIN OUTCOME MEASURE: Survival to discharge. RESULTS: We included 53 infants born at 30+4 (interquartile range 29+1 -31+2 ) weeks. Survival in fetuses expectantly managed during pregnancy was 48% (13/27) in left-sided CDH and 33% (2/6) in right-sided CDH. Survival in fetuses that underwent FETO therapy was 50% (6/12) in left-sided CDH and 25% (2/8) in right-sided CDH. The o/e LHR at baseline was positively associated with survival in cases expectantly managed during pregnancy (odds ratio [OR] 1.20, 95% CI 1.07-1.42, p < 0.01), but not in cases that received FETO therapy (OR 1.01, 95% CI 0.88-1.15, p = 0.87). Stomach position grade (p = 0.03) and o/e TFLV were associated with survival (p = 0.02); liver position was not (p = 0.13). CONCLUSIONS: In infants with CDH born at or before 32 weeks of gestation, prenatal imaging markers of disease severity were associated with postnatal survival.

Abnormalities of the corpus callosum. Can prenatal imaging predict the genetic status? Correlations between imaging phenotype and genotype.

OBJECTIVE: Recent studies have evaluated prenatal exome sequencing (pES) for abnormalities of the corpus callosum (CC). The objective of this study was to compare imaging phenotype and genotype findings. METHOD: This multicenter retrospective study included fetuses with abnormalities of the CC between 2018 and 2020 by ultrasound and/or MRI and for which pES was performed. Abnormalities of the CC were classified as complete (cACC) or partial (pACC) agenesis of the CC, short CC (sCC), callosal dysgenesis (CD), interhemispheric cyst (IHC), or pericallosal lipoma (PL), isolated or not. Only pathogenic (class 5) or likely pathogenic (class 4) (P/LP) variants were considered. RESULTS: 113 fetuses were included. pES identified P/LP variants for 3/29 isolated cACC, 3/19 isolated pACC, 0/10 isolated sCC, 5/10 isolated CD, 5/13 non-isolated cACC, 3/6 non-isolated pACC, 8/11 non-isolated CD and 0/12 isolated IHC and PL. Associated cerebellar abnormalities were significantly associated with P/LP variants (OR = 7.312, p = 0.027). No correlation was found between phenotype and genotype, except for fetuses with a tubulinopathy and an MTOR pathogenic variant. CONCLUSIONS: P/LP variants were more frequent in CD and in non-isolated abnormalities of the CC. No such variants were detected for fetuses with isolated sCC, IHC and PL.

Knowledge, acceptability and personal attitude toward pre-implantation 1 genetic testing (PGT) and pre-natal diagnosis (PND) for females carrying BRCA pathogenic variant according to fertility preservation experience.

PURPOSE: Preimplantation genetic testing (PGT-M) and prenatal diagnosis (PND) followed by medical termination of pregnancy when the fetus is affected are two procedures developed to avoid the transmission of a severe hereditary disease which can be proposed to females that carried BRCA pathogenic variants. These females can also be offered fertility preservation (FP) when diagnosed with cancer or even before a malignancy occurs. The aim of the study was to evaluate the acceptability and personal attitude of women carrying a BRCA mutation toward techniques that can prevent BRCA transmission to their progeny. METHODS: Female mutated for BRCA1 or BRCA2 were invited to complete an online survey of 49 queries anonymously between June and August 2022. RESULTS: A total of 87 participants responded to the online survey. Overall, 86.2% of women considered that PGT-M should be proposed to all BRCA mutation carriers regardless of the severity of the family history, and 47.1% considered or would consider PGT-M for themselves. For PND, these percentages were lower reaching 66.7% and 29.9%, respectively. Females with personal history of breast cancer or FP achievement were more prone to undergo PND for themselves despite the overall acceptability of this procedure. Among the subgroup who had undergone FP (n = 58), there was no significant difference in acceptance of principle and personal attitude toward PGT-M and PND compared to the group without FP. CONCLUSION: BRCA pathogenic variants female carriers do need information about reproductive issues, even if they are not prone to undergo PGT-M nor PND for themselves. TRIAL REGISTRATION NUMBER: N/A.

