Current status and future of genomics in fetal and maternal medicine: A scientific review commissioned by European Board and College of Obstetrics and Gynaecology (EBCOG).

This EBCOG guidance reviews the current and future status of genomics within fetal and maternal medicine. This document addresses the clinical uses of genetic testing in both screening and diagnostic testing prenatally. The role of genomics within fetal and maternal medicine is described. The research and future implications of genetic testing as well as the educational, ethical and economic implications of genomics are discussed.

Fetal neuroimaging applications for diagnosis and counseling of brain anomalies: Current practice and future diagnostic strategies.

Advances in fetal brain neuroimaging, especially fetal neurosonography and brain magnetic resonance imaging (MRI), allow safe and accurate anatomical assessments of fetal brain structures that serve as a foundation for prenatal diagnosis and counseling regarding fetal brain anomalies. Fetal neurosonography strategically assesses fetal brain anomalies suspected by screening ultrasound. Fetal brain MRI has unique technological features that overcome the anatomical limits of smaller fetal brain size and the unpredictable variable of intrauterine motion artifact. Recent studies of fetal brain MRI provide evidence of improved diagnostic and prognostic accuracy, beginning with prenatal diagnosis. Despite technological advances over the last several decades, the combined use of different qualitative structural biomarkers has limitations in providing an accurate prognosis. Quantitative analyses of fetal brain MRIs offer measurable imaging biomarkers that will more accurately associate with clinical outcomes. First-trimester ultrasound opens new opportunities for risk assessment and fetal brain anomaly diagnosis at the earliest time in pregnancy. This review includes a case vignette to illustrate how fetal brain MRI results interpreted by the fetal neurologist can improve diagnostic perspectives. The strength and limitations of conventional ultrasound and fetal brain MRI will be compared with recent research advances in quantitative methods to better correlate fetal neuroimaging biomarkers of neuropathology to predict functional childhood deficits. Discussion of these fetal sonogram and brain MRI advances will highlight the need for further interdisciplinary collaboration using complementary skills to continue improving clinical decision-making following precision medicine principles.

Interdisciplinary fetal neurology care: Current practice, challenges, and future directions.

As the field of fetal-neonatal neurology has expanded over the past 2 decades with increasingly complex diagnoses, multidisciplinary collaboration with many subspecialties including genetics, neonatology, obstetrics, maternal fetal medicine, surgical sub-specialties, cardiology, radiology, palliative care, and ethics has needed to evolve to strive to offer optimal patient care. While comprehensive care delivery with an inter-disciplinary approach is preferred, there are often barriers based on numerous health disparities especially in resource limited settings. Even in the context of comprehensive care, diagnostic and prognostic uncertainty lead to challenges for providers during fetal neurology consultations. We present a case that highlights advantages of a comprehensive multi-disciplinary team in caring for the medical and social challenges of patients faced with a fetal neurologic diagnosis. Inter-disciplinary training focusing on maternal, fetal, neonatal, and childhood neurodevelopmental course and collaboration among the numerous stakeholders that contribute to fetal neurology practice is needed to provide optimal counseling and care for families faced with a fetal neurological diagnosis.

The impact of prenatal screening tests on prenatal diagnosis in Taiwan from 2006 to 2019: a regional cohort study.

BACKGROUND: The purpose of this study is to evaluate the impact of prenatal screening tests on prenatal diagnosis in Taiwan's 14 years from 2006 to 2019. METHODS: The prenatal screening methods evolved from the second-trimester serum screening to combined first-trimester screening (cFTS) and then followed by the non-invasive cell-free DNA prenatal test (NIPT). The data used by the Department of Statistics, the Ministry of Health and Welfare and Department of Household Registration, Ministry of the Interior public website. RESULTS: This regional registry-based cohort retrospective study examined a total of 2,775,792 births from January 2006 to December 2019. The proportion of advanced maternal age (AMA) pregnancies increased from 11.63% in 2006 to 30.94% in 2019. Overall, invasive diagnostic testing was used in 87.22% of AMA pregnancies. The prenatal detection rate of trisomy 21 and 18 increased from 74.1% and 83.3% in 2006 to 96.9% and 98.8% in 2019, respectively. CONCLUSION: During the second-trimester and cFTS periods, the percentage of AMA pregnancies increased every year and the number of invasive procedures also accompany with increased percentage of AMA. However, during the period that NIPT were implemented, the percentage of invasive procedures decreased.

From non-invasive to invasive fetal therapy: A comprehensive review and current update.

