Molecular diagnostic yield of exome sequencing in a Chinese cohort of 512 fetuses with anomalies.

BACKGROUND: Currently, whole exome sequencing has been performed as a helpful complement in the prenatal setting in case of fetal anomalies. However, data on its clinical utility remain limited in practice. Herein, we reported our data of fetal exome sequencing in a cohort of 512 trios to evaluate its diagnostic yield. METHODS: In this retrospective cohort study, the couples performing prenatal exome sequencing were enrolled. Fetal phenotype was classified according to ultrasound and magnetic resonance imaging findings. Genetic variants were analyzed based on a phenotype-driven followed by genotype-driven approach in all trios. RESULTS: A total of 97 diagnostic variants in 65 genes were identified in 69 fetuses, with an average detection rate of 13.48%. Skeletal and renal system were the most frequently affected organs referred for whole exome sequencing, with the highest diagnostic rates. Among them, short femur and kidney cyst were the most common phenotype. Fetal growth restriction was the most frequently observed phenotype with a low detection rate (4.3%). Exome sequencing had limited value in isolated increased nuchal translucency and chest anomalies. CONCLUSIONS: This study provides our data on the detection rate of whole exome sequencing in fetal anomalies in a large cohort. It contributes to the expanding of phenotypic and genotypic spectrum.

Exploring the link between chromosomal polymorphisms and reproductive abnormalities.

OBJECTIVE: This work aimed to investigate the potential correlation between chromosomal polymorphisms and various reproductive abnormalities. METHODS: We examined 21,916 patients affected by infertility who sought care at the Department of Reproductive Medicine, Affiliated Hospital of Shandong Second Medical University between January 2018 and December 2022. A total of 2227 individuals identified as chromosomal polymorphism carriers constituted the polymorphism group, and 2245 individuals with normal chromosome karyotypes were randomly selected to form a control group. Clinical manifestations, histories of spontaneous miscarriage, abnormal reproductive developments, fetal abnormalities, and male sperm quality anomalies were statistically compared between these two groups. RESULTS: Of the 21,916 patients analyzed, 2227 displayed chromosomal polymorphism, representing a 10.16% detection rate. Amongst the male patients, 1622 out of 10,827 exhibited polymorphisms (14.98%), whereas 605 out of 11,089 females showed polymorphisms (5.46%). Female carriers in the polymorphism group, showed statistically significant increased rates of spontaneous abortion (29.75% vs. 18.54%), fetal anomalies (1.32% vs. 0.81%), and uterine abnormalities compared with the control group (1.32% vs. 0.81%). Male carriers in the polymorphism group had higher rates of spontaneous abortion in partners (22.87% vs. 10.37%), fetal anomalies (1.97% vs. 0.25%), compromised sperm quality (41.74% vs. 7.18%), testicular underdevelopment (2.28% vs. 0.92%), and hypogonadotropic hypogonadism (0.62% vs. 0.37%) compared with the control group. CONCLUSION: Chromosomal polymorphisms may have a certain negative effect on reproductive irregularities, including spontaneous abortions, fetal anomalies, and reduced sperm quality in males. Their clinical effects deserve further investigation.

Management, Outcome, Risk, and Expectation Classification for Structural Fetal Anomalies to Aid Antenatal Counseling: A Systematic Review.

The aim of this study was to propose Management, Outcome, Risk, and Expectation (MORE) as a risk based stratification to aid in antenatal parental counseling and decision making through a systematic review of published literature. A Preferred Reporting Items for Systematic Reviews and Meta Analyses compliant systematic review was conducted to include articles that covered antenatal counseling of pediatric surgical conditions. The following information was solicited for each anomaly: primary organ syste*-m of involvement, single or multi system anomaly, natural history of the disease, standard management of the anomaly, need for antenatal intervention, and whether the anomaly requires any alteration in the obstetric management. Twenty two studies were identified fulfilling the inclusion criteria, between 1993 and 2023. Only two studies were found to have GRADE A recommendation and Level I evidence. Most of the studies were review articles/ survey, and 6 studies were found to be retrospective observational studies. Based on the analysis of the solicited information, the anomalies were stratified into a group subsequently maturing them into a simplified MORE classification scheme which stressed the importance of Management (10, 45.45%), Outcome (9, 40.90%), Risk (9, 40.90%), and Expectation (10, 45.45%) categories during antenatal counseling. MORE classification of fetal structural anomalies is a simple but comprehensive framework to assist the physicians and other medical personnel antenatal parental counseling and decision making.

