Implementation of an Enhanced Prenatal Checklist to Increase Rates of Counseling of Prenatal Fetal Aneuploidy Testing.

Aim This study aims to assess the effect of implementing an enhanced prenatal genetic checklist to guide the provider's discussion on both screening and diagnostic options for fetal aneuploidy testing at the initial prenatal visit. Methods A retrospective quality improvement (QI) project was performed at a single, large, urban academic medical center. The implementation of this project was prospective; however, data was examined retrospectively after the QI initiative was implemented for three months. Patients were included if they were less than 24 weeks gestational age with a live intrauterine gestation at their initial obstetric (OB) visit. Patients less than 18 years old at the initial OB visit were excluded. The results were analyzed using the statistical software R. Chi-squared tests were used to examine proportional differences between the pre- and post-intervention groups with respect to demographic and clinical characteristics and documented genetic counseling discussions. Results A total of 416 patients were included in the final cohort. As measured by documentation, the rate of discussion of diagnostic prenatal genetic testing increased significantly from the pre-intervention proportion of 54% to the post-intervention proportion of 72% (p < 0.001). In the subgroup analysis of patients with advanced maternal age, the rate of discussion of diagnostic prenatal genetic testing increased significantly from the pre-intervention proportion of 53% to the post-intervention proportion of 83% (p = 0.003), and the rate of genetics counseling referrals made at the initial prenatal visit increased significantly from 4% pre-intervention to 38% post-intervention (p < 0.001). Conclusions The use of an enhanced prenatal genetic checklist led to increased discussion of diagnostic fetal aneuploidy testing and increased rates of referral to genetics counseling.

Wrongful birth and wrongful life lawsuits in obstetrics and gynecology.

Developments in preconception and prenatal technologies have led to undeniable advances in how health-care providers screen and treat patients. Despite these advances, at any point errors can occur leading to misdiagnosis or a missed diagnosis. In some instances, the missed information can lead to the birth of a child with health issues where short of the error, the decision to avoid conception or terminate the pregnancy might have been made. When these lapses unfold, there exists the potential for a wrongful birth or wrongful life lawsuit to ensue. While these 2 actions are based on the same set of events, they are distinct legal claims with varying degrees of judicial permissibility. Global legal acceptability of wrongful birth and life lawsuits tends to resemble patterns in the United States. Analyzing prior wrongful birth and wrongful life claims can reveal common trends in events leading to these types of lawsuits, as well as an understanding of their potential outcomes. A familiarity with wrongful birth and wrongful life lawsuits demonstrates how these cases are unique from other forms of prenatal or birth injury tort lawsuits and can provide insights to common shortcomings in clinical practice. Applying these lessons to clinical practice highlights key approaches towards limiting the risk of certain errors leading to wrongful birth and wrongful life lawsuits, with the goal of health-care providers offering high quality health care.

Challenges of prenatal diagnosis in obese pregnant women.

Obesity rates are increasing world-wide with most of the increase in women of the reproductive age group. While recognised as an important contributor to non-communicable diseases, pregnant women with obesity are particularly at risk of not only maternal and pregnant complications but also have an increased risk of congenital malformations. Furthermore, pregnant obese women are more likely to be older and therefore at a greater risk of aneuploidy. Prenatal diagnosis in these women especially those who are morbidly obese is challenging due not only to their weight but the implications of the increase adiposity on biochemical markers of aneuploidy. In this review we discuss the current challenges in providing prenatal diagnosis for these women including those related to the ergonomics of ultrasound and those inherent in them because of their obesity. Appropriate counselling for these women should include the lower sensitivity of the tests, the difficulties in performing some of the procedures (imaging and invasive testing) as well as the increased risk of structural abnormalities related to their obesity.

High-throughput mRNA sequencing of human placenta shows sex differences across gestation.

