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%.

Pregnancy outcomes in nulliparous women with positive first-trimester preterm preeclampsia screening test: the Great Obstetrical Syndromes cohort study.

BACKGROUND: The Fetal Medicine Foundation proposed a competing risks model for early identification of women at a high risk of preterm preeclampsia, typically associated with deep placentation disorders. The Great Obstetrical Syndromes include a spectrum of pregnancy complications (preeclampsia, intrauterine growth restriction, preterm birth, late spontaneous abortion, and abruptio placentae) that are also associated with deep placentation disorders. OBJECTIVE: This study aimed to estimate the rate of placenta-mediated pregnancy complications in nulliparous women with a positive first-trimester Fetal Medicine Foundation preterm preeclampsia screening test. STUDY DESIGN: We conducted a prospective cohort study of nulliparous women recruited at 11 to 14 weeks of gestation. Maternal characteristics, mean arterial blood pressure, levels of maternal serum biomarkers (pregnancy-associated plasma protein-A, placental growth factor, and soluble fms-like tyrosine kinase-1), and mean uterine artery pulsatility index were obtained to calculate the risk of preterm preeclampsia according to the Fetal Medicine Foundation algorithm. The predicted risks were dichotomized as a positive or negative test according to 2 risk cutoffs (1 in 70 and 1 in 100). The detection rate, false-positive rate, and positive and negative predictive values were calculated for placenta-mediated complications, including preeclampsia, small for gestational age (birthweight <10th percentile), fetal death, preterm birth, and a composite outcome, including any of the foregoing. The same analyses were computed for a composite of severe outcomes, including preterm preeclampsia, severe small for gestational age (less than third percentile), and fetal death. RESULTS: We included 4575 participants with complete observations, of whom 494 (10.8%) had an estimated risk of preterm preeclampsia of ≥1 in 70 and 728 (15.9%) had a risk of ≥1 in 100. The test based on a risk cutoff of 1 in 70 could have correctly predicted up to 27% of preeclampsia, 55% of preterm preeclampsia, 18% of small for gestational age, 24% of severe small for gestational age, and 37% of fetal deaths at a 10% false-positive rate. The test based on a cutoff of 1 in 100 could have predicted correctly up to 35% of preeclampsia, 69% of preterm preeclampsia, 25% of small for gestational age, 30% of severe small for gestational age, and 53% of fetal deaths at a 15% false-positive rate. The positive predictive value of a screening test for preterm preeclampsia of ≥1 in 70 was 3% for preterm preeclampsia, 32% for the composite outcome, and 9% for the severe composite outcome. CONCLUSION: Nulliparous women with a first-trimester positive preterm preeclampsia Fetal Medicine Foundation screening test are at a higher risk of both preterm preeclampsia and other severe placenta-mediated pregnancy complications. Approximately 1 woman of 10 identified as high risk by the Fetal Medicine Foundation algorithm developed at least 1 severe placenta-mediated pregnancy complication.

First-Trimester Preterm Preeclampsia Screening in Nulliparous Women: The Great Obstetrical Syndrome (GOS) Study.

OBJECTIVES: To estimate the ability of a combination of first-trimester markers to predict preterm preeclampsia in nulliparous women. METHODS: We conducted a prospective cohort study of nulliparous women with singleton gestations, recruited between 110 and 136 weeks gestation. Data on the following were collected: maternal age; ethnicity; chronic diseases; use of fertility treatment; body mass index; mean arterial blood pressure (MAP); serum levels of pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), alpha fetoprotein (AFP), free beta human chorionic gonadotropin (ß-hCG); and mean uterine artery pulsatility index (UtA-PI). We constructed a proportional hazard model for the prediction of preterm preeclampsia selected based on the Akaike information criterion. A receiver operating characteristic curve was created with the predicted risk from the final model. Our primary outcome was preterm preeclampsia and our secondary outcome was a composite of preeclampsia, small for gestational age, intrauterine death, and preterm birth. RESULTS: Among 4659 nulliparous women with singleton gestations, our final model included 4 variables: MAP MoM, log10PlGF MoM, log10AFP MoM and log10UtA-PI MoM. We obtained an area under the curve of 0.84 (95% CI 0.75-0.93) with a detection rate of preterm preeclampsia of 55% (95% CI 37%-73%) and a false-positive rate of 10%. Using a risk cut-off with a false-positive rate of 10%, the positive predictive value for our composite outcome was 33% (95% CI 29%-37%). CONCLUSIONS: The combination of MAP, maternal serum PlGF and AFP, and UtA-PI are useful to identify nulliparous women at high risk of preterm preeclampsia but also at high risk of other great obstetrical syndromes.

