Clinical Utility of the Prenatal BACs-on-Beads™ Assay in Invasive Prenatal Diagnosis

Background: The prenatal BACs-on-Beads™ (PNBoBs™) assay has been applied worldwide for prenatal diagnosis. However, there are neither guidelines nor consensus on choosing patients, sample types, or clinical pathways for using this technique. Moreover, different perspectives have emerged regarding its clinical value. This study aimed to evaluate its clinical utility in the context of clinical practice located in a prenatal diagnostic center in Xiamen, a city in southeast China.Methods: We tested 2,368 prenatal samples with multiple referral indications using both conventional karyotyping and PNBoBs™. Positive results from PNBoBs™ were verified using current gold-standard approaches.Results: The overall rates for the detection of pathogenic copy number variation (pCNV) by karyotyping and PNBoBs™ were 1.9% (46/2,368) and 2.0% (48/2,368), respectively. The overall detection rate of karyotyping combined with PNBoBs™ for pCNV was 2.3% (54/2,368). A total of 13 cases of copy number variation (CNV)with a normal karyotype were detected by PNBoBs™. Another case with a normal karyotype that was detected as a CNV of sex chromosomes by PNBoBs™ was validated to be maternal cell contamination by short tandem repeat analysis.Conclusion: Karyotyping combined with PNBoBs™ can improve both the yield and efficiency of prenatal diagnosis and is appropriate in the second trimester in all patients without fetal ultrasound anomalies who undergo invasive prenatal diagnosis.

Fast and Accurate U-Net Model for Fetal Ultrasound Image Segmentation

U-Net based algorithms, due to their complex computations, include limitations when they are used in clinical devices. In this paper, we addressed this problem through a novel U-Net based architecture that called fast and accurate U-Net for medical image segmentation task. The proposed fast and accurate U-Net model contains four tuned 2D-convolutional, 2D-transposed convolutional, and batch normalization layers as its main layers. There are four blocks in the encoder-decoder path. The results of our proposed architecture were evaluated using a prepared dataset for head circumference and abdominal circumference segmentation tasks, and a public dataset (HC18-Grand challenge dataset) for fetal head circumference measurement. The proposed fast network significantly improved the processing time in comparison with U-Net, dilated U-Net, R2U-Net, attention U-Net, and MFP U-Net. It took 0.47 seconds for segmenting a fetal abdominal image. In addition, over the prepared dataset using the proposed accurate model, Dice and Jaccard coefficients were 97.62% and 95.43% for fetal head segmentation, 95.07%, and 91.99% for fetal abdominal segmentation. Moreover, we have obtained the Dice and Jaccard coefficients of 97.45% and 95.00% using the public HC18-Grand challenge dataset. Based on the obtained results, we have concluded that a fine-tuned and a simple well-structured model used in clinical devices can outperform complex models.

Prenatal Diagnosis by Array Comparative Genomic Hybridization in Fetuses with Cardiac Abnormalities

Congenital heart defects (CHDs) appear in 8–10 out of 1000 live born newborns and are one of the most common causes of deaths. In fetuses, the congenital heart defects are found even 3–5 times more often. Currently, microarray comparative genomic hybridization (array CGH) is recommended by worldwide scientific organizations as a first-line test in the prenatal diagnosis of fetuses with sonographic abnormalities, especially cardiac defects. We present the results of the application of array CGH in 484 cases with prenatally diagnosed congenital heart diseases by fetal ultrasound scanning (256 isolated CHD and 228 CHD coexisting with other malformations). We identified pathogenic aberrations and likely pathogenic genetic loci for CHD in 165 fetuses and 9 copy number variants (CNVs) of unknown clinical significance. Prenatal array-CGH is a useful method allowing the identification of all unbalanced aberrations (number and structure) with a much higher resolution than the currently applied traditional assessment techniques karyotype. Due to this ability, we identified the etiology of heart defects in 37% of cases.

Fetal growth velocity references from a Chinese population–based fetal growth study

Background Fetal growth velocity standards have yet to be established for the Chinese population. This study aimed to establish such standards suitable for the Chinese population. Methods We performed a multicenter, population–based longitudinal cohort study including 9075 low–risk singleton pregnant women. Data were collected from the clinical records of 24 hospitals in 18 provinces of China. Demographic characteristics, reproductive history, fetal ultrasound measurements, and perinatal outcome data were collected. The fetal ultrasound measurements included biparietal diameter (BPD), abdominal circumference (AC), head circumference (HC), and femur diaphysis length (FDL). We used linear mixed models with cubic splines to model the trajectory of four ultrasound parameters and estimate fetal weight. Fetal growth velocity was determined by calculating the first derivative of fetal size curves. We also used logistic regression to estimate the association between fetal growth velocities in the bottom 10th percentile and adverse perinatal outcomes. Results Fetal growth velocity was not consistent over time or among individuals. The estimated fetal weight (EFW) steadily increased beginning at 12 gestational weeks and peaked at 35 gestational weeks. The maximum velocity was 211.71 g/week, and there was a steady decrease in velocity from 35 to 40 gestational weeks. The four ultrasound measurements increased in the early second trimester; BPD and HC peaked at 13 gestational weeks, AC at 14 gestational weeks, and FDL at 15 gestational weeks. BPD and HC also increased from 19 to 24 and 19 to 21 gestational weeks, respectively. EFW velocity in the bottom 10th percentile indicated higher risks of neonatal complications (odds ratio [OR] = 2.23, 95% confidence interval [CI]: 1.79–2.78) and preterm birth < 37 weeks (OR = 3.68, 95% CI: 2.64–5.14). Sensitivity analyses showed that EFW velocity in the bottom 10th percentile was significantly associated with more adverse pregnancy outcomes for appropriate–for–gestational age neonates. Conclusions We established fetal growth velocity curves for the Chinese population based on real–world clinical data. Our findings demonstrated that Chinese fetal growth patterns are somewhat different from those of other populations. Fetal growth velocity could provide more information to understand the risk of adverse perinatal outcomes, especially for appropriate–for–gestational age neonates.