INTRODUCTION: Fetal sex affects fetal and maternal health outcomes in pregnancy, but this connection remains poorly understood. As the placenta is the route of fetomaternal communication and derives from the fetal genome, placental gene expression sex differences may explain these outcomes. OBJECTIVES: We utilized next generation sequencing to study the normal human placenta in both sexes in first and third trimester to generate a normative transcriptome based on sex and gestation. STUDY DESIGN: We analyzed 124 first trimester (T1, 59 female and 65 male) and 43 third trimester (T3, 18 female and 25 male) samples for sex differences within each trimester and sex-specific gestational differences. RESULTS: Placenta shows more significant sexual dimorphism in T1, with 94 T1 and 26 T3 differentially expressed genes (DEGs). The sex chromosomes contributed 60.6% of DEGs in T1 and 80.8% of DEGs in T3, excluding X/Y pseudoautosomal regions. There were 6 DEGs from the pseudoautosomal regions, only significant in T1 and all upregulated in males. The distribution of DEGs on the X chromosome suggests genes on Xp (the short arm) may be particularly important in placental sex differences. Dosage compensation analysis of X/Y homolog genes shows expression is primarily contributed by the X chromosome. In sex-specific analyses of first versus third trimester, there were 2815 DEGs common to both sexes upregulated in T1, and 3263 common DEGs upregulated in T3. There were 7 female-exclusive DEGs upregulated in T1, 15 female-exclusive DEGs upregulated in T3, 10 male-exclusive DEGs upregulated in T1, and 20 male-exclusive DEGs upregulated in T3. DISCUSSION: This is the largest cohort of placentas across gestation from healthy pregnancies defining the normative sex dimorphic gene expression and sex common, sex specific and sex exclusive gene expression across gestation. The first trimester has the most sexually dimorphic transcripts, and the majority were upregulated in females compared to males in both trimesters. The short arm of the X chromosome and the pseudoautosomal region is particularly critical in defining sex differences in the first trimester placenta. As pregnancy is a dynamic state, sex specific DEGs across gestation may contribute to sex dimorphic changes in overall outcomes.

Prenatal diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency through molecular genetic analysis of the CYP21A2 gene.

PURPOSE: Deficiency of 21-hydroxylase (21-OHD) is an autosomal recessively inherited disorder that is characterized by adrenal insufficiency and androgen excess. This study was performed to investigate the clinical utility of prenatal diagnosis of 21-OHD using molecular genetic testing in families at risk. METHODS: This study included 27 pregnant women who had previously borne a child with 21-OHD. Fetal tissues were obtained using chorionic villus sampling (CVS) or amniocentesis. After the genomic DNA was isolated, Sanger sequencing of CYP21A2 and multiplex ligation-dependent probe amplification were performed. The clinical and endocrinological findings were reviewed retrospectively. RESULTS: A total of 39 prenatal genetic tests was performed on 27 pregnant women and their fetal tissues. The mean gestational age at the time of testing was 11.7 weeks for CVS and 17.5 weeks for amniocentesis. Eleven fetuses (28.2%) were diagnosed with 21-OHD. Among them, 10 fetuses (90.9%) harbored the same mutation as siblings who were previously diagnosed with 21-OHD. Among these, 4 fetuses (3 males and 1 female) identified as affected were born alive. All 4 patients have been treated with hydrocortisone, 9α-fludrocortisone, and sodium chloride since a mean of 3.7 days of life. The male patients did not show hyponatremia and dehydration, although they harbored pathogenic variants associated with the salt-wasting type of 21-OHD. CONCLUSION: This study demonstrated the diagnostic efficacy and clinical consequences of diagnosis by prenatal genetic testing in families at risk for 21-OHD. All patients identified as affected were treated with hydrocortisone and 9α-fludrocortisone early after birth, which can prevent a life-threatening adrenal crisis.

Preterm prelabor rupture of membranes after first-trimester chorionic villus sampling: A case report and review of the literature.

Rupture of membranes in the first trimester is extremely rare. Generally at this gestational age, rupture is a complication of invasive genetic testing. Little is known about the complications or sequelae of such an occurrence and therefore the management options are limited. This article reports the case of a 35-year-old woman who had rupture of membranes after chorionic villus sampling in the first trimester; it describes her pregnancy course and eventual positive outcome. Regardless of gestational age at time of fluid loss, treatment options are limited. This article reviews the evidence regarding first-trimester rupture and the outcomes of expectant management.

A Low-Cost, High-Fidelity Simulator for Transabdominal Chorionic Villus Sampling.