First Trimester Mean Arterial Pressure Measured Manually Versus Using an Automated Device and the Prediction of Preeclampsia: A Case-Cohort Study.

OBJECTIVE: First trimester mean arterial blood pressure (MAP) can be used to predict preeclampsia. This study aimed to compare the performance of first trimester MAP measured with an automated device using a standardized technique versus MAP taken manually in a typical clinical setting. METHODS: A case-cohort study niched into a prospective cohort of pregnant women recruited at 11-14 weeks was performed. MAP was measured with an automated device on both arms until stability was reached. These results were compared with the MAP measured with a manual device at the closest medical visit (between 10 and 15 weeks gestation) and noted in the medical charts. Receiver-operator characteristics curve analyses were used to estimate the predictive values of MAP measured by both techniques. RESULTS: Forty-one women with preeclampsia and 167 control patients were used for the comparisons. MAP measured with an automated device decreased significantly between 11 and 14 weeks gestation (P < 0.001). Moreover, MAP measured with an automated device was a better predictor of preeclampsia (area under the curve 0.70; 95% confidence interval 0.61-0.79) than MAP measured with a manual device in a clinical setting (area under the curve 0.60; 95% confidence interval 0.50-0.70). Taken alone, MAP measured with an automated device was associated with a detection rate of preeclampsia of 34%, for a false-positive rate of 10%. CONCLUSION: First trimester MAP can predict preeclampsia. This study demonstrated that MAP measured with an automated device using a standardized technique is a better predictor than MAP measured with a manual device.

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.

First-Trimester Uterine Artery Doppler for the Prediction of Preeclampsia in Nulliparous Women: The Great Obstetrical Syndrome Study.

OBJECTIVE: This study aimed to estimate the performance of first-trimester uterine artery (UtA) pulsatility index (PI) for the prediction of preeclampsia (PE). STUDY DESIGN: We conducted a prospective cohort study of nulliparous women with singleton gestation at 11 to 13 6/7 weeks. UtA-Doppler's was performed on both UtAs and the mean UtA-PI was reported in multiple of median (MoM) adjusted for gestational age. Using receiver operating characteristic curves and their area under the curves (AUC); we calculated the performance of UtA-PI for the prediction of PE. Proportional hazard models were used to develop prediction models combining UtA-PI and maternal characteristics. RESULTS: Out of 4,676 participants with completed follow-up, 232 (4.9%) developed PE, including 202 (4.3%) term and 30 (0.6%) preterm PE. Mean UtA-PI decreased with gestational age between 11 and 13 6/7 weeks (p < 0.001). First-trimester UtA-PI was associated with preterm (AUC: 0.69; 95% CI [confidence interval]: 0.57-0.80) but not with term (AUC: 0.52; 95% CI: 0.48-0.56) PE. UtA-PI combined with maternal characteristics could predict 45% of preterm PE at a false positive rate of 10%. CONCLUSION: First-trimester UtA-PI decreases with gestational age between 11 and 13 6/7 weeks and is associated with the risk of preterm but not term PE.

First-Trimester Placental Growth Factor for the Prediction of Preeclampsia in Nulliparous Women: The Great Obstetrical Syndromes Cohort Study.

