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BACKGROUND Fetal smallness affects 10% of pregnancies. These fetuses are at a higher risk of adverse outcomes. Their management using estimated fetal weight (EFW) and feto-maternal Doppler has a high sensitivity for adverse outcomes; however, more than 60% of fetuses are electively delivered at 37-38 weeks. On the other hand, the classification using angiogenic factors (AF) seems to have a lower false positive rate. Here we present a protocol for the GRAFD trial, which compares the management of small fetuses at term using AF or Doppler. OBJECTIVE The primary objective is to demonstrate that classification based on AF is not inferior to EFW and Doppler to detect fetuses at risk of adverse perinatal outcomes. METHODS This is a multicentre, open-label, randomized controlled trial conducted in 20 hospitals across Spain. A total of 1,030 singleton pregnancies with an EFW ≤10th percentile at 36+0 to 37+6 weeks will be recruited and randomly allocated to either the control or the intervention group. In the control group, standard Doppler-based management will be used. In the intervention group, cases with a soluble fms-like tyrosine kinase to placental growth factor ratio (sFlt-1/PlGF) ≥38 will be classified as fetal growth restriction (FGR), otherwise as small for gestational age (SGA). In both arms, FGR will be delivered at ≥37 weeks and SGA at ≥40 weeks. We will assess the differences between groups calculating the relative risks (RR) and their 95% confidence intervals. RESULTS The study is in the recruitment and data collection phase. The study results are expected to be published in peer-reviewed journals and disseminated at international conferences by the end of 2022 or in early 2023. CONCLUSIONS The AF-based protocol may reduce the number of pregnancies with classified as FGR without worsening perinatal outcomes. Moreover, reducing the number of unnecessary labor inductions would reduce costs and the risks derived from possible iatrogenic complications. Additionally, fewer inductions would lower the rate of early-term neonates, thus improving neonatal outcomes and potentially reducing long-term infant morbidities. CLINICALTRIAL NCT04502823

Objective: To determine the incidence of preeclampsia (PE) and preterm PE in Spain and to identify the risk factors for developing the disease. Methods: This is a multicenter prospective cohort study performed at six maternity units across Spain. Women with singleton pregnancies attending their first-trimester routine visit at the hospital were offered participation. Maternal and pregnancy characteristics, including mean arterial pressure, as well as ultrasound findings were recorded. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors for subsequent development of PE. Results:A total of 5868 pregnancies were recruited for this study, including 174 (3.0%) cases of PE, 47 (0.8%) cases of preterm PE and 127 (2.2%) cases of term PE. Median maternal age was 33.9 years (interquartile range: 30.1 to 36.9) and median gestational age at the routine visit was 12.7 weeks (interquartile range: 12.3 to 13.0). However, 293 (5.0%) of the women were on aspirin treatment during pregnancy, likely reducing the true incidence of the disease. As expected, increasing body mass index (P

Background: In women with a singleton pregnancy and sonographic short cervix in midgestation, vaginal administration of progesterone reduces the risk of early preterm birth and improves neonatal outcomes, without any demonstrable deleterious effects on childhood neurodevelopment. In women with twin pregnancies the rate of spontaneous early preterm birth is 10-times higher than in singletons and in this respect all twins are at increased risk of preterm birth. However, six trials in unselected twin pregnancies reported that vaginal progesterone from mid-gestation had no significant effect on the incidence of early preterm birth. Such apparent lack of effectiveness of progesterone in twins may be due to inadequate dosage or treatment which is started too late in pregnancy. Objective: The Early vaginal progesterone for the preVention of spontaneous prEterm birth iN TwinS: A randomized, placebo controlled, double-blinded trial (EVENTS) was designed to test the hypothesis that, among women with twin pregnancies, vaginal progesterone at a dose of 600 mg per day from 11-14 until 34 weeks’ gestation, as compared with placebo, would result in a significant reduction in the incidence of spontaneous preterm birth between 24+0 and 33+6 weeks. Methods: The trial was conducted at 22 hospitals in England, Spain, Bulgaria, Italy, Belgium and France. Women were randomly assigned in a 1:1 ratio, to receive either progesterone or placebo and in the random-sequence generation there was stratification according to participating center. Primary outcome was spontaneous birth between 24 +0 and 33+6 weeks’ gestation. Statistical analyses were performed on an intention-to-treat basis. Logistic regression analysis was used to determine the significance of difference in incidence of spontaneous birth between 24+0 and 33+6 weeks’ gestation between the progesterone and placebo groups, adjusting for the effect of participating centre, chrorionicity, parity and method of conception. Prespecified tests of treatment interaction effects with chrorionicity, parity, method of conception, compliance and cervical length at recruitment were performed. A post hoc analysis using mixed effects Cox regression was used for further exploration of the effect of progesterone on preterm birth. Results: We recruited 1,194 women between May 2017 and April 2019; 21 withdrew consent and 4 were lost to follow up, which left 582 in the progesterone group and 587 in the placebo group. Adherence was good, with reported intake of ≥80% of the required number of capsules in 81.4% of the participants. After excluding births before 24 weeks and indicated deliveries before 34 weeks, spontaneous birth between 24+0 and 33+6 weeks occurred in 10.4% (56/541) participants in the progesterone group and in 8.2% (44/538) in the placebo group (odds ratio in the progesterone group, adjusting for the effect of participating center, chrorionicity, parity and method of conception, 1.35; 95% CI 0.88 - 2.05; p=0.17). There was no evidence of interaction between the effects of treatment and chorionicity (p=0.28), parity (p=0.35) method of conception (p=0.56) and adherence (p=0.34); however, there was weak evidence of an interaction with cervical length (p=0.08) suggestive of harm to those with cervical length ≥30 mm (odds ratio 1.61, 95% CI 1.01-2.59) and potential benefit for those with cervical length