"Fetus as patient" indicates fundamental concept of fetal therapy. With advance in maternal serum analysis and fetal imaging, prenatal screening has become standard of care. Accurate diagnosis in early gestation allows intervention to reverse pathophysiology and delay progression immediately. Non-invasive, minimally invasive and invasive therapies demonstrate their therapeutic potential in certain diseases. Recently, stem cell and gene therapies have been developed to avoid irreversible impairment. To elevate efficacy of treatment modality, extensive studies should be conducted according to regulatory authority. Striking a balance between scientific and ethical integrity is essential, so long-term follow up should be arranged for protecting mother and fetus.

Prenatal molecular testing and diagnosis of Beckwith-Wiedemann syndrome.

OBJECTIVE: The objective of this study was to describe molecular findings and phenotypic features among individuals referred for prenatal Beckwith-Wiedemann syndrome (BWS) testing. METHODS: Molecular diagnostic testing was performed using a sensitive quantitative real-time PCR-based assay capable of detecting mosaic methylation to the level of 3% at IC1 and IC2. Sanger sequencing of CDKN1C was performed in cases with normal methylation. RESULTS: Of the 94 patients tested, a molecular diagnosis was identified for 25.5% of cases; 70.9% of diagnosed cases had loss of methylation at IC2, 4.2% had gain of methylation at IC1, 12.5% had paternal uniparental isodisomy, and 12.5% had CDKN1C loss-of-function variants. Methylation level changes in prenatal cases were significantly greater than changes identified in cases tested after birth. Cases with a prenatal molecular diagnosis had a significantly greater number of BWS-associated phenotypic features. The presence of either macroglossia or placentomegaly was most predictive of a BWS diagnosis. CONCLUSION: Our results support the consensus statement advocating BWS molecular testing for all patients with one or more BWS-associated prenatal features and suggest that low-level mosaic methylation changes may be uncommon among prenatal BWS diagnoses.

Evidence to Support the Clinical Utility of Prenatal Exome Sequencing in Evaluation of the Fetus with Congenital Anomalies: Scientific Impact Paper No. 64 [February] 2021.

Structural differences (congenital anomalies) in the makeup of the baby's heart, brain and other organs are found on antenatal ultrasound scans in up to 3% of pregnancies. These often have a genetic cause, arising because of changes in the chromosomes (which store our genetic material) or the DNA code that make up the genes. The more differences a baby has the more likely the risk of underlying genetic disease. If a structural difference is found, parents are usually offered a genetic test, which may be carried out on cells taken either from the placenta (chorionic villous sampling) or the fluid surrounding the baby (amniocentesis). At the moment, these cells are only tested for changes in the chromosomes and are only able to reveal the underlying cause in about 40% of unborn babies. Prenatal exome sequencing (ES) is a new genetic test, which, when combined with testing the DNA of both parents can find changes in the baby's genetic code. If a DNA change is found that can explain the structural changes seen on ultrasound, specific information about the underlying diagnosis can be given to the parents. Having this information can help parents make important decisions about their ongoing pregnancy, as well as help doctors to care for the mother and baby. Finding a genetic change can also help to understand how the condition has arisen and whether it might happen again in another pregnancy. It may also be possible to test for the genetic condition in future pregnancies. Although prenatal ES is an exciting new way to improve diagnosis rates for structural differences, it has some challenges. While the test is very detailed, it may not always find a genetic explanation and sometimes the results are difficult to interpret. For example, genetic changes can be found where their significance for the pregnancy is unclear. More recently, two studies have now shown that prenatal ES can find a genetic diagnosis in at least 10% of pregnancies with structural differences where standard chromosome testing has been negative. This paper reviews these studies, along with earlier evidence on ES and provides clinicians with guidance for future practice.

Uptake of fetal aneuploidy screening after the introduction of the non-invasive prenatal test: A national population-based register study.

