Expanding the phenotypic spectrum of LIG4 pathogenic variations: neuro-histopathological description of 4 fetuses with stenosis of the aqueduct.

Severe ventriculomegaly is a rare congenital brain defect, usually detected in utero, of poor neurodevelopmental prognosis. This ventricular enlargement can be the consequence of different mechanisms: either by a disruption of the cerebrospinal fluid circulation or abnormalities of its production/absorption. The aqueduct stenosis is one of the most frequent causes of obstructive ventriculomegaly, however, fewer than 10 genes have been linked to this condition and molecular bases remain often unknown. We report here 4 fetuses from 2 unrelated families presenting with ventriculomegaly at prenatal ultra-sonography as well as an aqueduct stenosis and skeletal abnormalities as revealed by fetal autopsy. Genome sequencing identified biallelic pathogenic variations in LIG4, a DNA-repair gene responsible for the LIG4 syndrome which associates a wide range of clinical manifestations including developmental delay, microcephaly, short stature, radiation hypersensitivity and immunodeficiency. Thus, not only this report expands the phenotype spectrum of LIG4-related disorders, adding ventriculomegaly due to aqueduct stenosis, but we also provide the first neuropathological description of fetuses carrying LIG4 pathogenic biallelic variations.

Second-trimester medical abortion after exposure to lorlatinib during early pregnancy, a case report.

Use of Lorlatinib, a third-generation tyrosine kinase inhibitor currently indicated in the treatment of non-small-cell lung cancer (NSCLC) with ALK or ROS1 gene fusion, is formally contra-indicated during pregnancy due to teratogenic effects observed during pre-clinical studies. We report the case of a 38-year-old woman with a ROS1-positive NSCLC, successfully treated with lorlatinib as second line therapy, who became pregnant while on treatment. Due to significant disease progression 12 weeks after lorlatinib stop and the great uncertainty on the pregnancy outcome, she finally decided to interrupt the pregnancy at 22 weeks of gestation. Echography and gross infant examination did not reveal any malformation. Pregnancies occurring under this kind of new oncologic treatment is expected to happen more frequently in the future. It seems therefore important to us to report any information on the topic to increase our level of knowledge and improve decision-making.

[Factors Associated with Prolonged Duration of Labor in Medical Termination of Pregnancy in the 2nd and 3rd Trimesters]. / Facteurs associés à une durée de travail prolongée en cas d'interruption médicale de grossesse aux 2e et 3e trimestres.

OBJECTIVE: In the context of a medical termination of pregnancy, prolonged labor may accentuate the difficulty of women's experience and increase the risk of associated complications. The factors associated with prolonged labor are not known. Reducing the duration of labor could limit these complications. Determining the relevant factors associated with prolonged labor defined as a delay between the onset of induction and delivery greater than or equal to 12hours and comparing the complications rates between the two groups. METHOD: We conducted a retrospective study at Port Royal Maternity Hospital from 2017 to 2019, including medical terminations of pregnancy by vaginal delivery in the 2nd and 3rd trimesters for fetal or maternal reasons. RESULTS: Two hundred twenty-seven patients were included and divided into two comparative groups based on the duration of labor: labor <12h (n=173) and labor ≥12h (n=54). The mean maternal age was 33.7 years. Forty-four percent of patients were nulliparous, 15.8 % had a history of cesarean section. The average gestational age was 20+2 weeks of gestation. The average duration of labor was 9.7hours. The duration of labor was greater than 24hours in 3% of cases (7/227). Advanced gestational age (22+3 vs. 20+5 p=0,04) and nulliparity (p=0.01) were associated with prolonged labor. Two other intermediate factors, not independent of the duration of labor, were significant: long time to rupture of membranes (239min vs. 427min p<0,01) and an unfavorable Bishop score at rupture (p=0,003). In both groups, the complications were placental retention and the occurrence of fever during labor. CONCLUSION: Two main factors affecting labor duration were identified in this study (term and nulliparity). This knowledge could allow women to be better informed about the expected time of labor and the potential associated risks.

Terminal 6q deletions cause brain malformations, a phenotype mimicking heterozygous DLL1 pathogenic variants: A multicenter retrospective case series.