INTRODUCTION: Chorionic villus sampling (CVS) remains essential for first-trimester genetic diagnosis, yet clinical volume may be insufficient to train new clinicians in the technique. Available simulation models are expensive, require animal parts or specialized resins, and cannot be stored for repeated use. METHODS: We present a model for trans-abdominal CVS (TA-CVS) which is constructed from readily available materials costing less than $10 and can be refrigerated and re-used to train maternal-fetal medicine fellows in CVS. RESULTS: All three attending physicians performing TA-CVS at our institution described the model as an accurate visual and tactile simulation, prompting its integration into our fellowship curriculum. To date, two senior fellows have achieved competency on the simulator and begun to perform clinical CVS under supervision, one of whom is an author on this paper. Both fellows and attendings indicated that the simulator provided a valuable tool for repeated practice prior to clinical CVS. Simulators are now maintained on the unit and have been re-used for 3 months and dozens of simulated procedures each without any apparent qualitative degradation in performance. DISCUSSION/CONCLUSION: We describe a low-cost easily constructed, durable, high-fidelity simulator for TA-CVS.

Perinatal Outcomes in Foetuses with Increased Nuchal Translucency and Normal Karyotype: A Retrospective Cohort Study from the United Arab Emirates.

This retrospective case-controlled study analysed the outcome of pregnancies with first-trimester enlarged nuchal translucency (NT) and a normal karyotype. A total of 479 pregnancies with first-trimester NT measurements were grouped as control (370 cases; normal NT) and study (109 cases; enlarged NT, ≥95th percentile; with normal karyotype). Adverse outcomes included miscarriage, intrauterine foetal death, termination of pregnancy, neonatal death, and structural/chromosomal/genetic abnormalities. The study was conducted between June 2016 and June 2022 at the Foetal Maternal Unit of Kanad Hospital, UAE. Overall, the live birth rate in the study group was significantly lower (74.3%) compared to the control (94.1%, p < 0.001). All pregnancy outcomes of this group significantly differed compared to the control. The observed miscarriage level was 9.2% (vs. 1.1%, p < 0.001), intrauterine foetal death was 2.8% (vs. 0%, p = 0.001), spontaneous preterm birthwas 11% (vs. 4.9%, p = 0.020), and termination of pregnancy was 3.7% (vs. 0%, p < 0.001). The presence of foetal abnormalities was also significantly higher in the enlarged NT group at 21% (vs. 3.3%, p < 0.001). Results indicate that enlarged NT is associated with adverse pregnancy outcomes even when the karyotype is normal. Based on these results, a comprehensive review of the guidelines for counselling and managing pregnancies with enlarged NT and a normal karyotype is recommended.

Genetic counseling practices among outpatient obstetric providers in the Northeast.

