Expanded conventional first trimester screening.

OBJECTIVE: The study aims to determine the performance of a five (5) serum marker plus ultrasound screening protocol for T21, T18 and T13. METHOD: Specimens from 331 unaffected, 34 T21, 19 T18 and 8 T13 cases were analyzed for free Beta human chorionic gonadotropin, pregnancy-associated plasma protein A, alpha-fetoprotein, placental growth factor and dimeric inhibin A. Gaussian distributions of multiples of the median values were used to estimate modeled false positive and detection rates (DR). RESULTS: For T21, at a 1/300 risk cut-off, DR of screening with all five serum markers along with nuchal translucency and nasal bone was 98% at a 1.2% false positive rate (FPR). Using a 1/1000 cut-off, the DR was 99% with a 2.6% FPR. For T18/13 with free Beta human chorionic gonadotropin, pregnancy-associated plasma protein A, placental growth factor and nuchal translucency at a 1/150 cut-off, DR was 95% at a 0.5% FPR while at a 1/500 risk cut-off, DR was 97% at a 1.2% FPR. CONCLUSION: An expanded conventional screening test can achieve very high DRs with low FPRs. Such screening fits well with proposed contingency protocols utilizing cell-free DNA as a secondary or reflex but also provides the advantages of identification of pregnancies at risk for other adverse outcomes such as early-onset preeclampsia. © 2017 Eurofins NTD, LLC. Prenatal Diagnosis published by John Wiley & Sons, Ltd.

Extrapolation of maternal weight in sequential aneuploidy screening.

OBJECTIVE: The aim of this study was to determine the impact on the risk calculation of various ways of handling maternal weight when these data are provided in the first part but not the second part of a sequential screening protocol. METHOD: A retrospective analysis of 38,986 sequential screens was carried out in which weight was provided in both the first and second trimesters. Three potential strategies for calculating multiples of the median values when the weight is not recorded at the time of second trimester risk evaluation were evaluated. First, perform no weight adjustment. Second, use the first trimester weight. Third, use the predicted second trimester weight on the basis of the first trimester weight. To predict the second trimester weight, we used a random-effects, multi-level model. RESULTS: The screen positive rate for Down syndrome was 3.0% (1151/38,986) and trisomy 18 alone 0.12% (47/38,986). The three strategies resulted in 196 (0.50%), 41 (0.11%), and 23 (0.06%) patients switching risk categories with the no adjustment, first trimester weight, and predicted weight strategies, respectively. CONCLUSION: Utilizing the first trimester weight or the predicted second trimester weight in sequential screening when second trimester weight is not provided offers an affordable alternative for laboratories to provide robust risk calculations and interpretations without requiring excessive use of resources.

Quality of nuchal translucency measurements correlates with broader aspects of program rigor and culture of excellence.

INTRODUCTION: To determine if nuchal translucency (NT) quality correlates with the extent to which clinics vary in rigor and quality control. METHODS: We correlated NT performance quality (bias and precision) of 246,000 patients with two alternative measures of clinic culture - % of cases for whom nasal bone (NB) measurements were performed and % of requisitions correctly filled for race-ethnicity and weight. RESULTS: When requisition errors occurred in <5% of cases, the average MoM (multiple of the median) was 0.97. When >5% (33%), the curve lowered to 0.93 MoM (p < 0.001) with both bias and precision of measurements impaired. Likewise, for centers with NB >90%, MoM was 0.99 compared to those <10% at 0.93 (p < 0.001). Precision and bias were highly correlated (p < 0.001). CONCLUSIONS: Rigor in NT measurements has improved, but the discussion has been confined to individuals. Progressive educational and remediation strategies need to expand to a second dimension - clinics themselves. Cross-clinic variation in NT quality exists independent of individual variation in NT quality, and two divergent indices of program rigor are associated with NT quality. Quality control must be program wide, and to effect continued improvement in the quality of NT results across time, the cultures of clinics must become a target for intervention.

Comparison of two management options for labor induction following unsuccessful prostaglandin E2 ripening.