Predicting the risk of respiratory distress in newborns with congenital pulmonary malformations.

OBJECTIVES: Most children with prenatally diagnosed congenital pulmonary malformations (CPMs) are asymptomatic at birth. We aimed to develop a parsimonious prognostic model for predicting the risk of neonatal respiratory distress (NRD) in preterm and term infants with CPM, based on the prenatal attributes of the malformation. METHODS: MALFPULM is a prospective population-based nationally representative cohort including 436 pregnant women. The main predictive variable was the CPM volume ratio (CVR) measured at diagnosis (CVR first) and the highest CVR measured (CVR max). Separate models were estimated for preterm and term infants and were validated by bootstrapping. RESULTS: In total, 67 of the 383 neonates studied (17%) had NRD. For infants born at term (>37 weeks, n=351), the most parsimonious model included CVR max as the only predictive variable (receiver operating characteristic (ROC) curve area: 0.70±0.04, negative predictive value: 0.91). The probability of NRD increased linearly with increasing CVR max and remained below 10% for CVR max <0.4. In preterm infants (n=32), both CVR max and gestational age were important predictors of the risk of NRD (ROC: 0.85±0.07). Models based on CVR first had a similar predictive ability. CONCLUSIONS: Predictive models based exclusively on CVR measurements had a high negative predictive value in infants born at term. Our study results could contribute to the individualised general risk assessment to guide decisions about the need for newborns with prenatally diagnosed CPM to be delivered at specialised centres.

The randomized Tracheal Occlusion To Accelerate Lung growth (TOTAL)-trials on fetal surgery for congenital diaphragmatic hernia: reanalysis using pooled data.

BACKGROUND: Two randomized controlled trials compared the neonatal and infant outcomes after fetoscopic endoluminal tracheal occlusion with expectant prenatal management in fetuses with severe and moderate isolated congenital diaphragmatic hernia, respectively. Fetoscopic endoluminal tracheal occlusion was carried out at 27+0 to 29+6 weeks' gestation (referred to as "early") for severe and at 30+0 to 31+6 weeks ("late") for moderate hypoplasia. The reported absolute increase in the survival to discharge was 13% (95% confidence interval, -1 to 28; P=.059) and 25% (95% confidence interval, 6-46; P=.0091) for moderate and severe hypoplasia. OBJECTIVE: Data from the 2 trials were pooled to study the heterogeneity of the treatment effect by observed over expected lung-to-head ratio and explore the effect of gestational age at balloon insertion. STUDY DESIGN: Individual participant data from the 2 trials were reanalyzed. Women were assessed between 2008 and 2020 at 14 experienced fetoscopic endoluminal tracheal occlusion centers and were randomized in a 1:1 ratio to either expectant management or fetoscopic endoluminal tracheal occlusion. All received standardized postnatal management. The combined data involved 287 patients (196 with moderate hypoplasia and 91 with severe hypoplasia). The primary endpoint was survival to discharge from the neonatal intensive care unit. The secondary endpoints were survival to 6 months of age, survival to 6 months without oxygen supplementation, and gestational age at live birth. Penalized regression was used with the following covariates: intervention (fetoscopic endoluminal tracheal occlusion vs expectant), early balloon insertion (yes vs no), observed over expected lung-to-head ratio, liver herniation (yes vs no), and trial (severe vs moderate). The interaction between intervention and the observed over expected lung-to-head ratio was evaluated to study treatment effect heterogeneity. RESULTS: For survival to discharge, the adjusted odds ratio of fetoscopic endoluminal tracheal occlusion was 1.78 (95% confidence interval, 1.05-3.01; P=.031). The additional effect of early balloon insertion was highly uncertain (adjusted odds ratio, 1.53; 95% confidence interval, 0.60-3.91; P=.370). When combining these 2 effects, the adjusted odds ratio of fetoscopic endoluminal tracheal occlusion with early balloon insertion was 2.73 (95% confidence interval, 1.15-6.49). The results for survival to 6 months and survival to 6 months without oxygen dependence were comparable. The gestational age at delivery was on average 1.7 weeks earlier (95% confidence interval, 1.1-2.3) following fetoscopic endoluminal tracheal occlusion with late insertion and 3.2 weeks earlier (95% confidence interval, 2.3-4.1) following fetoscopic endoluminal tracheal occlusion with early insertion compared with expectant management. There was no evidence that the effect of fetoscopic endoluminal tracheal occlusion depended on the observed over expected lung-to-head ratio for any of the endpoints. CONCLUSION: This analysis suggests that fetoscopic endoluminal tracheal occlusion increases survival for both moderate and severe lung hypoplasia. The difference between the results for the Tracheal Occlusion To Accelerate Lung growth trials, when considered apart, may be because of the difference in the time point of balloon insertion. However, the effect of the time point of balloon insertion could not be robustly assessed because of a small sample size and the confounding effect of disease severity. Fetoscopic endoluminal tracheal occlusion with early balloon insertion in particular strongly increases the risk for preterm delivery.

