Renal and extra-renal phenotypes in a fetus with a de novo pathogenic variant in the HNF1B gene.

We report a fetus with prenatal ultrasound at 21 gestational weeks showing left cystic renal dysplasia with subcapsular cysts and echogenic parenchyma, right echogenic kidney with absent corticomedullary differentiation, and left congenital diaphragmatic hernia (CDH) with bowel herniation, with intestinal atresia (IA) found on postmortem examination. Whole genome sequencing of fetal blood DNA revealed a heterozygous pathogenic variant c.344 + 2 T>G in the HNF1B gene (NM_000458). Sanger sequencing of the parental samples suggested that it arose de novo in the fetus. HNF1B-associated disorders affect multiple organs with significant phenotypic heterogeneity. In pediatric and adult patients, renal cystic disease and cystic dysplasia are the dominant phenotypes. In prenatal settings, renal anomaly is also the most common presentation, typically with bilateral hyperechogenic kidneys. Our case presented with two uncommon extra-renal phenotypes of CDH and IA besides the typical bilateral cystic renal dysplasia. This association has been reported in fetuses with 17q12 microdeletion but not with HNF1B point mutation. Our case is the first prenatal report of such an association and highlights the possible causal relationship of HNF1B defects with CDH and IA in addition to the typical renal anomalies.

Maternally inherited autosomal dominant PLAG-1 related Silver Russell syndrome in a fetus with intra-uterine growth restriction.

We report a case of maternally inherited autosomal dominant PLAG-1 related Silver Russell syndrome (SRS) in a fetus with IUGR and a mother who had growth and feeding problems in early life, dextrocardia and an atrio-ventricular septal defect. Amniocentesis was performed due to marked intra-uterine growth restriction (IUGR). The array was normal. Whole exome sequencing (WES) revealed a maternally inherited heterozygous likely pathogenic variant in PLAG1 (NM_002655.3): c.402delT p.(Gly135Aspfs*94). This variant has not been reported previously. PLAG1 pathogenic variants are associated with autosomal dominant Silver Russell syndrome, which fits with the clinical phenotypes of both fetus and mother. PLAG1 variants have previously been reported post-natally in Silver Russell syndrome, but the phenotype tends to be milder than in 11p15.5 methylation-related cases with fewer physical features. Although cardiac anomalies are uncommon in SRS, they have been previously reported. To our knowledge, dextrocardia has not been previously associated with SRS and there were no other potential causative genetic variants found. This report aims to highlight this rare type of SRS as a cause of IUGR.

Prenatal Diagnosis and Pregnancy Outcomes of Fetuses With Orofacial Cleft: A Retrospective Cohort Study in Two Centres in Hong Kong.

OBJECTIVE: To evaluate the local incidence of orofacial cleft (OFC) encountered in fetal morphology scan and prenatal diagnosis, genetic etiology of fetuses with or without other structural abnormalities, and their pregnancy outcomes. DESIGN: Retrospective cohort study. SETTING: Two maternal fetal medicine units, tertiary hospitals, Hong Kong. PARTICIPANTS: All pregnant women with antenatal diagnosis of fetal OFC between January 2016 and December 2020 (N = 66). RESULTS: OFC has an incidence of 0.13% among pregnancies in Hong Kong and 28.8% (19/66) were syndromic cleft that exhibited other fetal structural anomalies. There were 55 cases (84.6%) who opted for invasive prenatal diagnostic testing. Genetic defects were identified in 25.8% (17/66) of this cohort, including 14 pathogenic variants. The detection rate in the syndromic cases is 68.4% (13/19) which was significantly higher than 8.5% (4/47) among non-syndromic cases. Aneuploidies would be the most common cause, accounting for 9.1% (6/66). Chromosomal microarray analysis (CMA) provided an incremental diagnostic yield of 6.1% compared to conventional karyotyping. A total of 29 live births including 3 cases of a variant of uncertain significance and 26 cases without genetic abnormalities detected have continued pregnancy to birth. There were 87.5% (21/24) without detectable pathogenic genetic abnormality reported good long-term outcomes. The chance of OFC fetuses having a good long-term outcome was significantly higher if no genomic variant was detected (P < .001). CONCLUSIONS: Invasive prenatal tests with CMA should be offered to pregnancies with OFC regardless of the type. It has provided incremental diagnostic yield over conventional karyotyping and helped in prenatal and genetic counseling. A negative result in non-syndromic OFC favors couples to keep the pregnancy.