Clinical Validation of Fetal cfDNA Analysis Using Rolling-Circle-Replication and Imaging Technology in Osaka (CRITO Study)

Background: Noninvasive prenatal genetic testing (NIPT) has been adopted as the first choice for aneuploidy screening. The purposes of this study were to investigate the accuracy of Vanadis® NIPT (hereafter CRITO-NIPT) in order to gain a deeper insight into the reasons for discrepancies, as well as to discuss the role of fetal ultrasound. Methods: Between 2019 and 2020, CRITO-NIPT was performed in 1218 cases of patients who underwent CVS or amniocentesis after a detailed fetal ultrasound exam and genetic counseling. The CRITO-NIPT results were compared with the genetic results. In cases of test discrepancies, the placentae were collected for detailed genetic research, and the pre-procedure fetal ultrasound findings were referred to. Results: The positive predictive value of T21, T18, and T13 was 93.55%, 88.46%, and 100%, respectively. In 90% of the of false positive (FP) cases, the placentae were examined. In 75% of the CRITO FP-T21 cases, placental mosaicism, or a demised twin’s T21, were confirmed. There were complicated mosaic cases, including tetrasomy 21/trisomy7 and monosomy 21/trisomy21 cases. In one of three no-call cases, an intermediate deletion of chromosome 13 was detected. Conclusions: The CRITO study investigated the mechanism of false positives, and the detailed mechanisms in mosaic and no-call cases. There have hitherto been no reports that have provided insight by partitioning the placenta to compare the NIPT and invasive test results, nor that have provided detailed ultrasound findings in the cases of discordant results, revealing the demonstrated importance of, and necessity for, detailed ultrasonography. This article describes the potential of rolling-circle replication as a powerful biosensing platform, as well as the importance of examining the fetus in detail with ultrasound. However, we should remember that the potential applications raise ethical and social concerns that go beyond aneuploidy and its methodology.

Echogenic Intestine: a Case of Intrauterine Fetal Demise at Term

Introduction/Objective Parvovirus B19 is a non-enveloped, single-stranded DNA virus that preferentially infects early erythroids, and is commonly associated with second trimester hydrops fetalis. Third trimester non-hydropic intrauterine fetal demise due to parvovirus B19 infection with associated pathologic changes has rarely been described, particularly in the context of IgG seroconverted mother. Methods/Case Report We present a case of a 37 weeks’ gestation stillborn female fetus born to a 29 year-old mother who presented with lack of fetal movement for one day. Fetal ultrasound demonstrated diffuse intestinal echogenicity. Maternal parvovirus B19 IgG level was high (5.48, reference: &lt;=0.90 Index). Postmortem examination revealed a non-dysmorphic fetus. Gross examination was unremarkable. Microscopic examination of small intestine revealed mucosal inflammation and multifocal calcifications. Prominent extramedullary hematopoiesis was present in the liver. Viral cytopathic effect was noted microscopically within nucleated red blood cells present intravascularly within chorionic villi, small intestine, liver, and spleen. Parvovirus B19 infection was confirmed by immunohistochemistry. Results (if a Case Study enter NA) NA Conclusion The cause of clinically puzzling intrauterine fetal demise at term with prominent intestinal echogenicity on ultrasound was determined to be parvovirus B19 infection on postmortem examination. We emphasize the possibility of this diagnostic differential in non-hydropic, third trimester fetal demise in presence of maternal IgG seroconversion and lack of signs of active infection.

Placental Mesenchymal Dysplasia, An Exceedingly Rare Entity and Challenging Diagnosis

Introduction/Objective Placental mesenchymal dysplasia (PMD) is an extremely rare entity with an incidence of only 0.02/1000 deliveries. Methods/Case Report We present a case of a 26 year-old female Gravida 3, Para 1 with intrauterine pregnancy at 37 weeks of gestation. Fetal ultrasound showed mildly cystic upper portion of the placenta. The noninvasive prenatal testing was negative for triploidy. A viable healthy female infant was delivered with no maternal complications. On gross examination, placenta was heavy with approximately 25% incomplete cotyledons. Placental maternal surface showed, spongiform cut surfaces admixed with multiple cystic structures ranging in size from 0.5 to 1.5 cm and markedly dilated blood vessels. Histopathologic examination revealed markedly enlarged villi, mesenchymal hyperplasia, and hyper vascularity of small vessels. No trophoblast proliferation was identified. Subsequently, the diagnosis of PMD was made. Results (if a Case Study enter NA) NA Conclusion PMD is a rare anomaly which is characterized by placentomegaly and grape like vesicles resembling molar pregnancy. Etiologies include imbalance of paternal and maternal alleles, androgenetic and bi-parental mosaicism, and Beckwith Weidman Syndrome (BWS). Differential diagnosis includes partial molar pregnancy, complete mole with co-existing normal fetus, hemangioma, subchorionic hematoma, confined placental mosaicism and hydropic complications. Histologic features, ancillary studies including immunohistochemistry and genetic testing are helpful in differentiating PMD. PMD is an underdiagnosed entity with increased risk of premature delivery and intrauterine fetal death. It is pertinent for the clinicians to be aware of this entity for optimal patient management.