INTRODUCTION: The introduction of the non-invasive prenatal test (NIPT) has shifted the prenatal screening landscape. Countries are exploring ways to integrate NIPT in their national prenatal screening programs, either as a first- or second-tier test. This study aimed to describe how the uptake of fetal aneuploidy screening changed after the introduction of NIPT as a second-tier and as a first-tier test within the national prenatal screening program of the Netherlands. MATERIAL AND METHODS: A population-based register study in the Netherlands, recording uptake of fetal aneuploidy screening. Data from all pregnant women choosing to have the first-trimester combined test (FCT) or first-tier NIPT between January 2007 and March 2019 were retrospectively collected using national registration systems. Uptake percentages for fetal aneuploidy screening (FCT and NIPT) were calculated and stratified by region and maternal age. Statistical significance was determined using trend analysis and chi-squared tests. RESULTS: Between 2007 and 2013 FCT uptake increased from 14.8% to 29.5% (P = .004). In April 2014 NIPT was introduced as a second-tier test for high-risk women after FCT (TRIDENT-1 study). FCT uptake rose from 29.5% in 2013 to 34.2% in 2015 (P < .0001). After the introduction of NIPT as a first-tier test for all women in April 2017 (TRIDENT-2 study), FCT uptake declined significantly from 35.8% in 2016 to 2.6% in 2018 (P < .0001). NIPT uptake increased to 43.4% in 2018. Regionally, NIPT uptake ranged from 31.8% to 67.9%. Total uptake (FCT and NIPT) between 2007 and 2018 increased significantly from 14.8% to 45.9% (P < .0001). However, total uptake stabilized at 46% for both years of TRIDENT-2 (April 2017-March 2019). CONCLUSIONS: An increase in total fetal aneuploidy screening uptake up to 45.9% was observed after the introduction of NIPT. Uptake appears to have stabilized within a year after introducing first-tier NIPT.

Socioeconomic barriers to prenatal diagnosis of critical congenital heart disease.

OBJECTIVE: The study was designed to assess the impact of socioeconomic barriers on the rate of prenatal diagnosis of critical congenital heart disease (CCHD). METHODS: This was a retrospective review of the Medicaid analytic extract (MAX) dataset, a national Medicaid administrative claims database with linked maternal-infant claims, from 2007 to 2012. Infants with CCHD were identified by searching for International Classification of Diseases (ICD) 9 codes and Procedural Coding System (PCS) codes for CCHD within the first 6 months after the delivery date. Multivariate logistic regression was used to evaluate the effect of maternal and socioeconomic factors on the prenatal diagnosis rate. RESULTS: There were 4702 mother-infant dyads included in the analysis. The prenatal diagnosis rate of CCHD was 27.9%. Factors independently associated with odds of prenatal diagnosis of CCHD were presence of maternal diabetes (OR, 2.055; P < .001), ZIP code level median household income (OR, 1.005; P = .015), sonographer labor quotient (OR, 1.804; P = .047), the year of the delivery (OR, 1.155; P < .001), and needing a view other than a 4 chamber or outflow tract view to obtain the diagnosis (OR, 0.383; P < .001). CONCLUSION: Maternal health, diabetes, socioeconomic factors, and access to sonographers impacts prenatal diagnosis of CCHD.

A report on the impact of rapid prenatal exome sequencing on the clinical management of 52 ongoing pregnancies: a retrospective review.

OBJECTIVE: Studies have shown that prenatal exome sequencing (PES) improves diagnostic yield in cases of fetal structural malformation. We have retrospectively analysed PES cases from two of the largest fetal medicine centres in the UK to determine the impact of results on management of a pregnancy. DESIGN: A retrospective review of clinical case notes. SETTING: Two tertiary fetal medicine centres. POPULATION: Pregnancies with fetal structural abnormalities referred to clinical genetics via a multidisciplinary team. METHODS: We retrospectively reviewed the notes of all patients who had undergone PES. DNA samples were obtained via chorionic villus sampling or amniocentesis. Variants were filtered using patient-specific panels and interpreted using American College of Medical Genetics guidelines. RESULTS: A molecular diagnosis was made in 42% (18/43) ongoing pregnancies; of this group, there was a significant management implication in 44% (8/18). A positive result contributed to the decision to terminate a pregnancy in 16% (7/43) of cases. A negative result had a significant impact on management in two cases by affirming the decision to continue pregnancy. CONCLUSIONS: We demonstrate that the results of PES can inform pregnancy management. Challenges include variant interpretation with limited phenotype information. These results emphasise the importance of the MDT and collecting phenotype and variant data. As this testing is soon to be widely available, we should look to move beyond diagnostic yield as a measure of the value of PES. TWEETABLE ABSTRACT: Prenatal exome sequencing can aid decision-making in pregnancy management; review ahead of routine implementation in NHS.

Confirmation rate of cell free DNA screening for sex chromosomal abnormalities according to the method of confirmatory testing.