First Trimester Screening for Gestational Diabetes Mellitus with Maternal Factors and Biomarkers.

INTRODUCTION: This study aimed to identify risk factors among maternal characteristics, obstetric history, and first trimester preeclampsia-specific biomarkers that were associated with subsequent development of gestational diabetes mellitus (GDM) and evaluate the performance of the prediction models. METHODS: This study was a secondary analysis of a prospective cohort study. The performance of the prediction models was assessed by area under the receiver operating characteristic curve (AUROC). RESULTS: A total of 837 (8.9%) cases of GDM and 8,535 (91.1%) unaffected cases were included. The AUROC of the prediction model combining maternal characteristics and obstetric history (0.735) was better than that of the model utilizing maternal characteristics (AUROC 0.708) and preeclampsia-specific biomarkers (AUROC 0.566). Among the preeclampsia-specific biomarkers, the mean arterial pressure (MAP) contributed to the increasing risk of GDM; however, its addition did not improve the AUROC of the model combining maternal characteristics and obstetric history (0.738). CONCLUSION: The first trimester prediction model for GDM with maternal characteristics and obstetric history achieves moderate predictability. The inclusion of MAP in the model combining maternal characteristics and obstetric history does not improve the screening performance for GDM. Future studies are needed to explore the effect of blood pressure control from early pregnancy on preventing GDM.

The use of ultrasound, fibronectin and other parameters to predict the success of labour induction.

Induction of labour is a common obstetrical procedure and is undertaken when the benefits of delivery are considered to outweigh the risks of continuation of pregnancy. However, more than one-fifth of induction cases fail to result in vaginal births and lead to unplanned caesarean deliveries, which compromise the birth experience and have negative clinical and resource implications. The need for accurate prediction of successful labour induction is increasingly recognised and many researchers have attempted to evaluate the potential predictability of different factors including maternal characteristics, Bishop score, various biochemical markers and ultrasound markers and derive predictive models to address this issue.

Trio-Based Low-Pass Genome Sequencing Reveals Characteristics and Significance of Rare Copy Number Variants in Prenatal Diagnosis.

Background: Low-pass genome sequencing (GS) detects clinically significant copy number variants (CNVs) in prenatal diagnosis. However, detection at improved resolutions leads to an increase in the number of CNVs identified, increasing the difficulty of clinical interpretation and management. Methods: Trio-based low-pass GS was performed in 315 pregnancies undergoing invasive testing. Rare CNVs detected in the fetuses were investigated. The characteristics of rare CNVs were described and compared to curated CNVs in other studies. Results: A total of 603 rare CNVs, namely, 597 constitutional and 6 mosaic CNVs, were detected in 272 fetuses (272/315, 86.3%), providing 1.9 rare CNVs per fetus (603/315). Most CNVs were smaller than 1 Mb (562/603, 93.2%), while 1% (6/603) were mosaic. Forty-six de novo (7.6%, 46/603) CNVs were detected in 11.4% (36/315) of the cases. Eighty-four CNVs (74 fetuses, 23.5%) involved disease-causing genes of which the mode of inheritance was crucial for interpretation and assessment of recurrence risk. Overall, 31 pathogenic/likely pathogenic CNVs were detected, among which 25.8% (8/31) were small (<100 kb; n = 3) or mosaic CNVs (n = 5). Conclusion: We examined the landscape of rare CNVs with parental inheritance assignment and demonstrated that they occur frequently in prenatal diagnosis. This information has clinical implications regarding genetic counseling and consideration for trio-based CNV analysis.

The Use of Somatex Shunt for Fetal Pleural Effusion: A Cohort of 8 Procedures.

INTRODUCTION: Fetal pleural effusion may require in utero shunting which is associated with procedure-related complications. OBJECTIVE: To evaluate the efficacy and complications of the newly designed Somatex shunt in treating fetal pleural effusion. METHODS: Consecutive cases with primary fetal pleural effusion who were treated with the Somatex shunt between 2018 and 2019 were evaluated. Perinatal outcomes and complications were retrospectively analyzed. RESULTS: There were 6 cases of unilateral and 1 case of bilateral pleural effusion, and hence a total of 8 pleuroamniotic shunting procedures were performed. The median gestational age at diagnosis and shunting was 20.7 and 22.6 weeks, respectively. All 8 procedures were successful, achieving complete in utero drainage. All but one were live births (85.7%) with a median gestational age of 38 weeks. The single case of in utero death occurred 4.7 weeks after successful shunting, and no cause could be identified after autopsy. The rates of preterm birth and premature rupture of membranes were 33.3% (2/6) and 16.7% (1/6), respectively. Four of the 8 procedures (50%) had minor shunt-related complications such as dislodgement and entrapment, occurring at a median of 7.7 weeks after shunting. None of the shunts became blocked. CONCLUSIONS: The Somatex shunt is effective in relieving fetal pleural effusions with good survival rate. Overall, it was a safe instrument, though minor shunt complications occurred.