OBJECTIVE: Terminal 6q deletion is a rare genetic condition associated with a neurodevelopmental disorder characterized by intellectual disability and structural brain anomalies. Interestingly, a similar phenotype is observed in patients harboring pathogenic variants in the DLL1 gene. Our study aimed to further characterize the prenatal phenotype of this syndrome as well as to attempt to establish phenotype-genotype correlations. METHOD: We collected ultrasound findings from 22 fetuses diagnosed with a pure 6qter deletion. We reviewed the literature and compared our 22 cases with 14 fetuses previously reported as well as with patients with heterozygous DLL1 pathogenic variants. RESULTS: Brain structural alterations were observed in all fetuses. The most common findings (>70%) were cerebellar hypoplasia, ventriculomegaly, and corpus callosum abnormalities. Gyration abnormalities were observed in 46% of cases. Occasional findings included cerebral heterotopia, aqueductal stenosis, vertebral malformations, dysmorphic features, and kidney abnormalities. CONCLUSION: This is the first series of fetuses diagnosed with pure terminal 6q deletion. Based on our findings, we emphasize the prenatal sonographic anomalies, which may suggest the syndrome. Furthermore, this study highlights the importance of chromosomal microarray analysis to search for submicroscopic deletions of the 6q27 region involving the DLL1 gene in fetuses with these malformations.

Megacystis in the first trimester of pregnancy: Prognostic factors and perinatal outcomes.

OBJECTIVE: To determine whether bladder size is associated with an unfavorable neonatal outcome, in the case of first-trimester megacystis. MATERIALS AND METHODS: This was a retrospective observational study between 2009 and 2019 in two prenatal diagnosis centers. The inclusion criterion was an enlarged bladder (> 7 mm) diagnosed at the first ultrasound exam between 11 and 13+6 weeks of gestation. The main study endpoint was neonatal outcome based on bladder size. An adverse outcome was defined by the completion of a medical termination of pregnancy, the occurrence of in utero fetal death, or a neonatal death. Neonatal survival was considered as a favorable outcome and was defined by a live birth, with or without normal renal function, and with a normal karyotype. RESULTS: Among 75 cases of first-trimester megacystis referred to prenatal diagnosis centers and included, there were 63 (84%) adverse outcomes and 12 (16%) live births. Fetuses with a bladder diameter of less than 12.5 mm may have a favorable outcome, with or without urological problems, with a high sensitivity (83.3%) and specificity (87.3%), area under the ROC curve = 0.93, 95% CI (0.86-0.99), p< 0.001. Fetal autopsy was performed in 52 (82.5%) cases of adverse outcome. In the 12 cases of favorable outcome, pediatric follow-up was normal and non-pathological in 8 (66.7%). CONCLUSION: Bladder diameter appears to be a predictive marker for neonatal outcome. Fetuses with smaller megacystis (7-10 mm) have a significantly higher chance of progressing to a favorable outcome. Urethral stenosis and atresia are the main diagnoses made when first-trimester megacystis is observed. Karyotyping is important regardless of bladder diameter.

Cancer during pregnancy: Factors associated with termination of pregnancy and perinatal outcomes.

BACKGROUND: Cancer during pregnancy is rare (about 1/1000 pregnancies) and its diagnosis raises the question of whether or not to continue the pregnancy. OBJECTIVES: The primary objective of our study was to evaluate associated factors with termination of pregnancy in cases of cancer during pregnancy. Secondary objectives were to evaluate maternal and neonatal outcomes when pregnancy is continued. STUDY DESIGN: We conducted a retrospective, single-center study between January 2009 and December 2019 including 2 groups of patients those who underwent termination of pregnancy and those who continued pregnancy. Patients were distributed in 3 categories breast cancer, blood cancer and other cancers. RESULTS: A total of 71 pregnancies associated with cancer were included. Twenty patients (28.16 %) underwent termination of pregnancy. The median gestational age at diagnosis was significantly earlier in the termination of pregnancy group compared with the ongoing pregnancy group (9 vs 22 weeks, p < 0.01). Blood cancer was more frequent in the termination group 7 (35 %) compared to continuous pregnancy 8 (15.7 %) as other cancers 8 (40 %) in the termination group vs 5 (9,8 %). Conversely breast cancer what was less frequent in the termination group 5 (25 %) vs 38 (74,5 %) (p < 0.01). In the continued pregnancy group, there was a high rate of induced prematurity (35.5 %) and scheduled delivery to optimize maternal oncologic management (78.4 %). CONCLUSION: The rate of termination of pregnancy remains high particularly in case of non-breast cancer and early pregnancy detection. Scheduled preterm birth is frequent when pregnancy is continued in order to optimize of cancer management.