BACKGROUND: The American College of Obstetricians and Gynecologists recommends all pregnant people be offered genetic screening and diagnostic testing regardless of risk factors. Previous studies have demonstrated disparities in referrals for genetic testing by race outside of pregnancy, but limited data exist regarding genetic counseling practices during pregnancy. OBJECTIVE: This study aimed to describe how patient, provider, and practice demographics influence the offering of diagnostic prenatal genetic testing by outpatient prenatal care providers. STUDY DESIGN: This was a multicenter anonymous survey study conducted between October 2021 and March 2022. Outpatient prenatal care providers, including family medicine and obstetrics attendings, residents, maternal-fetal medicine fellows, nurse practitioners, physician assistants, and midwives, were surveyed about their genetic counseling practices and practice demographics. The primary outcome was the proportion of respondents who answered "yes, all patients" to the survey question "Do you offer diagnostic genetic testing to all patients?" The secondary outcomes included the association between patient and practice demographics and offering diagnostic testing. Diagnostic testing was defined as chorionic villus sampling or amniocentesis. Screening genetic tests were defined as sequential screen, quadruple screen, cell-free DNA screening, or "other." The chi-square test or Fisher exact test was used as appropriate. For the outcome answers of diagnostic testing, logistic regression was performed to assess the association between the answer of diagnostic genetic testing and the current training level of providers, race and ethnicity, and insurance status variables. Multivariable analysis was performed to adjust for confounders. RESULTS: A total of 635 outpatient prenatal care providers across 7 sites were sent the survey. Overall, 419 providers responded for a total response rate of 66%. Of the providers who responded, most were attendings (44.9%), followed by residents (37.5%). Providers indicated the race, insurance status, and primary language of their patient population. Screening genetic testing was offered by 98% of providers. Per provider report, 37% offered diagnostic testing to all patients, 18% did not offer it at all, and 44% only offered it if certain patient factors were present. Moreover, 54.8% of attendings reported universally offering diagnostic testing. On univariable analysis, residents were less likely to offer diagnostic testing than attendings (odds ratio, 0.18; 95% confidence interval, 0.11-0.30). Providers who serve non-Hispanic Black, Hispanic Black, and other Hispanic patients were less likely to report offering diagnostic testing than other patient populations. Providers who served non-Hispanic Whites were more likely to offer diagnostic testing (odds ratio, 2.26; 95% confidence interval, 1.51-3.39). Patient populations who were primarily privately insured were more likely to be offered diagnostic testing compared with primarily publicly insured patients (odds ratio, 6.25; 95% confidence interval, 3.60-10.85). Providers who served a primarily English-speaking population were more likely to offer diagnostic genetic testing than other patient populations (odds ratio, 0.43; 95% confidence interval, 0.26-0.69). On multivariable analysis, the factors that remained significantly associated with offering diagnostic testing included level of training (resident odds ratio, 0.33; 95% confidence interval, 0.17-0.62; P=.0006; advanced practice provider odds ratio, 0.34; 95% confidence interval, 0.15-0.82; P=.02), having at least one-third of the patient population identify as "other Hispanic" (odds ratio, 0.42; 95% confidence interval, 0.23-0.77; P=.005), and having private insurance instead of public insurance (primarily private insured odds ratio, 2.84; 95% confidence interval, 1.20-6.74; P=.02). CONCLUSION: Although offering genetic screening and diagnostic testing to all patients is recommended, no provider group universally offers diagnostic testing. Providers who serve populations from a racial and ethnic minority, those with public insurance, and those whose primary language is not English are less likely to report universally offering diagnostic genetic testing.

Evaluation of Fetal and Maternal Outcomes in Chorion Villus Sampling (CVS).

Background: Chorionic villus sampling (CVS) is one of the invasive diagnostic methods used to diagnose chromosomal, genetic, and metabolic diseases in the embryonic period. The use of this method is associated with maternal and fetal consequences, the most serious of which is abortion. Therefore, the present study was conducted to investigate the incidence of these consequences and the factors affecting the incidence of abortion. Materials and Methods: A cross-sectional study was performed on 98 pregnant women with CVS indications. Maternal and fetal outcomes including abortion, vaginal bleeding, subchorionic hematoma, premature rupture of membrane (PROM), chorioamnionitis, preterm delivery, limb abnormality, fetal growth retardation, and preeclampsia were recorded. Results: The results of the present study showed that the incidence of fetal outcomes including fetal growth failure, premature rupture of membranes, abortion, and limb abnormalities was 4.1%, 7.1%, 3.1%, and 1%, and the incidence of maternal outcomes including preterm delivery, subchorionic hematoma, preeclampsia, and hemorrhage was 14.3%, 3.1%, 6.1%, and 10.2%, respectively. In addition, a decrease in free BHCG and an increase in NT were significantly associated with the occurrence of abortion (OR: 0.11 and 4.25, respectively, P value < 0.05). Conclusion: It should be noted that due to a long time between placental sampling and the occurrence of vaginal bleeding, premature rupture of membrane, and preterm delivery, it seems that placental sampling has no effect. In addition, only a decrease in free BHCG or an increase in NT significantly increased the chance of miscarriage.

Prenatal diagnosis after high chance non-invasive prenatal testing for trisomies 21, 18 and 13, chorionic villus sampling or amniocentesis? - Experience at a district general hospital in the United Kingdom.

The non-invasive prenatal testing (NIPT) analyses cell-free DNA (cfDNA) derived from the placental tissue in the maternal circulation. Though highly sensitive and specific, a major limitation is in cases of confined placental mosaicism (CPM). Whether to perform chorionic villus sampling (CVS) or amniocentesis to confirm a positive NIPT result is controversial. One major drawback of CVS is that cytogenetic diagnosis may not always reflect the true chromosomal make-up of the fetus. This work, therefore, proposes the use of amniocentesis in the presence of normal ultrasound findings, and the option of either CVS or amniocentesis when there are abnormal USS findings.

