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.

Prenatal diagnosis of fetal growth restriction with polyhydramnios, etiology and impact on postnatal outcome

To assess the spectrum of different etiologies, the intrauterine course, outcome and possible prognostic markers in prenatally detected fetal growth restriction (FGR) combined with polyhydramnios. Retrospective study of 153 cases with FGR combined with Polyhydramnios diagnosed by prenatal ultrasound over a period of 17 years. Charts were reviewed for ultrasound findings, prenatal and postnatal outcome. All cases were categorized into etiological groups and examined for differences. Five etiological groups were identified: chromosomal anomalies (n = 64, 41.8%), complex malformation syndromes (n = 37, 24.1%), isolated malformations (n = 24, 15.7%), musculoskeletal disorders (n = 14, 9.2%) and prenatal non-anomalous fetuses (n = 14, 9.2%). Subgroups showed significant disparities in initial diagnosis of combination of both pathologies, Ratio AFI/ gestational weeks and Doppler ultrasound examinations. Overall mortality rate was 64.7%. Fetuses prenatally assigned to be non-anomalous, showed further complications in 42.9% (n = 6). Fetuses prenatally diagnosed with FGR combined with polyhydramnios are affected by a high morbidity and mortality. Five etiologic groups can be differentiated, showing significant disparities in prenatal and postnatal outcome. Even without recognizable patterns prenatally, long-term-follow up is necessary, as neurodevelopmental or growth delay may occur.

Outcomes of Complete Surgical Repair Versus Palliative Intervention in Neonates with Tetralogy of Fallot

Background: Surgical management of symptomatic neonates with Tetralogy of Fallot (TOF) is controversial. Either primary surgical repair (EPSR) in neonates with TOF or a staged palliation with initial palliative intervention (PI). Aim: Compare outcomes of neonates with TOF who had EPSR and those who had PI. Materials and Methods: The study utilized the US National Inpatient Sample dataset for the years 2000 to 2018. Patients with EPSR and those with PI (aortic to pulmonary shunt or cardiac catheter palliative intervention) identified. Results: A total of 29,292 neonates with TOF were identified; of them 1726 neonates had EPSR, 4363 had PI. Hospital mortality was similar in both groups (PI 7.4% vs EPSR 8.0%, p = 0.41). Patient in the PI group had more comorbidities; chromosomal anomalies (PI 13.2% vs. ESPR 7.8%, p < 0.001), prematurity (PI 15.1% vs. EPSR 10.4%, p < 0.001), and low birth weight < 2500 grams (PI 15.4% vs. EPSR 10.3%, p < 0.001). Median length of stay and median cost of hospitalization were significantly higher in the EPSR (25 days vs. 19 days, and $312,405 vs. $191,863, respectively, p < 0.001). Conclusion: EPSR had similar mortality to PI but comes with a higher resource utilization and complications. If we include the cumulative morbidity and resource utilization associated with a two staged repair, EPSR could be proven as a better strategy in symptomatic neonates with TOF. A prospective superiority study on symptomatic neonates with TOF randomized to either ESPR or PI is needed to further answer this question.

A Case of Inherited t(4;10)(q26;q26.2) Chromosomal Translocation Elucidated by Multiple Chromosomal and Molecular Analyses. Case Report and Review of the Literature

We present a complex chromosomal anomaly identified using cytogenetic and molecular methods. The child was diagnosed during the neonatal period with a multiple congenital anomalies syndrome characterized by: flattened occipital region; slight turricephaly; tall and broad forehead; hypertelorism; deep-set eyes; down slanting and short palpebral fissures; epicanthic folds; prominent nose with wide root and bulbous tip; microstomia; micro-retrognathia, large, short philtrum with prominent reliefs; low set, prominent ears; and congenital heart disease. The GTG banding karyotype showed a 46,XY,der(10)(10pter→10q26.2::4q26→4qter) chromosomal formula and his mother presented an apparently balanced reciprocal translocation: 46,XX,t(4;10)(q26;q26.2). The chromosomal anomalies of the child were confirmed by MLPA, and supplementary investigation discovered a quadruplication of the 4q35.2 region. The mother has a triplication of the same chromosomal fragment (4q35.2). Using array-CGH, we described the anomalies completely. Thus, the boy has a 71,057 kb triplication of the 4q26–q35.2 region, a 562 kb microdeletion in the 10q26.3 region, and a 795 kb quadruplication of the 4q35.2 region, while the mother presents a 795 kb triplication of the 4q35.2 region. Analyzing these data, we consider that the boy’s phenotype is influenced only by the 4q partial trisomy. We compare our case with similar cases, and we review the literature data.

Development of a Discrete Choice Experiment (DCE) questionnaire to elicit values by pregnant women and decision-makers for the expansion of a NIPS-based prenatal screening program

BackgroundIn an accountable world, being able to take into account the value given by relevant stakeholders to an intervention that could be offered to the population is considered as desirable. DCE is an approach particularly suited for the measurement of such values in the field of prenatal care. Yet, DCE studies in the field of prenatal screening have focused mainly on pregnant women and their care providers but have neglected another key actor, the decision-makers. The objective of the study was to develop a DCE instrument applicable to pregnant women and decision-makers, for the evaluation of new conditions to be added to a screening program for fetal chromosomal anomalies.MethodsAn instrument development study was undertaken. Methods employed included a literature review, a qualitative study performed on pregnant women and decision-makers, and a pilot project to validate the developed instrument and test the feasibility of its administration through an online survey platform. ResultsAn initial list of ten attributes and levels were built from the information provided by the literature review and the qualitative research component of the study. Seven attributes were built based on responses provided by participants from both groups. Two attributes were built from what was said by women only and one from what was said by decision-makers only. Search for consensus through consultations and a focus group discussion led to the retention of eight attributes. A pilot project was then performed with 33 pregnant women. This led to the exclusion of one attribute that showed poor influence on the choice making. The final version of the instrument contains seven attributes.ConclusionThis paper presents the construction of a DCE instrument that can be administered to pregnant women on the demand side, and decision-makers on the supply side. Such an instrument to measure the social desirability of an intervention could be an added value to the decision-making process of Health Technology Assessment agencies.