Glucagon-Like Peptide-1 Receptor Agonist Use in Pregnancy: A Review.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are peptide analogues that are used to treat type 2 diabetes mellitus (T2DM) and obesity. The first medication in this class, Exenatide, was approved in 2005, and these medications, specifically Semaglutide, have become more popular in recent years due to their pronounced effects on glycemic control, weight reduction, and cardiovascular health. Due to successful weight loss from these medications, many women previously diagnosed with oligomenorrhea and unable to conceive have experienced unplanned pregnancies while taking the medications. However, there is currently little data for clinicians to use in counseling patients in cases of accidental periconceptional exposure. In some studies examining small animals exposed to GLP-1RAs in pregnancy, there has been evidence of adverse outcomes in the offspring, including decreased fetal growth, skeletal and visceral anomalies, and embryonic death. Although there are no prospective studies in humans, case reports, cohort studies, and population-based studies have not shown a pattern of congenital anomalies in infants. A recent large, observational, population-based cohort study examined 938 pregnancies affected by T2DM and compared outcomes from periconceptional exposure to GLP-1RAs and insulin. The authors concluded there was not a significantly increased risk of major congenital malformations in patients taking GLP-1RAs, although there was no information on maternal glycemic control or diabetic fetopathy. As diabetic embryopathy is directly related to the degree of maternal hyperglycemia and not the diagnosis of diabetes itself, it is not possible to make this conclusion without this information. Furthermore, there is little evidence available regarding fetal growth restriction, embryonic or fetal death, or other potential complications. At this time, patients should be counseled there is not enough evidence to predict any adverse effects, or the lack thereof, of periconceptional exposure of GLP-1RAs during pregnancy. We recommend that all patients use contraception to prevent unintended pregnancy while taking GLP-1RAs.

Antenatal reproductive screening for pregnant people including preconception: Provides the best reproductive opportunity for informed consent, quality, and safety.

INTRODUCTION: This antenatal screening review will include reproductive screening evidence and approaches for pre-conception and post-conception, using first to third trimester screening opportunities. METHODS: Focused antenatal screening peer-reviewed publications were evaluated and summarized. RESULTS: Evidenced-based reproductive antenatal screening elements should be offered and discussed, with the pregnancy planning or pregnant person, during Preconception (genetic carrier screening for reproductive partners, personal and family (including reproductive partner) history review for increased genetic and pregnancy morbidity risks); First Trimester (fetal dating with ultrasound; fetal aneuploidy screening plus consideration for expanded fetal morbidity criteria, if appropriate; pregnant person preeclampsia screening; early fetal anatomy screening; early fetal cardiac screening); Second Trimester for standard fetal anatomy screening (18-22 weeks) including cardiac; pregnant person placental and cord pathology screening; pregnant person preterm birth screening with cervical length measurement); Third Trimester (fetal growth surveillance; continued preterm birth risk surveillance). CONCLUSION: Antenatal reproductive screening has multiple elements, is complex, is time-consuming, and requires the use of pre- and post-testing counselling for most screening elements. The use of preconception and trimesters 'one to three' requires clear patient understanding and buy-in. Informed consent and knowledge transfer is a main goal for antenatal reproductive screening approaches.

Differences in Person-Centered Care in Fetal Care Centers: Results from the U.S. Pilot Study of the PCC-FCC Scale.

