Cell-free DNA test for fetal chromosomal abnormalities in multiple pregnancies.

INTRODUCTION: This study aimed to report the screening performance of cell-free DNA (cfDNA) testing for chromosomal abnormalities in twins, triplets, and vanishing twin pregnancies. MATERIAL AND METHODS: Data were obtained from pregnant women with a multiple pregnancy or a vanishing twin pregnancy at ≥10 weeks' gestation who requested self-financed cfDNA testing between May 2015 and December 2021. Those that had positive screening results had diagnostic confirmatory procedures after counseling and consent. The performance of screening of the cfDNA test was determined by calculating confirmation rate and combined false-positive rate (cFPR). RESULTS: Data from 292 women were included after exclusion of those lost to follow-up, with no-result on cfDNA testing, or had reductions. Of the 292 pregnancies, 10 (3.4%) were triplets, including no cases of trisomy 21 and trisomy 18; 249 (85.3%) were twins, including 3 cases of trisomy 21 and no cases of trisomy 18 and 13; and 33 (11.3%) were vanishing twins, including 3 cases of trisomy 21 and 1 case of trisomy 18. The median (IQR) maternal age was 34 years (31-37). For triplet pregnancies, the initial no-result rate was 10.3% (95% confidence interval [CI] 3.6-26.4), all with results after redraw. For twin pregnancies, the initial no-result rate was 12.9% (95% CI 9.6-17.0), and the no-result rate after redraw was 1.6% (95% CI 0.7-3.6). For vanishing twins, there were no cases with no-result. All triplets had low-risk cfDNA results. The confirmation rate for trisomy 21 was 100% with a FPR at 0% due to the small number of positive cases for twins. For vanishing twins, one high-risk case for trisomy 21 and the only high-risk case for trisomy 18 were confirmed with a cFPR of 8.3% (n = 2/24; 95% CI 2.3-25.9). CONCLUSIONS: cfDNA testing in twin pregnancies has sufficient screening performance for trisomy 21 but the number of affected cases for other conditions is limited to draw any meaningful conclusion. The use of cfDNA testing in triplet pregnancies and vanishing twins remains an area for further research.

Evaluation of first trimester maternal serum inhibin-A for preeclampsia screening.

BACKGROUND: International professional organizations recommend aspirin prophylaxis to women screened high risk for preterm preeclampsia (PE) in the first trimester. The UK Fetal Medicine Foundation (FMF) screening test for preterm PE using mean arterial pressure (MAP), uterine artery pulsatility index (UTPI) and placental growth factor (PlGF) was demonstrated to have lower detection rate (DR) in Asian population studies. Additional biomarkers are therefore needed in Asian women to improve screening DRs as a significant proportion of women with preterm and term PE are currently not identified. OBJECTIVES: To evaluate maternal serum inhibin-A at 11-13 weeks as an alternative to PlGF or as an additional biomarker within the FMF screening test for preterm PE. STUDY DESIGN: This is a nested case-control study using pregnancies initially screened at 11-13 weeks for preterm PE using the FMF triple test in a non-intervention study conducted between December 2016 and June 2018. Inhibin-A levels were retrospectively measured in 1,792 singleton pregnancies, 112 (1.7%) with PE matched for time of initial screening with 1,680 unaffected pregnancies. Inhibin-A levels were transformed to multiple of the expected median (MoM). The distribution of log10 inhibin-A MoM in PE and unaffected pregnancies and the association between log10 inhibin-A MoM and gestational age (GA) at delivery in PE were assessed. The screening performance determined by area under receiver operating characteristic curves (AUC) and detection rates (DRs) at a 10% fixed false positive rate (FPR), for preterm and term PE was determined. All risks for preterm and term PE were based on the FMF competing risk model and Bayes theorem. Differences in AUC (ΔAUC) between different biomarker combinations were compared using the Delong test. McNemar's test was used to assess the off-diagonal change in screening performance at a fixed 10% FPR after adding inhibin-A or replacing PlGF in the preterm PE adjusted risk estimation model. RESULTS: Inhibin-A levels in unaffected pregnancies were significantly dependent on GA, maternal age and weight and were lower in parous women with no previous history of PE. Mean log10 inhibin-A MoM in any-onset PE (p<0.001), preterm (p<0.001) and term PE (p = 0.015) pregnancies were all significantly higher than that of unaffected pregnancies. Log10 inhibin-A MoM was inversely but not significantly correlated (p = 0.165) with GA at delivery in PE pregnancies. Replacing PlGF with inhibin-A in the FMF triple test reduced AUC and DR from 0.859 and 64.86% to 0.837 and 54.05%, the ΔAUC was not statistically significant. AUC and DR when adding inhibin-A to the FMF triple test were 0.814, 54.05% and the -0.045 reduction in AUC was statistically significant (p = 0.001). At a fixed 10% FPR, replacing PlGF with inhibin-A identified 1 (2.7%) additional pregnancy but missed 5 (13.5%) pregnancies which subsequently developed preterm PE identified by the FMF triple test. Adding inhibin-A missed 4 (10.8%) pregnancies and did not identify any additional pregnancies with preterm PE. CONCLUSION: Replacing PlGF by inhibin-A or adding inhibin-A as an additional biomarker in and to the FMF triple screening test for preterm PE does not improve screening performance and will fail to identify pregnancies that are currently identified by the FMF triple test.