BACKGROUND: First-trimester maternal serum markers have been associated with preeclampsia (PE). We aimed to evaluate the performance of first-trimester placental growth factor (PlGF) for the prediction of PE in nulliparous women. SUBJECTS AND METHODS: We conducted a prospective cohort study of nulliparous women with singleton pregnancy at 11-13 weeks. Maternal serum PlGF concentration was measured using B·R·A·H·M·S PlGFplus KRYPTOR automated assays and reported in multiple of the median adjusted for gestational age. We used proportional hazard models, along with receiver operating characteristic curves and areas under the curve (AUC). RESULTS: Out of 4,652 participants, we observed 232 (4.9%) cases of PE including 202 (4.3%) term and 30 (0.6%) preterm PE. PlGF was associated with the risk of term (AUC = 0.61, 95% confidence interval [CI] 0.57-0.65) and preterm PE (AUC = 0.73, 95% CI 0.64-0.83). The models were improved with the addition of maternal characteristics (AUC for term PE 0.66, 95% CI 0.62-0.71; AUC for preterm PE 0.81, 95% CI 0.72-0.91; p < 0.01). At a false-positive rate of 10%, PlGF combined with maternal characteristics could have predicted 26% of term and 55% of preterm PE. The addition of pregnancy-associated plasma protein A did not significantly improve the prediction models. CONCLUSION: First-trimester PlGF combined with maternal characteristics is useful to predict preterm PE in nulliparous women.

First-Trimester Uterine Artery Doppler for the Prediction of SGA at Birth: The Great Obstetrical Syndromes Study.

OBJECTIVE: To estimate the role of first-trimester uterine artery pulsatility index (UtA-PI) for the prediction of small-for-gestational age (SGA). METHODS: We conducted a prospective cohort study of nulliparous women with singleton pregnancy (Great Obstetrical Syndromes study). UtA-PI was performed at 11 + 0 to 13 + 6 weeks and was reported in multiple of median (MoM). SGA was defined as birth weight below the 10th percentile and stratified as term or preterm SGA. Receiver operating characteristic curves analyses with their area under the curve (AUC) were used to estimate the predictive values of UtA-PI, alone and UtA-PI combined with maternal characteristics. We computed the detection rate and false-positive rate (FPR) of the SOGC SGA screening guidelines in our population. RESULTS: Of 4610 participants, SGA was identified in 486 pregnancies (10.3%), including 15 (0.3%) associated with preterm delivery. Compared with unaffected pregnancies, the mean log UtA-PI was significantly higher in term SGA and preterm SGA. The difference between preterm SGA and unaffected pregnancies remains significant after exclusion of SGA without preeclampsia. First-trimester UtA-PI was more predictive of preterm (AUC: 0.89) than term (AUC: 0.60) SGA (P < 0.01). Combined with maternal characteristics, UtA-PI could have predicted 64% of preterm and 20% of term SGA (10% FPR). The SOGC guidelines criteria for early screening of SGA had a detection rate of 21% for a FPR of 21%. CONCLUSIONS: First-trimester UtA-PI can be used to predict SGA, but mainly preterm SGA. The current SOGC guidelines criteria for SGA screening are not efficient in nulliparous women.

First Trimester Screening for Fetal Aneuploidies Using Placental Growth Factor: The Great Obstetrical Syndrome (GOS) Study.

OBJECTIVE: This study sought to estimate the ability of first trimester maternal serum placental growth factor (PlGF) to identify fetal aneuploidies. METHODS: A prospective cohort study of singleton pregnancy at 11 to 13 weeks was conducted. Maternal serum PlGF concentration was measured using BRAHMS PlGF plus KRYPTOR automated assays (Thermo Scientific BRAHMS, Hennigsdorf, Germany). PlGF and nuchal translucency were log-transformed and reported as multiples of the median (MoM) adjusted for crown-rump length. Detection rates were calculated using receiver-operator characteristic curves. RESULTS: The study observed 21 cases of fetal aneuploidies (0.4%) out of 4765 participants. Trisomy 21 (13 cases; 0.85 MoM; interquartile range [IQR] 0.80-0.93), trisomy 18 (two cases; 0.77 MoM; IQR 0.66-0.87) and trisomy 13 (two cases; 0.68 MoM; IQR 0.61-0.75) were associated with low PlGF concentrations. The low PlGF values observed in the cases of monosomy X (two cases; 0.85 MoM; IQR 0.82-0.88, P = 0.05), triploidy (0.78 MoM, P = 0.11), and 47,XX,i(22)(p10) (0.18 MoM, P = 0.08) were not statistically different from the controls. A model including maternal age, nuchal translucency, and PlGF could have identified all (95% CI 83%-100%) cases of trisomy 21 and six of the other fetal aneuploidies (75%) at a false-positive rate of 9%. CONCLUSION: Low first trimester PlGF is associated with an increased risk of fetal aneuploidy. PlGF combined with first trimester ultrasound (nuchal translucency, uterine artery Doppler, and early fetal anatomy) could identify not only women at high risk for preeclampsia, but also fetuses at high risk of aneuploidy for optimal further testing (non-invasive testing for common aneuploidy screening or chorionic villus sampling for full screening and diagnosis).