OBJECTIVE: We report findings from a U.S. mixed-methods pilot study of the Person-Centered Care in Fetal Care Centers (PCC-FCC) Scale. METHODS: Participants, who received care at a U.S. Fetal Care Center (FCC) between 2017 and 2021, completed an online questionnaire providing sociodemographic details, specifics about the care received, qualitative experiences, and scores from the PCC-FCC Scale. RESULTS: Participants' (n = 247) PCC-FCC scores and qualitative feedback indicate high perceived person-centered care (PCC), particularly in areas of care coordination, respectful care, and patient education. However, 8% scored below the midpoint, and 38% of comments were negative, especially regarding expectation setting, preparation for post-intervention maternal health, and psychosocial support. Public insurance was associated with higher total PCC-FCC (p = 0.03) and Factor 2 scores (p = 0.02) compared to those with private insurance. The qualitative themes trust, clarity, comprehensive care, compassion, and belonging further elucidate the concept of PCC in FCCs. CONCLUSION: The PCC-FCC Scale pilot study revealed strong overall PCC in FCCs, yet variability in patient experiences suggests areas needing improvement, including expectation setting, preparation for post-intervention maternal health, and psychosocial support. Future research must prioritize diverse samples and continued mixed methodologies to better understand the role of insurance and identify other potential disparities, ensuring comprehensive representation of the FCC patient population.

The Role of Social Determinants in Diagnosis Timing for Fetal Care Center-Eligible Conditions: A Scoping Review.

Timely identification of fetal conditions enables comprehensive evaluation, counseling, postnatal planning, and prenatal treatments. This study assessed the existing evidence on how social determinants of health (SDOH) influence diagnosis timing of fetal conditions appropriate for care in fetal care centers (FCCs). Eligible studies were conducted in the U.S. and published in English after 1999. We employed the Healthy People 2020 SDOH framework to categorize and analyze data from 16 studies, where 86% focused solely on congenital heart disease (CHD). Studies primarily focused on individual-level SDOH, with only 36% addressing structural-level factors. A total of 31 distinct indicators of SDOH were identified, with 68% being unique to individual studies. Indicators often varied in definition and specificity. Three studies covered all five SDOH categories in the Healthy People 2020 Framework. Studies revealed varying and often conflicting associations with SDOH indicators, with race and ethnicity being the most explored (100%), followed by socioeconomic status (69%), maternal age (57%), residence (43%), and structural factors (29%). Our findings highlight the need for more comprehensive research, including conditions beyond CHD, and the establishment of consensus on indicators of SDOH. Such efforts are necessary to gain a deeper understanding of the underlying factors driving disparities in fetal diagnosis and treatment.

Psychological sequelae following second-trimester termination of pregnancy: A longitudinal study.

INTRODUCTION: The decision to terminate a pregnancy due to fetal anomalies can have a significant emotional impact, especially in second-trimester terminations. Previous studies on the psychological consequences of pregnancy termination have had limitations, and little is known about the outcomes for partners and the impact of fetal donation. Therefore, we aimed to investigate the psychological effects of second-trimester pregnancy termination and identify factors associated with outcomes in both women and men, including donation of fetal remains to science. MATERIAL AND METHODS: A longitudinal cohort study was conducted at the Amsterdam UMC in the Netherlands, involving women and partners who underwent termination at or before 23 weeks and 6 days of gestation. Questionnaires were administered at termination, 6 weeks, and 4 months after. We utilized validated questionnaires to assess psychological morbidity (grief, post-traumatic stress and postnatal depression and quality of life [QoL]), and factors that could potentially influence outcomes. RESULTS: Of 241 participants, women displayed more pronounced psychological distress than men, though both groups improved over time. Four months after termination, 27.4% of women and 9.1% of men showed signs of pathological grief. Scores indicative for postnatal depression occurred in 19.8% women and 4.1% of men. A prior psychiatric history was a consistent predictor of poorer outcomes. Fetal donation to the Dutch Fetal Biobank was associated with reduced likelihood of symptoms of complicated grief four months after termination. CONCLUSIONS: Second-trimester termination of pregnancy for fetal anomalies can lead to psychological morbidity, particularly in women. However, there is a notable improvement over time for both groups. Individuals with prior psychiatric history appear more vulnerable post-termination. Also, fetal donation to science did not have a negative impact on psychological well-being.

The Role of Midwives in US Perinatal Palliative Care: A Scoping Review.

