First-trimester screening for early and late preeclampsia using maternal characteristics, biomarkers, and estimated placental volume.

BACKGROUND: Preeclampsia is a major cause of perinatal morbidity and mortality. First-trimester screening has been shown to be effective in selecting patients at an increased risk for preeclampsia in some studies. OBJECTIVE: We sought to evaluate the feasibility of screening for preeclampsia in the first trimester based on maternal characteristics, medical history, biomarkers, and placental volume. STUDY DESIGN: This is a prospective observational nonintervention cohort study in an unselected US population. Patients who presented for an ultrasound examination between 11-13+6 weeks' gestation were included. The following parameters were assessed and were used to calculate the risk of preeclampsia: maternal characteristics (demographic, anthropometric, and medical history), maternal biomarkers (mean arterial pressure, uterine artery pulsatility index, placental growth factor, pregnancy-associated plasma protein A, and maternal serum alpha-fetoprotein), and estimated placental volume. After delivery, medical records were searched for the diagnosis of preeclampsia. Detection rates for early-onset preeclampsia (<34 weeks' gestation) and later-onset preeclampsia (≥34 weeks' gestation) for 5% and 10% false-positive rates using various combinations of markers were calculated. RESULTS: We screened 1288 patients of whom 1068 (82.99%) were available for analysis. In all, 46 (4.3%) developed preeclampsia, with 13 (1.22%) having early-onset preeclampsia and 33 (3.09%) having late-onset preeclampsia. Using maternal characteristics, serum biomarkers, and uterine artery pulsatility index, the detection rate of early-onset preeclampsia for either 5% or 10% false-positive rate was 85%. With the same protocol, the detection rates for preeclampsia with delivery <37 weeks were 52% and 60% for 5% and 10% false-positive rates, respectively. Based on maternal characteristics, the detection rates for late-onset preeclampsia were 15% and 48% for 5% and 10%, while for preeclampsia at ≥37 weeks' gestation the detection rates were 24% and 43%, respectively. The detection rates for late-onset preeclampsia and preeclampsia with delivery at >37 weeks' gestation were not improved by the addition of biomarkers. CONCLUSION: Screening for preeclampsia at 11-13+6 weeks' gestation using maternal characteristics and biomarkers is associated with a high detection rate for a low false-positive rate. Screening for late-onset preeclampsia yields a much poorer performance. In this study the utility of estimated placental volume and mean arterial pressure was limited but larger studies are needed to ultimately determine the effectiveness of these markers.

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.

Incorporation of dried blood alpha fetoprotein into traditional first trimester Down syndrome screening service.

OBJECTIVE: The aim of this study was to determine whether incorporation of dried blood alpha fetoprotein (AFP) into first trimester screening using the biochemical markers free Beta human chorionic gonadotropin (hCG) and pregnancy-associated plasma protein A (PAPP-A) can improve screening performance. METHODS: A retrospective study of 34 Down syndrome and 1185 unaffected dried blood specimens. First trimester dried blood AFP was performed using in-house immunofluorometric time-resolved assay. False positive and detection rates were determined from modeling. RESULTS: The multiple of the median in Down syndrome cases was 0.73. At a fixed 5% false positive rate, incorporating AFP into a free Beta hCG, PAPP-A, and nuchal translucency protocol adds 2% detection resulting in detection rates of 92% to 94% depending on the gestational age of the blood draw. At a fixed 90% detection rate, AFP reduced the false positive rate by 1.0 to 1.6 percentage points depending on gestational age. Using a cutoff of 1/1000, the combination of free beta hCG, PAPP-A, AFP, and nuchal translucency achieved a detection rate of 96% with a false positive rate of 8.4% to 9.9%. Adding in nasal bone increased detection to 98% while reducing false positive rates to 4.1% to 4.7%. CONCLUSION: Inclusion of dried blood AFP into traditional first trimester screening improves detection while optimizing contingent protocols so that cell-free fetal DNA testing may be offered in a more cost effective manner.

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.

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.

First trimester Down syndrome screening with dried blood spots using a dual analyte free beta hCG and PAPP-A immunofluorometric assay.

OBJECTIVE: To determine the effectiveness of first trimester Down syndrome screening with dried blood spots using a dual analyte free beta human chorionic gonadotrophin (hCG)/pregnancy-associated plasma protein A (PAPP-A) immunofluorometric assay. METHOD: An initial retrospective study of 54 Down syndrome cases and 1064 control specimens was performed followed by a series of 146,513 specimens from routine screening. Detection rates at a fixed 5% false-positive rate were determined separately based on reference data from the retrospective study set and then adjusted based on the routine screening study set. RESULTS: On the basis of the retrospective analysis, the estimated detection rate using free beta hCG, PAPP-A and maternal age varied from 78% at 9 weeks of pregnancy to 70% at 13 weeks of pregnancy. Using a combined protocol, including NT, the detection rate varied from 92 to 90% between 9 and 13 weeks of gestation. Adjusting distribution parameters based on the routine screening dataset reduced the detection rate by at most 1%. CONCLUSION: Analysis of free beta hCG and PAPP-A using a dual analyte dried blood spot assay is an effective tool in Down syndrome screening, adding an important option for those considering implementation or modification of existing prenatal screening programs.

