New Prospects for Prenatal Diagnosis and Fetal Therapy

Despite significant progress in trisomy 21 (T21) diagnostic tools, amniocentesis is still used for the confirmation of an abnormal fetal karyotype. Invasive tests carry the potential risk of miscarriage; thus, screening biomarkers are commonly used before undergoing invasive procedures. In our study, we investigated the possible application of oxidative stress markers in the prenatal screening of trisomy 21. The DNA/RNA oxidative stress damage products (OSDPs), advanced glycation end (AGE) products, ischemia-modified albumin (IMA), alfa-1-antitrypsin (A1AT), asprosin, and vitamin D concentrations were measured in both maternal plasma and amniotic fluid in trisomy 21 (T21) and euploid pregnancies. The obtained results indicated increased levels of DNA/RNA OSDPs and asprosin with simultaneous decreased levels of vitamin D and A1AT in the study group. The diagnostic utility of the plasma measurement based on the area under the received operative characteristic (ROC) curve (AUC) calculation of asprosin (AUC = 0.965), IMA (AUC = 0.880), AGE (AUC = 0.846) and DNA/RNA OSDPs (AUC = 0.506) in T21 screening was demonstrated. The obtained results indicate a potential role for the application of oxidative stress markers in the prenatal screening of T21 with the highest screening utility of plasma asprosin. Full article

Fetal fractional limb volume is a useful measure for predicting birth weight and newborn adiposity; however, a normal growth curve has been reported solely in the United States. As the birth weight of neonates in Japan is significantly lower than that in the US, fetal fractional limb volume is likely to be smaller in the Japanese population. This study aimed to define the normal growth curve of fractional arm volume (AVol) and thigh volume (TVol) in the Japanese population. Ultrasound scans of 453 AVol and TVol pairs were obtained; each AVol and TVol percentile at each gestational age was calculated. The measured AVol and TVol at each gestational week were also converted to z-scores based on a previous report. The growth curves increased linearly until the second trimester and exponentially in the third trimester. Linear regression showed a significant negative correlation between gestational age and AVol and TVol z-scores. The growth pattern of fetal fractional limb volume in the Japanese population is consistent with, but smaller than, that reported in the US; this difference becomes greater as the gestational age progresses. Full article

Prenatal screening for Down syndrome (DS) is based on both noninvasive and invasive methods. Noninvasive, cell-free fetal DNA genetic tests are expensive, whereas biochemical methods remain imprecise. Amniocentesis is the most frequently used invasive diagnosis procedure, characterized by 99.8% diagnostic efficiency and less than 1% risk of miscarriage. The aim of this study was to evaluate the screening value of apolipoprotein E (ApoE) as a potential noninvasive biomarker for prenatal DS assessment. This study was conducted on a group of female patients who decided to undergo routine amniocentesis between the 15th and 18th week of pregnancy at the Department of Reproduction and Gynecological Endocrinology of the Medical University of Bialystok, Poland. For the purpose of this study, 20 women with DS fetuses were selected as the study group, and 20 healthy pregnant women with euploid fetus karyotypes as the control group. The plasma levels of ApoE were significantly higher in the study group compared to healthy subjects (p < 0.05). The area under the receiver operating characteristic (ROC) curve was 0.978 (p < 0.001), with the cut-off set to 1.37 mg/mL, which was characterized by 80% of sensitivity and 100% of specificity. The high sensitivity and specificity demonstrate the screening utility of maternal ApoE concentration in prenatal fetal DS screening. Full article

Maternal and pediatric delivery outcomes may vary in patients who underwent open fetal myelomeningocele repair and elected to deliver at the fetal center where their fetal intervention was performed versus at the referring physician’s hospital. A prospective cohort study of 88 patients were evaluated following in utero open fetal myelomeningocele repair at a single fetal center between the years 2011–2019. Exclusion criteria included patients that delivered within two weeks of the procedure (n = 6), or if a patient was lost to follow-up (n = 1). Of 82 patients meeting inclusion criteria, 36 (44%) patients were delivered at the fetal center that performed fetal intervention, and 46 (56%) were delivered locally. Comparative statistics found that with the exception of parity, baseline characteristics and pre-operative variables did not differ between the groups. No differences in oligohydramnios incidence, preterm rupture of membranes, gestational age at delivery or delivery indications were found. Patients who delivered with a referring physician were more likely to be multiparous (p = 0.015). With the exception of a longer neonatal intensive care unit (NICU) stay in the fetal center group (median 30.0 vs. 11.0 days, p = 0.004), there were no differences in neonatal outcomes, including wound dehiscence, cerebrospinal fluid leakage, patch management, ventricular diversion, or prematurity complications. Therefore, we conclude that it is safe to allow patients to travel home for obstetric and neonatal management after open fetal myelomeningocele repair. Full article