Building low-cost simulators for invasive ultrasound-guided procedures using the V-model.

The use of medical simulators for training technical and diagnostic skills has rapidly increased over the past decade. Yet, most available medical simulators have not been developed based on a structured evaluation of their intended uses but rather out of expected commercial value. Moreover, educators often struggle to access simulators because of cost or because no simulators have been developed for a particular procedure. In this report, we introduce "the V-model" as a conceptual framework to illustrate how simulator development can be guided by the intended uses in an iterative fashion. Applying a needs-based conceptual framework when developing simulators is important to increase the accessibility and sustainability of simulation-based medical education. It will minimize the developmental barriers and costs, while at the same time improving educational outcomes. Two new simulators for invasive ultrasound-guided procedures are used as examples, the chorionic villus sampling model and the ultrasound-guided aspiration trainer. Our conceptual framework and the use cases can serve as a template for future simulator development and documentation hereof.

Severe maternal thrombocytopenia and prenatal invasive procedures: still a grey zone.

Management of severe thrombocytopenia, particularly of ITP, in pregnancy is mainly based on expert consensus and clinical experience while there are no clear indications about the minimum platelet count requested for prenatal diagnosis invasive procedures. Since the lack of specific recommendations we reported our clinical management of a patient suffering from severe thrombocytopenia, undergoing amniocentesis. Due to the anecdotic possibility of maternal and fetal bleeding in case of severe thrombocytopenia, prophylaxis with IVIG or even corticosteroids could be considered as a safer strategy to prevent post-procedural adverse outcomes.

Resultados perinatales tras prueba diagnóstica invasiva en el embarazo / Perinatal outcomes after invasive diagnostic test in pregnancy

Introducción: Las técnicas invasivas de diagnóstico prenatal nos permiten realizar pruebas genéticas. El desarrollo de técnicas no invasivas ha reducido su uso. Clásicamente se ha afirmado que, tras realizar la técnica invasiva, la tasa de pérdida fetal se sitúa en torno al 1%. Los datos publicados son heterogéneos, y aunque todo indica que se ha sobrestimado el riesgo, necesitamos realizar nuevos estudios. Material y métodos: En nuestro estudio retrospectivo unicéntrico analizamos los procedimientos realizados mediante técnicas invasivas de diagnóstico prenatal entre 2011 y 2019, incluyendo 832 técnicas invasivas realizadas. Los resultados perinatales se comparan con el grupo control de mujeres embarazadas (n=1.734). Resultados: La tasa de pérdida fetal temprana para las diferentes técnicas fue de 1,1% para amniocentesis, del 1,6% para biopsia corial transvaginal y del 0,5% para biopsia corial abdominal, con una tasa total del 1,1%, sin diferencias estadísticamente significativas entre ellas (p=0,57). Encontramos diferencias en el desenlace fetal, en cuanto a la variable pérdida fetal temprana, en relación con los intentos realizados (cuando se hacían tres intentos aumentaba el riesgo). Al comparar los resultados perinatales posparto del grupo sometido a técnicas con el grupo control, se encontró una mayor tasa de cesáreas en el grupo estudio (28,9% vs 20,5%), además de una menor edad gestacional media al parto (38,33 vs. 38,95 semanas). Discusión: Cuando la técnica invasiva se realiza en el momento adecuado y con no más de dos intentos, consideramos que el riesgo de pérdida fetal no se ve afectado por su realización, siendo igual al de la población general.(AU)