INTRODUCTION: Perinatal palliative care (PPC) is a rapidly growing and essential reproductive health care option for pregnant persons with a diagnosed life-limiting fetal condition who continue their pregnancy. The provision of PPC is within the scope of basic midwifery competencies, and midwives are well-positioned to make unique and valuable contributions to interprofessional PPC teams. However, little is known about midwives' past or current involvement in PPC in the United States. METHODS: This scoping review of the literature investigated what is known about the role of midwives in PPC in the United States. Multiple databases of published literature were used for this review: PubMed, CINAHL, Embase, Web of Science, ProQuest, Google Scholar, and relevant citations from identified studies. All types of English language publications addressing midwives' involvement in PPC in the United States were included, without any limitations on publication date. RESULTS: The role and contributions of midwives in PPC is not well represented in existing literature. Of the 259 results identified, 7 publications met criteria for inclusion. These included 5 case reports, one quantitative research article, and one conference abstract. Midwives are involved in PPC through the provision of direct clinical care (including antepartum, intrapartum, postpartum, neonatal, bereavement, postmortem, and follow-up care) and care planning and coordination as part of an interprofessional team. DISCUSSION: Despite midwives being uniquely positioned to provide holistic, family-centered, and person-centered care in situations of pregnancy with life-limiting fetal conditions, there is limited literature about their involvement in PPC in the United States. PPC should be incorporated into midwifery education and training programs. Midwives should play a central role in shaping future research and policies to ensure the accessibility and quality of PPC.

Introduction of a nationwide first-trimester anomaly scan in the Dutch national screening program.

BACKGROUND: A significant proportion of major fetal structural anomalies can be detected in the first trimester by ultrasound examination. However, the test performance of the first-trimester anomaly scan performed in a low-risk population as part of a nationwide prenatal screening program is unknown. Potential benefits of the first-trimester anomaly scan include early detection of fetal anomalies, providing parents with more time for reproductive decision-making. OBJECTIVE: To investigate the uptake, test performance, and time to a final prenatal diagnosis after referral. STUDY DESIGN: A nationwide implementation study was conducted in the Netherlands (November 2021-November 2022). The FTAS was performed between 12+3 and 14+3 weeks of gestation by certified sonographers using a standard protocol. Women were referred to a tertiary care center if anomalies were suspected. Uptake, test performance, and time to a final prenatal diagnosis (days between referral and date of final diagnosis/prognosis for reproductive decision-making) were determined. Test performance was calculated for first-trimester major congenital anomalies, such as anencephaly and holoprosencephaly and all diagnosed anomalies <24 weeks of gestation. RESULTS: The first-trimester anomaly scan uptake was 74.9% (129,704/173,129). In 1.0% (1313/129,704), an anomaly was suspected, of which 54.9% (n=721) had abnormal findings on the detailed first-trimester diagnostic scan and 44.6% (n=586) showed normal results. In 0.5% (n=6), intrauterine fetal death occurred. In the total group of 721 cases with abnormal findings, 332 structural anomalies, 117 genetic anomalies, 82 other findings (abnormal fetal biometry, sonomarkers, placental/umbilical cord anomaly, an-/oligohydramnios), and 189 cases with transient findings (defined as ultrasound findings which resolved <24 weeks of gestation) were found, with 1 case having an unknown outcome. 0.9% (n=1164) of all cases with a normal first-trimester anomaly scan were diagnosed with a fetal anomaly in the second trimester. Test performance included a sensitivity of 84.6% (126/149) for first-trimester major congenital anomalies and 31.6% (537/1701) for all types of anomalies. Specificity for all anomalies was 99.2% (98,055/98,830); positive predictive value 40.9% (537/1312); negative predictive value 98.8% (98,055/99,219); positive likelihood ratio 40.3; negative likelihood ratio 0.7; false positive rate 0.8% (775/98,830), and false negative rate 68.4% (1164/1701). The median time to diagnosis for structural anomalies was 20 days (6-43 days; median gestational age 16+3), for genetic anomalies 17 days (8.5-27.5 days; median gestational age 15+6 weeks), and for first-trimester major congenital anomalies 9 days (5-22 days; median gestational age 14+6 weeks). CONCLUSION: The performance of a newly introduced nationwide first-trimester anomaly scan in a low-risk population showed a high sensitivity for first-trimester major congenital anomalies and a lower sensitivity for all anomalies combined. The program was accompanied by a referral rate of 1.0%, of which 59.1% involved cases where anomalies were either not confirmed or resolved before 24 weeks gestation. Timing of diagnosis was around 16 weeks of gestation for referred cases. To evaluate the balance between benefits and potential harm of the first-trimester anomaly scan within a nationwide prenatal screening program, it is essential to assess the effectiveness of the program over time and to consider the perspectives of both women and their partners, as well as healthcare professionals.

