Term planned delivery based on fetal growth assessment with or without the cerebroplacental ratio in low-risk pregnancies (RATIO37): an international, multicentre, open-label, randomised controlled trial.

BACKGROUND: The cerebroplacental ratio is associated with perinatal mortality and morbidity, but it is unknown whether routine measurement improves pregnancy outcomes. We aimed to evaluate whether the addition of cerebroplacental ratio measurement to the standard ultrasound growth assessment near term reduces perinatal mortality and severe neonatal morbidity, compared with growth assessment alone. METHODS: RATIO37 was a randomised, open-label, multicentre, pragmatic trial, conducted in low-risk pregnant women, recruited from nine hospitals over six countries. The eligibility criteria were designed to be broad; participants were required to be 18 years or older, with an ultrasound-dated confirmed singleton pregnancy in the first trimester, an alive fetus with no congenital malformations at the routine second-trimester ultrasound, an absence of adverse medical or obstetric history, and the capacity to give informed consent. Women were randomly assigned in a 1:1 ratio (block size 100) using a web-based system to either the concealed group or revealed group. In the revealed group, the cerebroplacental ratio value was known by clinicians, and if below the fifth centile, a planned delivery after 37 weeks was recommended. In the concealed group, women and clinicians were blinded to the cerebroplacental ratio value. All participants underwent ultrasound at 36 + 0 to 37 + 6 weeks of gestation with growth assessment and Doppler evaluation. In both groups, planned delivery was recommended when the estimated fetal weight was below the tenth centile. The primary outcome was perinatal mortality from 24 weeks' gestation to infant discharge. The study is registered at ClinicalTrials.gov (NCT02907242) and is now closed. FINDINGS: Between July 29, 2016, and Aug 3, 2021, we enrolled 11 214 women, of whom 9492 (84·6%) completed the trial and were eligible for analysis (4774 in the concealed group and 4718 in the revealed group). Perinatal mortality occurred in 13 (0·3%) of 4774 pregnancies in the concealed group and 13 (0·3%) of 4718 in the revealed group (OR 1·45 [95% CI 0·76-2·76]; p=0·262). Overall, severe neonatal morbidity occurred in 35 (0·73%) newborns in the concealed group and 18 (0·38%) in the revealed group (OR 0·58 [95% CI 0·40-0·83]; p=0·003). Severe neurological morbidity occurred in 13 (0·27%) newborns in the concealed group and nine (0·19%) in the revealed group (OR 0·56 [95% CI 0·25-1·24]; p=0·153). Severe non-neurological morbidity occurred in 23 (0·48%) newborns in the concealed group and nine (0·19%) in the revealed group (0·58 [95% CI 0·39-0·87]; p=0·009). Maternal adverse events were not collected. INTERPRETATION: Planned delivery at term based on ultrasound fetal growth assessment and cerebroplacental ratio at term was not followed by a reduction of perinatal mortality although significantly reduced severe neonatal morbidity compared with fetal growth assessment alone. FUNDING: La Caixa foundation, Cerebra Foundation for the Brain Injured Child, Agència per la Gestió d'Ajuts Universitaris i de Recerca, and Instituto de Salud Carlos III.

Performance of the INTERGROWTH-21st and World Health Organization fetal growth charts for the detection of small-for-gestational age neonates in Latin America.

OBJECTIVE: To evaluate the performance of INTERGROWTH-21st (IG-21st ) and World Health Organization (WHO) fetal growth charts to identify small-for-gestational-age (SGA) and fetal growth restriction (FGR) neonates, as well as their specific risks for adverse neonatal outcomes. METHODS: Multicenter cross-sectional study including 67 968 live births from 10 maternity units across four Latin American countries. According to each standard, neonates were classified as SGA and FGR (birth weight <10th and less than third centiles, respectively). The relative risk (RR) and diagnostic performance for a low APGAR score and low ponderal index were calculated for each standard. RESULTS: WHO charts identified more neonates as SGA than IG-21st (13.9% vs 7%, respectively). Neonates classified as having FGR by both standards had the highest RR for a low APGAR (RR, 5.57 [95% confidence interval (CI), 3.99-7.78]), followed by those who were SGA by both curves (RR, 3.27 [95% CI, 2.52-4.24]), while neonates with SGA identified by WHO alone did not have an additional risk (RR, 0.87 [95% CI, 0.55-1.39]). Furthermore, the diagnostic odds ratio for a low APGAR was higher when IG-21st was used. CONCLUSION: In a population from Latin America, the WHO charts seem to identify more SGA neonates, but the diagnostic performance of the IG-21st charts for low APGAR score and low ponderal index is better.

