First-trimester screening for Down syndrome using quadruple maternal biochemical markers.

OBJECTIVES: Placental growth factor (PlGF) is used for first-trimester preeclampsia screening and could be combined with other biochemical markers for Down syndrome screening. We aim to estimate the predictive value of the combination of pregnancy-associated plasma protein (PAPP-A), free ß-human chorionic gonadotropin (free ß-hCG), placental growth factor (PlGF) and α-fetoprotein (AFP) with and without nuchal translucency. METHODS: Singleton pregnancies recruited at 11-14 weeks and followed until delivery. The four maternal markers were measured using Kryptor (ThermoFisher-BRAHMS) and adjusted for gestational age and maternal characteristics. The risk of Down syndrome was calculated using the Fetal Medicine Foundation algorithm and multivariate linear regression analyses in all cases and in 2,200 controls. Receiver-operator characteristic (ROC) curves were used to calculate the detection and false-positive rates. RESULTS: Twenty-six (0.2%) cases of Down syndrome were diagnosed among 13,386 participants. The combination of the four biomarkers could have detected 88% (95% CI: 72-97%) of the cases at a false-positive rate of 13% (95% CI: 12-15%). The addition of nuchal translucency would have increased the detection rate to 96% (95% CI: 82-99%) at a false-positive rate of 4% (95% CI: 4-5%) using a 1:300 cut-off and to 100% (95% CI: 89-100%) at a false-positive rate of 6% (95% CI: 5-8%) using a 1:500 cut-off. CONCLUSIONS: First-trimester screening using biochemical markers allows the identification of approximately 88% of Down syndrome cases for a false-positive rate of 13%. The addition of nuchal translucency raises the detection rate above 95% with a false-positive rate below 5%.

Evaluation of midtrimester cervical length thresholds for the prediction of spontaneous preterm birth.

INTRODUCTION: To estimate the optimal midtrimester cervical length (CL) threshold for the prediction of spontaneous preterm birth (sPTB) in asymptomatic pregnant women. MATERIAL AND METHODS: This is a prospective observational cohort study including asymptomatic women with singleton pregnancies who underwent CL measurement by transabdominal and/or transvaginal ultrasound between 19°/7 and 216/7 weeks of gestation. All CL ≤30 mm from transabdominal ultrasound were confirmed by transvaginal ultrasound. Primary outcomes were sPTB <35 and <37 weeks. RESULTS: Out of 3,449 participants, 28 (0.8%) had a sPTB before 35 weeks and 99 (2.9%) had a sPTB before 37 weeks. Receiver operating characteristics (ROC) curves suggest that a cut-off of 30 mm was the optimal CL to predict sPTB before 35 weeks (sensitivity: 43%; specificity: 97%) and sPTB before 37 weeks (sensitivity: 21%; specificity: 97%). While a CL <25 mm was an important risk factor for sPTB before 35 weeks (relative risk: 31; 95% confidence interval: 13-73), women with a CL between 25 and 30 mm were also at greater risk (relative risk: 12; 95% confidence interval: 4 - 35) compared to women with CL ≥30 mm. DISCUSSION: A midtrimester CL <30 mm should be considered to identify women at high-risk of sPTB.

Proteomic Analysis of Maternal Urine for the Early Detection of Preeclampsia and Fetal Growth Restriction.

BACKGROUND: To explore the use of maternal urine proteome for the identification of preeclampsia biomarkers. METHODS: Maternal urine samples from women with and without preeclampsia were used for protein discovery followed by a validation study. The targeted proteins of interest were then measured in urine samples collected at 20-24 and 30-34 weeks among nine women who developed preeclampsia, one woman with fetal growth restriction, and 20 women with uncomplicated pregnancies from a longitudinal study. Protein identification and quantification was obtained using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: Among the 1108 urine proteins quantified in the discovery study, 21 were upregulated in preeclampsia and selected for validation. Nineteen (90%) proteins were confirmed as upregulated in preeclampsia cases. Among them, two proteins, ceruloplasmin and serpin A7, were upregulated at 20-24 weeks and 30-34 weeks of gestation (p < 0.05) in cases of preeclampsia, and could have served to identify 60% of women who subsequently developed preeclampsia and/or fetal growth restriction at 20-24 weeks of gestation, and 78% at 30-34 weeks, for a false-positive rate of 10%. CONCLUSIONS: Proteomic profiling of maternal urine can differentiate women with and without preeclampsia. Several proteins including ceruloplasmin and serpin A7 are upregulated in maternal urine before the diagnosis of preeclampsia and potentially fetal growth restriction.

The association between maternal placental growth factor and placental maternal vascular malperfusion lesions.

