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Unusual fetal arthrogryposis on ultrasound should draw attention to look for additional lower limb anomalies. Precise genetic counseling may be obtained from deletion on Xq11.2 as for ZC4H2 gene sequencing diagnostic for Wieacker‐Wolff syndrome.

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Although the prognosis of CHARGE syndrome can be highly variable from mild until severe, final diagnosis is difficult to establish in utero. The aim of our study is to compare antenatal and postnatal findings in a retrospective cohort of 10 successive patients with a positive CHD7 gene variant in order to identify the specific prenatal features for CHARGE syndrome diagnosis. Fetal ultrasound, follow-up and supplementary investigations are collected and compared to postnatal findings. Congenital heart defect (7/10), choanal atresia (7/10) and tracheoesophageal atresia (4/10) are the most frequent fetal anomalies found. Inner and external ear anomalies appear as the keystone (constant features) for prenatal diagnosis of CHARGE syndrome in fetuses with multiple anomalies and normal microarray karyotype. External ear malformations are identified in all cases by 3D ultrasound when carefully evaluated. MRI and temporal bone CT-Scan are second line useful tools to assess the diagnosis when looking for semicircular canal agenesis, arhinencephaly and/or choanal atresia. Before availability of prenatal exome sequencing in clinical routine, present findings lead to the recommendation that fetuses, with congenital heart defect (mainly septal and conotruncal), cleft lip/palate or unexplained polyhydramnios should carefully be screened for clues suggesting CHARGE syndrome using 2D and 3D ultrasound, MRI and temporal bone CT-Scan. When CHARGE syndrome is suspected with normal molecular karyotype, CHD7 gene sequencing must be offered.

We herein report the case of abnormal umbilical-venous return in which the antenatal ultrasound enabled us to establish the diagnosis of umbilical-systemic shunt (Type 1 according to Achiron (Achiron and Kivilevitch, 2016)). Due to the concomitant associations of cardiomegaly, intrauterine growth retardation, oligohydramnios, and left-lobe hypoplasia with agenesis of the intrahepatic umbilical vein - left portal vein - ductus venosus, a poor prognosis (11.1% survival) was to be expected. In spite of development of pulmonary arterial hypertension at birth, which was promptly treated, the evolution was nevertheless good, both on clinical and ultrasound follow-up.

Antenatal diagnosis of cardio-facio-cutaneous syndrome: prenatal characteristics and contribution of fetal facial dysmorphic signs in utero. This paper is a case study and review of literature. “RASopathies” is the term coined for a group of genetic diseases that share modulation inside the MAPKinase pathway. Mutations inside the coding sequence of any of these genes may be responsible for the upregulation of the RAS pathway, leading on the clinical level to Type 1 Neurofibromatosis (NF1), Noonan syndrome (NS), Costello syndrome (CS), Multiple Lentigines, Loose Anagen Hair syndrome, Cardio-Facio-Cutaneous syndrome (CFCS), and, more recently, Legius syndrome. While the postnatal presentation of this group is well-known, prenatal findings are less well recognized. The presence of a RASopathy during the prenatal period can be suspected on account of non-specific abnormalities: polyhydramnios, cystic hygroma or high nuchal translucency, macrosomia with proportionate short long bones, macrocephaly, renal, lymphatic, or cardiac defects. The current case report underlines the characteristic dysmorphic facial features on 3D-ultrasound (hypertelorism, down-slanting palpebral fissures, a long and marked philtrum, and low-set posteriorly rotated ears) that allow for a “RASopathy” to be postulated. After detecting a copy number variation (CNV) absence on a CGH array, we performed a RASopathy gene panel analysis, which identified a so-far unreported heterozygous de novo mutation in the BRAF gene (namely NM_004333.4 : c.1396 G > C ; p.Gly466Arg). Genetic counseling has, therefore, focused on the diagnosis of a RASopathy and predictable phenotype of CFCS, a distinct entity characterized by an increased risk of intellectual disability and early-onset feeding problems. We suggest that a more detailed prenatal facial evaluation should be performed in fetuses presenting high nuchal thickness, heart defects, or unusual findings, along with the absence of a CNV on a CGH array. Due to the dysmorphic facial features, targeted RASopathy genes are presumed to likely to be responsible for NS, CFCS, and CS.