OBJECTIVE: We sought to compare the likelihood of a vaginal delivery (VD) using oxytocin, with and without a cervical ripening balloon, in nulliparous women who did not respond to initial ripening with prostaglandin E2 (PGE2). METHODS: We a performed a retrospective cohort study of nulliparous women with a singleton pregnancy at term who underwent cervical ripening with vaginal PGE2 between October 2015 and March 2019. Patients who did not respond to PGE2 ripening (bishop score (BS) of 6 or less with cervical dilation less than 3 cm) were stratified into two groups based on management: sequential ripening with a cervical ripening balloon in addition to oxytocin versus oxytocin alone. Patients who had PGE2 for less than 6 h, a BS greater than 6 after ripening, rupture of membranes or missing data were excluded. The primary outcome was VD. Secondary outcomes included VD within 24 h of induction, time from induction to delivery, rates of chorioamnionitis and postpartum hemorrhage, presence of meconium, neonatal birthweight, NICU admission, 5 min apgar < 5, and umbilical cord pH < 7. Statistical analysis included Chi-squared, Fisher's exact and Mann-Whitney U tests, as well as logistic regression. Odds ratios (ORs) were calculated and adjusted for significant confounders using backwards-stepwise logistic regression. For time to delivery, a Cox proportional hazard regression was used to determine the hazard ratio (HR) and adjusted HR. RESULTS: 840 patients underwent cervical ripening with PGE2 during the study period. After the exclusion criteria were applied, 272 cases comprised the study cohort. Of those, 123 (45%) continued labor induction with a cervical ripening balloon and oxytocin and 149 (55%) continued labor induction with oxytocin alone. Baseline characteristics such as age, BMI, ethnicity, gestational age at induction and number of women undergoing elective induction were similar between both groups. There was no statistically significant difference in the likelihood of VD (oxytocin and cervical ripening balloon: 62.6% vs. oxytocin alone: 50.3%; a OR 1.61, p = .07) or rate of secondary outcomes between the two groups. Patients in the oxytocin alone group had a higher BS after PGE2 ripening, although both were very low (3 vs. 2, p < .0001).". Additionally, there were significantly more patients undergoing full PGE2 ripening for 12 h in the cervical ripening balloon and oxytocin group compared to oxytocin alone (65.9% vs. 49.7%, p = .02). CONCLUSION: Our data did not show a difference in VD rate in nulliparous women unresponsive to PGE2 ripening who underwent continued induction with oxytocin and cervical ripening balloon compared to oxytocin alone. Larger studies investigating the utility of sequential ripening and determining the optimal induction method following unsuccessful ripening are needed.

First-trimester screening in triplets.

OBJECTIVE: The purpose of this study was to determine the performance of Down syndrome screening in triplet pregnancy. STUDY DESIGN: Nuchal translucency (NT; n = 794), nasal bone (n = 219), and biochemistry (n = 198) were evaluated in triplet pregnancy. Screening performance was evaluated with the use of delta and Gaussian models. RESULTS: The median multiples of the median values for free beta human chorionic gonadotropin and pregnancy-associated plasma protein A were 2.86 and 3.48, respectively. A significant correlation in delta NT within pregnancy was observed (0.46-0.68). The modeled false-positive rates were 11.7%, 7.4%, and 8.9% with the delta model and 11.9%, 6.6%, and 12.0% with the Gaussian model for NT, NT + nasal bone, and NT + biochemistry. Based on simulation, the detection rate at 12 weeks' gestation was 78%, 93%, and 80% for NT, NT + nasal bone, and NT + biochemistry at a 10% false-positive rate using either the delta or Gaussian models. CONCLUSION: In triplet pregnancy, the addition of nasal bone lowers the false-positive rate of nuchal translucency screening. More data are required on the effectiveness of biochemistry.

Evaluation of Syndecan-1 as a Novel Biomarker for Adverse Pregnancy Outcomes.

