Initial Clinical Experience with NIPT for Rare Autosomal Aneuploidies and Large Copy Number Variations

Objective: Amniocentesis, chorionic villi sampling and first trimester combined testing are able to screen for common trisomies 13, 18, and 21 and other atypical chromosomal anomalies (ACA). The most frequent atypical aberrations reported are rare autosomal aneuploidies (RAA) and copy number variations (CNV), which are deletions or duplications of various sizes. We evaluated the clinical outcome of non-invasive prenatal testing (NIPT) results positive for RAA and large CNVs to determine the clinical significance of these abnormal results. Methods: Genome-wide NIPT was performed on 3664 eligible patient samples at a single genetics center. For patients with positive NIPT reports, the prescribing physician was asked retrospectively to provide clinical follow-up information using a standardized questionnaire. Results: RAAs and CNVs (>7 Mb) were detected in 0.5%, and 0.2% of tested cases, respectively. Follow up on pregnancies with an NIPT-positive result for RAA revealed signs of placental insufficiency or intra-uterine death in 50% of the cases and normal outcome at the time of birth in the other 50% of cases. We showed that CNV testing by NIPT allows for the detection of unbalanced translocations and relevant maternal health conditions. Conclusion: NIPT for aneuploidies of all autosomes and large CNVs of at least 7 Mb has a low “non-reportable”-rate (<0.2%) and allows the detection of additional conditions of clinical significance.

Lung volume head ratio: A potential parameter for prediction of respiratory distress in newborn

Objective: To evaluate the role of fetal lung biometry profile including fetal lung volume head ratio (LVHR) in predicting the occurrence of respiratory distress (RD) in early preterm newborn. Material and Method: Prospective analytical cohort study was done to evaluate the clinical value of fetal sonographic measures such as the total lung area (TLA), total lung volume (TLV), total lung area head ratio (TLHR), lung volume head ratio (LVHR) was measured in pregnant women between 30 to 34 week gestation , expected to deliver within the next 72 hours. The cases with RD were compared with controls who had normal outcome. Result: Total 30(27.4%) out of 110 subjects undergoing early preterm delivery had RD rest 80(72.6%) were controls. The total lung area was 694.1±373.1 mm2 in cases whereas 1149.0 ± 506 .7 mm2 in controls, with significant difference between the two groups(p<0.001). Similarly the lung volume (p<0.001) and the lung volume head ratio was significantly less (P<0.001) in cases compared to controls. The total lung volume was a better parameter (sensitivity-73.7%; specificity-86.4%) compared to total lung area (Sensitivity - 68.4%, Specificity - 81.5%). Among the lung head ratios, LVHR had best sensitivity - 95.5%, Specificity - 80.3%, PPV-58.3%, NPV - 97.0% at the cut off of 46.5. Conclusion: Respiratory distress was observed in nearly one-third of the preterm infants born between 30 and 34 weeks and could be predicted accurately in over nine out of ten cases using the novel parameter TLVR.

Fetal heart rate development during labour

Background Fresh stillbirths (FSB) and very early neonatal deaths (VEND) are important global challenges with 2.6 million deaths annually. The vast majority of these deaths occur in low- and low-middle income countries. Assessment of the fetal well-being during pregnancy, labour, and birth is normally conducted by monitoring the fetal heart rate (FHR). The heart rate of newborns is reported to increase shortly after birth, but a corresponding trend in how FHR changes just before birth for normal and adverse outcomes has not been studied. In this work, we utilise FHR measurements collected from 3711 labours from a low and low-middle income country to study how the FHR changes towards the end of the labour. The FHR development is also studied in groups defined by the neonatal well-being 24 h after birth. Methods A signal pre-processing method was applied to identify and remove time periods in the FHR signal where the signal is less trustworthy. We suggest an analysis framework to study the FHR development using the median FHR of all measured heart rates within a 10-min window. The FHR trend is found for labours with a normal outcome, neonates still admitted for observation and perinatal mortality, i.e. FSB and VEND. Finally, we study how the spread of the FHR changes over time during labour. Results When studying all labours, there is a drop in median FHR from 134 beats per minute (bpm) to 119 bpm the last 150 min before birth. The change in FHR was significant ($$p<0.05$$ p < 0.05 ) using Wilcoxon signed-rank test. A drop in median FHR as well as an increased spread in FHR is observed for all defined outcome groups in the same interval. Conclusion A significant drop in FHR the last 150 min before birth is seen for all neonates with a normal outcome or still admitted to the NCU at 24 h after birth. The observed earlier and larger drop in the perinatal mortality group may indicate that they struggle to endure the physical strain of labour, and that an earlier intervention could potentially save lives. Due to the low amount of data in the perinatal mortality group, a larger dataset is required to validate the drop for this group.

Aspects of prenatal ultrasound diagnostics of fetal commissural pathology. Part I: normal development (the corpus callosum and other major telencephalic commissures)

The corpus callosum pathology is associated with over 350 different congenital syndromes. In this article development of the main forebrain commissures in fetus ranging from 11 to 16 weeks of gestation at prenatal ultrasound are presented. This is the first sonographic study to describe the prenatal sonographic appearance of the main forebrain commissures in fetus and we speculate that cases with pathology of the corpus callosum and normal outcome might be result of the presence a residual interhemispheric connection.

