Sonographically determined anomalies and outcome in 170 chromosomally abnormal fetuses

Structural pathology and outcome were studied in 170 chromosomally abnormal fetuses. Numerical chromosomal abnormalities were established in 158 (93 per cent) cases, of which 110 (71 per cent) represented trisomies, 30 (18 per cent) Turner syndrome, and 18 (11 per cent) triploidy. Structural chromosomal abnormalities were diagnosed in 12 (7 per cent) cases. Gestational age at referral was significantly shorter for pregnancies with Turner syndrome than for the other chromosomal abnormalities. Referral before 20 weeks of gestation was mainly based on fetal structural pathology alone (92 per cent); after 20 weeks, patients were referred because of structural pathology combined with small for gestational age, oligohydramnios, or polyhydramnios. Referral as a result of suspected multiple organ pathology occurred in 73.5 per cent of pregnancies. An abnormal amniotic fluid volume was present in 59/170 (34.5 per cent) chromosomally affected pregnancies, i.e., oligohydramnios in 31 and polyhydramnios in 28 cases. Birth weight was below the tenth percentile in over half of the chromosomally abnormal fetuses, except for Turnersyndrome. Fetal outcome was poor, with a survival rate at 1 month of 30 per cent for trisomies which was mainly determined by trisomy 21 (14/18=77.5 per cent)

Increased prevalence of abnormal vertebral patterning in fetuses and neonates with trisomy 21

Purpose: To assess the prevalence of an abnormal number of ribs in a cohort of fetuses and neonates with trisomy 21 and compare this with a subgroup of fetuses without anomalies. Materials and methods: Radiographs of 67 deceased fetuses, neonates, and infants that were diagnosed with trisomy 21 were reviewed. Terminations of pregnancy were included. The control group was composed of 107 deceased fetuses, neonates, and infants without known chromosomal abnormalities, structural malformations, infections or placental pathology. Cases in which the number of thoracic ribs or presence of cervical ribs could not be reliably assessed were excluded. The literature concerning vertebral patterning in trisomy 21 cases and healthy subjects was reviewed. Results: Absent or rudimentary 12th thoracic ribs were found in 26/54 (48.1%) cases with trisomy 21 and cervical ribs were present in 27/47 (57.4%) cases. This prevalence was significantly higher compared to controls (28/100, 28.0%, Χ2(1) = 6.252, p = .012 and 28/97, 28.9%, Χ2(1) = 10.955, p < .001, respectively). Conclusions: Rudimentary or absent 12th thoracic ribs and cervical ribs are significantly more prevalent in deceased fetuses and infants with trisomy 21

Antenatal Workup of Early Megacystis and Selection of Candidates for Fetal Therapy

Objective: To investigate the best criteria for discriminating fetuses with isolated posterior urethral valves from those theoretically not eligible for fetal treatment because of complex megacystis, high chance of spontaneous resolution, and urethral atresia. Methods: A retrospective national study was conducted in fetuses with megacystis detected before 17 weeks’ gestation (early megacystis). Results: In total, 142 cases with fetal megacystis were included in the study: 52 with lower urinary tract obstruction, 29 with normal micturition at birth, and 61 with miscellaneous syndromal associations, chromosomal and multiple structural abnormalities (complex megacystis). Only a nuchal translucency > 95th centile, and not a longitudinal bladder diameter ≤15 mm (p = 0.24), significantly increased the risk of complex megacystis (p 12 mm, and without ultrasound evidence of umbilical cord cysts