Feasibility, Reliability, and Agreement of Transperineal Ultrasound Measurement: Results from a Longitudinal Cohort Study.

OBJECTIVES: To evaluate the feasibility, reliability, and agreement of serial transperineal ultrasound (TPU) assessment of fetal head station (parasagittal angle of progression [psAOP], head-perineum distance [HPD], and head-symphysis distance [HSD]) and sonographic cervical dilatation (SCD), compared to fetal head station and cervical dilatation determined by vaginal examination, respectively. METHODS: This was a prospective longitudinal study in singleton pregnancies undergoing induction of labor at term. Paired assessment of fetal head station and cervical dilatation by vaginal examination, with TPU assessment of psAOP, HPD, HSD, and SCD was made serially. Feasibility, correlation, reliability, and agreement were determined. RESULTS: 1,139 paired measurements among 326 women were included. psAOP and HPD were achievable in all assessments. HSD was not achievable in 3.4% (11/326) due to high fetal head station. Fetal head station by vaginal examination was positively correlated with psAOP (rho = 0.70) but negatively correlated with HPD (rho = -0.57) and HSD (rho = -0.52). The feasibility to measure SCD reduced as cervical dilatation increased. Cervical dilatation and SCD were positively correlated (rho = 0.96) with strong agreement (concordant correlation coefficient = 0.925). CONCLUSIONS: Measurements of psAOP and HPD are feasible and correlate significantly with fetal head station by vaginal examination. Measurement of HSD is not feasible when fetal head station is high. Measurement of SCD is feasible, but it is more difficult in the advanced stage of labor. The correlation, reliability, and agreement between SCD and cervical dilatation by vaginal examination are high.

Perioperative prophylactic internal iliac artery balloon occlusion in the prevention of postpartum hemorrhage in placenta previa: a randomized controlled trial.

BACKGROUND: Placenta previa remains one of the major causes of massive postpartum hemorrhage and maternal mortality worldwide. OBJECTIVE: To determine whether internal iliac artery balloon occlusion during cesarean delivery for placenta previa could reduce postpartum hemorrhage and other maternal complications. STUDY DESIGN: This was a prospective randomized controlled trial conducted at a tertiary university obstetric unit in Hong Kong. Pregnant women who were diagnosed to have placenta previa at 34 weeks (defined as lower placenta edge within 2 cm from the internal os) and required cesarean delivery were invited to participate. Eligible pregnant women were randomized into internal iliac artery balloon occlusion (Occlusion) group or standard management (Control) group. Those randomized to the Occlusion group had internal iliac artery balloon catheter placement performed before cesarean delivery and then balloon inflation after delivery of the baby. The primary outcome was the reduction of postpartum hemorrhage in those with internal iliac artery balloon occlusion. Secondary outcome measures included hemoglobin drop after delivery; amount of blood product transfusion; incidence of hysterectomy; maternal complications including renal failure, ischemic liver, disseminated intravascular coagulation, and adult respiratory distress syndrome; length of stay in hospital; admission to intensive care unit; and maternal death. RESULTS: Between May 2016 and September 2018, 40 women were randomized (20 in each group). Demographic and obstetric characteristics were similar between the 2 groups. In the Occlusion group, 3 women did not receive the scheduled procedure, as it was preceded by antepartum hemorrhage that required emergency cesarean delivery, and 1 woman had repeated scan at 36 weeks showing the placental edge was slightly more than 2 cm from the internal os. Intention-to-treat analysis found no significant differences between the Occlusion and the Control groups regarding to the median intraoperative blood loss (1451 [1024-2388] mL vs 1454 [888-2300] mL; P = .945), the median length of surgery (49 [30-62] min vs 37 [30-51] min; P = .204), or the need for blood transfusion during operation (57.9% vs 50.0%; P = .621). None of the patients had rebleeding after operation, complication related to internal iliac artery procedure, or any other maternal complications. Reanalyzing the data using on-treatment approach showed the same results. CONCLUSION: The use of prophylactic internal iliac artery balloon occlusion in placenta previa patients undergoing cesarean delivery did not reduce postpartum hemorrhage or have any effect on maternal or neonatal morbidity.