First-trimester screening with nasal bone in twins.

OBJECTIVE: The purpose of this study was to evaluate the Down syndrome detection rate at a 5% screen positive rate in first-trimester screening for twins. STUDY DESIGN: This was a retrospective study from August 2005 to July 2007 of twins who underwent first-trimester screening with nuchal translucency, nasal bone, pregnancy-associated plasma protein-A, and free beta-hCG. Risks were calculated on the basis of the Fetal Medicine Foundation twin algorithm. The model simulated distributions of unaffected and affected cases at 12 weeks of gestation. RESULTS: Two thousand ninety-four twin pregnancies (4188 fetuses) met the inclusion criteria. The addition of nasal bone to nuchal translucency, pregnancy-associated plasma protein-A, and free beta-hCG increased the Down syndrome detection rate from 79-89% at a 5% screen-positive rate. CONCLUSION: In twins, first-trimester screening with nasal bone is valuable. The improved Down syndrome detection rate can help these high-risk patients with the decision-making process of whether to pursue invasive testing with its associated pregnancy loss risk.

First-trimester screening for trisomies 21 and 18.

BACKGROUND: Screening for aneuploid pregnancies is routinely performed after 15 weeks of gestation and has a sensitivity of approximately 65 percent, with a false positive rate of 5 percent. First-trimester markers of aneuploidy have been developed, but their use in combination has not been adequately evaluated in clinical practice. METHODS: We conducted a multicenter study of screening for trisomies 21 and 18 among patients with pregnancies between 74 and 97 days of gestation, based on maternal age, maternal levels of free beta human chorionic gonadotropin and pregnancy-associated plasma protein A, and ultrasonographic measurement of fetal nuchal translucency. A screening result was considered to be positive for trisomy 21 if the calculated risk was at least 1 in 270 pregnancies and positive for trisomy 18 if the risk was at least 1 in 150. RESULTS: Screening was completed in 8514 patients with singleton pregnancies. This approach to screening identified 85.2 percent of the 61 cases of Down's syndrome (95 percent confidence interval, 73.8 to 93.0), with a false positive rate of 9.4 percent (95 percent confidence interval, 8.8 to 10.1). At a false positive rate of 5 percent, the detection rate was 78.7 percent (95 percent confidence interval, 66.3 to 88.1). Screening identified 90.9 percent of the 11 cases of trisomy 18 (95 percent confidence interval, 58.7 to 99.8), with a 2 percent false positive rate. Among women 35 years of age or older, screening identified 89.8 percent of fetuses with trisomy 21, with a false positive rate of 15.2 percent, and 100 percent of fetuses with trisomy 18. CONCLUSIONS: First-trimester screening for trisomies 21 and 18 on the basis of maternal age, maternal levels of free beta human chorionic gonadotropin and pregnancy-associated plasma protein A, and measurement of fetal nuchal translucency has good sensitivity at an acceptable false positive rate.

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.

Maternal Serum Screening Markers and Adverse Outcome: A New Perspective.

There have been a number of studies evaluating the association of aneuploidy serum markers with adverse pregnancy outcome. More recently, the development of potential treatments for these adverse outcomes as well as the introduction of cell-free fetal DNA (cffDNA) screening for aneuploidy necessitates a re-evaluation of the benefit of serum markers in the identification of adverse outcomes. Analysis of the literature indicates that the serum markers tend to perform better in identifying pregnancies at risk for the more severe but less frequent form of individual pregnancy complications rather than the more frequent but milder forms of the condition. As a result, studies which evaluate the association of biomarkers with a broad definition of a given condition may underestimate the ability of such markers to identify pregnancies that are destined to develop the more severe form of the condition. Consideration of general population screening using cffDNA solely must be weighed against the fact that traditional screening using serum markers enables detection of severe pregnancy complications, not detectable with cffDNA, of which many may be amenable to treatment options.

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.

First-trimester maternal dried blood Down syndrome screening marker levels in early pregnancy loss.