To determine if circulating levels of maternal syndecan-1, a part of the endothelial glycocalyx, change over gestational weeks 11-13 and if first trimester serum syndecan-1 levels are aberrant in women with adverse pregnancy outcomes vs. controls. Dried blood samples from 300 randomly selected women (100 each from gestational weeks 11, 12, and 13) who delivered at Northwell Health were assessed for syndecan-1 levels. Subjects were segregated by gestational age and maternal weight at the time of blood draw. Gestational age-specific medians were determined by linear regression of median syndecan-1 values vs. gestational age. Multiples of the median (MoMs) = syndecan-1/respective gestational age-specific regressed median. After determining a normal range, we performed a case-control study. Cases (n = 119) were singleton pregnancies with preeclampsia or fetal growth restriction who delivered at 20-36 6/7 weeks with 1st trimester conventional aneuploidy screens; 2 controls (n = 238) per case were identified and assessed. Syndecan-1 levels were determined by ELISA. Data were reported as MoMs and analyzed based on Wilcoxon rank-sum test and Fisher's exact test. A progressive and significant increase in median circulating Sdc1 concentrations was observed from gestational weeks 11-13 (p < 0.001). There was no significant difference in median syndecan-1 MoM values among cases and controls (p = 0.22). However, a subgroup of cases (17.6%) had extreme syndecan-1 values (≤ 0.5MoM) vs. 6.7% of controls (p = 0.003, OR = 3.0). Serum syndecan-1 concentrations significantly increase during gestational weeks 11-13. Extremely low 1st trimester serum syndecan-1 values are associated with an increased risk of adverse pregnancy outcome.

Recurrence of extreme serum analytes in consecutive pregnancies and association with obstetrical outcomes.

OBJECTIVE: To evaluate if presence of extreme maternal serum biochemical analytes recurs in consecutive pregnancies. We hypothesized that presence of >1 extreme analyte in prior pregnancy is associated with increased risk of adverse pregnancy outcome in subsequent pregnancy. METHODS: Retrospective cohort study of singleton pregnancies evaluated and delivered in 2 consecutive pregnancies (2011-2015). Adverse outcomes were defined as indicated preterm delivery before 37 completed weeks due to preeclampsia, fetal growth restriction or other complications. RESULTS: First and second trimester maternal serum analytes were assessed in 1434 patients in 2 consecutive pregnancies. The presence of >1 extreme serum analyte in prior pregnancy significantly increased likelihood of >1 extreme analyte in subsequent pregnancy. The likelihood increased as number of prior extreme markers increased. In patients with normal outcomes and 2 or more extreme serum analytes in prior pregnancy, there was an increased incidence of adverse pregnancy outcomes in subsequent pregnancy with relative risk (RR) of 5.42 [95% CI 1.6-18.3]. CONCLUSIONS: The presence of more than 1 extreme serum marker in one pregnancy increases likelihood of recurrence in subsequent pregnancies. Risk of adverse outcomes in subsequent pregnancy can be evaluated based on biochemistry results as well as prior pregnancy outcomes.

Elevated maternal serum-free ß-human chorionic gonadotropin (ß-hCG) and reduced risk of spontaneous preterm delivery.

Objective: To evaluate the relationship between first and second trimester maternal serum-free ß-hCG and the risk of spontaneous preterm delivery (PTD). Study design: This was a case-control study of women evaluated and delivered at our institution from 2011 to 2015. Spontaneous PTD was defined as delivery before 37 weeks due to spontaneous preterm labor or premature rupture of membranes. Patient with multifetal gestation and those with medically indicated term or PTD were excluded. Results: Of 877 women meeting the inclusion criteria, 173 delivered preterm and 704 delivered at term, and 8.1% had high free ß-hCG in one or both trimesters. High maternal first and/or second trimester free ß-hCG (≥95th percentile) was associated with lower rates of PTD. Thirty-two women with high free ß-hCG in both first and second trimesters delivered at term. Gestational age at delivery and birth weights were lower in women who did not have high free ß-hCG in any trimester. Low free ß-hCG (≤5th percentile) in either trimester was not associated with an increased or decreased likelihood of PTD. Logistic regression demonstrated an independent association of high free ß-hCG (≥95th percentile) with a reduced likelihood of PTD. Stratified analysis revealed a stronger impact of this association in women with no prior history of PTD. Conclusions: High free ß-hCG, in the absence of risk factors for medically indicated PTD, is associated with a reduced likelihood of spontaneous PTD and may represent a marker indicating lower risk.

Meta-analysis of first trimester Down syndrome screening studies: free beta-human chorionic gonadotropin significantly outperforms intact human chorionic gonadotropin in a multimarker protocol.