Fetal megacystis: a lot more than LUTO

ABSTRACT Objective Fetal megacystis presents a challenge in terms of counseling and management because of its varied etiology and evolution. The aim of this study was to present a comprehensive overview of the underlying etiologies and structural anomalies associated with fetal megacystis. Methods This was a retrospective multicenter study of cases referred to the fetal medicine unit of one of the eight academic hospitals in The Netherlands with a diagnosis of fetal megacystis. For each case, data on and measurements of fetal urinary tract and associated structural anomalies were collected. All available postmortem examinations and postnatal investigations were reviewed in order to establish the final diagnosis. In the first trimester, fetal megacystis was defined as longitudinal bladder diameter (LBD) ≥ 7 mm, and in the second and third trimesters as an enlarged bladder failing to empty during an extended ultrasound examination lasting at least 40 min. Results Of the 541 pregnancies with fetal megacystis, it was isolated (or solely accompanied by other signs of lower urinary tract obstruction (LUTO)) in 360 (67%) cases and associated with other abnormal ultrasound findings in 181 (33%) cases. The most common associated ultrasound anomaly was an increased nuchal translucency thickness (22%), followed by single umbilical artery (10%) and cardiac defect (10%). A final diagnosis was established in 418 cases, including 222 (53%) cases with isolated LUTO and 60 (14%) infants with normal micturition or minor isolated urological anomalies. In the remaining 136 (33%) cases, concomitant developmental or chromosomal abnormality or genetic syndrome was diagnosed. Overall, 40 chromosomal abnormalities were diagnosed, including trisomy 18 (n = 24), trisomy 21 (n = 5), Turner syndrome (n = 5), trisomy 13 (n = 3) and 22q11 deletion (n = 3). Thirty-two cases presented with anorectal malformations involving the anus, rectum and urogenital tract. In cases with confirmed urethral and anal atresia, megacystis occurred early in pregnancy and the bladder appeared severely distended (the LBD (in mm) was equal to or greater than twice the gestational age (in weeks)). Fetal macrosomia was detected in six cases and an overgrowth syndrome was detected in four cases, comprising two infants with Beckwith–Wiedemann syndrome and two with Sotos syndrome. Megacystis-microcolon-intestinal hypoperistalsis syndrome was diagnosed in five (1%) cases and prenatally suspected only in one case. Conclusions Although the main cause of fetal megacystis is LUTO, an enlarged fetal bladder can also be present as a concomitant finding of miscellaneous genetic syndromes, developmental disturbances and chromosomal abnormalities. We provide an overview of the structural anomalies and congenital disorders associated with fetal megacystis and propose a practical guide for the differential diagnosis of genetic syndromes and chromosomal and developmental abnormalities in pregnancies presenting with fetal megacystis, focusing on the morphological examination of the fetus

Ultrasound markers for prediction of complex gastroschisis and adverse outcome: longitudinal prospective nationwide cohort study

Objectives: To identify antenatal ultrasound markers that can differentiate between simple and complex gastroschisis and assess their predictive value. Methods: This was a prospective nationwide study of pregnancies with isolated fetal gastroschisis that underwent serial longitudinal ultrasound examination at regular specified intervals between 20 and 37 weeks' gestation. The primary outcome was simple or complex (i.e. involving bowel atresia, volvulus, perforation or necrosis) gastroschisis at birth. Fetal biometry (abdominal circumference and estimated fetal weight), the occurrence of polyhydramnios, intra- and extra-abdominal bowel diameters and the pulsatility index (PI) of the superior mesenteric artery (SMA) were assessed. Linear mixed modeling was used to compare the individual trajectories of cases with simple and those with complex gastroschisis, and logistic regression analysis was used to estimate the strength of association between the ultrasound parameters and outcome. Results: Of 104 pregnancies with isolated fetal gastroschisis included, four ended in intrauterine death. Eighty-one (81%) liveborn infants with simple and 19 (19%) with complex gastroschisis were included in the analysis. We found no relationship between fetal biometric variables and complex gastroschisis. The SMA-PI was significantly lower in fetuses with gastroschisis than in healthy controls, but did not differentiate between simple and complex gastroschisis. Both intra- and extra-abdominal bowel diameters were larger in cases with complex, compared to those with simple, gastroschisis (P < 0.001 and P < 0.005, respectively). The presence of intra-abdominal bowel diameter ≥ 97.7th percentile on at least three occasions, not necessarily on successive examinations, was associated with an increased risk of the fetus having complex gastroschisis (relative risk, 1.56 (95% CI, 1.02–2.10); P = 0.006; positive predictive value, 50.0%; negative predictive value, 81.4%). Conclusions: This large prospective longitudinal study found that intra-abdominal bowel dilatation when present repeatedly during fetal development can differentiate between simple and complex gastroschisis; however, the positive predictive value is low, and therefore the clinical usefulness of this marker is limited