Genome-Wide Cell-Free DNA Test for Fetal Chromosomal Abnormalities and Variants: Unrestricted Versus Restricted Reporting.

This study aimed to compare the screening performance of genome-wide cfDNA testing for chromosomal abnormalities between two periods where additional findings were reported and not reported. Data were obtained from consecutive pregnant women with a singleton pregnancy at ≥10 weeks who requested cfDNA testing during 2015-2019. The performance of screening of the cfDNA test was determined by calculating the concordance rate, detection rate, and false-positive rate. Data from 3981 women were included. The no-result rates were similar between the two reporting periods (2.04% vs. 2.08%). Concordance rates for trisomy 21 and 18 were 100% and 100%, respectively. There were two cases tested high risk for trisomy 13, with a concordance rate of 0%. In total, 12 cases were high risk for any sex chromosome aneuploidy with an overall concordance of 75%, and 15 cases tested high risk for any rare autosomal trisomy, with a 13.3% concordance rate. The detection rates for trisomy 21 and 18 were 100% and 100%, respectively. For any SCA, the detection rate was 90%. For the two reporting periods, the combined false-positive rates were 0.93% and 0.17%, which were significantly different (p = 0.002). Restricting the reporting of additional findings from genome-wide cfDNA analysis has reduced the false-positive rate but without a reduction in the no-result rate.

Prelabor short-term variability in fetal heart rate by computerized cardiotocogram and maternal fetal doppler indices for the prediction of labor outcomes.

OBJECTIVES: To investigate (i) the association between pre-labor maternal-fetal Dopplers and fetal heart rate short-term variability (FHR STV) with arterial cord blood pH and (ii) the potential value of pre-labor maternal-fetal Dopplers, FHR STV and Dawes-Redman criteria in predicting composite neonatal morbidity at term in a cohort of unselected women. METHOD: A prospective study in 218 women with term singleton pregnancy in latent phase of labor or due to undergo induction of labor. Data on maternal characteristics, maternal-fetal Dopplers indices and computerized cardiotocography (CTG) findings of FHR STV and Dawes-Redman criteria were collected. Pearson correlation analysis was used to determine the relationship between maternal-fetal Dopplers and FHR STV and arterial cord blood pH. Logistic regression analysis was used to determine which factors amongst maternal characteristics, labor onset, indication of labor induction, estimated fetal weight (EFW), maternal-fetal Dopplers, FHR STV and Dawes-Redman criteria were significant predictors of composite neonatal morbidity and arterial cord blood pH less than 7.2. RESULT: Of the 218 cases, 12 (5.5%) women were delivered by emergency operative delivery for pathological CTG, and 42 babies (19.3%) had composite neonatal morbidities. Arterial cord blood pH was not associated with maternal-fetal Doppler indices and FHR STV, but rather it was associated with maternal age and body mass index. The composite neonatal morbidity and arterial cord blood pH less than 7.2 were not significantly associated with maternal characteristics, labor onset, indication of labor induction, pre-labor assessment of EFW, maternal-fetal Doppler indices, FHR STV and Dawes-Redman criteria by computerized CTG. CONCLUSION: In unselected women in latent phase of labor or undergoing induction of labor at term, admission maternal-fetal Doppler indices, FHR STV and Dawes-Redman criteria are not predictive of composite neonatal morbidity.