OBJECTIVE: The purpose of this study was to compare free beta and intact human chorionic gonadotropin in first trimester screening with pregnancy-associated plasma protein-A and nuchal translucency. STUDY DESIGN: A Monte Carlo simulation trial was conducted based on a literature review of the PUBMED database (1966 to November 2005). RESULTS: In younger patients (< 35 years), detection of Down syndrome increased by 4, 5, 6, and 7 percentage points when free beta was added to pregnancy-associated plasma protein-A and nuchal translucency compared with 0, 0, 2, and 4 percentage points for intact human chorionic gonadotropin at 9-12 weeks' gestation, respectively. In advanced maternal age patients (> or = 35), inclusion of free beta-human chorionic gonadotropin reduced the false-positive rate by 2.5, 3.1, 3.8, and 4.4 percentage points compared with 0.1, 0.3, 1.0, and 2.2 percentage points for intact human chorionic gonadotropin at 9-12 weeks, respectively. CONCLUSION: The results of our analysis suggest that in a first-trimester Down syndrome screening protocol free beta-human chorionic gonadotropin achieves higher sensitivity and lower false-positive results than intact human chorionic gonadotropin . Moreover, intact human chorionic gonadotropin does not add substantially to screening performance until the end of the first trimester.

Screening for Open Neural Tube Defects.

Biochemical prenatal screening was initiated with the use of maternal serum alpha fetoprotein to screen for open neural tube defects. Screening now includes multiple marker and sequential screening protocols involving serum and ultrasound markers to screen for aneuploidy. Recently cell-free DNA screening for aneuploidy has been initiated, but does not screen for neural tube defects. Although ultrasound is highly effective in identifying neural tube defects in high-risk populations, in decentralized health systems maternal serum screening still plays a significant role. Abnormal maternal serum alpha fetoprotein alone or in combination with other markers may indicate adverse pregnancy outcome in the absence of open neural tube defects.

Impact of blood collection method on first-trimester dried blood free Beta hCG and PAPP-A.

Background Analysis of dried blood specimens has been an integral part of laboratory medicine dating back to the early 1960s when they were introduced as part of neonatal screening programs. More recently, they have been used in Down syndrome screening programmes. Dried blood spot specimens can be collected either by finger-stick or by traditional venipuncture and spotted onto filter paper. We sought to evaluate whether first-trimester free Beta hCG and PAPP-A multiples of the median (MoMs) were different in dried blood specimens collected via finger-stick compared to specimens collected via venipuncture. Methods A total of 2786 consecutive dried blood specimens were evaluated including 2144 collected using finger-stick and 644 specimens collected using venipuncture and spotted onto filter paper. Linear regression was used to assess the overall impact of collection method on dried blood free Beta hCG and PAPP-A and the impact of collection method on the trend of dried blood free Beta hCG and PAPP-A with transport time. Results For finger-stick and venipuncture, the median for free Beta hCG MoM was 0.99 and 1.04, respectively while the median PAPP-A MoM was 1.00 and 1.01, respectively. The regression formula for free Beta hCG was ln(MoM) = -0.00918 + 0.05112×Venipuncture + 0.00299×Days -0.00983×Days×Venipuncture and for PAPP-A the formula was ln(MoM) = -0.01000 + 0.04779×Venipuncture -0.00051×Days -0.02117×Days×Venipuncture. None of the coefficients were significant. Conclusions Collection method does not impact MoM values. Thus, centres have flexibility in the collection method utilized while being able to use a single reference database for all dried blood specimens.

Impact of blood collection method on first-trimester dried blood free Beta hCG and PAPP-A.

BACKGROUND: Analysis of dried blood specimens has been an integral part of laboratory medicine dating back to the early 1960s when they were introduced as part of neonatal screening programs. More recently, they have been used in Down syndrome screening programmes. Dried blood spot specimens can be collected either by finger-stick or by traditional venipuncture and spotted onto filter paper. We sought to evaluate whether first-trimester free Beta hCG and PAPP-A multiples of the median (MoMs) were different in dried blood specimens collected via finger-stick compared to specimens collected via venipuncture. METHODS: A total of 2786 consecutive dried blood specimens were evaluated including 2144 collected using finger-stick and 644 specimens collected using venipuncture and spotted onto filter paper. Linear regression was used to assess the overall impact of collection method on dried blood free Beta hCG and PAPP-A and the impact of collection method on the trend of dried blood free Beta hCG and PAPP-A with transport time. RESULTS: For finger-stick and venipuncture, the median for free Beta hCG MoM was 0.99 and 1.04, respectively while the median PAPP-A MoM was 1.00 and 1.01, respectively. The regression formula for free Beta hCG was ln(MoM) = -0.00918 + 0.05112×Venipuncture + 0.00299×Days -0.00983×Days×Venipuncture and for PAPP-A the formula was ln(MoM) = -0.01000 + 0.04779×Venipuncture -0.00051×Days -0.02117×Days×Venipuncture. None of the coefficients were significant. CONCLUSIONS: Collection method does not impact MoM values. Thus, centres have flexibility in the collection method utilized while being able to use a single reference database for all dried blood specimens.