Guidelines on the management of gestational diabetes (GDM) instruct physicians to involve ultrasound-based monitoring of fetal growth in addition to blood glucose. So far, glucose control besides clinical parameters like maternal body mass index (BMI) and gestational weight gain have been shown to predict neonatal outcome. We aimed to evaluate the discriminative ability of fetal abdominal subcutaneous tissue (FAST) in addition to standard ultrasound parameters like abdominal circumference (AC) and estimated fetal weight (EFW) for perinatal complications like large for gestational age (LGA), hypoglycemia, hyperbilirubinemia, mode of delivery and admission to neonatal intensive care unit (NICU). Ultrasound data and neonatal outcome was collected of 805 GDM cases from 2012 to 2016: 3205 FAST, 3195 AC-measurements and 3190 EFW calculations were included. AC, EFW and FAST increased linear with gestational age. Combining ultrasound and clinical parameters improved predictive power for LGA. In the subgroup where fetuses grow with an AC > 75th additional adding of FAST to standard ultrasound parameters increased predictive power for hypoglycemia. Our results confirm inclusion of ultrasound parameters to be beneficial in monitoring GDM pregnancies. Additional FAST determination revealed to be of potential clinical relevance in the subgroup AC > 75th percentile. Full article

Anogenital distance (AGD) is a biomarker for the prenatal hormonal environment. Androgen excess is a key element in polycystic ovary syndrome (PCOS). The aim of this study was to assess the sonographic foetal AGD in a population of PCOS mothers in comparison to the general population. Foetal AGD was measured prospectively by 2D ultrasound in PCOS mothers and compared to prenatal AGD nomograms. The results were interpreted regarding maternal and foetal characteristics. The mean sonographic foetal AGD centile measurement in PCOS mothers was significantly longer in comparison to the general population (86.04% ± 18.22; p < 0.001). Estimated foetal weight and birthweight were appropriate for gestational age and did not correlate with AGD. Sonographic foetal AGD was significantly longer in PCOS diabetic mothers and in those who conceived following assisted reproduction treatments when compared to the general population (p < 0.001). Our results support the role of AGD as a biomarker of the prenatal hormonal environment and provide evidence for the hyperandrogenic effect in PCOS pregnancies on foetal androgenic status and genitalia development. Full article

An aberrant right subclavian artery (ARSA) can be overlooked by the conventional method as described by Chaoui et al., due to acoustic shadowing. The aim of this study was to evaluate the feasibility and accuracy of a novel screening method for ARSA by demonstrating the brachiocephalic artery bifurcation, referred to as the “No ARSA” sign. A prospective study conducted at a tertiary care center between 2018 and 2019 included unselected pregnant patients at a median gestational age of 15.1 (14.2–22.1; IQR (inter-quartile range)) weeks, who had been referred for a routine or targeted anomaly scan. All participants were scanned for the presence or absence of ARSA using both the conventional and the novel “No ARSA” methods for validation purposes. A total of 226 unselected patients were enrolled in the study. The “No ARSA” sign was visualized in 218 fetuses (96.5%). In the remaining 8 cases (3.5%), the “No ARSA” sign was not demonstrated. In these fetuses, an ARSA was visualized by the conventional method. The new method exhibited 100% feasibility and was in complete agreement with the conventional method. Intra- and inter-observer agreement was excellent (κ = 1). The results of the study suggest that the “No ARSA” sign is an efficient and reliable screening tool for ARSA. Full article

Copy number variations of the 15q11.2 region at breakpoints 1-2 (BP1-BP2) have been associated with variable phenotypes and low penetrance. Detection of such variations in the prenatal setting can result in significant parental anxiety. The clinical significance of pre- and postnatally detected 15q11.2 BP1-BP2 deletions and duplications was assessed. Of 11,004 chromosomal microarray tests performed in a single referral lab (7596 prenatal, 3408 postnatal), deletions were detected in 66 cases: 39 in prenatal tests (0.51%) and 27 in postnatal tests (0.79%). Duplications were detected in 94 cases: 62 prenatal tests (0.82%) and 32 postnatal tests (0.94%). The prevalence of deletions and duplications among clinically indicated prenatal tests (0.57% and 0.9%, respectively) did not differ significantly in comparison to unindicated tests (0.49% and 0.78%, respectively). The prevalence of deletions and duplications among postnatal tests performed for clinical indications was similar to the prevalence in healthy individuals (0.73% and 1% vs. 0.98% and 0.74%, respectively). The calculated penetrance of deletions and duplications over the background risk was 2.18% and 1.16%, respectively. We conclude that the pathogenicity of 15q11.2 BP1-BP2 deletions and duplications is low. Opting out the report of these copy number variations to both clinicians and couples should be considered. Full article

