Julien Saada

Efficacy of Selective Arterial Embolisation for the Treatment of Life-Threatening Post-Partum Haemorrhage in a Large Population

Background The objective of this study was to assess efficacy and determine the optimal indication of selective arterial embolisation (SAE) in patients with life-threatening post-partum haemorrhage (PPH). Methodology/Principal Findings One hundred and two patients with PPH underwent SAE and were included from January 1998 to January 2002 in our university care center. Embolisation was considered effective when no other surgical procedure was required. Univariate and multivariate statistical analysis were performed. SAE was effective for 73 patients (71.5%), while 29 required surgical procedures. SAE was effective in 88.6% of women with uterine atony that was associated with positive outcome (OR 4.13, 1.35–12.60), whereas caesarean deliveries (OR 0.16, 0.04–0.5) and haemodynamic shock (OR 0.21, 0.07–0.60) were associated with high failure rates, 47.6% and 39.1%, respectively. Conclusions/Significance Success rate for SAE observed in a large population is lower than previously reported. It is most likely to succeed for uterine atony but not recommended in case of haemodynamic shock or after caesarean section.

A homozygous PDE6D mutation in Joubert syndrome impairs targeting of farnesylated INPP5E protein to the primary cilium

Joubert syndrome (JS) is characterized by a distinctive cerebellar structural defect, namely the « molar tooth sign ». JS is genetically heterogeneous, involving 20 genes identified to date, which are all required for cilia biogenesis and/or function. In a consanguineous family with JS associated with optic nerve coloboma, kidney hypoplasia, and polydactyly, combined exome sequencing and mapping identified a homozygous splice‐site mutation in PDE6D, encoding a prenyl‐binding protein. We found that pde6d depletion in zebrafish leads to renal and retinal developmental anomalies and wild‐type but not mutant PDE6D is able to rescue this phenotype. Proteomic analysis identified INPP5E, whose mutations also lead to JS or mental retardation, obesity, congenital retinal dystrophy, and micropenis syndromes, as novel prenyl‐dependent cargo of PDE6D. Mutant PDE6D shows reduced binding to INPP5E, which fails to localize to primary cilia in patient fibroblasts and tissues. Furthermore, mutant PDE6D is unable to bind to GTP‐bound ARL3, which acts as a cargo‐release factor for PDE6D‐bound INPP5E. Altogether, these results indicate that PDE6D is required for INPP5E ciliary targeting and suggest a broader role for PDE6D in targeting other prenylated proteins to the cilia. This study identifies PDE6D as a novel JS disease gene and provides the first evidence of prenyl‐binding‐dependent trafficking in ciliopathies.

Prenatal Cortical Hyperostosis With COL1A1 Gene Mutation

Infantile cortical hyperostosis (Caffey disease) is benign and self‐limiting when it presents near or after birth but it is usually lethal when it presents earlier. We present the clinical, ultrasonic, radiographic, and pathologic findings in an instructive case of early onset prenatal cortical hyperostosis. The pregnancy of a 21‐year‐old woman was medically terminated at 30 weeks of gestation after a diagnosis of severe osteogenesis imperfecta. Prenatal ultrasounds showed short long bones. Postmortem radiographs showed hyperostosis in long bones, ribs and mandible. The affected skeleton showed marked bony sclerosis and ballooning of the diaphyses of the long bones with periosteal sclerosis. A complete autopsy showed characteristic histologic findings of infantile cortical hyperostosis in affected bones. A missense mutation (3040C → T) in exon 41 the gene encoding the alpha 1 chain of type I collagen was found in fetus pulmonary tissue. Neither the severe form nor the mild form of prenatal cortical hyperostosis were thought to be related to collagen I mutations. Our study indicates that a heterozygous 3040C → T mutation can also be found in lethal prenatal cortical hyperostosis.

Stomach position in prediction of survival in left‐sided congenital diaphragmatic hernia with or without fetoscopic endoluminal tracheal occlusion

To investigate the value of fetal stomach position in predicting postnatal outcome in left‐sided congenital diaphragmatic hernia (CDH) with and without fetoscopic endoluminal tracheal occlusion (FETO).

Combining keratinocyte growth factor transfection into the airways and tracheal occlusion in a fetal sheep model of congenital diaphragmatic hernia

In utero tracheal occlusion (TO) has been developed to improve the lung hypoplasia associated with congenital diaphragmatic hernia (CDH). However, although TO stimulates fetal lung growth, it results in a decrease of alveolar type II cells (ATII) and surfactant production. Because keratinocyte growth factor (KGF) is a potent stimulus of ATII proliferation and maturation, we evaluated, in a fetal lamb model of CDH, a gene therapy strategy combining TO and ovine KGF transfection into the fetal airways using bisguanidinium‐tren‐cholesterol/dioleoyl‐phosphatidylethanolamine (BGTC/DOPE) cationic liposomes.