Screening for open neural tube defects.

Maternal serum screening for congenital anomalies began over 30 years ago with the advent of alpha-fetoprotein (AFP) screening for open neural tube defects. It was from these screening programs that the more complex multiple marker Down syndrome screening programs developed. However, today open neural tube defect screening remains a relatively simple approach. In recent times, questions arise about the validity of the risk assessment associated with neural tube defect screening because of the impact of folate acid enrichment in diets and lack of outcome ascertainment. However, it still remains true that those with elevated AFP levels are at higher risk for having a pregnancy affected with open neural tube defect.

Undermeasurement of nuchal translucencies: implications for screening.

OBJECTIVE: To analyze the maximum nuchal translucency from 327 centers to determine whether a more-than-expected number of centers had maximum nuchal translucency of 2.5 mm or less (approximately 4% of nuchal translucency values should be 2.5 mm or higher). METHODS: We analyzed data from 182,669 nuchal translucency cases at centers in which at least 100 nuchal translucency examinations were performed from July 2008 through June 2009 and investigated the appropriateness of the distribution of values. We then investigated the likelihood of the skewing of the distribution seen using a 100 simulations of such modeled data. RESULTS: Based on a binomial distribution, the chance that a center would have no nuchal translucency values above 2.5 mm is 1.7% for 100 patients per center, and 0.2% for 150 patients per center. Additionally, the median multiples of the median should shift by approximately 2.5% if all nuchal translucency values higher than 2.5 mm are excluded from the population. Our data show that 7.3% of centers had a maximum nuchal translucency of to 2.5 mm or less, and more than 20% have never reported an nuchal translucency of greater than 3 mm. The maximum nuchal translucency at a center correlated positively with its median multiple of the median. Centers with no nuchal translucency values greater than 2.5 mm also have nearly 50% of their ultrasonographers with excessive low nuchal translucency (greater than 10% of cases less than fifth percentile). CONCLUSION: Too many centers have a maximum nuchal translucency of 2.5 mm or lower, low median nuchal translucency, and excessive low nuchal translucency, indicating that data from these centers are not representative of the expected distribution of nuchal translucencies. Our data suggest a systematic undermeasurement of nuchal translucency. LEVEL OF EVIDENCE: III.

Maternal weight and ethnic adjustment within a first-trimester Down syndrome and trisomy 18 screening program.

OBJECTIVE(S): To estimate weight and ethnic group correction factors for first-trimester screening markers. METHODS: Ethnic-specific median MoM free beta hCG and pregnancy associated plasma protein A (PAPP-A) and delta nuchal translucency values were calculated for cohorts of maternal weight (20 lb each) using data from 51,206 patients undergoing first-trimester screening. False-positive rates for Down syndrome and trisomy 18 were evaluated both prior to and after weight and ethnicity adjustment. RESULTS: Free beta hCG and PAPP-A significantly decreased with increasing maternal weight while nuchal translucency increased by a clinically insignificant amount. For free beta hCG the regression formula indicated that after accounting for maternal weight MoM values were 16% higher for African Americans, 6% higher for Asians and 9% lower for Hispanics compared to Caucasians (p < 0.001, p = 0.001, p < 0.001, respectively) but there was no significant difference for Asian Indians. For PAPP-A, MoM values were 35% higher for African Americans (p < 0.001) but were not significantly different for the other ethnic groups compared to Caucasians. Down syndrome false-positive rates did not vary with maternal weight prior to (p = 0.291) or after weight adjustment of biochemistry (p = 0.054). Trisomy 18 false-positive rates varied significantly with weight both before (OR = 1.455 per 20-pound increase, p < 0.001) and after (OR = 1.066 per 20-pound increase, p = 0.01) weight adjustment of biochemistry; however, the odds ratio was greatly reduced after weight adjustment. CONCLUSION(S): The first-trimester screening markers, free beta hCG, PAPP-A and nuchal translucency vary with maternal weight and ethnicity. Adjustment of free beta hCG and PAPP-A is indicated but adjustment of nuchal translucency results may not be necessary.