Background: For acute adnexal torsion of pregnant women, appropriate treatment based on an accurate diagnosis is especially important for fertility preservation and timely treatment. The 2017 American College of Obstetricians and Gynecologists (ACOG) Committee Opinion No. 723 announced its practice-changing guidelines to ensure that diagnostic magnetic resonance imaging (MRI) conducted during the first trimester and gadolinium exposure at any time during pregnancy are safe for fetal stability. Unfortunately, few studies have been performed to evaluate the usefulness of the diagnostic accuracy of MRI for acute adnexal torsion during pregnancy. Objective: We sought to determine the efficacy of diagnostic MRI modality using multiparameter for maternal adnexal torsion during pregnancy. Methods: From 1 January 2007 to 31 January 2019, 131 pregnant with MRI tests were reviewed. In this retrospective cohort study, 94 women were excluded due to conditions other than an adnexal mass, and 37 were identified through MRI analyses conducted before surgery for suspected adnexal torsion. The primary outcome was the diagnostic accuracy of sonography and MRI, and the secondary outcome was the usefulness of Apparent diffusion coefficient (ADC) values for predicting the severity of hemorrhagic infarction between the medulla and cortex of the torsed ovarian parenchyma. Results: Our study demonstrates that in the diagnosis of adnexal torsion during pregnancy, the sensitivity, specificity, positive predictive value, and negative predictive value are 62.5%, 83.3%, 90.9%, and 45.5% for sonography and 100%, 77.8%, 90.5%, and 100% for MRI. MRI results in surgical-proven adnexal torsion patients revealed unilocular ovarian cysts (36.8% (7/19)), multilocular ovarian cysts (31.6% (6/19)), and near normal-appearing ovaries (31.6% (6/19)). Pathology in adnexal torsion revealed a corpus luteal ovarian cyst (63.2% (12/19)) and underlying adnexal pathology (46.8% (7/19)). Maternal adnexal torsion during pregnancy was more likely to occur in corpus luteal ovarian cysts than in underlying adnexal masses (odds ratio, 2.14; 95% confidence interval (CI), 0.428–10.738). MRI features for adnexal torsion were as follows: tubal wall thickness, 100% (19/19); ovarian stromal (medullary) edema, 100% (19/19); symmetrical or asymmetrical ovarian cystic wall, 100%(19/19); prominent follicles in the ovarian parenchyma periphery, 57.9% (11/19); periadenxal fat stranding, 84.2% (16/19); uterine deviation to the twisted side, 21.1% (4/19); and peritoneal fluid, 42.1% (8/19). The signal intensity of the ADC values of the ovarian medulla and cortex were compared between the cystectomy and detorsion (CD) and salpingo-oophorectomy (SO) groups. The ADC values of the CD and SO groups were 1.81 ± 0.09 × 10⁻³ mm²/s and 1.91 ± 0.18 × 10⁻³ mm²/s, respectively (P = 0.209), in the ovarian medulla and 1.37 ± 0.32 × 10⁻³ mm²/s and 0.96 ± 0.36 × 10⁻³ mm²/s, respectively (P = 0.022), in the ovarian cortex. The optimal cut-off value of ADC values for predictable total necrosis in the torsed ovarian cortex was ≤ 1.31 × 10⁻³ mm²/s (area under the curve (AUC) = 0.81; 95% CI 0.611–1.0; P = 0.028). Conclusion: Our data showed that maternal adnexal torsion during pregnancy occurred in most corpus luteal cystic ovary cases and some normal-appearing ovary during the 1st and 2nd trimesters of gestation. Therefore, this study is the first study to elaborate on the existence or usefulness of the diagnostic MRI for acute maternal adnexal torsion during pregnancy and to provide a predictive diagnosis of the severity of hemorrhagic infarction for deciding surgical radicality. Full article

The aim of this paper is to review the outcomes and discuss the genetic and non-genetic aetiology of nonimmune hydrops fetalis in order to support differential ultrasound and genetic evaluations and family counselling. This single-centre study includes all cases of nonimmune hydrops fetalis diagnosed prenatally from 2009 to 2019. Two sources of data were used for this study (prenatal and neonatal) to compare and summarise the findings. Data from genetic testing and ultrasound scans were collected. In total, 33 pregnant women with prenatally diagnosed nonimmune hydrops fetalis were studied. The data included 30 cases of singleton (91%) and three cases (9%) of twin pregnancies. There were 14 survivors (43%), seven cases of postnatal deaths (21%), four cases of intrauterine foetal demises (12%), four cases of termination of pregnancy (12%), and four women without a follow up (12%). The total number of chromosomally normal singleton pregnancies was 29 (88%), and 14 foetuses had an anatomical abnormality detected on the ultrasound scan. The chance of survival was the highest in cases of isolated, idiopathic hydrops fetalis, which in most cases was due to an undetectable intrauterine infection. In many cases, the diagnosis could not be established throughout pregnancy. Each case of nonimmune hydrops fetalis should thus be analysed individually. Full article