Quantitative analysis of renal vascularization in fetuses with urinary tract obstruction by three-dimensional power-Doppler

OBJECTIVE To evaluate the applicability of 3-dimensional evaluation of renal vascularization for predicting postnatal renal function in fetuses with suspected urinary obstruction. STUDY DESIGN Fetuses were evaluated by 3-dimensional power-Doppler histogram, and vascular indices were estimated. Depth between the probe and the renal cortex was also evaluated. Postnatal follow-up was obtained in all cases and the main outcome was renal impairment. RESULTS Twenty-three fetuses with urinary dilatation (cases) and 73 with normal renal morphology (controls) were included in the current study. Five (21.7%) cases developed renal impairment. Vascularization index and vascularization and flow index were significantly lower in fetuses that developed renal impairment compared with those with normal renal function (P = .009 and P = .036, respectively). The 3 vascular indexes correlated with depth. Percentage of depth-corrected vascularization index and vascularization flow index were lower in fetuses developing postnatal renal failure. CONCLUSION Fetal renal vascularity (vascularization index and vascularization and flow index) was significantly lower in fetuses that developed renal impairment.

Teaching invasive prenatal procedures: effectiveness of two simple simulators in training

Chorionic villus sampling (CVS) and amniocentesis are the major tools of invasive prenatal diagnosis. We studied the effectiveness of two simulators in training in invasive procedures.

Sonographic Evaluation of Fetal Conus Medullaris and Filum Terminale

Background: Sonographic evaluation of the fetal conus medullaris (CM) level is not reproducible. The objectives of this study were to determine the normal position of the fetal CM during pregnancy as well as the normal intradural filum terminale (FT) length and to evaluate their use in detecting tethered cord. Methods: This is a prospective evaluation of normal singleton pregnancies examined by sonography from 17 weeks of gestation to term. Each sonographer had to identify the top of the first sacral vertebra (S1) to measure the distance between it and the conus extremity (CM-S1 distance). The intradural FT distance was measured with 5- to 8-MHz probes. Results: 194 consecutive pregnant women were included. The CM and intradural FT were demonstrated clearly in 164 (84%) cases. The mean CM-S1 distance was 20.6 mm (range 0.5-42). The mean intradural FT distance was 27.9 mm (range 6.6-49.3). Linear regression analysis showed a significant association between both those distances and gestational age (p < 0.05). In cases of tethered cord, the mean CM-S1 distance and the mean intradural FT distance were both below the 5th percentile. Conclusion: Prenatal evaluation of the CM and the intradural FT is feasible and reproducible and seems useful in detecting tethered cord.

Prenatal Diagnosis of a 2.5 Mb De Novo 17q24.1q24.2 Deletion Encompassing KPNA2 and PSMD12 Genes in a Fetus with Craniofacial Dysmorphism, Equinovarus Feet, and Syndactyly

Interstitial 17q24.1 or 17q24.2 deletions were reported after conventional cytogenetic analysis or chromosomal microarray analysis in patients presenting intellectual disability, facial dysmorphism, and/or malformations. We report on a fetus with craniofacial dysmorphism, talipes equinovarus, and syndactyly associated with a de novo 2.5 Mb 17q24.1q24.2 deletion. Among the deleted genes, KPNA2 and PSMD12 are discussed for the correlation with the fetal phenotype. This is the first case of prenatal diagnosis of 17q24.1q24.2 deletion.

Modulation of free corticotrophin-releasing hormone, adrenal and placental steroid hormone levels induced by mifepristone during pregnancy.

Mifepristone is a progesterone receptor antagonist widely used in obstetrics. The aim of the study was to focus on free corticotrophin-releasing hormone (CRH) and also describe modulation of adrenal and placental steroid hormone concentrations induced by mifepristone. Methods: Twenty-six women were enrolled in the study. They received mifepristone for termination of pregnancy. Maternal blood samples were retrieved before administration of mifepristone (600 mg) and 48 h after, just before induction of labor. Bound and free CRH levels were determined in maternal blood concomitantly with cortisol, estriol, progesterone and SDHEA levels. Also paired fetal cord blood samples were collected. Results: Maternal plasmatic CRH level did not change after mifepristone absorption but free CRH increased significantly (0.500 ± 0.326 vs. 0.388 ± 0.303 ng/ml, p = 0.040). A significant decrease of progesterone was observed (83.6 ± 49.3 vs. 95.6 ± 54.9 ng/ml, p = 0.001) with a lower progesterone/estriol ratio (26.9 ± 15.7 vs. 40.7 ± 31.1, p = 0.004). There was a strong association between maternal and fetal free CRH (r2 = 0.675, p = 0.001), cortisol (r2 = 0.570, p = 0.019), and positive but modest correlation for progesterone (r2 = 0.341, p = 0.046) and estriol (r2 = 0.379, p = 0.025) levels. Conclusion: Mifepristone has an effect on free CRH level and changes the estriol-progesterone balance.