Evaluation of categories of intrapartum fetal heart rate tracings in pregnancies complicated with fetal growth restriction and its relation to perinatal outcome

Background: Intrapartum FHR monitoring is widely used during labour as changes in FHR precede brain injury, so timely response to abnormal FHR patterns might be effective in preventing it. There is a strong association between stillbirth and FGR which warrants intensive intrapartum fetal surveillance for optimal perinatal outcome. In this study we aimed to classify intrapartum FHR tracings into different categories in FGR pregnancies and correlate with perinatal outcome.Methods: A total 100 singleton pregnant women >34 weeks gestation with FGR were included in study. FHR tracings were followed throughout first and second stage of labour. FHR tracing were categorized into NICHD 3-tier classification as category I, II and III. Maternal and neonatal outome in each category were analysed.Results: Mean duration of category I tracings was 9.05 hours, category II was 7.66 hours and that of category III was 0.49 hours. During late active phase 25/95 patients with category I FHR tracings had vaginal delivery, 62/95 had category II FHR tracings, of which 95.1% had vaginal delivery and 4.9% had instrumental. 8/95 with category III FHR tracings required caesarean section. All patients with category I tracings had normal neonatal outcome, among patients with category II FHR tracings, 74.6% had normal whereas 25.4% had adverse outcome, all with category III FHR tracings had adverse outcome.Conclusions: Categorizing FHR tracings is helpful to distinguish neonates who are likely to have normal outcome from those who are at risk for fetal hypoxia. When the category II tracings are present, it requires more vigilant monitoring and decision taking.

Somatic mutations reveal widespread mosaicism and mutagenesis in human placentas

ABSTRACTClinical investigations of human fetuses have revealed that placentas occasionally harbour chromosomal aberrations that are absent from the fetus1. The basis of this genetic segregation of the placenta, termed confined placental mosaicism, remains unknown. Here, we investigated the phylogeny of human placentas reconstructed from somatic mutations, using whole genome sequencing of 86 placental biopsies and of 106 microdissections. We found that every placental biopsy represented a clonal expansion that is genetically distinct. Biopsies exhibited a genomic landscape akin to childhood cancer, in terms of mutation burden and mutational imprints. Furthermore, unlike any other human normal tissue studied to date, placental genomes commonly harboured copy number changes. Reconstructing phylogenetic relationships between tissues from the same pregnancy, revealed that developmental bottlenecks confined placental tissues, by separating trophectodermal from inner cell mass-derived lineages. Of particular note were cases in which inner cell mass-derived and placental lineages fully segregated within a few cell divisions of the zygote. Such early embryonic bottlenecks may enable the normalisation of zygotic aneuploidy. We observed direct evidence for this in a case of mosaic trisomic rescue. Our findings reveal cancer-like mutagenesis in placental tissues and portray confined mosaicism as the normal outcome of placental development.

Placenta Pathology From Term Born Neonates With Normal or Adverse Outcome

Background The incidence of umbilical cord or placental parenchyma abnormalities associated with mortality or morbidity of term infants is lacking. Methods Placentas of 55 antepartum stillbirths (APD), 21 intrapartum stillbirths (IPD), 12 neonatal deaths (ND), and 80 admissions to a level 3 neonatal intensive care unit (NS) were studied and compared with 439 placentas from neonates from normal term pregnancies and normal outcome after vaginal delivery (NPVD) and with 105 placentas after an elective caesarian sections (NPEC). Results NPVD and NPEC placentas showed no or one abnormality in 70% and placentas from stillbirth showed two or more abnormalities in 80% of cases. APD placentas more frequently had a low weight and less formation of terminal villi. Hypercoiling was more often present in all study groups. Severe chronic villitis was almost exclusively present in APD placentas. Chorioamnionitis was significantly more frequent in APD, IPD and NS placentas and funisitis was more often observed in IPD and NS placentas. Conclusion Multiple placental abnormalities are significantly more frequent in placentas from term neonates with severe perinatal morbidity and mortality. These placental abnormalities are thought to be associated with disturbed oxygen transfer or with inflammation.

Risk factors, types and outcomes of arterial ischemic stroke in Polish pediatric patients: a retrospective single-center study

IntroductionVarious neurological complications may occur as a consequence of arterial ischemic stroke (AIS) and have an impact on daily activity of the patients, costs of their medical care and rehabilitation. The aim of this study was to analyze risk factors, stroke symptoms and post-stroke consequences in Polish pediatric patients depending on stroke subtype.Material and methodsWe retrospectively reviewed 77 children under the age of 18 years following their first AIS. Patients were white, Polish Caucasians, recruited in the Department of Pediatric Neurology at the Medical University of Silesia in Katowice (Poland). Statistical analysis was performed using Statistica 12.0.ResultsGender differed significantly between stroke subgroups (p = 0.030). The presence of focal cerebral arteriopathy (FCA) and chronic diseases was associated with type of AIS (p = 0.003 and p = 0.050, respectively). An outcome without neurological deterioration (normal outcome) was observed in 43% of children with lacunar anterior circulation infarct (LACI). Hemiparesis was present in almost all children with total anterior circulation infarct (TACI), in two thirds of children with partial anterior circulation infarct (PACI) and in almost 50% of children with LACI or posterior circulation infarct (POCI). In every child with hemiplegia the stroke symptom evolved into hemiparesis at follow-up. Additionally, patients with a normal outcome were older at the time of AIS than those with at least one neurological consequence (OR = 0.894, p = 0.034).ConclusionsThe presence and number of neurological outcomes depend on stroke subtypes. A relation between the presence of post-stroke deficits and age at onset was observed. The odds of deficit after ischemic stroke decreases by an average of 10.6% if the child is 1 year older at the time of AIS.