OBJECTIVE: To examine the positive predictive value (PPV) of cfDNA screening for sex chromosome aneuploidies (SCA) in a large series of over 90 000 patients. METHODS: Retrospective study based on samples that were sent to Cenata, a private laboratory which uses the Harmony Prenatal Test. The SCA high-risk results were stratified according to the method of diagnostic testing and according to karyotype result. RESULTS: The study population consisted of 144 cases. The CfDNA test indicated monosomy X, XXX, XXY, and XYY in 62, 37, 40, and 5 cases, respectively. The overall PPV was 38.9% (30.9-47.4), 29.0% (18.2-42.9) for monosomy X, 29.7% (15.9-47.9) for 47,XXX, 57.5% (40.9-73.0) for 47,XXY, and 80.0% (28.4-99.5) for 47,XYY). A total of 112 (77.8%) women with a high-risk result for SCAs opted for prenatal karyotyping. In this group, there were significant differences in the PPV if the karyotype was assessed by amniocentesis or by CVS: 29.5% vs 50.0%. This significant difference was driven by the monosomy X result which shows a significantly higher PPV in CVS (54.6% (23.4-83.3) vs 17.1% (6.6-33.6)). For the other SCAs, the differences were not significant. CONCLUSION: PPV of an abnormal cfDNA test for SCAs is low, particularly for monosomy X. The confirmation rate depends on the type of confirmatory test.

The Reproductive Journey in the Genomic Era: From Preconception to Childhood.

It is estimated that around 10-15% of the population have problems achieving a pregnancy. Assisted reproduction techniques implemented and enforced by personalized genomic medicine have paved the way for millions of infertile patients to become parents. Nevertheless, having a baby is just the first challenge to overcome in the reproductive journey, the most important is to obtain a healthy baby free of any genetic condition that can be prevented. Prevention of congenital anomalies throughout the lifespan of the patient must be a global health priority. Congenital disorders can be defined as structural or functional anomalies that occur during intrauterine life and can be identified prenatally, at birth, or sometimes may only be detected later during childhood. It is considered a frequent group of disorders, affecting 3-6% of the population, and one of the leading causes of morbidity and mortality. Congenital anomalies can represent up to 30-50% of infant mortality in developed countries. Genetics plays a substantial role in the pathogenesis of congenital anomalies. This becomes especially important in some ethnic communities or populations where the incidence and levels of consanguinity are higher. The impact of genetic disorders during childhood is high, representing 20-30% of all infant deaths and 11.1% of pediatric hospital admissions. With these data, obtaining a precise genetic diagnosis is one of the main aspects of a preventive medicine approach in developed countries. The field of reproductive health has changed dramatically from traditional non-molecular visual microscope-based techniques (i.e., fluorescence in situ hybridization (FISH) or G-banding karyotype), to the latest molecular high-throughput techniques such as next-generation sequencing (NGS). Genome-wide technologies are applied along the different stages of the reproductive health lifecycle from preconception carrier screening and pre-implantation genetic testing, to prenatal and postnatal testing. The aim of this paper is to assess the new horizon opened by technologies such as next-generation sequencing (NGS), in new strategies, as a genomic precision diagnostic tool to understand the mechanisms underlying genetic conditions during the "reproductive journey".

Trends in prenatal diagnosis: An analysis of 40 years of Medical Subject Heading (MeSH) terms in publications.

OBJECTIVE: To understand the evolution of the field of prenatal diagnosis over the past four decades. METHOD: We analyzed the publications in the journal Prenatal Diagnosis from its inception in 1980 to 2019 using Medical Subject Headings (MeSH) to examine the major research topics and trends. The results were analyzed by 10-year intervals. RESULTS: Publications on prenatal cytogenetics, congenital anomalies and fetal imaging predominated during the first three decades, with a steady increase in molecular genetics over time. Publications on NIPT did not appear until the most recent decade and are likely under-counted because there was no MeSH term for NIPT until 2020. CONCLUSION: The topics covered in Prenatal Diagnosis articles have evolved considerably over the past four decades and reflect a response to advances in technology and widespread incorporation of prenatal screening and diagnosis into standard obstetric care. The strengths of this analysis are its objective nature, its use of the standard MeSH terms used for coding, and application of a novel cluster analysis to visualize trends. The analysis also pointed out the fact that MeSH terms in this sub-specialty area are often inconsistent due to manually coding based on individual subject matter expertise.

The radiologic diagnosis of skeletal dysplasias: past, present and future.

Skeletal dysplasias have been recognised since recorded history began. The advent of radiography at the beginning of the 20th century and the subsequent introduction of departments of radiology have had tremendous impact and allowed conditions to be identified by their specific radiographic phenotypes. This has been enhanced by the addition of cross-sectional modalities (ultrasound, computed tomography and magnetic resonance imaging), which have allowed for prenatal recognition and diagnosis of skeletal dysplasias, and by the recent explosion in identified genes. There are more than 400 recognised skeletal dysplasias, many of which (due to their rarity) the practising clinician (radiologist, paediatrician, geneticist) may never come across. This article provides a historical overview of aids to the radiologic diagnosis of skeletal dysplasias.