Labor progress determined by ultrasound is different in women requiring cesarean delivery from those who experience a vaginal delivery following induction of labor.

BACKGROUND: The diagnosis of labor dystocia generally is determined by the deviation of labor progress, which is assessed by the use of a partogram. Recently, intrapartum transperineal ultrasound for the assessment of fetal head descent has been introduced to assess labor progress in the first stage of labor in a more objective and noninvasive way. OBJECTIVE: The objective of the study was to determine the differences in labor progress by the use of serial transperineal ultrasound assessment of fetal head descent between women having vaginal and cesarean delivery. STUDY DESIGN: This was a prospective longitudinal study performed in 315 women with singleton pregnancy who were undergoing labor induction at term between December 2016 and December 2017. Paired assessment of cervical dilation and fetal head station by vaginal examination and transperineal ultrasonographic assessment of parasagittal angle of progression and head-perineum distance were made serially after the commencement of labor induction. According to the hospital protocol, assessment was performed every 24 hours and 4 hours, respectively, during latent and active phases of labor. The researchers and the clinical team were blinded to each other's findings. The repeated measures data were analyzed by mixed effect models. To determine the effect of mode of delivery on the association between parasagittal angle of progression and head-perineum distance against fetal head station and cervical dilation, the significance of the interaction term between each mode of delivery and fetal head station or cervical dilation was determined, which accounted for parity and obesity. Area under receiver-operating characteristic curve was used to evaluate the performance of serial intrapartum sonography in predicting women with cesarean delivery because of failure to progress. RESULTS: The total number of paired vaginal examination and ultrasound assessments was 1198, with a median of 3 per woman. The median assessment-to-assessment interval was 4.6 hours (interquartile range, 4.3-5.1 hours). Women who achieved vaginal delivery (n=261) had steeper slopes of parasagittal angle of progression and head-perineum distance against fetal head station and cervical dilation than those who achieved cesarean delivery (n=54). Objectively, an additional decrease of 5.11 and 1.37 degrees in parasagittal angle of progression was observed for an unit increase in fetal head station and cervical dilation, respectively, in women who required cesarean delivery (P<.01; P=.01), compared with women who achieved vaginal delivery, after taking account of repeated measures from individuals and confounding factors. The respective additional increases in head-perineum distance for a unit increase in fetal head station and cervical dilation were 0.27 cm (P<.01) and 0.12 cm (P<.01). A combination of maternal characteristics with the temporal changes of parasagittal angle of progression for an unit increase in fetal head station achieved an area under receiver-operating characteristic curve of 0.85 (95% confidence interval, 0.76-0.94), with sensitivity of 79% and specificity of 80%, for the prediction of women who required cesarean delivery because of failure to progress. CONCLUSION: The differences in labor progress between vaginal and cesarean delivery have been illustrated objectively by serial intrapartum transperineal ultrasonographic assessment of fetal head descent. This tool is potentially predictive of women who will require cesarean delivery because of failure to progress.

Factors that affect ultrasound-determined labor progress in women undergoing induction of labor.