Fetal scalp blood sampling: Do pH and lactates provide the same information?

OBJECTIVE: Assess the discordance between scalp pH and lactates performed from the same sample during labor. METHOD: This single-center retrospective study included all women with a singleton fetus who had at least one fetal blood sample taken during labor. Some of them had up to seven samples. Scalp pH was the reference parameter for obstetric decision-making. The correlation between the pH and lactates was studied using Pearson coefficient. By categorizing the values as normal, pre-acidosis and acidosis, we were able to estimate agreement with Cohen's kappa coefficient. The frequency of discordance in the categorization and the factors related to it were studied with univariate and multivariable analyses. Cases of severe acidosis at birth (cord pH < 7.00) and cases with acidosis scalp lactates but normal scalp pH were analyzed. RESULTS: We analyzed 480 samples from 268 fetuses among the 2644 deliveries during the study periode. Fetal blood sampling represented 10 % of deliveries. The scalp pH and lactates results were strongly correlated (r=-0.83), but their agreement was only fair (K = 0.36). In 29.4 % of cases, pH and lactates were discordant. Factors related to discordance were meconium-stained fluid, sampling at full dilation and multiple sampling. Six infants (2.2 %) had severe acidosis at birth. Cases' analyses did not allow to conclude severe acidosis could have been avoided using scalp lactates for obstetric decision-making. CONCLUSION: For more than a quarter of the samples, results were discordant between scalp pH and lactates, especially when cervix was full dilated and when the amniotic fluid was meconium-stained. A randomized controlled trial comparing the relevance of each parameter according to the obstetrical situation would be necessary.

Factors associated with neonatal hypoxic ischemic encephalopathy in infants with an umbilical artery pH less than 7.00.

OBJECTIVE: Our objective was to identify factors associated with hypoxic-ischemic encephalopathy (HIE) among newborns with an umbilical pH < 7.00. STUDY DESIGN: Case-control study during a four-year study period in a single academic tertiary-center, including all neonates ≥35 weeks with an umbilical pH < 7.00. Cases were neonates with HIE, regardless of Sarnat classification, and controls were neonates without signs of HIE. We used univariate and multivariate analysis to compare the maternal, obstetric, and neonatal characteristics of cases and controls. RESULTS: Among 21,211 births, 179 neonates≥35 weeks (0.84%) had an umbilical pH < 7.00. One hundred and forty-seven(82.1%) newborns had severe asphyxia without HIE, 32(17.9%) had HIE and 21(11.7%) needed therapeutic hypothermia. Neonates with HIE were significantly more likely to have 5-minute Apgar score<7(75% versus 15.7% P < 0.01), together with a lower mean umbilical arterial pH (6.84 versus 6.95, P < 0.01) and lower mean base deficits (-17.0 versus -12.7, P < 0.01). Factors significantly associated with HIE were the mother being overweight(28.1% for cases versus 14.3% for controls, adjusted OR=4.6[1.4-15.2]) or obese(25.0% versus 13.6%, aOR=15.5[1.1-12.5]), smoking(18.7% versus 5.4%, aOR=5.8[1.6-21.2]), a sentinel event as cord prolaps or placenta abruption (34.4% versus 13.6%, aOR=2.7[1.1-7.2]), and decreased fetal heart rate variability(68.7% versus 44.2%, aOR=2.8[1.1-6.9]). CONCLUSION: Among neonates with an umbilical cord pH < 7.00, those with HIE had a more severe metabolic acidosis. Maternal factors associated with HIE among newborns with an umbilical pH < 7.00, were being overweight or obese, and smoking, and the associated obstetric factors were a sentinel event and decreased fetal heart rate variability.

Fetal diagnosis of right cardiac ventricular aneurysms: A report of three cases.

Congenital ventricular aneurysms and diverticula are rare congenital heart diseases, currently accessible to prenatal diagnosis. Information on the natural course of ventricular aneurysm or diverticulum detected during fetal life is limited as there are only few case reports and case series enumerating the defect. We aimed to describe through three cases, the prenatal features and clinical outcomes of fetal cardiac aneurysms. The first one was diagnosed during the second trimester and spontaneous evolution was favorable. The two others were diagnosed in the first trimester with a large and early pericardial effusion. For one, the parents opted for termination of pregnancy at 15 weeks of gestation and the other showed a spontaneous regression of the effusion and no hemodynamic compromise.