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Differences of sex development (DSDs) are a group of congenital conditions characterized by a discrepancy between chromosomal, gonadal, and genital sex development of an individual, with significant impact on medical, psychological and reproductive life. The genetic heterogeneity of DSDs complicates the diagnosis and almost half of the patients remains undiagnosed. In this context, chromosomal imbalances in syndromic DSD patients may help to identify new genes implicated in DSDs. In this study, we aimed at describing the burden of chromosomal imbalances including submicroscopic ones (copy number variants or CNVs) in a cohort of prenatal syndromic DSD patients, and review their role in DSDs. Our patients carried at least one pathogenic or likely pathogenic chromosomal imbalance/CNV or low-level mosaicism for aneuploidy. Almost half of the cases resulted from an unbalanced chromosomal rearrangement. Chromosome 9p/q, 4p/q, 3q and 11q anomalies were more frequently observed. Review of the literature confirmed the causative role of CNVs in DSDs, either in disruption of known DSD-causing genes (SOX9, NR0B1, NR5A1, AR, ATRX, …) or as a tool to suspect new genes in DSDs (HOXD cluster, ADCY2, EMX2, CAMK1D, …). Recurrent CNVs of regulatory elements without coding sequence content (i.e. duplications/deletions upstream of SOX3 or SOX9) confirm detection of CNVs as a mean to explore our non-coding genome. Thus, CNV detection remains a powerful tool to explore undiagnosed DSDs, either through routine techniques or through emerging technologies such as long-read whole genome sequencing or optical genome mapping., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

The 22q11 region is prone to generating recurring Copy Number Variations (CNVs) as a result of the large numbers of Low Copy Repeats (LCRs). Typical duplications encompass the LCR-A-to-D region but atypical duplications of various sizes have also been reported. These duplications are responsible for highly variable phenotypes with incomplete penetrance and expressivity, which is challenging for adequate genetic counselling, especially in the prenatal period. To better delineate prenatal phenotypes associated with these CNVs, we report here a clinical and molecular description of twelve cases (9 foetuses and 3 deceased new-borns babies) carrying recurrent 22q11 duplications (diagnosed via aCGH), along with a review of the existing literature. 22q11 duplications were inherited from an apparently healthy parent in almost 60% of the cases. Other CNVs were diagnosed for 8% of the cases. Increased nuchal translucency and cardiac anomalies (CHD) were the most prominent phenotypes observed, along with mild renal and skeletal anomalies. Duplications encompassing the LCR-C-to-D region (and the CRKL gene) seemed more likely to generate CHDs and renal malformations. Cleft lip/palate were observed in foetuses with duplications encompassing the LCR-A-to-B region or the SPECC1L gene, as previously suggested. However, genotype-phenotype correlations remain difficult to ascertain. Second-hit point variants, epigenetic or environmental variations could play a role in the phenotypic variability of 22q11 duplications, but remain a challenge for assessment in the short period of pregnancy., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background: The efficacy of prophylaxis to prevent prenatal toxoplasmosis transmission is controversial, without any previous randomized clinical trial. In France, spiramycin is usually prescribed for maternal seroconversions. A more potent pyrimethamine + sulfadiazine regimen is used to treat congenital toxoplasmosis and is offered in some countries as prophylaxis., Objective: We sought to compare the efficacy and tolerance of pyrimethamine + sulfadiazine vs spiramycin to reduce placental transmission., Study Design: This was a randomized, open-label trial in 36 French centers, comparing pyrimethamine (50 mg qd) + sulfadiazine (1 g tid) with folinic acid vs spiramycin (1 g tid) following toxoplasmosis seroconversion., Results: In all, 143 women were randomized from November 2010 through January 2014. An amniocentesis was later performed in 131 cases, with a positive Toxoplasma gondii polymerase chain reaction in 7/67 (10.4%) in the pyrimethamine + sulfadiazine group vs 13/64 (20.3%) in the spiramycin group. Cerebral ultrasound anomalies appeared in 0/73 fetuses in the pyrimethamine + sulfadiazine group, vs 6/70 in the spiramycin group (P = .01). Two of these pregnancies were terminated. Transmission rates, excluding 18 children with undefined status, were 12/65 in the pyrimethamine + sulfadiazine group (18.5%), vs 18/60 in the spiramycin group (30%, P = .147), equivalent to an odds ratio of 0.53 (95% confidence interval, 0.23-1.22) and which after adjustment tended to be stronger (P = .03 for interaction) when treatment started within 3 weeks of seroconversion (95% confidence interval, 0.00-1.63). Two women had severe rashes, both with pyrimethamine + sulfadiazine., Conclusion: There was a trend toward lower transmission with pyrimethamine + sulfadiazine, but it did not reach statistical significance, possibly for lack of statistical power because enrollment was discontinued. There were also no fetal cerebral toxoplasmosis lesions in the pyrimethamine + sulfadiazine group. These promising results encourage further research on chemoprophylaxis to prevent congenital toxoplasmosis., (Copyright © 2018. Published by Elsevier Inc.)

