Prenatal screening for preeclampsia: the roles of placental growth factor and pregnancy-associated plasma protein A in the first trimester and placental growth factor and soluble fms-like tyrosine kinase 1-placental growth factor ratio in the early second trimester.

BACKGROUND: Professional societies have recommended universal first trimester screening for preeclampsia and a second or third trimester soluble fms-like tyrosine kinase-1-placental growth factor ratio test to assess for preeclampsia and its severity. However, it may not be feasible to implement the most optimal screening protocol for preeclampsia in the first trimester which uses a combination of maternal characteristics, maternal biophysical and biochemical markers due to limitations in the access to uterine artery doppler ultrasound. There are inconsistent findings on how early in the second trimester the fms-like tyrosine kinase-1-placental growth factor ratio begins to provide useful information in preeclampsia prediction. OBJECTIVE: This study aimed to assess the accuracy of (1) a combination of maternal characteristics, maternal serum pregnancy-associated plasma protein A, and placental growth factor in the screening for preeclampsia in the first trimester; and (2) placental growth factor or soluble fms-like tyrosine kinase-1-placental growth factor ratio in the prediction of preeclampsia in the early second trimester. STUDY DESIGN: This retrospective case-control study used frozen residual blood samples from women who had aneuploidy screening and delivered at a tertiary center. The case group included pregnancies with gestational hypertension or preeclampsia (further classified as early-onset [birth at <34 weeks' gestation] and preterm preeclampsia [birth at <37 weeks' gestation]). Each case was matched with 3 control pregnancies by date of blood sample draw, gestational age at first blood sample draw, maternal age, maternal ethnicity, type of multiple-marker screening, and amount of residual sample. Mann-Whitney U tests were used to assess the associations between serum markers and the risk of preeclampsia. Logistic regressions were used to assess if the risk of preeclampsia can be predicted using a combination of maternal characteristics and serum markers. RESULTS: The case group included 146 preeclampsia and 295 gestational hypertension cases. Compared with the controls, preeclampsia cases had significantly lower first-trimester pregnancy-associated plasma protein A and placental growth factor. At a 20% false-positive rate, 71% of early-onset and 58% of preterm preeclampsia cases can be predicted using maternal characteristics, pregnancy-associated plasma protein A, and placental growth factor. Preeclampsia cases had lower second-trimester placental growth factor and a higher soluble fms-like tyrosine kinase-1-placental growth factor ratio. At a 10% false-positive rate, 80% and 53% of early-onset preeclampsia can be predicted using maternal characteristics and placental growth factor or soluble fms-like tyrosine kinase-1-placental growth factor ratio, respectively. CONCLUSION: The current first-trimester aneuploidy screening programs may be expanded to identify women at increased risk of developing preeclampsia. Early in the second trimester, placental growth factor alone provided better prediction for preeclampsia compared with the soluble fms-like tyrosine kinase-1-placental growth factor ratio.

Modified multiple marker aneuploidy screening as a primary screening test for preeclampsia.

BACKGROUND: Abnormal levels of maternal biochemical markers used in multiple marker aneuploidy screening have been associated with adverse pregnancy outcomes. This study aims to assess if a combination of maternal characteristics and biochemical markers in the first and second trimesters can be used to screen for preeclampsia (PE). The secondary aim was to assess this combination in identifying pregnancies at risk for gestational hypertension and preterm birth. METHODS: This case-control study used information on maternal characteristics and residual blood samples from pregnant women who have undergone multiple marker aneuploidy screening. The median multiple of the median (MoM) of first and second trimester biochemical markers in cases (women with PE, gestational hypertension and preterm birth) and controls were compared. Biochemical markers included pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PlGF), human chorionic gonadotropin (hCG), alpha feto-protein (AFP), unconjugated estriol (uE3) and Inhibin A. Logistic regression analysis was used to estimate screening performance using different marker combinations. Screening performance was defined as detection rate (DR) and false positive rate (FPR). Preterm and early-onset preeclampsia PE were defined as women with PE who delivered at < 37 and < 34 weeks of gestation, respectively. RESULTS: There were 147 pregnancies with PE (81 term, 49 preterm and 17 early-onset), 295 with gestational hypertension, and 166 preterm birth. Compared to controls, PE cases had significantly lower median MoM of PAPP-A (0.77 vs 1.10, p < 0.0001), PlGF (0.76 vs 1.01, p < 0.0001) and free-ß hCG (0.81 vs. 0.98, p < 0.001) in the first trimester along with PAPP-A (0.82 vs 0.99, p < 0.01) and PlGF (0.75 vs 1.02, p < 0.0001) in the second trimester. The lowest first trimester PAPP-A, PlGF and free ß-hCG were seen in those with preterm and early-onset PE. At a 20% FPR, 67% of preterm and 76% of early-onset PE cases can be predicted using a combination of maternal characteristics with PAPP-A and PlGF in the first trimester. The corresponding DR was 58% for gestational hypertension and 36% for preterm birth cases. CONCLUSIONS: Maternal characteristics with first trimester PAPP-A and PlGF measured for aneuploidy screening provided reasonable accuracy in identifying women at risk of developing early onset PE, allowing triage of high-risk women for further investigation and risk-reducing therapy. This combination was less accurate in predicting women who have gestational hypertension or preterm birth.

Prenatal screening for trisomy 21: a comparative performance and cost analysis of different screening strategies.

BACKGROUND: Prenatal screening for chromosome aneuploidies have constantly been evolving, especially with the introduction of cell-free fetal DNA (cfDNA) screening in the most recent years. This study compares the performance, costs and timing of test results of three cfDNA screening implementation strategies: contingent, reflex and primary. METHODS: We modelled enhanced first trimester screening (eFTS) as the first-tier test in contingent or reflex strategies. cfDNA test was performed contingent on or reflex from eFTS results. A comparison was made between cfDNA screening using sequencing technology and Rolling Circle Amplification (RCA)/imaging solution. All model assumptions were based on results from previous publications or information from the Ontario prenatal screening population. RESULTS: At an eFTS risk cut-off of ≥1/1000, contingent and reflex cfDNA screening have the same detection rate (DR) (94%) for trisomy 21. Reflex cfDNA screening using RCA/Imaging solution provided the lowest false positive rate and cost. The number of women requiring genetic counselling and diagnostic testing was significantly reduced and women received their cfDNA screening result 9 days sooner compared with the contingent model. While primary cfDNA screening improved the trisomy 21 DR by 3-5%, it was more costly and more women required diagnostic testing. CONCLUSION: Reflex cfDNA screening is the most cost-effective prenatal screening strategy. It can improve the efficiency of prenatal aneuploidy screening by reducing the number of patient visits and providing more timely results.

Prenatal diagnosis of Jeune-like syndromes with two-dimensional and three-dimensional sonography.

The purpose of this article is to describe the use of three-dimensional sonography as an adjuvant to two-dimensional sonography facilitating an earlier and more definitive diagnosis of Jeune and Jeune-like syndromes in the second trimester. We report two cases in which three-dimensional sonography facilitated the diagnosis of these malformations. A diagnosis of Jeune syndrome was made in our first case. Our second case was found to be short-rib polydactyly syndrome Type IV. Three-dimensional skeletal survey visualized short ribs, short limbs, the presence of normal scapulae, and the absence of polydactyly in both cases. Three-dimensional sonography can assist two-dimensional sonography in providing a more accurate display of skeletal anomalies, limb abnormalities, and facial features.