Acute symptoms of depression and traumatic stress in men and women who terminate pregnancy after the detection of fetal anomaly: A prospective observational study.

OBJECTIVE: To assess acute and long-term stress in men and women after the detection of fetal anomalies leading to pregnancy termination. DESIGN: Prospective observational study. SETTING: Tertiary referral centre for fetal medicine. POPULATION: From the initial sample of 180 pregnant women with a fetal anomaly detected by ultrasound examination, a total of 87 women terminated their pregnancy, with 72 partners included in the sample. At the time of detection, the group of women (n = 93) and their partners (n = 81) who did not terminate the pregnancy following a diagnosis were included as a comparison group. METHODS: These women and their partners were asked to complete the Edinburgh Postnatal Depression Scale (EPDS) and the Impact of Events Scale (IES) questionnaires, both at the time of initial detection and at 6 weeks after the termination of the pregnancy. MAIN OUTCOME MEASURES: Responses to the EPDS and the IES at the time of initial detection and at 6 weeks after pregnancy termination. RESULTS: Women who underwent pregnancy termination reported higher symptom levels of depression, but not traumatic stress, prior to the termination than women who chose not to terminate their pregnancy. Among men, there was a difference across depression and all subscales of traumatic stress (e.g. IES intrusion: mean difference 5.31; 95% CI 2.32-8.31). Women experienced more depressive symptoms over time than men (ß = 4.33, P < 0.001) and higher symptom levels on all subscales of traumatic stress (e.g. IES intrusion: ß = 5.27; P < 0.001). CONCLUSIONS: Overall, our study underscores the heightened levels of depression and traumatic stress experienced by prospective parents, particularly prior to the decision to terminate a pregnancy following the detection of a fetal anomaly. Although women generally report more pronounced symptoms, it is noteworthy that men also experience considerable traumatic stress during this challenging time.

Amniocentesis in pregnancies at or beyond 24 weeks: an international multicenter study.