Purpose: Termination of pregnancy without feticide (TOPWF) is poorly known in France and far less practiced than palliative care after term birth of a child having a lethal pathology. Few teams consider it and its practice remains confidential. This survey tries to describe it., Material and Methods: A national survey was realized in 2014 using a questionnaire sent to 50 centers of prenatal diagnosis depending on a perinatal diagnosis center in France., Results: Thirty-one centers answered the questionnaire. Seven teams shared their experience of TOPWF after 22-24 weeks gestation (WG). This practice concerned fetuses affected by "lethal" pathologies. The absence of feticide followed a parental request or a proposal of the medical team, after individual discussion in a multidisciplinary meeting. All the children born alive after TOPWF benefited of palliative care. The 24 other centers having answered our investigation performed systematically the feticide beyond 22-24 WG. They so wished "to protect" the fetus, the parents and the nursing team. A majority of these teams faced parental demands of abstention of feticide but few of them answered it favorably., Conclusion: A robust "palliative culture" seems essential to allow the nursing team to consider the development of TOPWF., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Objectives: To study the pregnancies followed at Rennes University Hospital from 2006 to 2012, after prenatal diagnosis of lethal fetal condition and prenatal project of palliative care at birth consisting of comfort care emphasizing parent-child encounters and bonding., Material and Methods: Retrospective study of 20 pregnancies with diagnosis of lethal fetal condition where parents accepted antenatally the proposal or sought for palliative care at birth., Results: Diagnosis was made at a median age of 20 weeks gestation (12-33). Birth occurred at 37.4 WG, 6 caesarean sections were performed for maternal conditions. Six cases of hypoplastic left heart syndrome (HLHS) share common characteristics: good Apgar score, prolonged survival (26hours to 159days) transfer to neonatology ward (6) or later at home (4). In four multiple pregnancies, the choice of SP mainly contributed to protect healthy twins during pregnancy. In birth room, there was no need for invasive procedure or drugs. Death: one occurred during labor, 8 in birth room before H2, others in neonatal ward before d4 (excluding HLHS)., Conclusion: These data will enable better antenatal preparation of both teams and parents. Lifetime, however short, allowed parents to meet with their child alive this permitting collection of memory traces and bonding., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Objectives: After the establishment of a palliative care protocol (PC) in the delivery room, study how the postnatal management decision was taken and in particular how PC was developed., Material and Methods: Retrospective analysis of births between 22 and 25+6 WG, in Rennes University Hospital, during 21 months., Results: Twenty-seven women meeting the criteria gave birth to 32 live children. Decision making (intensive care or PC) was fast but shared with the parents, mainly on the criterion of the term. The delivery was vaginal for 24 children. Thirteen children were resuscitated. Nineteen children received comfort care, their life was less than 3 hours, 18/19 were supported by their parents., Conclusion: The management of these births is consistent with current recommendations, decisions are individualized but often informally. The secondary prognostic criteria could be better taken into account. Obstetrical and pediatric management is consistent. The PC protocol is fairly well used but the collective decisions should be more formally organized and transcribed more accurately in the records, the requirements for analgesics should be based on clinical assessments., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

We analyzed 16 cases of hypoplastic left heart syndrome (HLHS) submitted to the multidisciplinary center at Rennes Teaching Hospital from 2006 to 2010 for prenatal diagnosis. The information given to parents at the moment of choice is capital for them to make their own decision: in our team the real choice for parents stands between termination of pregnancy (TOP) and palliative care (PC). The Norwood procedure is rarely proposed to parents in France and it is performed in very few centers. Heart transplant is never proposed nor done at this age. The objectives of our study were to understand the reasons for the choice of PC, take stock of our experience of PC, and relate the benefits but also the disadvantages of PC. Over the 16 patients whose fetus had HLHS, 9 requested TOP, while 7 others wanted to live their pregnancy and meet their child at birth, therefore requesting neonatal PC. No family asked for the Norwood procedure. Four children died within the first days (D1, D2, D4, D9), 2 others died at 5 and 7 months, 1 child was operated on for coarctation of the aorta (unknown before birth) and is still alive 1.5 years later. Maternal motivations to continue the pregnancy were clearly described for 2 of the 7 cases: religious prohibition of TOP in 1 case, negative experiences of previous abortions in the second case. In another case, the parents hesitated between PC and Norwood surgery. For the other women, the reasons were less clearly expressed. In our series, HLHS is the first indication for PC from prenatal diagnosis (7/16 cases in the same period) while in the literature, heart diseases are the second cause of TOP after the neurological causes. The overrepresentation of this pathology in the families who opt for PC may be due to the unconscious image that both professionals and families have of HLHS: severity of an inevitably fatal disease, rapid postnatal death, and no suffering. Our study may change this view: a child was in fact carrying a curable defect which was discovered 12 days after birth, 2 children died at 5 and 7 months, and 5 of 6 children had major analgesics at the end of life. Nevertheless, the families were supported and followed by the PC network, except 1 who ruptured all contacts in a context of presumed intense suffering, but the other 6 do not regret their choice despite the difficulties., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