We report a case of vanishing gastroschisis visualized by antenatal ultrasound with a 7-year long term follow-up. Currently, the child is still dependent on daily parenteral nutrition with no signs of hepatotoxicity. To our knowledge, it's the fourth case with a long-term follow-up. Vanishing gastroschisis is a rare complication of gastroschisis. However, physicians should be aware of it because its prognosis is worse than classical gastroschisis. When a vanishing gastroschisis is visualized or suspected by antenatal ultrasound, prenatal counseling is required with explanations about the risk of short bowel syndrome, the need of parenteral nutrition and related complications (inflammatory colitis, sepsis, liver failure and organ transplant). Mortality rate was initially around 93%, and dropped to 27% after the years 2000 (versus 10% for classical gastroschisis). After birth, all children will require surgery, and sometimes autologous gastro-intestinal reconstruction. Most survivors (68%) could be taken off the TPN. Unfortunately, long-term outcomes for children with vanishing gastroschisis are still missing in current literature.

We report the successful outcome of a patient with anti-M antibodies with a previous history of severe hemolysis of erythrocytes. Serial plasma exchange from the first trimester combined with ultrasound monitoring of the fetal middle cerebral artery blood velocity was implemented. This management allowed a favorable pregnancy outcome of an infant born by an elective caesarean section at 32 weeks 6/7 with a normal Apgar score at 8/9/10. The other therapeutic alternatives such as intravenous immunoglobulin and in utero fetal blood transfusions are discussed.

Objectives To describe fetal spectrum and echocardiographic characteristics of anomalous systemic venous return (ASVR, cardinal veins) without other structural heart defects (isolated ASVR), evaluate associated extracardiac and genetic anomalies and review neonatal outcome. Methods From 2003 to 2009, 369 consecutive fetuses were diagnosed with cardiac malformation, including 27 cases with an isolated ASVR. The following variables were collected: type of ASVR, extracardiac anomalies, karyotype and short-term outcome. Results The most common forms of ASVR were persistent left superior vena cava (SVC) (n = 15) and interrupted inferior vena cava (IVC) (n = 6). The other ASVR types were a persistent left SVC without a right SVC (n = 4), bilateral agenesis of the SVC with cephalic venous drainage toward the IVC through the azygos system (n = 1) and total ASVR to the coronary sinus (n = 1). Genetic disorders were confirmed in five cases, all with a persistent left SVC, with extracardiac anomalies present in four of them. Ten other patients had extracardiac anomalies detected prenatally or postnatally. When available, ASVR diagnosis was confirmed postnatally in all cases. Conclusion Isolated ASVRs can be accurately diagnosed prenatally and are frequently associated with extracardiac and genetic anomalies. A detailed morphological ultrasound and fetal karyotype should be suggested. Neonatal outcome was mainly related to the associated anomalies. Copyright © 2011 John Wiley & Sons, Ltd.

The present study investigates a new surgical approach in the treatment of left diaphragmatic hernia in fetal sheep. We postulated that unlike tracheal occlusion where both lungs are occluded, selective left main bronchus occlusion (LMBO) would accelerate growth of only the left lung, reduce left visceral herniation, and recover space in the both thoraces necessary for lung development.Left-sided congenital diaphragmatic hernia (CDH) was surgically created in 8 fetal lambs at approximately 65 days of gestation; in 4 of these animals, LMBO was performed at approximately 118 days. Four sham-operated animals served as controls. Lambs were delivered by hysterotomy at 137 days. We measured lung-to-body weight ratios, alveolar surface area, septal wall thickness, and AE2 cell density in the left and right lungs.Left main bronchus occlusion increased (P.05) left lung growth causing severe right mediastinal shift but failed to reduce herniated abdominal viscera in 3 of 4 lambs. Wet lung-to-body weight ratio in LMBO group was similar to that of the control group; however, this was achieved by overgrowth of left lung, whereas the right wet lung-to-body weight ratio remained low. In the LMBO group, right lung AE2 cell density was higher than that of control group and not different to that of the CDH group.Left main bronchus occlusion failed to restore normal pulmonary development in CDH.