Prenatal Diagnosis of COL4A1 Mutations in Eight Cases: Further Delineation of the Neurohistopathological Phenotype.

BACKGROUND: Increasing number of mutations responsible for vascular lesions, leading to ischemic or hemorrhagic stroke in young adults, has been identified in the recent years. It has been demonstrated in both mice and humans, that mutations in COL4A1 gene promote cerebral hemorrhages. In humans, both adults and children may be affected, and the spectrum has been broadened recently to neonates and fetuses. METHODS: We present a cohort of eight COL4A1 mutated fetuses in which cerebral hemorrhages were detected by ultrasound leading to elective terminations of pregnancy. RESULTS: Our neuropathological studies demonstrated a strikingly similar pathological pattern, dominated by supra- and infratentorial multifocal hemorrhagic lesions of various abundance and age in the vicinity of enlarged small vessels having a discontinuous wall. This was constantly associated with a spectrum of supratentorial post-ischemic damages of the grey and white matters. Morphometric studies of brain vessels confirmed vascular dilation and hypervascularization in both grey and white matters and severe attenuation of the smooth-muscle actin staining in the white matter. CONCLUSION: These observations add to the rare human neuropathological phenotype of COL4A1 mutations. Its recognition is mandatory to enhance the number of tested patients in the future, as well as the genetic counseling of parents.

State of the art of antenatal diagnosis and management of vein of Galen aneurysmal malformations.

Vein of Galen aneurysmal malformation (VGAM) is a severe rare vascular anomaly whose prognosis depends on cerebral and cardiac consequences that can be hard to diagnose, let alone predict in utero. We performed an updated review to summarize current research on the genetics, ultrasound and MRI of VGAM that could help in the diagnosis and management of VGAM. Prenatal diagnosis of VGAM has greatly improved in recent years. Ultrasound allows in utero detection of VGAM in most cases now and is the best exam for prenatal cardiac evaluation. Tricuspid insufficiency is the only cardiac feature associated with poor prognosis. Cardiomegaly may indicate a risk of cardiac failure at birth and should prompt discussion of birth in a specialized facility. Ultrasound can identify constituted cerebral lesions, but MRI diagnoses early signs of cerebral hemodynamic changes, notably through the detection of pseudo-feeders. Genetic exploration should be proposed after VGAM diagnosis. Ultrasound and MRI are essential complementary tools for the diagnosis of VGAM, but also for prognostic evaluation, and provide information for the counseling of parents and optimal management of the pregnancy.