INTRODUCTION: Placental Growth Factor (PlGF) is used for the prediction of preeclampsia (PE), a syndrome associated with maternal vascular malperfusion (MVM). Our goal is to determine the correlation between PlGF and MVM. MATERIAL AND METHODS: We performed a secondary analysis of the PEARL study that included nulliparous women with PE (cases), and low-risk nulliparous women recruited in early pregnancy (controls). All participants provided blood samples at diagnosis of PE (cases), or between 26 and 34 weeks (controls) for measurement of PlGF (B·R·A·H·M·S plus KRYPTOR automated assays), that was transformed into multiple of median (MoM). Placental examination was performed for the diagnosis of MVM based on the Amsterdam Placental Workshop Group Consensus Statement. Nonparametric tests and receiver operating characteristic (ROC) curves were used to compare PlGF in pregnancies with, and without PE, stratified by the presence of MVM. RESULTS: Third trimester PlGF was lower in PE cases with MVM (N = 20; median: 0.04 MoM; interquartile: 0.03-0.09; p<0.0001), and in controls with MVM (N = 4; 0.30MoM; 0.07-0.52; p = 0.002) compared to controls without MVM (N = 29; 0.99 MoM; 0.67-1.52). PlGF in PE cases without MVM (N = 5; 0.18 MoM; 0.17-1.64) was not significantly different than in controls without MVM but the sample size was small. ROC curve demonstrated a greater predictability of PlGF for PE with MVM than PE without MVM (AUC: 0.99 vs. 0.38; p<0.0001). DISCUSSION: Third trimester PlGF is a better predictor of PE associated with MVM than a predictor of PE without MVM. We hypothesize that PlGF is a stronger marker of MVM than PE.

Pathological investigation of placentas in preeclampsia (the PEARL study).

INTRODUCTION: Preeclampsia (PE), but mainly preterm PE, is associated with deep placentation disorders. We aimed to compare placental pathologies in pregnancies affected by term and preterm PE compared to normal pregnancies. METHODS: We performed a prospective case-cohort study. Low-risk nulliparous women were recruited in the first trimester and women who developed PE were recruited at diagnosis. Placental pathologies were reported according to the Amsterdam Placental Workshop Group Consensus Statement and were compared between cases and controls. PE cases stratified as term (≥37 weeks) and preterm PE (<37 weeks). Our primary outcome was maternal vascular malperfusion (MVM). RESULTS: Twenty-four women who developed preterm PE were compared to 10 women who developed term PE and 41 women without PE. Preterm PE (92%) was associated with more MVM than term PE (10%, p < 0.01) and controls (4%, p < 0.01), but the rate of MVM was similar between term PE and controls (p = 0.56). Preterm PE was also associated with more placental infarcts (65% vs. 20% vs. 15%); advanced villous maturation (91% vs. 30% vs. 1%); and hypoplastic villous maturation (70% vs. 10% vs. 3%); and moderate to severe decidual vasculopathy (56% vs. 10% vs. 3%) than term PE and controls (all p < 0.05). CONCLUSION: Most cases of preterm PE are associated with MVM, placental infarcts, advanced and/or hypoplastic villous maturation, and moderate to severe decidual vasculopathy, while it is infrequent in term PE and pregnancies without PE. Preterm and term preeclampsia have a different pathologic process that should be considered for their prevention and clinical management.

Heparin for preventing adverse obstetrical outcomes in pregnant women with antiphospholipid syndrome, a systematic review and meta-analysis.

BACKGROUND: We performed a systematic review and meta-analysis to assess the efficacy and safety of heparin for preventing adverse obstetrical outcomes in pregnant women with antiphospholipid syndrome (APS). METHODS: We reviewed randomized controlled trials from CENTRAL, EMBASE, MEDLINE, and Web of science (inception to November 5th 2019), and relevant article reference lists. Two reviewers independently screened and extracted data from trials investigating heparin, including Low Molecular Weight Heparin (LMWH) and unfractionated heparin (UFH) at any dose, associated or not with aspirin, compared to any comparator group in pregnant women with APS. Internal validity was assessed in duplicate using the Cochrane Risk of Bias tool. The strength of evidence was assessed in duplicate using the Grading of Recommendations Assessment, Development and Evaluation framework. Our primary outcome was live birth rate. Secondary outcomes included preeclampsia, preterm birth, intra-uterine growth restriction (IUGR) and thromboembolism. Safety outcomes included maternal or neonatal bleedings, heparin-induced thrombocytopenia and allergy. Subgroup analyses were conducted to explore heterogeneity. RESULTS: From 2395 identified citations, 13 trials (1916 patients) met inclusion criteria. Heparin, associated or not with aspirin, significantly increased the rate of live birth compared to any comparator (RR 1.20; 95 % CI 1.09-1.33, I2 = 67 %, 1916 patients, low-certainty evidence). In subgroup analyses, LMWH and UFH were independently associated with greater rates of live birth: RR 1.15 (95 % CI 1.04-1.28, I2 = 71 %, 1684 patients, 9 trials) and RR 1.45 (95 % CI 1.16-1.81, I2 = 19 %, 149 patients, 4 trials) respectively. Heparin associated or not to aspirin, significantly decreased the rate of preeclampsia compared to any comparator (RR 0.32; 95 % CI 0.12-0.87, I2 = 0%, 465 patients, 8 trials) but was not associated with differential rates of preterm birth nor IUGR. Heparin was associated with minor bleeding (bruises, epistaxis): RR 2.58 (95 % CI 1.03-6.43, I2 = 16 %, 653 patients, 9 trials). No serious maternal or neonatal adverse events were reported in the included studies. CONCLUSIONS: In pregnant women with APS, heparin, associated or not to aspirin, significantly improved the live birth rate compared to any comparator and decreased the risk of preeclampsia, without increasing maternal and neonatal severe morbidity.