Introduction: Invasive prenatal diagnostic techniques allow us to conduct genetic tests. The development of non-invasive techniques has reduced their use. The foetal loss rate following an invasive procedure is considered to be around 1%. The published data is heterogeneous however, although everything indicates that the risk has been overestimated, we need to conduct further studies. Material and methods: In our single-centre retrospective study we analysed the procedures carried out using invasive prenatal diagnostic techniques between 2011 and 2019. A total of 832 invasive techniques were performed. Perinatal results are compared with a control group of pregnant women (n=1734). Results: The early foetal loss rate for the different techniques were 1.1% for amniocentesis, 1.6% for transvaginal chorionic biopsy and 5% for abdominal chorionic biopsy, with a total rate of 1.1%, without statistically significant differences between them (P=.57). We found differences in foetal outcome, in terms of variable early foetal loss, related to the attempts made (when three attempts were made, the risk increased). When comparing the perinatal outcomes after delivery of the group that underwent techniques with the control group, a higher rate of caesarean sections was found in the study group (28.9% vs 20.5%), in addition to lower mean gestational age at delivery (38.33 vs. 38.95 weeks). Discussion: When the invasive technique is performed at the right time and with no more than two attempts, we consider that the risk of foetal loss is not affected, and is equal to that of the general population.(AU)

Screening and diagnosis of chromosomal abnormalities in twin pregnancy.

Twin pregnancies are at an increased risk of adverse pregnancy and perinatal outcome as compared to singleton gestations, mainly as the consequence of the higher rate of preterm birth, chromosomal as well as structural anomalies, placental abnormalities, and complications unique to monochorionic placentation. Screening for chromosomal anomalies poses diagnostic and management challenges when applied to twin pregnancies. The recent implementation of cell-free fetal DNA (cffDNA) in clinical practice raises the questions whether a more accurate test should be offered to twin pregnancies in view of the higher false positive rate of traditional screening and the higher risk of fetal loss following amniocentesis or chorionic villus sampling (CVS) in multiple gestations. Finally, twin pregnancies require a tailored approach for aneuploidy screening, such as nuchal translucency (NT) or crown rump length discordance, discordant fetal anomalies, or monoamniotic gestations. The present review aims to provide an up-to-date critical appraisal of screening and prenatal diagnosis of chromosomal abnormalities in twin pregnancies.

Majority of transferred mosaic embryos developed healthy live births revealed by a preclinical study using embryonic morphology assessment and noninvasive PGT-A on cell-free DNA in blastocoel fluid.

PURPOSE: This preclinical study aimed to evaluate whether using transferred mosaic embryos (primarily selected by embryonic morphology assessment (EMA) and compared by the noninvasive preimplantation genetic testing for aneuploidy (niPGT-A) on cell-free DNA in blastocoel fluid (BF)) increases the rates of clinical pregnancies (CPs) and healthy live births (HLBs) and to investigate whether niPGT-A could provide valuable genetic information for the EMA-selected transferred mosaic embryos. METHODS: This study collected 215 blastocyst culture samples and 182 BF samples. Cell-free DNA from the BF was amplified and examined by next-generation sequencing-based niPGT-A. All 182 patients underwent EMA. However, only 147 underwent in vitro fertilization and embryo transfer, and only 113 clinical outcomes were followed up. Comprehensive chromosome screening for the chorionic villus sampling of spontaneous miscarriages and noninvasive prenatal testing for ongoing pregnancies were also performed. RESULTS: The implantation rate was 77.55% in 147 transferred high-quality embryos selected by EMA. Among 113 CPs, 16 led to spontaneous miscarriage (14.16%), and 97 resulted in HLBs (85.84%). According to the niPGT-A results for 113 patients with clinical outcomes, 80.4% had CP (euploid, 20.54%; single aneuploid, 1.79%; mosaic chromosome aneuploid and/or segmental aneuploid, 58.04%). Of all the mosaic aneuploids, 90.76% were false positive, transforming to euploid. CONCLUSIONS: Transferred EMA-selected embryos showed higher implantation rates. The niPGT-A of BF provided valuable genetic status ("-ploid") information, which helped reduce aneuploid-induced implantation failure and miscarriage, thereby increasing the CP and HLB rates. Additionally, majority of the transferred embryos with complex/chaotic mosaic aneuploid would likely develop HLBs.