Objective Limited information is available about long-term outcomes in children treated prenatally for lower urinary tract obstruction. Our aim was to evaluate outcomes in children treated in utero with vesicoamniotic shunts. Methods Clinical outcomes in 20 pregnancies with a singleton male fetus, oligo/anhydramnios, and lower urinary tract obstruction were studied using chart review and phone and written clinical questionnaire for parents, pediatricians, and urologists. Results Overall 1-year survival was 91%. Two neonatal deaths occurred from pulmonary hypoplasia. Mean gestational age at delivery was 34.6 weeks, mean days from shunting to delivery were 84.4, and mean birth weight was 2,574 g. Prenatal urinary prognosis was good in 13, borderline in 2, and poor in 3 of the survivors. Mean age at follow-up was 5.83 years. Posterior urethral valves were confirmed in 7 males, urethral atresia in 4, and prune belly syndrome in 7. Eight children had acceptable renal function, 4 had mild insufficiency, and 6 required dialysis and eventual renal transplant. Eleven children had normal bladder function with spontaneous voiding, 6 required catheterization, and 1 child still had a vesicostomy. Height and weight were below the 25th percentile in 9 children. Persistent respiratory problems were present in 8, musculoskeletal problems in 9, and frequent urinary tract infections were reported in 9. Health-related quality of life results in our group with lower urinary tract obstruction were similar to those in a healthy child population. Conclusion Male children who underwent prenatal bladder shunting were neurodevelopmentally normal. Although one third of the surviving babies required dialysis and transplantation, the majority have acceptable renal and bladder function and report satisfactory quality of life. Level of evidence III.

Congenital diaphragmatic hernia (CDH) impairs fetal lung growth and increases the density of alveolar epithelial type 2 (AE2) cells. There is controversy whether surfactant protein (SP) expression is altered in CDH. The primary aim of this study was to assess SP expression (mRNA and protein) in the left and right lungs of fetal sheep with and without a diaphragmatic hernia (DH). Left-sided DH was created in four fetal sheep at 65 days of gestational age (g.a.). Sham-operated animals were used as controls. At 138 days g.a., lungs were harvested and the following parameters were measured: SP-A, -B, and -C mRNA expression (Northern blot), SP-A and -B expression (Western blot), and AE2 cell density (immunohistochemistry). The lung weight-to-body weight ratio was reduced by 42% in DH animals. The left-to-right lung weight ratio was lower in DH animals (0.47 +/- 0.03 vs. 0.69 +/- 0.03), indicative of asymmetric lung growth. SP-A, -B, and -C mRNA expression were increased by 61.7%, 32.9%, and 75.5%, respectively, in the left lungs of DH animals. SP-A and SP-B were also increased in DH. In the right lung, SP expression (mRNA and protein) was not different between groups. AE2 cell density was higher (by 67%) in the left but not right lungs of DH animals. Although DH in fetal sheep results in significant lung hypoplasia, SP expression is not reduced. On the contrary, SP expression was increased in the ipsilateral lung of fetuses with left-sided DH. Furthermore, AE2 cell density is increased in DH, suggesting that the increase in SP mRNA and protein levels is due to increases AE2 cell number. Our data further support the premise that fetal lung hypoplasia favors an AE2 phenotype.

Objective: Severe previable twin-to-twin transfusion syndrome (TTTS) is associated with a high fetal loss rate and is therefore usually treated. In this paper, serial amniodrainage and inter-twin septostomy are reviewed in terms of technical aspects and fetal outcome. Study design: A review of the literature using a MEDLINE DATA search between 1990 and 2000 was done in order to describe the mechanisms and technical aspects of both procedures with their physiopathological consequences. In addition, data from our experience with septostomy are given. Results: Amniodrainage increases survival rate, with outcome ranging from 40 to 87% (mean: 56%). Inter-twin septostomy is associated with a mean fetal survival rate ranging from 57 to 83% (mean: 70%). Conclusion: In severe TTTS, amniodrainage and septostomy are simple therapeutic alternatives with a survival rate similar to what is currently reported for laser coagulation of placental vessels.

To describe fetal spectrum and echocardiographic characteristics of anomalous systemic venous return (ASVR, cardinal veins) without other structural heart defects (isolated ASVR), evaluate associated extracardiac and genetic anomalies and review neonatal outcome.From 2003 to 2009, 369 consecutive fetuses were diagnosed with cardiac malformation, including 27 cases with an isolated ASVR. The following variables were collected: type of ASVR, extracardiac anomalies, karyotype and short-term outcome.The most common forms of ASVR were persistent left superior vena cava (SVC) (n = 15) and interrupted inferior vena cava (IVC) (n = 6). The other ASVR types were a persistent left SVC without a right SVC (n = 4), bilateral agenesis of the SVC with cephalic venous drainage toward the IVC through the azygos system (n = 1) and total ASVR to the coronary sinus (n = 1). Genetic disorders were confirmed in five cases, all with a persistent left SVC, with extracardiac anomalies present in four of them. Ten other patients had extracardiac anomalies detected prenatally or postnatally. When available, ASVR diagnosis was confirmed postnatally in all cases.Isolated ASVRs can be accurately diagnosed prenatally and are frequently associated with extracardiac and genetic anomalies. A detailed morphological ultrasound and fetal karyotype should be suggested. Neonatal outcome was mainly related to the associated anomalies.