Does Low PAPP-A Predict Adverse Placenta-Mediated Outcomes in a Low-Risk Nulliparous Population? the Great Obstetrical Syndromes (GOS) Study.

OBJECTIVE: First-trimester low concentration of pregnancy-associated plasma protein A (PAPP-A) has been associated with adverse perinatal outcomes in high-risk populations. This study aimed to estimate the ability of PAPP-A to identify adverse outcomes in a low-risk population. METHODS: The study investigators recruited nulliparous women with singleton pregnancy at their 11-13-week ultrasound scan. Serum samples were collected, and maternal PAPP-A concentration was measured using the B⋅R⋅A⋅H⋅M⋅S PAPP-A KRYPTOR (ThermoFisher Scientific, Hennigsdorf, Germany) automated assay. PAPP-A was reported in multiple of median (MoM) adjusted for GA. Participants were followed until delivery for pregnancy outcomes including preeclampsia (PE), SGA <3rd percentile, and fetal death. Receiver operating characteristic curves with the area under the curve (AUC) were used to evaluate the predictive value of PAPP-A. The investigators calculated the detection rates (DRs) and positive predictive values (PPVs) of a PAPP-A < 0.4 MoM. RESULTS: The study investigators recruited 4739 eligible participants at a mean GA of 13 ± 6 weeks. The investigators observed 232 (4.9%) cases of PE, 84 (1.8%) cases of SGA, and 14 (0.3%) fetal deaths. PAPP-A was moderately associated with PE (AUC 0.57; 95% CI 0.53-0.61) and SGA (AUC 0.62; 95% CI 0.56-0.69), but not with fetal death (AUC 0.43; 95% CI 0.23-0.63). PAPP-A < 0.4 MoM was observed in 364 (7.7%) participants and had poor predictive values for PE (DR 9.8%; PPV 6.3%), SGA (DR 18.1%; PPV 4.4%), and fetal death (DR 21.4%; PPV 0.9%). CONCLUSION: Isolated first trimester PAPP-A has a limited predictive value for adverse pregnancy outcomes (other than trisomies). Low PAPP-A (<0.4 MoM) should be used in combination with other markers for the prediction of PE, SGA, or fetal death, and it does not constitute an indication for low-dose aspirin.

Maternal Characteristics for the Prediction of Preeclampsia in Nulliparous Women: The Great Obstetrical Syndromes (GOS) Study.

OBJECTIVE: Low-dose aspirin started in early pregnancy significantly reduces the risk of preeclampsia (PE) in high-risk women, especially preterm PE. This study aimed to evaluate the influence of maternal characteristics on the risk of PE in nulliparous women. METHODS: The Great Obstetrical Syndromes (GOS) study recruited nulliparous women with singleton pregnancies at 11 to 13 weeks. The following maternal characteristics were collected: age, BMI, ethnicity, chronic diseases, smoking, and assisted reproductive technologies. Relative weight analyses were conducted, and predictive multivariate proportional hazard models were constructed. Receiver operating characteristic curve analyses with their area under the curve (AUC) were used to evaluate the value of each factor for the prediction of PE and preterm PE. The study also evaluated the SOGC guidelines for identification of women at high risk of PE. RESULTS: Of 4739 participants, 232 (4.9%) developed PE, including 30 (0.6%) with preterm PE. In univariate analyses, only BMI was significantly associated with the risk of PE (AUC 0.60; 95% CI 0.55-0.65) and preterm PE (AUC 0.64; 95% CI 054-0.73). Adding other maternal characteristics to BMI had a non-significant and marginal impact on the discriminative ability to the models for PE (AUC 0.62; 95% CI 0.58-0.66) and preterm PE (AUC 0.65; 95% CI 0.56-0.74). At a false-positive rate of 10%, maternal characteristics could have predicted 23% of PE and 19% of preterm PE. The SOGC guidelines were not discriminant for PE (detecting 96% of PE and 93% of preterm PE with a 94% false-positive rate). CONCLUSION: In nulliparous women, BMI is the most discriminant maternal characteristic for the prediction of PE. Maternal characteristics should not be used alone to identify nulliparous women at high risk of PE.