BACKGROUND: The traditional approach to the assessment of labor progress is by digital vaginal examination; however, it is subjective and imprecise. Recent studies have investigated the role of transperineal ultrasonographic assessment of fetal head descent by measuring the angle of progression and head-perineum distance. OBJECTIVE: The objective of this study was to evaluate factors that affected labor progress, which were defined by the transperineal ultrasonographic parameters, in women who achieved vaginal delivery. STUDY DESIGN: This was a prospective longitudinal study performed in 315 women with singleton pregnancy who underwent labor induction at term between December 2016 and December 2017. Paired assessment of cervical dilation and fetal head station by vaginal examination and transperineal ultrasonographic assessment of fetal head descent (parasagittal angle of progression and head-perineum distance) were made serially after the commencement of labor induction until full cervical dilation. The researchers were blinded to the findings of the clinical team's vaginal examination and vice versa. The repeated measure data were analyzed by mixed effect models to identify the significant factors (age ≥35 years, obesity, parity, methods of labor induction, and epidural anesthesia) that affected the relationship between parasagittal angle of progression and head-perineum distance against fetal head station and cervical dilation. RESULTS: The total number of paired vaginal examination and transperineal ultrasonographic assessments among the 261 women (82.9%) with vaginal delivery was 945, with a median of 3 per woman. The median assessment-to-assessment interval was 4.6 hours (interquartile range, 4.3-5.2). Multiparity and mechanical methods of labor induction were associated with a faster rate of fetal head descent, which was determined by head-perineum distance against fetal head station, than nulliparity and the use of a slow-release vaginal pessary, respectively. An additional increase of 0.10 cm in head-perineum distance was observed, for an unit increase in fetal head station in nulliparous women (P=.03) and women who had a slow-release vaginal pessary (P=.02), compared with multiparous women and those who had mechanical methods for labor induction. The use of epidural anesthesia was associated with a slower rate of fetal head descent, which was determined by both parasagittal angle of progression and head-perineum distance, against fetal head station. An additional decrease of 3.66 degrees in parasagittal angle of progression (P=.04) and an additional increase in 0.33 cm in head-perineum distance (P≤.001) were observed for a unit increase in fetal head station in women with the use of epidural anesthesia, compared with those without. Obese women had higher head-perineum distance overall, compared with normal weight women; at different cross-sections of time periods, obesity appeared to be associated with a slower rate of change between head-perineum distance and cervical dilation. Advanced maternal age did not affect transperineal ultrasound-determined labor progress (P>.05). CONCLUSION: Parity, methods of labor induction, the use of epidural anesthesia, and obesity affect labor progress, which has been illustrated objectively by serial transperineal ultrasonographic assessment of fetal head descent.

Measurement of retropubic tissue thickness using intrapartum transperineal ultrasound to assess cephalopelvic disproportion.

PURPOSE: First, to describe a new method of assessing cephalopelvic disproportion by measuring the retropubic tissue thickness (RTT), and second, to determine whether RTT was associated with an eventual delivery by cesarean section. METHODS: Three-dimensional transperineal ultrasound scans were performed on 129 laboring nulliparous women to obtain 3-dimensional volume datasets for assessing RTT. RTT was measured off-line by three operators (A, B, and C) as the shortest distance between the capsule of the pubic symphysis and the outer border of the fetal skull. The intraoperator repeatability of operator A and the interoperator reproducibility among A, B, and C were determined. The RTT in women who were delivered by cesarean section due to failure to progress was compared to that of women who had a vaginal delivery. RESULTS: The intraoperator repeatability for RTT was 1.2 mm. The overall RTT interoperator interclass correlation was 0.97 (0.95-0.98). The RTT in women who had a spontaneous, instrumental, or cesarean delivery was 1.16±0.32 cm, 1.12±0.25 cm, and 0.94±0.25 cm, respectively. Women who were delivered by cesarean section had a significantly smaller RTT than women who had a spontaneous delivery (P=0.008). There was no statistically significant difference in RTT between patients who had a normal vaginal delivery and patients who had an instrumental delivery (P=0.990), or between those who had an instrumental delivery and those who had a cesarean delivery after the Bonferroni correction (P=0.120). CONCLUSION: RTT can be measured with satisfactory intraoperator repeatability and interoperator reproducibility. RTT was significantly smaller in women who eventually had a cesarean delivery than in those who had a vaginal delivery.

Phonological awareness of Cantonese-speaking pre-school children with cochlear implants.

The study investigated the phonological awareness abilities of Cantonese-speaking pre-schoolers with cochlear implants. Participants were 15 Cantonese-speaking children with cochlear implants (CIs) aged 3.08-6.10, chronological-age-matched with 15 children with normal hearing. Each participant performed 10 tasks evaluating different levels of phonological awareness abilities and phonological knowledge. The results showed that pre-schoolers with cochlear implants and their normal hearing peers had similar levels of syllable awareness, phoneme awareness and rhyme awareness. However, cochlear implant users showed significantly poorer performance on tone awareness and phonological knowledge tasks than their normal hearing peers. Cantonese-speaking pre-schoolers with cochlear implants were able to develop phonological awareness. However, the cochlear implants might not provide enough tonal information for children with hearing impairment for tonal lexical comprehension. Incomplete speech and language stimulation may affect phonological knowledge development in Cantonese-speaking pre-schoolers with cochlear implants.