Fetal lung development may be impaired by some congenital anomalies or in utero events. Animal models are used to understand the pathophysiology of these diseases and explore therapeutic strategies. Our group has an interest in the prenatal management of congenital diaphragmatic hernia (CDH). Isolated CDH remains associated with a 30% mortality because of lung hypoplasia and pulmonary hypertension. On day 23 of gestation (pseudoglandular stage) CDH was created in both ovarian-end fetuses (n= 28) in 14 time-mated pregnant white rabbits (hybrid of Dendermonde and New-Zealand White). At term (day 30) all survived operated fetuses and size-matched controls were harvested. Fetuses/lungs were assigned randomly to formalin fixation either under pressure of 25 cm H2O (CDH25 n=5; CTR25 n=5) or without (0 cm H2O (CDH0 n=7; CTR0 n=7). Fetuses and lungs were first weighed, and then the lungs were processed for morphometry. Pulmonary development was evaluated by lung-to-body weight ratio (LBWR) and airway and vascular morphometry. Surgical induction of CDH does reduce the LBWR to hypoplastic levels. The contralateral lung weight is 81% of what is expected, whereas the ipsilateral lung is only 46% of the normal. This was accompagnied by a loss of conducting airway generations, precisely, terminal bronchioles (TB), which were surrounded by less alveoli. The ipsilateral CDH lung demonstrated a thickened media in the peripheral arteries as well. As a result, in the severely hypoplastic ipsilateral lung, an airway fixation pressure of 25 H2O has no significant effect on the morphometric indices. The contralateral lung has a normal amount of alveoli around a single TB, which also behave like alveoli of the normal lung, i.e. expand under pressure fixation. The present study on severely hypoplastic lungs that never respirated, shows that in contrast to normal lungs, the morphometric indices are not significantly influenced by a difference in fixation pressure. Increasing fixation pressure seems to expand the lung only when sufficient alveolated parenchyma is present.

A woman was referred for fetal echocardiography at 21 + 3 weeks' gestation on suspicion of mitral valve (MV) atresia with left ventricular (LV) hypoplasia and an ostium primum atrial septal defect (ASD). No associated extracardiac or chromosomal anomalies were identified. [...]

Objectives To review prenatal findings, short- and long-term outcomes of giant omphaloceles (GO) managed at a single institution (1996–2001). Methods Prenatal findings and early postnatal outcomes were retrospectively reviewed. Clinical short- and long-term outcomes were analyzed in eight and five children respectively. Parents and physicians of the children were surveyed by written questionnaires about the children's subsequent health issues. (IRB 2002-2-2683). Results Seventeen pregnancies with GO were identified: Eight fetuses were live born, four ended in (terminations), two died in utero and three were lost to follow-up. Live-born fetuses had prenatal ascites, extreme levocardia and were delivered by cesarean section at a mean of 37 weeks' gestation with a mean birth weight of 2903 g. All neonates required intubation. Two infants (2/8) died within one year. Four of the six survivors had respiratory insufficiency with a mean ventilation time of 76 days. Respiratory and feeding problems complicated the early neonatal course. Long-term follow-up was available for five patients (mean age of 33.2 months). Asthma, recurrent pulmonary infections, feeding problems, gastroesophageal reflux and failure to thrive were the major problems. Conclusions Respiratory and feeding problems were the most common neonatal and long-term medical management issues. Parents need to be counseled prenatally about the probability of multiple surgeries and long hospitalization following birth. Copyright © 2004 John Wiley & Sons, Ltd.

Respiratory insufficiency is a significant cause of mortality and morbidity among infants with anterior abdominal wall defects (AWD). The aim of this study was to evaluate the pulmonary effects in a fetal rabbit model where gastroschisis was induced at midgestation. Gastroschisis (GAS) was created in 20 rabbit fetuses on day 22 or 23 of gestation (pseudoglandular phase; term = 31-32 days). The amniotic sacs of 13 fetuses were subjected to hysterotomy and amniotomy only (HYST), while 13 underwent a sham laparotomy which was immediately closed by sutures (SHAM). Eleven nonoperated littermates served as internal controls (CTR). Fetuses were harvested by cesarean section on day 31 of gestation prior to respiration. Pulmonary response was evaluated by left lung to body weight ratio (LWBWR), airway morphometry, and density of type II pneumocytes, as evaluated by the number of surfactant protein B-positive cells. Fetuses from the GAS group had significantly lower body weights than did CTR (P = 0.0129). Of these fetuses, 27% were growth-restricted, i.e., with a body weight under the 10th percentile of the CTR population. There were no differences in left lung weight and LWBWR among the GAS and CTR groups. Moreover, the GAS group had similar alveolar size, alveolar wall thickness, and type II cell density as CTR fetuses. Only mean terminal bronchiolar density (MTBD), which is inversely related to the alveolar space, was slightly increased in the GAS group, but without reaching significance (P = 0.0821). No effect on lung growth and maturation could be demonstrated in this study.