First-Trimester Abdominal Adipose Tissue Thickness to Predict Gestational Diabetes.

OBJECTIVE: To estimate the discriminative capacity of first-trimester subcutaneous (SATT), visceral (VATT), and total (TATT) adipose tissue thickness in predicting gestational diabetes mellitus (GDM), including that requiring insulin. METHODS: We prospectively recruited a cohort of 1048 nulliparous women. Ultrasound images were used to determine abdominal SATT, VATT, and TATT at 11 to 14 weeks' gestation. Multivariate logistic regression models were used to predict GDM, as well as insulin-requiring GDM. Model discrimination was expressed as area under the curve (AUC). RESULTS: SATT (AUC 0.66, 95% CI 0.59-0.73), VATT (AUC 0.65, 95% CI 0.58-0.73), and TATT (AUC 0.68, 95% CI 0.61-0.76) were each associated with subsequent GDM. The respective AUC values for insulin-requiring GDM were 0.70 (95% CI 0.61-0.79), 0.73 (95% CI 0.65-0.82), and 0.76 (95% CI 0.67-0.84). At a false-positive rate of 10%, the detection rate for insulin-requiring GDM was 19% for maternal age ≥35 years, 31% for a BMI ≥31.6 kg/m2, and 31% for TATT ≥61 mm, increasing to 42% in the model comprising all three measures. CONCLUSION: First-trimester ultrasound measurement of adipose tissue is associated with a higher chance of developing GDM, especially insulin-requiring GDM.

Comparative Study of Abdominal Versus Transvaginal Ultrasound for Uterine Artery Doppler Velocimetry at 11 to 13 Weeks.

OBJECTIVES: To compare the first-trimester uterine artery pulsatility index (PI) measured by abdominal and transvaginal ultrasound (US). METHODS: We performed a prospective study of singleton pregnant women recruited at 11 to 13 weeks' gestation. The mean uterine artery PI was obtained by abdominal followed by transvaginal US. The mean of the left and right uterine artery PIs was used, and differences between approaches were computed. The intraclass correlation coefficient and a Bland-Altman plot were used to compare the two approaches. RESULTS: Data were available for 940 participants, including 928 (99%) with uterine artery PIs obtained on both uterine sides. The mean uterine artery PI decreased with gestational age in both approaches (P < .001). We observed a moderate correlation between abdominal and transvaginal mean uterine artery PIs (intraclass correlation coefficient, 0.72; 95% confidence interval, 0.69 to 0.75). Values obtained by abdominal US (median, 1.70, interquartile range, 1.35 to 2.09) were greater than those obtained by transvaginal US (median, 1.65; interquartile range, 1.37 to 1.99). There was a significant increase in differences as average measurements became higher (P < .01). CONCLUSIONS: The first-trimester mean uterine artery PI decreases with gestational age in both approaches. Abdominal US could be associated with greater uterine artery PI values than transvaginal US, especially at higher measurements. The first-trimester uterine artery PI for prediction of adverse perinatal outcomes should be adjusted for gestational age and possibly for the US approach.

Body mass index and the risk of hypertensive disorders of pregnancy: the great obstetrical syndromes (GOS) study.