We report the case of a female patient exhibiting multiple congenital malformations including diaphragmatic hernia and heart defect. Cytogenetic studies (including karyotype, FISH and array-CGH) showed a de novo terminal deletion (6.9 Mb) on chromosome 15 in association with a recombinant X chromosome bearing a 9-Mb Xp duplication and a 46-Mb Xq deletion distal to XIST. The recombinant X chromosome was caused by a maternal inv(X)(p22.31q22.3). The X chromosome inactivation pattern was skewed in the patient suggesting a possible inactivation of the recombinant X chromosome. Considering these results, the phenotype was linked to the de novo terminal 15q deletion. These results strengthen the assumption that array-CGH should be applied to each fetus/newborn with multiple congenital malformations., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

A parturient in the 37th week of gestation is referred to the obstetrical emergency ward for an acute abdominal pain with vomiting and fever. Few hours after her admission, a caesarean section is performed for acute fetal distress. It gave birth to a 3940 g healthy newborn. An abundant and milky peritoneal fluid is noted during the C-section related to a major hypertriglyceridemia (84,47 g/L) which induced an acute pancreatitis explaining the early symptoms. The patient is then hospitalized in surgical reanimation: heparin and a low fat diet led to a quick decrease of triglyceridemia and the healing of the acute pancreatitis. We review the most recent literature about acute pancreatitis during pregnancy, especially induced by hypertriglyceridemia, and the different management option: heparin, parenteral nutrition or plasmapheresis.

Neuroblastoma, the most common malignant tumor in the neonatal period is metastatic in 25 to 50% of cases. While the prognosis of antenatal neuroblastoma is often considered as favorable, included in the most common metastatic stage (Stage IV S), it can lead to fetal or neonatal death. We report a case of a fetus with a stage IV neuroblastoma who died in utero. The most important prognostic factor is tumor stage, making sonographic detection of metastasis essential. Nevertheless, accurate staging remains difficult by sonography. When metastatic neuroblastoma is suspected, sonographic survey has to be reinforced, and if serious criteria such as massive hepatomegaly, placentomegally or hydrops appear, delivery must be considered.

A part of preterm labor with intact membranes seems to be related to amniotic infection or local inflammatory process. In these cases, amniotic fluid is collected by amniocentesis for bacteriological studies: amniotic cultures are positive in 10% and polymerase chain reaction (PCR) in 40-50%. Interleukin 6 (IL6) concentrations are elevated in cases with amniotic infection and in some cases with negative cultures. IL6 amniotic concentrations are predictive of premature delivery and neonatal morbidity. Matrix metalloproteinases (MMP) are endogenous enzymes implicated in membrane weakening. Amniotic concentrations of these enzymes seem to be predictive of premature delivery and neonatal prognosis. Furthermore, at the time of genetic amniocentesis, IL6 and MMP concentrations are markers for preterm delivery. In the second half of gestation, amniocentesis is a safe procedure complicated in less than 1% of cases, although specific evaluation in cases of premature labor is missing. Nevertheless, as long as there is no evidence of any benefit in this procedure, there is no indication for amniocentesis in premature labor with intact membranes in general practice.

Two cases of pulmonary oedema during beta 2-adrenergic agonist therapy in pre-eclampsia pregnant patients are reported. In our first case, the pulmonary oedema was exceptionally severe, because the patient (twins at 26 SA) had to be intubated and ventilated, but the caesarean section was performed only 6 weeks later. These two clinical observations underline the fact that B2 adrenergic agonist are not indicated for the treatment of preeclampsy. Furthermore they suggest that such patients should be rapidly admitted to intensive care units.