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.

Hyperandrogenism, Elevated 17-Hydroxyprogesterone and Its Urinary Metabolites in a Young Woman with Ovarian Steroid Cell Tumor, Not Otherwise Specified: Case Report and Review of the Literature.

We describe a case of a 24-year-old overweight woman who presented with hirsutism, secondary amenorrhea, clitoromegaly, and symptoms of diabetes mellitus (DM). While a diagnosis of polycystic ovary syndrome (PCOS) with its associated metabolic disturbances was initially considered, serum total testosterone, androstenedione, and 17-hydroxyprogesterone (17-OHP) measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) were significantly increased. As 17-OHP did not increase upon ACTH (Synacthen) stimulation and the urinary steroid profile (USP) was compatible with an ovarian source of 17-OHP excess rather than adrenal, non classical congenital adrenal hyperplasia (NCCAH) was unlikely and an androgen-secreting tumor was suspected. Transabdominal ultrasound revealed the presence of an enlarged right ovary with a polycystic ovary morphology and no discrete mass. Transvaginal ultrasound and [18F]- fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) enabled the localization of a right ovarian tumor. Laparoscopic right salpingo-oophorectomy was performed and a histological diagnosis of steroid cell tumor, not otherwise specified (SCT-NOS) was made. Hyperandrogenism and menstrual disturbances resolved postoperatively. A literature review revealed that 17-OHP-secreting SCT-NOS may uncommonly show positive responses to ACTH stimulation similar to 21-hydroxylase deficiency. Alternatively, USP might be useful in localizing the source of 17-OHP to the ovaries. Its diagnostic performance should be evaluated in further studies.

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.

Pre-Induction Transperineal Ultrasound Assessment for the Prediction of Labor Outcome.

OBJECTIVE: To examine (1) the concordance of manual and automated para-symphyseal angle of progression (psAOP) measurements, (2) the repeatability of psAOP, head-symphysis distance, head-perineum distance, and sonographic cervical dilatation, and (3) the value of transperineal ultrasound (TPU) in predicting induction of labor (IOL) outcome. METHODS: We performed a prospective study in 308 women with singleton pregnancies undergoing IOL at term. Logistic regression analysis was used to determine which maternal factors, Bishop score, method of IOL, and TPU parameters were significant predictors of cesarean section (CS) and CS due to no progress (CS-NP). RESULTS: There was vaginal delivery in 225 (83.0%) and CS in 46 (17.0%) cases. The intra-class correlation coefficient between manual and automated psAOP was 0.866, but automated psAOP was 4.6° wider than manual measurement. All TPU parameters had an inter-observer intra-class correlation coefficient > 0.800. Significant independent prediction of CS and CS-NP was provided by maternal factors, previous vaginal delivery, and psAOP. There was no improvement in area under the receiver-operating characteristic curve with the addition of psAOP to maternal factors. CONCLUSIONS: All TPU parameters are reproducible. Comparing the three TPU parameters for fetal head station, only psAOP is a significant independent predictor of CS; however, it is unlikely to be useful in predicting IOL outcome.