BACKGROUND: Amniocentesis for genetic diagnosis is most commonly done between 15 and 22 weeks of gestation but can be performed at later gestational ages. The safety and genetic diagnostic accuracy of amniocentesis have been well-established through numerous large-scale multicenter studies for procedures before 24 weeks, but comprehensive data on late amniocentesis remain sparse. OBJECTIVE: To evaluate the indications, diagnostic yield, safety, and maternal and fetal outcomes associated with amniocentesis performed at or beyond 24 weeks of gestation. STUDY DESIGN: We conducted an international multicenter retrospective cohort study examining pregnant individuals who underwent amniocentesis for prenatal diagnostic testing at gestational ages between 24w0d and 36w6d. The study, spanning from 2011 to 2022, involved 9 referral centers. We included singleton or twin pregnancies with documented outcomes, excluding cases where other invasive procedures were performed during pregnancy or if amniocentesis was conducted for obstetric indications. We analyzed indications for late amniocentesis, types of genetic tests performed, their results, and the diagnostic yield, along with pregnancy outcomes and postprocedure complications. RESULTS: Of the 752 pregnant individuals included in our study, late amniocentesis was primarily performed for the prenatal diagnosis of structural anomalies (91.6%), followed by suspected fetal infection (2.3%) and high-risk findings from cell-free DNA screening (1.9%). The median gestational age at the time of the procedure was 28w5d, and 98.3% of pregnant individuals received results of genetic testing before birth or pregnancy termination. The diagnostic yield was 22.9%, and a diagnosis was made 2.4 times more often for fetuses with anomalies in multiple organ systems (36.4%) compared to those with anomalies in a single organ system (15.3%). Additionally, the diagnostic yield varied depending on the specific organ system involved, with the highest yield for musculoskeletal anomalies (36.7%) and hydrops fetalis (36.4%) when a single organ system or entity was affected. The most prevalent genetic diagnoses were aneuploidies (46.8%), followed by copy number variants (26.3%) and monogenic disorders (22.2%). The median gestational age at delivery was 38w3d, with an average of 59 days between the procedure and delivery date. The overall complication rate within 2 weeks postprocedure was 1.2%. We found no significant difference in the rate of preterm delivery between pregnant individuals undergoing amniocentesis between 24 and 28 weeks and those between 28 and 32 weeks, reinforcing the procedure's safety across these gestational periods. CONCLUSION: Late amniocentesis, at or after 24 weeks of gestation, especially for pregnancies complicated by multiple congenital anomalies, has a high diagnostic yield and a low complication rate, underscoring its clinical utility. It provides pregnant individuals and their providers with a comprehensive diagnostic evaluation and results before delivery, enabling informed counseling and optimized perinatal and neonatal care planning.

Incidental Finding of Ante-natal Fetal Neck Mass With Post-delivery Imaging and Follow-Up.

Most fetal anomalies can be detected during the second trimester of chromosomal anomaly screening. However, even an experienced sonographer might fail to notice a fetal neck mass during this screening and would be diagnosed at a later point in time. In this case report, we have followed up on an incidentally detected case of fetal neck mass on antenatal sonography with post-delivery ultrasound and contrast-enhanced computed tomography.

Magnetic resonance imaging in the second trimester as a complement to ultrasound for diagnosis of fetal anomalies.

Background: Fetal ultrasound has limitations, especially if the patient is obese or in cases with oligohydramnios. Magnetic resonance imaging (MRI) can then be used as a complement, but only few studies have focused on examinations in the second trimester. Purpose: To validate MRI as a complement to diagnose fetal anomalies in the second trimester. Material and Methods: This retrospective study retrieved data from January 2008 to July 2012 from the Fetal Medicine Unit and Department of Radiology at Uppsala University Hospital. Ultrasound and MRI findings were reviewed in 121 fetuses in relation to the final diagnosis, including postpartum follow-up and autopsy results. Results: Of the 121 fetuses, 51 (42%) had a CNS anomaly and 70 (58%) a non-CNS anomaly diagnosed or suspected. MRI provided additional information in 21% of all cases without changing the management and revealed information that changed the management of the pregnancy in 13%. When a CNS anomaly was detected or suspected, the MRI provided additional information in 22% and changed the management in 10%. The corresponding figures for non-CNS cases were 21% and 16%, respectively. The proportion of cases with additional information that changed the management was especially high in patients with a BMI >30 kg/m2 (25%) and in patients with oligohydramnios (38%). In five cases in category III, false-positive ultrasound findings were identified. Conclusions: MRI in the second trimester complements ultrasound and improves diagnosis of fetal CNS- and non-CNS anomalies especially when oligohydramnios or maternal obesity is present.

Medical Implications of Restricting Abortions on Women Diagnosed With Fetal Anomalies Following the Overturn of Roe v. Wade: A Scoping Review.