Prenatal ultrasound parameters in single-suture craniosynostosis

textabstractIntroduction: Although single-suture craniosynostosis is diagnosed sporadically during pregnancy, timely referral is critical for its treatment. Additionally, craniosynostosis leads to increased maternofetal trauma during birth. In the Netherlands, 95% of pregnant women receive a standard ultrasound at around 20 weeks of gestation, potentially an ideal setting for detecting craniosynostosis prenatally. To enhance the prenatal detection of the metopic and the sagittal suture synostosis, we wished to identify new screening parameters. Materials and methods: We retrospectively analyzed data of the 20-week anomaly scan in trigonocephaly patients (n = 41), scaphocephaly patients (n = 41), and matched controls (n = 82). We measured six different cranial dimensions, including head circumference, biparietal diameter, and occipito-frontal diameter, defining the cephalic index as the ratio between biparietal and occipito-frontal diameter. Results: Prenatal biometric measurements did not differ significantly between trigonocephaly patients and controls. Although significantly lower in scaphocephaly patients (0.76 versus 0.79; p = .000), the cephalic index by itself is not appropriate for screening at 20 weeks of gestation. Longitudinal analysis suggests that a deflection in BPD curve is found in scaphocephaly patients, starting at 20 weeks of gestation. Conclusions: Prenatal biometric measurements do not differ significantly between trigonocephaly patients and controls. The CI is lower in scaphocephaly patients. A deflection in BPD curve should be followed by 3 D imaging of the cranial sutures

Exploring copy number variants in deceased fetuses and neonates with abnormal vertebral patterns and cervical ribs

Background: Cervical patterning abnormalities are rare in the general population, but one variant, cervical ribs, is particularly common in deceased fetuses and neonates. The discrepancy between the incidence in the general population and early mortality is likely due to indirect selection against cervical ribs. The cause for the co-occurrence of cervical ribs and adverse outcome remains unidentified. Copy number variations resulting in gain or loss of specific genes involved in development and patterning could play a causative role. Methods: Radiographs of 374 deceased fetuses and infants, including terminations of pregnancies, stillbirths and neonatal deaths, were assessed. Copy number profiles of 265 patients were determined using single nucleotide polymorphism array. Results: 274/374 patients (73.3%) had an abnormal vertebral pattern, which was associated with congenital abnormalities. Cervical ribs were present in 188/374 (50.3%) and were more common in stillbirths (69/128 [53.9%]) and terminations of pregnancies (101/188 [53.7%]), compared to live births (18/58, 31.0%). Large (likely) deleterious copy number variants and aneuploidies were prevalent in these patients. None of the rare copy number variants were recurrent or overlapped with candidate genes for vertebral patterning. Conclusions: The large variety of copy number variants in deceased fetuses and neonates with similar abnormalities of the vertebral pattern probably reflects the etiological heterogeneity of vertebral patterning abnormalities. This genetic heterogeneity corresponds with the hypothesis that cervical ribs can be regarded as a sign of disruption of critical, highly interactive stages of embryogenesis. The vertebral pattern can probably provide valuable information regarding fetal and neonatal outcome

Valproic Acid Disrupts Hematopoiesis in Xenopus Laevis Through the Inhibition of Histone Deacetylase 3.

Histone deacetylases (HDACs) are important regulators of developmental processes and cellular functions. However, their role in hematopoiesis has not been determined, and in Xenopus laevis, a specific function for HDACs has yet to be identified. In the present work, we employed the class I selective HDAC inhibitor, valproic acid (VPA), to identify hdac3 as an essential mediator of primitive hematopoiesis. Exposure to VPA during gastrulation results in a marked and specific block of primitive hematopoiesis in Xenopus embryos. Furthermore, pharmacological and loss of function studies demonstrate that hdac3 functions downstream of bmp4 signaling and is specifically required for primitive erythropoiesis. We also describe here that runx1 is activated by bmp4 in an HDAC-dependent manner. Consistent with this, restoring runx1 expression partially rescues VPA mediated hematopoietic defects. We further identify that the effects of HDAC inhibition on primitive hematopoiesis is conserved in mammals, as yolk sac hematopoiesis in mouse is also blocked with exposure to VPA. Lastly, we identify a bicarbonate transporter as the primary means for VPA to enter the embryos. Our findings demonstrate for the first time a critical role for hdac3 in primitive hematopoiesis, and indicate that specific developmental defects associated with exposure to VPA, a significant teratogen in humans, arise through inhibition of class I HDACs