Progressive trends in prenatal genetic screening / Tendencias progresivas en el cribado genético prenatal

According to the global report on birth defects in 2021, it is estimated that 8 million children are born with birth defects of genetic origin annually. These birth defects vary in their degree of severity; where some types are mild and do not require treatment but others may necessitate lifelong medications or even cause instant death just after birth. That is why prenatal screening is doubtless necessary to detect such genetic defects before birth aiming to drop the tragedy of these children off. Recently, this approach has been developing towards non-invasive techniques that reduce the risk of miscarriage, which was common in the old-fashioned invasive ones. Non-invasive Prenatal Tests (NIPTs) like Chromosomal Microarray Analysis (CMA) and cell-free fetal DNA (cffDNA) caused a breakthrough in the screening methods of chromosomal aneuploidies. Thanks to their benefits, NIPTs are considered a fundamental clinical approach for pregnant women’ screening in multiple countries. Thence, this paper gives prominence to the recentness of NIPTs along with each’s assets, liabilities, and prospective recommendations. In addition, it would demonstrate the importance of modern molecular technologies like next-generation sequencing (NGS) which are enforced for the appliance of NIPTs. (AU)

Según el informe mundial sobre anomalías congénitas de 2021, se estima que anualmente nacen 8 millones de niños con anomalías congénitas de origen genético. Estos defectos de nacimiento varían en su grado de severidad; donde algunos tipos son leves y no requieren tratamiento, pero otros pueden necesitar medicamentos de por vida o incluso causar la muerte instantánea justo después del nacimiento. Por eso es sin duda necesario el cribado prenatal para detectar tales defectos genéticos antes del nacimiento con el fin de acabar con la tragedia de estos niños. Recientemente, este enfoque se ha ido desarrollando hacia técnicas no invasivas que reducen el riesgo de aborto espontáneo, que era común en las antiguas invasivas. Las pruebas prenatales no invasivas (NIPT) como el análisis de micromatrices cromosómicas (CMA) y el ADN fetal libre de células (cffDNA) provocaron un gran avance en los métodos de detección de aneuploidías cromosómicas. Gracias a sus beneficios, las NIPT se consideran un enfoque clínico fundamental para la detección de mujeres embarazadas en múltiples países. Por lo tanto, este documento destaca la actualidad de los NIPT junto con los activos, pasivos y recomendaciones prospectivas de cada uno. Además, demostraría la importancia de las tecnologías moleculares modernas, como la secuenciación de próxima generación (NGS), que se aplican para la aplicación de NIPT. (AU)

Genome-Wide Copy Number Variant and High-Throughput Transcriptomics Analyses of Placental Tissues Underscore Persisting Child Susceptibility in At-Risk Pregnancies Cleared in Standard Genetic Testing.

Several studies have shown that children from pregnancies with estimated first-trimester risk based on fetal nuchal translucency thickness and abnormal maternal serum pregnancy protein and hormone levels maintain a higher likelihood of adverse outcomes, even if initial testing for known genetic conditions is negative. We used the Finnish InTraUterine cohort (ITU), which is a comprehensively characterized perinatal cohort consisting of 943 mothers and their babies followed throughout pregnancy and 18 months postnatally, including mothers shortlisted for prenatal genetic testing but cleared for major aneuploidies (cases: n = 544, 57.7%) and control pregnancies (n = 399, 42.3%). Using genome-wide genotyping and RNA sequencing of first-trimester and term placental tissue, combined with medical information from registry data and maternal self-report data, we investigated potential negative medical outcomes and genetic susceptibility to disease and their correlates in placenta gene expression. Case mothers did not present with higher levels of depression, perceived stress, or anxiety during pregnancy. Case children were significantly diagnosed more often with congenital malformations of the circulatory system (4.12 (95% CI [1.22−13.93]) higher hazard) and presented with significantly more copy number duplications as compared to controls (burden analysis, based on all copy number variants (CNVs) with at most 10% frequency, 823 called duplications in 297 cases versus 626 called duplications in 277 controls, p = 0.01). Fifteen genes showed differential gene expression (FDR < 0.1) in association with congenital malformations in first-trimester but not term placenta. These were significantly enriched for genes associated with placental dysfunction. In spite of normal routine follow-up prenatal testing results in early pregnancy, case children presented with an increased likelihood of negative outcomes, which should prompt vigilance in follow-up during pregnancy and after birth.

Pregnancy outcome of confined placental mosaicism: meta-analysis of cohort studies.