This scoping review addresses the potential maternal health outcomes of abortion restrictions in the U.S. by studying and analyzing the reported effects of abortion bans or limitations globally. The goal was to examine the medical implications for pregnant women who are unable to abort fetuses that have severe medical anomalies due to imposed restrictions. EMBASE, Medline, and CINAHL databases were searched for studies published in English concerning the medical implications of abortion restrictions in any country prior to the overturn of Roe v. Wade in 2022. For the search criteria using Boolean operators, keywords included the terms "fetal anomaly," "abortion ban," and "implications." Inclusion criteria incorporated studies published between 1980 and 2021, and controlled experimental research studies aimed to evaluate interventions were excluded. This resulted in 469 records initially found. Duplicate records were removed, and two separate tier reviews were conducted. Eleven reviewers independently screened abstracts and titles of 332 records to ascertain eligibility. Eligibility included pregnant women diagnosed with fetal anomalies, women denied access to safe abortions, and the maternal and fetal medical impacts of this. Three reviewers in the second screening independently read 36 full articles to further assess eligibility, resulting in 14 articles in the final review. Findings from this study showed that abortion bans in countries around the world have led to health complications in women seeking illegal abortion services, a decline in maternal mental health, including stress and depression, various medical complications such as obstructed labor, and an increase in high-risk fetuses born with severe deficits. The findings of this review portend similar negative consequences to be experienced by women who are subject to stricter abortion laws in the U.S.

Dolutegravir and Folic Acid Interaction during Neural System Development in Zebrafish Embryos.

Dolutegravir (DTG) is one of the most prescribed antiretroviral drugs for treating people with HIV infection, including women of child-bearing potential or pregnant. Nonetheless, neuropsychiatric symptoms are frequently reported. Early reports suggested that, probably in relation to folic acid (FA) shortage, DTG may induce neural tube defects in infants born to women taking the drug during pregnancy. Subsequent reports did not definitively confirm these findings. Recent studies in animal models have highlighted the association between DTG exposure in utero and congenital anomalies, and an increased risk of neurologic abnormalities in children exposed during in utero life has been reported. Underlying mechanisms for DTG-related neurologic symptoms and congenital anomalies are not fully understood. We aimed to deepen our knowledge on the neurodevelopmental effects of DTG exposure and further explore the protective role of FA by the use of zebrafish embryos. We treated embryos at 4 and up to 144 h post fertilization (hpf) with a subtherapeutic DTG concentration (1 µM) and observed the disruption of the anterior-posterior axis and several morphological malformations in the developing brain that were both prevented by pre-exposure (2 hpf) and rescued by post-exposure (10 hpf) with FA. By whole-mount in situ hybridization with riboprobes for genes that are crucial during the early phases of neurodevelopment (ntl, pax2a, ngn1, neurod1) and by in vivo visualization of the transgenic Tg(ngn1:EGFP) zebrafish line, we found that DTG induced severe neurodevelopmental defects over time in most regions of the nervous system (notochord, midbrain-hindbrain boundary, eye, forebrain, midbrain, hindbrain, spinal cord) that were mostly but not completely rescued by FA supplementation. Of note, we observed the disruption of ngn1 expression in the dopaminergic regions of the developing forebrain, spinal cord neurons and spinal motor neuron projections, with the depletion of the tyrosine hydroxylase (TH)+ dopaminergic neurons of the dorsal diencephalon and the strong reduction in larvae locomotion. Our study further supports previous evidence that DTG can interfere with FA pathways in the developing brain but also provides new insights regarding the mechanisms involved in the increased risk of DTG-associated fetal neurodevelopmental defects and adverse neurologic outcomes in in utero exposed children, suggesting the impairment of dopaminergic pathways.

European association of perinatal medicine (EAPM) position statement: Screening, diagnosis and management of congenital anomalies of the umbilical cord.

Congenital anomalies of the umbilical cord are associated with an increased risk of pregnancy and perinatal complications. Some anomalies of the cord have a higher prevalence than other fetal structural anomalies. The most common anomalies are the absence of an umbilical artery and velamentous insertion of the cord (with or without vasa previa). These anomalies, even when not associated with fetal structural defects, increase the risk of adverse perinatal outcome including, fetal growth restriction and stillbirth. In the absence of prenatal diagnosis, vasa previa is associated with the highest perinatal morbidity and mortality of all congenital anomalies of the umbilical cord. Most cases can be detected by ultrasound from the beginning of the second trimester and should be included in the routine mid-pregnancy ultrasound examination. Documentation should include cord insertion site, number of vessels in the cord, and if other pathologies have been detected. Pregnancies at increased risk of velamentous cord insertion should be screened for vasa previa using transvaginal ultrasound and colour Doppler imaging. If a velamentous cord insertion or isolated single umbilical artery is detected, individualised follow-up during pregnancy and tailored obstetric management are indicated.