Objective: To investigate the potential value of uterine artery Doppler at 30 34 weeks’ gestation in the prediction of adverse perinatal outcome. Methods: Screening study in 30,780 singleton pregnancies at 30 34 weeks. Uterine artery pulsatility index (PI) was measured and the values were converted to multiples of the median (MoM) after adjustment from variables in maternal characteristics and medical history that affect the measurements. Multivariable logistic regression analysis was used to determine if uterine artery PI had a significant additional contribution to maternal characteristics, medical history and obstetric factors in predicting adverse outcome. The detection rate (DR) and false positive rate (FPR) of screening by uterine artery PI were estimated for stillbirth, cesarean section for fetal distress, umbilical arter ial cord blood pH 95 th percentile in screening for each adverse outcome was poor with DR of 6 16% and FPR of 5 6%. T he DR of high uterine artery PI for adverse outcome was higher in the SGA than non SGA groups, including 24% vs. 13% for stillbirth , 15% vs. 5% for cesarean section for fetal distress, 22% vs. 9% for low cord blood pH and 20% vs. 3% for low Apgar score. Conclusion: High uterine artery PI at 30 34 weeks’ gestation may be useful in the prediction of adverse perinatal outcome in pregnancies with SGA fetuses, but not in those with non SGA fetuses.

Objective To investigate the potential value of biophysical and biochemical markers at 30–34 weeks' gestation in the prediction of adverse perinatal outcome. Methods This was a screening study in 8268 singleton pregnancies at 30–34 weeks' gestation. Estimated fetal weight (EFW), uterine artery (UtA) pulsatility index (PI), umbilical artery (UA) PI, fetal middle cerebral artery (MCA) PI, mean arterial pressure (MAP), serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were measured. The detection rate (DR) and false-positive rate (FPR) of screening by each biomarker were estimated for stillbirth, pre-eclampsia, delivery of small-for-gestational-age (SGA) neonate, Cesarean section for fetal distress before or during labor, umbilical arterial cord blood pH ≤7.0 or umbilical venous cord blood pH ≤7.1, 5-min Apgar score < 7 and admission to the neonatal unit (NNU). Results Multivariable regression analysis demonstrated that significant prediction of PE was provided by PlGF, sFlt-1, MAP and MCA-PI, with a DR of 98% for PE delivering < 37 weeks' gestation and 56% for those delivering ≥ 37 weeks, at a 10% FPR. Prediction of SGA was provided by EFW, PlGF, sFlt-1, UtA-PI, UA-PI and MCA-PI, with a DR of 88% for SGA delivering < 37 and 51% for those delivering ≥ 37 weeks' gestation, at a 10% FPR. Prediction of stillbirth was provided by EFW, UtA-PI and MCA-PI, with DR of 30% at 10% FPR. Prediction of Cesarean section for fetal distress before labor was provided by EFW, sFlt-1, UtA-PI and UA-PI, with a DR of 90% at a 10% FPR. Prediction of fetal distress in labor was provided by EFW and sFlt-1, with a DR of 16% at a 10% FPR. There were no significant differences from the normal outcome group in any of the biomarkers for low cord blood pH, low Apgar score or NNU admission for cases other than those with PE and/or SGA. Conclusion At 30–34 weeks' gestation, biomarkers of impaired placentation and fetal hypoxemia provide good prediction of PE, SGA and fetal distress before labor, but poor or no prediction of stillbirth and adverse events in labor or after birth. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Objective To investigate the potential value of biophysical and biochemical markers at 35–37 weeks' gestation in the prediction of adverse perinatal outcome. Methods This was a screening study in 3953 singleton pregnancies at 35–37 weeks' gestation. Estimated fetal weight (EFW), uterine artery pulsatility index (UtA-PI), umbilical artery (UA)-PI, fetal middle cerebral artery (MCA)-PI, mean arterial pressure (MAP), serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were measured. The detection rate (DR) and false-positive rate (FPR) of screening by each biomarker were estimated for pre-eclampsia (PE), delivery of small-for-gestational-age (SGA) neonates, Cesarean section for fetal distress before or during labor, umbilical arterial cord blood pH ≤ 7.0 or umbilical venous cord blood pH ≤ 7.1, 5-min Apgar score < 7 and admission to the neonatal unit (NNU). Results Multivariable regression analysis demonstrated that significant prediction of PE was provided by PlGF, sFlt-1 and MAP, with a DR of 73% at a 10% FPR. Prediction of SGA was provided by EFW, PlGF and UtA-PI, with a DR of 63% at a 10% FPR. Prediction of Cesarean section for fetal distress before labor was provided by EFW and UA-PI with DR of 100% at 10% FPR. Prediction of fetal distress in labor was provided by EFW and sFlt-1, with a DR of 15% at a 10% FPR. There were no significant differences between those with a normal outcome and those with low cord blood pH, low Apgar score or NNU admission for any of the biomarkers assessed. Conclusion At 35–37 weeks' gestation biomarkers of impaired placentation and fetal hypoxemia provide good prediction of PE, SGA and fetal distress before labor, but poor or no prediction of adverse events in labor or after birth. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.