OBJECTIVE: To determine the association of free beta hCG and PAPP-A measured during first-trimester Down syndrome risk assessment with early pregnancy loss when blood is drawn prior to scheduled ultrasound. METHODS: Maternal dried blood samples were collected prior to the ultrasound exam for Down syndrome risk assessment. Free beta hCG and PAPP-A levels in 55 patients who experienced loss of pregnancy prior to their scheduled ultrasound appointment were compared to 6464 control pregnancies using logistic regression. RESULTS: Low levels of free beta hCG and PAPP-A were associated with increased risk of early pregnancy loss. The detection rate of early pregnancy loss for a fixed 5% false-positive rate using free beta alone, PAPP-A alone and a combination of the two were 47, 36 and 49%, respectively. CONCLUSION: Free beta hCG and PAPP-A can identify pregnancies at increased risk for early pregnancy loss. More studies are needed to determine whether further evaluation of these pregnancies prior to the scheduled ultrasound is warranted.

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.

First-trimester screening for trisomy-21 using a simplified method to assess the presence or absence of the fetal nasal bone.

OBJECTIVE: To determine the benefit of including nasal bone assessment in addition to standard first-trimester markers (nuchal translucency, free beta human chorionic gonadotropin and pregnancy-associated plasma protein A) as a screening test for Down syndrome, using a strict criterion for classification of nasal bone absence. STUDY DESIGN: Nasal bone assessment was conducted in 2411 patients with crown-rump length between 45 and 84 mm, including 15 patients with Down syndrome. A patient was considered to have an absent nasal bone only if there was no evidence of present nasal bone. Unlike other studies, nasal bone was classified as present when there was evidence of a thin echogenic line under the skin. Simulation studies were conducted to assess the detection rate and false-positive rate of a combined first-trimester screening protocol including nasal bone assessment. RESULTS: There were 9 of 2396 (0.4%) unaffected cases with absent nasal bone (95% confidence interval 0.2%, 0.7%) and 8 of 15 (53.3%) Down syndrome cases (95% confidence interval 26.6%, 78.7%). Using a 1 in 250 risk cut-off, the detection rate of standard first-trimester screening was 87%, with a false-positive rate of 4.3%. Incorporating nasal bone measurement improved the detection rate of Down syndrome to 90% and reduced the false-positive rate to 2.5%. CONCLUSION: The use of a strict criterion to determine nasal bone absence leads to fewer cases classified as absent and may simplify the implementation of nasal bone as a marker for first-trimester screening, resulting in lower false-positives and higher detection, compared with other current screening protocols.

First trimester screening with free beta-hCG, PAPP-A and nuchal translucency in pregnancies conceived with assisted reproduction.

OBJECTIVE: To evaluate the effect of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) on free beta-human chorionic gonadotrophin (beta-hCG), pregnancy-associated plasma protein A (PAPP-A) and nuchal translucency (NT). METHODS: First trimester maternal dried whole blood specimens from 74 singleton pregnancies (32 by IVF and 42 by ICSI) and 30 twin pregnancies (16 by IVF and 14 by ICSI) in which conception was achieved with assisted reproduction techniques were matched with five controls resulting in 370 singleton controls and 150 twin controls. NT was measured using the Fetal Medicine Foundation protocol. Free beta-hCG, PAPP-A and NT levels were compared between the IVF and control groups and between the ICSI and control groups using the Mann-Whitney U test. RESULTS: In singleton pregnancies, the only significant difference was a 21% (95% CI: -35%--7%) reduction in PAPP-A in IVF cases. In twin pregnancies, the only significant difference was a 12% (95% CI: -34%--3%) reduction in NT in IVF cases. In singleton pregnancies, the false-positive rate for Down syndrome screening was 1.4% and 1.9% greater for the IVF and ICSI groups, respectively, compared to controls for a general screening population. CONCLUSIONS: Patients undergoing assisted reproduction techniques should be counseled about the possibility of increased false-positive rates. Larger studies are needed to confirm this observation and to develop appropriate adjustment factors to reduce false-positive rates.

Combined first-trimester versus second-trimester serum screening for Down syndrome: a cost analysis.

OBJECTIVE: The purpose of this study was to compare the cost-effectiveness of combined first-trimester screening for fetal Down syndrome with second-trimester maternal serum triple screening. STUDY DESIGN: A first-trimester screening approach that used nuchal translucency measurement and maternal serum screening was evaluated against second-trimester maternal serum triple screening in a hypothetic population. Screening sensitivities and screen-positive rates were 91% and 5% for the first-trimester approach and 70% and 7.5% for the second-trimester approach, respectively. The costs of fetal Down syndrome, live-born Down syndrome cost, and total costs (screening plus live-born costs) were calculated for each screening program. RESULTS: First-trimester screening was associated with lower screening and live-born Down syndrome costs versus second-trimester serum screening. Total Down syndrome screening costs were 29.1% lower with first-trimester screening. CONCLUSION: In this hypothetic model, combined first-trimester screening for fetal Down syndrome was more cost-effective than universal second-trimester triple serum screening.