Perinatal outcomes between immediate vs deferred selective termination in dichorionic twin pregnancies with fetal congenital anomalies: a French multicenter study.

BACKGROUND: Because selective termination for discordant dichorionic twin anomalies carries a risk of pregnancy loss, deferring the procedure until the third trimester can be considered in settings where it is legal. OBJECTIVE: To determine whether perinatal outcomes were more favorable following deferred rather than immediate selective termination. STUDY DESIGN: A French multicenter retrospective study from 2012 to 2023 on dichorionic twin pregnancies with selective termination for fetal conditions, which were diagnosed before 24 weeks gestation. Pregnancies with additional risk factors for late miscarriage were excluded. We defined 2 groups according to the intention to perform selective termination within 2 weeks after the diagnosis of the severe fetal anomaly was established (immediate selective termination) or to wait until the third trimester (deferred selective termination). The primary outcome was perinatal survival at 28 days of life. Secondary outcomes were pregnancy losses before 24 weeks gestation and preterm delivery. RESULTS: Of 390 pregnancies, 258 were in the immediate selective termination group and 132 in the deferred selective termination group. Baseline characteristics were similar in both groups. Overall survival of the healthy co-twin was 93.8% (242/258) in the immediate selective termination group vs 100% (132/132) in the deferred selective termination group (P<.01). Preterm birth <37 weeks gestation was lower in the immediate than in the deferred selective termination group (66.7% vs 20.2%; P<.01); preterm birth <28 weeks gestation and <32 weeks gestation did not differ significantly (respectively 1.7% vs 0.8%; P=.66 and 8.26% vs 11.4%; P=.36). In the deferred selective termination group, an emergency procedure was performed in 11.3% (15/132) because of threatened preterm labor, of which 3.7% (5/132) for imminent delivery. CONCLUSION: Overall survival after selective termination was high regardless of the gestational age at which the procedure was performed. Postponing selective termination until the third trimester seems to improve survival, whereas immediate selective termination reduces the risk of preterm delivery. Furthermore, deferred selective termination requires an expert center capable of performing the selective termination procedure on an emergency basis if required.

Prenatal Diagnosis by Trio Clinical Exome Sequencing: Single Center Experience.

Fetal anomalies, characterized by structural or functional abnormalities occurring during intrauterine life, pose a significant medical challenge, with a notable prevalence, affecting approximately 2-3% of live births and 20% of spontaneous miscarriages. This study aims to identify the genetic cause of ultrasound anomalies through clinical exome sequencing (CES) analysis. The focus is on utilizing CES analysis in a trio setting, involving the fetuses and both parents. To achieve this objective, prenatal trio clinical exome sequencing was conducted in 51 fetuseses exhibiting ultrasound anomalies with previously negative results from chromosomal microarray (CMA) analysis. The study revealed pathogenic variants in 24% of the analyzed cases (12 out of 51). It is worth noting that the findings include de novo variants in 50% of cases and the transmission of causative variants from asymptomatic parents in 50% of cases. Trio clinical exome sequencing stands out as a crucial tool in advancing prenatal diagnostics, surpassing the effectiveness of relying solely on chromosomal microarray analysis. This underscores its potential to become a routine diagnostic standard in prenatal care, particularly for cases involving ultrasound anomalies.

Clinical Practice Guidelines and Recommendations by the World Association of Perinatal Medicine and Perinatal Medicine Foundation: Reporting Suspected Findings from Fetal Central Nervous System Examination.

These guidelines follow the mission of the World Association of Perinatal Medicine, in collaboration with the Perinatal Medicine Foundation, which brings together groups and individuals worldwide, with the aim to improve prenatal detection of central nervous system anomalies and the appropriate referral of pregnancies with suspected fetal anomalies. In addition, this document provides further guidance for healthcare practitioners with the goal of standardizing the description of ultrasonographic abnormal findings.