This paper intends to demonstrate that the conservative management of triplet pregnancy after delivery of one foetus is a feasible and reasonable approach. Three cases of triplet pregnancy with successful conservative management after miscarriage of one foetus, are presented and compared with cases in the literature. The route of delivery, as well as the role of tocolysis, cerclage, prophylactic antibiotic therapy and corticosteroids are discussed. Guidelines for conservative treatment are proposed. The deliveries of our three pregnancies were delayed by 63, 44 and 22 days respectively. Foetal and neonatal evolution are normal in five of the remaining foetuses. Only one intrauterine death is observed. No maternal complications with sequelae are reported. After abortion of the first triplet, contractions often persist and the birth of the two remaining foetuses may be unavoidable. Nevertheless, in our experience, confirmed by some reports in the literature, prolongation of the pregnancy after expulsion of the first foetus is possible. It can be achieved by cervical cerclage associated with tocolytic and antibiotic therapy. This management is not associated with significantly increased foetal-maternal morbidity.

106 www.thelancet.com Vol 380 July 14, 2012 reveal that, at the fi rst laparoscopy 7 days before the graft (Jan 30, 2003), an ovarian cyst suggestive of a corpus luteum was found on the left ovary. Luteal-phase progesterone was found not only in the maternal serum (10·3 μg/L) but also in the peritoneal fl uid (29·3 μg/L). This hormonal assessment, omitted by Donnez and colleagues, confi rms the evidence of ovulation 1 week before ovarian transplantation. Moreover, in the Methods section, Donnez and colleagues state that “From January, 2001, to Dec ember, 2002, the patient had only one ovulatory cycle shown by a progesterone concentration of 10 ng/mL”. This confi rms that the patient had spontaneous ovulations at least twice before the graft and was not in ovarian failure as reported in the Summary: “After her cancer treat ment, the patient had premature ovarian failure”. In light of these hormonal data, we cannot conclude whether the pregnancy resulted from the transplant or from the in-situ ovary. This conclusion accords with that of Oktay and Tilly, who suggested that “Donnez and colleagues fall short of providing conclusive evidence for the fi rst pregnancy after this procedure”. Therefore we would like to retract our correspondence about this case report, since we want to ensure the integrity of the literature.

There is a growing body of evidence that thrombophilia is linked to several obstetrical complications, most likely through uteroplacental vascular insufficiency. Very few studies have however evaluated whether alterations of the uteroplacental blood flow, as assessed functionally by Doppler ultrasound analysis, are associated with thrombophilic abnormalities in women with late pregnancy complications. Forty-nine non-smoking women followed during their whole pregnancy in the High Risk Pregnancy Clinic of the Cliniques Universitaires Saint-Luc, Brussels, in 2003 were enrolled in this retrospective study. They all had an unexplained late pregnancy complication (intrauterine growth retardation (IUGR) (n=34), intrauterine fetal death (IUFD) (n=4), preeclampsia (n=11)). They were not treated with anti-thrombotic agents. They all had a complete thrombophilic work-up (functional antithrombin, protein C and S assays, homocystein level, antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies), activated protein C resistance, G20210A prothrombin gene mutation). Doppler evaluation of the uterine arteries (assessed by the presence of bilateral notches after 26 weeks) and umbilical arteries (assessed by resistance index above 90th percentile) was performed. Thrombophilic abnormalities were identified in 8 of 49 (16%) women (factor V Leiden (FVL) (n=4), G20210A prothrombin gene mutation (n=2) and isolated anticardiolipin antibodies (n=2)). Of the 49 women, 20 had an abnormal Doppler (uterine (n=5) and umbilical (n=15)) including IUGR (n=13), IUFD (n=2) and preeclampsia (n=5). Four women with thrombophilia were found to have Doppler abnormalities (4/20; 20%) while most women with Doppler alterations had no thrombophilia. In conclusion, abnormal uteroplacental Doppler findings are frequently found in women with late pregnancy complications. They do not seem to be correlated with the presence of thrombophilic abnormalities even if thrombophilia seems to be more frequent in obstetrical complications.