Objective: To estimate the association between first-trimester body mass index (BMI) and the different types of hypertensive disorders of pregnancy (HDP). Methods: A prospective cohort of nulliparous women recruited at 11-13 weeks. Height and weight were measured and BMI was reported as binary (more or less than 30 kg/m2), categorical (World Health Organization classification), and continuous variables. Participants were followed for development of any HDP, including preeclampsia and preterm preeclampsia. Receiver operating characteristic curves and their area under the curve (AUC) were used along with multivariate logistic regressions to develop predictive models combining BMI with other maternal characteristics. Results: We recruited 4683 eligible participants including 645 (14%) affected by obesity. Obesity was associated with greater risks of HDP (22.5 versus 8.5%, p < .0001), preeclampsia (10.2 versus 4.3%, p < .0001), and preterm preeclampsia (1.6 versus 0.6%, p = .006). BMI categories (AUC: 0.65; 95%CI: 0.56-0.74) and BMI combined with maternal characteristics (AUC: 0.76; 95%CI: 0.69-0.83) were better predictors of preterm preeclampsia than BMI as binary variable (AUC: 0.58; 95%CI: 0.50-0.66). Conclusions: Obesity and BMI are associated with the risk of all types of HDP. Optimal prediction of preterm preeclampsia is achieved by using BMI as a continuous variable combined with other maternal characteristics.

Association between fertility treatments and early placentation markers.

INTRODUCTION: Pregnancies resulting from fertility treatments are at higher risk of placenta-mediated complications. Hence, we aimed to estimate the association between fertility treatment and levels of first-trimester markers of placentation. METHODS: We conducted a cohort study in an academic center from 03/2011 to 12/2014. Adult nulliparous women with singleton pregnancies were recruited between 11 + 0 and 13 + 6 weeks of gestation. Data on maternal characteristics, medical history, and pregnancies conceived through fertility treatments (whether ovulation agents, insemination or assisted reproductive technologies) were collected. Maternal serum concentrations of PlGF, sFlt-1, PAPP-A, AFP, and free ß-hCG were obtained, and notches and UtA-PI were measured using Doppler ultrasound. Mean Multiple of the Medians (MoM) and frequencies were computed to estimate the mean differences (MD) or risk ratios (RR) comparing fertility treatment to spontaneous pregnancies. RESULTS: 427 (9%) pregnancies out of 4815 were conceived through fertility treatments, using ovulation agents (n = 233, 5%), insemination (n = 174, 4%) and/or assisted reproductive technologies (n = 85, 2%). The latter were associated with significantly lower log10PAPP-A MoM (adjusted MD: -0.02, 95%CI: -0.04 to -0.01), lower log10PlGF MoM (adjusted MD: -0.04, 95%CI: -0.06 to -0.01) and higher log10free ß-hCG MoM (adjusted MD: 0.05, 95%CI: 0.01 to 0.09) compared to spontaneous pregnancies. Ovulation agents and insemination were associated with the presence of notches (adjusted RR: 1.24, 95%CI: 1.14 to 1.35; and 1.27, 95%CI: 1.15 to 1.42, respectively) and higher log10UtA-PI MoM (adjusted MD: 0.16, 95%CI: 0.08 to 0.24; and 0.17, 95%CI: 0.07 to 0.27, respectively) than spontaneous pregnancies. CONCLUSION: Fertility treatments are associated with significant variations in markers of placentation.

Screening for small for gestational age using third-trimester ultrasound markers: protocol for a systematic review and meta-analysis of screening test accuracy.

BACKGROUND: Fetal growth restriction (FGR) is a complication of pregnancy associated with major neonatal morbidity and commonly diagnosed at birth based on birth weight below the 5th or the 10th centile. There is no consensus on the use of routine third-trimester ultrasound for the detection of FGR in a general population. This systematic review aims to estimate the performance of third-trimester ultrasound markers in the screening for babies who are small for gestational age in low-risk or general population. METHODS: A systematic review of screening test accuracy will be conducted. The databases MEDLINE, Embase, Cochrane Library, and Web of Science will be searched from their inception until December 2017, as well as reference lists of included studies and previous related review articles. Studies screening for FGR in a low-risk or general population using third-trimester ultrasound markers and reporting low birth weight for gestational age (small for gestational age at birth) as a reference will be eligible. Two reviewers will independently screen references for inclusion, assess the risk of bias, and extract data. The Quality Assessment of Diagnostic Accuracy Study 2 (QUADAS-2) tool will be used to assess the methodological quality and validity of individual studies. The hierarchal summary receiver operating characteristic and random effects hierarchal bivariate models (Bivariate) will be used to estimate the pooled sensitivity and specificity of each ultrasound marker and to compare the discriminative ability of the different ultrasound markers. Subgroup and sensitivity analyses will be performed to explore the heterogeneity between studies and to assess the effect of screening tests' characteristics (e.g., timing) on their discriminative ability. DISCUSSION: This systematic review will determine the relevance of routine third-trimester ultrasound markers in the screening for FGR in low-risk or general population and their usefulness in standard pregnancy care. Additionally, this knowledge synthesis represents a step in the optimization of the discriminative ability of third-trimester ultrasound and predictive tools, allowing for targeted interventions aiming at the reduction of FGR complications and ultimately improving infants' health. SYSTEMATIC REVIEW REGISTRATION: This protocol has been registered at PROSPERO: international prospective register of systematic reviews. The register number is CRD42018085564 .