OBJECTIVE: This study aimed to assess the rate of adverse obstetrical and neonatal outcomes in pregnancies diagnosed with confined placental mosaicism relative to that of unaffected controls. DATA SOURCES: Web-based databases were searched using relevant key words, and articles published from 1980 to February 2022 were retrieved. STUDY ELIGIBILITY CRITERIA: Observational studies in English language including ≥10 cases of singleton pregnancies with diagnosis of confined placental mosaicism were included. The diagnosis was established after detection of any chromosomal abnormality at chorionic villus sampling for any indication, followed by normal karyotype from amniotic fluid or neonatal leukocyte culture. METHODS: Two authors independently screened the references for eligibility, data extraction, and assessment of methodological quality using the Newcastle-Ottawa scale. All available obstetrical and neonatal outcomes were recorded. Random-effect meta-analysis was performed to estimate pooled odds ratios and 95% confidence intervals of available outcomes in pregnancies with and without confined placental mosaicism. Statistical heterogeneity was evaluated with I2 statistics (International Prospective Register of Systematic Reviews registration number: CRD42021260319). RESULTS: Of the 80 articles reviewed, 8 retrospective matched-cohort studies (708 cases of confined placental mosaicism and 11,599 unaffected controls) compared cases with and without confined placental mosaicism and were included in the meta-analysis. The risk of delivering small-for-gestational-age neonates was significantly increased in confined placental mosaicism pregnancies according to crude analysis (odds ratio, 2.45; 95% confidence interval, 1.23-4.89; I2=72%) and to sensitivity analysis of high-quality studies (odds ratio, 3.65; 95% confidence interval, 2.43-5.57; I2=0%). Similarly, confined placental mosaicism resulted in an increased risk of birthweight below the third centile (odds ratio, 5.33; 95% confidence interval, 1.19-24.19; I2= 83%). Subgroup analysis revealed that the risk of delivering small-for-gestational-age neonates was 3-fold higher for confined placental mosaicism excluding trisomy 16, and 11-fold higher for cases including trisomy 16 only vs unaffected controls, respectively. No difference was found in the risk of low birthweight and preterm birth (at <37 weeks' gestation). Other outcomes were insufficiently reported, therefore they were not analyzed. CONCLUSION: Pregnant women prenatally diagnosed with confined placental mosaicism have an increased risk of impaired fetal growth, suggesting the need for intensified antenatal surveillance.

Prenatal Diagnosis Using Chromosomal Microarray Analysis in High-Risk Pregnancies.

Background: To assess the value of chromosomal microarray analysis (CMA) during the prenatal diagnosis of high-risk pregnancies. Methods: Between January 2016 and November 2021, we included 178 chorionic villi and 859 amniocentesis samples from consecutive cases at a multiple tertiary hospital. Each of these high-risk singleton pregnancies had at least one of the following indications: (1) advanced maternal age (AMA; ≥35 years; 546, 52.7%); (2) fetal structural abnormality on ultrasound (197, 19.0%); (3) high-risk first- or second-trimester Down syndrome screen (189, 18.2%), including increased nuchal translucency (≥3.5 mm; 90, 8.7%); or (4) previous pregnancy, child, or family history (105, 10.1%) affected by chromosomal abnormality or genetic disorder. Both G-banding karyotype analysis and CMA were performed. DNA was extracted directly and examined with oligonucleotide array-based comparative genomic hybridization. Results: Aneuploidies were detected by both G-banding karyotyping and CMA in 42/1037 (4.05%) cases. Among the 979 cases with normal karyotypes, 110 (10.6%) cases had copy number variants (CNVs) in CMA, including 30 (2.9%) cases with reported pathogenic and likely pathogenic CNVs ≥ 400 kb, 37 (3.6%) with nonreported VOUS, benign, or likely benign CNVs ≥ 400 kb, and 43 (4.1%) with nonreported CNVs < 400 kb. Of the 58 (5.6%) cases with aneuploidy rearrangements, 42 (4.1%) were diagnosed by both G-banding karyotyping and CMA; four inversions, six balanced translocations, and six low mosaic rates were not detected with CMA. Conclusions: CMA is an effective first step for the prenatal diagnosis of high-risk pregnancies with fetal structural anomalies found in ultrasonography or upon positive findings.