Placental Growth Factor and Soluble, Fms-Like Tyrosine Kinase-1 in Preeclampsia: A Case-Cohort (PEARL) Study.

OBJECTIVE: Preeclampsia is associated with a higher maternal blood levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and lower levels of placental growth factor (PlGF) that appear before clinical onset. We aimed to estimate the normal progression of these biomarkers in normal pregnancies and in those affected by preeclampsia. METHODS: We conducted a case-cohort study including low-risk nulliparous women recruited at 11-13 weeks gestation (cohort) and women with preeclampsia (cases). Maternal blood was collected at different points during pregnancy including at the time of diagnosis of preeclampsia for cases. Maternal serum PlGF and sFlt-1 concentrations and the sFlt-1/PlGF ratio were measured using B•R•A•H•M•S plus KRYPTOR automated assays and were compared between patients in both groups matched for gestational age. Cases were stratified as early- (≤34 weeks), intermediate- (35-37 weeks) and late-onset (>37 weeks) preeclampsia. RESULTS: The cohort consisted of 45 women whose results were compared with those of 31 women who developed preeclampsia, diagnosed at a median gestational age of 32 weeks (range 25-38 weeks). We observed that sFlt-1, PlGF and their ratio fluctuated during pregnancy in both groups, with a significant correlation with gestational age after 28 weeks (P < 0.05). We observed a significant difference between cases and controls, with a median ratio 100 times higher in early preeclampsia (P < 0.001), 13 times higher in intermediate preeclampsia (P < 0.001), but no significant difference between groups in late-onset preeclampsia with matched controls. CONCLUSION: PlGF, sFlt-1, and their ratio may be useful in the prediction and diagnosis of early- and intermediate-onset preeclampsia but are not useful for late-onset preeclampsia.

Evolution of Down Syndrome Prenatal Screening Clinical Practices in Québec.

OBJECTIVE: Prenatal screening for Down syndrome (DS) has evolved greatly over the last decades with the improvement of first- and second-trimester serum screening and the introduction of cell-free fetal DNA. This study aimed to estimate the impact of such changes on practices. METHODS: This retrospective cohort study included fetuses and newborns diagnosed with DS between 2005-2007 and 2015-2017 in the single obstetrical care centre in Québec City. Data were collected on the prenatal screening method, diagnosis, and delivery. The median was compared between the study periods. RESULTS: Complete clinical data were available for only 78 (66%) of 119 cases of DS. Significant changes were observed in screening methods, including an increase in the use of first-trimester serum, ultrasound, and cell-free fetal DNA. No significant changes were noted in terms of gestational age at diagnosis (median [interquartile range; IQR]: 17.0 [16.0-20.9] weeks in 2005-2007 vs. 17.9 [16.3-22.5] weeks in 2015-2017; P = 0.49) and delivery or termination of pregnancy (median 20.9 [IQR 18.0-23.3] weeks in 2005-2007 vs. 21.3 [18.4-23.4] weeks in 2015-2017; P = 0.46). The methods of diagnosis did not change significantly over the decade, with amniocentesis used 85% and 79% of the time, respectively (P = 0.19). CONCLUSION: The increased use of first-trimester screening and cell-free fetal DNA tests was not associated with earlier diagnosis of DS or earlier delivery or termination of pregnancy. The use of chorionic villus sampling should be encouraged for DS diagnosis when indicated because it could reduce the gestational age at diagnosis and termination if requested.

Use of Antenatal Corticosteroid Therapy: A Descriptive Study of Clinical Practice Trends.

OBJECTIVES: Antenatal corticosteroids (ACS) received within 7 days of delivery reduce perinatal morbidity and mortality associated with preterm birth. We aimed to describe the trends of ACS administration over the last decade. METHODS: A cohort study of women who received ACS in 2006, 2011, and 2016 at the CHU de Québec-Université Laval was conducted. The indication, GA at ACS, and GA at birth, were collected in 150 women randomly selected in each studied year. Our main endpoints were the frequency of ACS administration within 7 days of delivery and between 48 hours and 7 days before delivery. RESULTS: We included 447 women who received ACS at a median GA of 31.4 (range 23.6-39.0) weeks. No women received ACS after 35 weeks in 2006 and 2011. The administration of ACS for indicated delivery between 35 and 39 weeks occurred only in the last study period. Among women for whom ACS was initiated before 35 weeks, 31% received ACS in the 7 days before delivery, and only 13% received ACS between 48 hours and 7 days before birth (varying from 12% to 16%, P = 0.57). Threatened preterm labour or short cervix were the indication for ACS initiation in 39% women who received ACS before 35 weeks, but less than 5% of these women delivered between 2 and 7 days and more than 90% delivered after 14 days. CONCLUSIONS: Administration of ACS remains suboptimal. Threatened preterm labour and short cervix are poorly related to optimal use of ACS therapy.