Intra-amniotic inflammation and child neurodevelopment: a systematic review protocol.

BACKGROUND: Intra-amniotic inflammation is associated with adverse pregnancy and neonatal outcomes. However, the impact on child neurodevelopment remains unclear. We aim to assess the effect of intra-amniotic inflammation on neurodevelopmental outcomes in children. METHODS: The databases MEDLINE, Embase, CINAHL, and Cochrane will be searched from their inception until November 2017. Randomized trials and cohort studies in which inflammatory markers were measured in amniotic fluid collected by amniocentesis and in which infant's neurodevelopment was assessed will be eligible. Two reviewers will independently select eligible studies, assess their risk of bias, and extract data. Results will be compared and a third party will be consulted in case of disagreement. Our primary outcome of interest is child neurodevelopment, assessed with either a validated tool or by revision of medical records for specific diagnosis. Secondary outcomes will include abnormal brain imaging. Relative risks will be pooled and sensitivity analyses will be performed for the indication of amniocentesis, gestational age at amniocentesis, gestational age at delivery, and fetal sex. Risk of bias will be assessed using the Cochrane Collaboration's tool for assessing the risk of bias in randomized trials or an adapted version of the ROBINS-1 for the risk of bias in non-randomized studies. DISCUSSION: This systematic review will report the current evidence regarding the association between amniotic inflammation and child neurodevelopment, and the modifiers of this association. The review will generate new hypotheses on pathological pathways and will guide future research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2017 65065.

First-trimester mean arterial blood pressure and the risk of preeclampsia: The Great Obstetrical Syndromes (GOS) study.

OBJECTIVE: To estimate the predictive value of first-trimester mean arterial pressure (MAP) for the hypertensive disorders of pregnancy (HDP). STUDY METHODS: We performed a prospective cohort study of nulliparous women recruited at 110/7-136/7 weeks. MAP was calculated from blood pressure measured on both arms simultaneously using an automated device taking a series of recordings until blood pressure stability was reached. MAP was reported as multiples of the median adjusted for gestational age. Participants were followed for development of gestational hypertension (GH), preeclampsia (PE), preterm PE (<37 weeks) and early-onset (EO) PE (<34 weeks). Receiver operating characteristic curves and the area under the curve (AUC) were used to estimate the predictive values of MAP. Multivariate logistic regressions were used to develop predictive models combining MAP and maternal characteristics. RESULTS: We obtained complete follow-up in 4700 (99%) out of 4749 eligible participants. GH without PE was observed in 250 (5.3%) participants, and PE in 241 (5.1%), including 33 (0.7%) preterm PE and 10 (0.2%) EO-PE. First-trimester MAP was associated with GH (AUC: 0.77; 95%CI: 0.74-0.80); term PE (0.73; 95%CI: 0.70-0.76), preterm PE (0.80; 95%CI: 0.73-0.87) and EO-PE (0.79; 95%CI: 0.62-0.96). At a 10% false-positive rate, first-trimester MAP could have predicted 39% of GH, 34% of term PE, 48% of preterm PE and 60% of EO-PE. The addition of maternal characteristics improved the predictive values (to 40%, 37%, 55% and 70%, respectively). CONCLUSION: First-trimester MAP is a strong predictor of GH and PE in nulliparous women.