Perinatal outcomes of pregestational hypertension according to blood pressure range at 11-14 week scan: Impact of the 2017 ACC/AHA guidelines.

Objective: The aim of this study was to evaluate the impact on perinatal outcomes related to placental insufficiency with the application of the new 2017 ACC/AHA guidelines to a group of chronic hypertensive pregnancies during their first-trimester assessment. Study design: This retrospective cohort study included pregnancies with preconceptional hypertension and known perinatal outcomes. In the first trimester, a combined screening for preterm preeclampsia (p-PE) was performed, including blood pressure (BP), mean uterine artery Doppler, and maternal characteristics. Patients were divided, according to the 2017 ACC/AHA consensus, into the following groups: elevated or less, Stage 1, and Stage 2. For adverse perinatal outcome assessment, univariate and multivariate regression analyses were performed, considering the "elevated or less" group as a reference. Odds ratios (OR) were compared with linear trend analysis. The main outcomes measured were preterm PE and FGR < 3 rd percentile. Results: Of the 130 included patients, 59 (45.4%) were classified as elevated or less, 47 (36.2%) as Stage 1, and 24 (18.4%) as Stage 2. p-PE showed a significant increase according to BP range [7% (OR = 1.0), 19.6% (OR = 3.2), and 21.7% (OR = 3.7)]; trend p = 0.02, for elevated or less, Stage 1, and Stage 2, respectively. There was a non-significant increased trend of FGR < 3 rd percentile according to the BP stage. The best multivariate predictive model for p-PE included a previous PE background (OR = 15) and mean arterial pressure in mmHg (OR = 1.1). Conclusion: The use of the 2017 ACC/AHA consensus in pregnancies with chronic hypertension identifies an intermediate risk group for placental-mediated diseases.

Concordance of the risk of neonatal respiratory morbidity assessed by quantitative ultrasound lung texture analysis in fetuses of twin pregnancies.

To evaluate the concordance of the risk of neonatal respiratory morbidity (NRM) assessed by quantitative ultrasound lung texture analysis (QuantusFLM) between twin fetuses of the same pregnancy. Prospective study conducted in twin pregnancies. Fetal ultrasound lung images were obtained at 26.0-38.6 weeks of gestation. Categorical (high or low) and continuous results of the risk of NRM were compared between twins. Fetal ultrasound lung images from 131 pairs (262 images) of twins were included. The images were classified into three gestational age ranges: Group 1 (26.0-29.6 weeks, 78 images, 39 pairs [29.8%]); Group 2 (30.0-33.6 weeks, 98 images, 49 pairs [37.4%]) and Group 3 (34.0-38.6 weeks, 86 images, 43 pairs [32.8%]). Concordance was good in Groups 1 and 3 and moderate in Group 2. In Groups 2 and 3 at least one fetus presented high-risk results in 26.5% and 11.6% of twin pairs, respectively. Only gestational age < 32 weeks, gestational diabetes mellitus, and spontaneous conception were associated with a high risk of NRM in Group 2. There was good concordance of the risk of NRM between twins < 30.0 weeks and > 34.0 weeks. From 30.0 to 33.6 weeks 26.5% of the twin pairs had discordant results, with moderate concordance of the risk of NRM.

Human cDC1s display constitutive activation of the UPR sensor IRE1.

The intracellular mechanisms safeguarding DC function are of biomedical interest in several immune-related diseases. Type 1 conventional DCs (cDC1s) are prominent targets of immunotherapy typified by constitutive activation of the unfolded protein response (UPR) sensor IRE1. Through its RNase domain, IRE1 regulates key processes in cDC1s including survival, ER architecture and function. However, most evidence linking IRE1 RNase with cDC1 biology emerges from mouse studies and it is currently unknown whether human cDC1s also activate the enzyme to preserve cellular homeostasis. In this work, we report that human cDC1s constitutively activate IRE1 RNase in steady state, which is evidenced by marked expression of IRE1, XBP1s, and target genes, and low levels of mRNA substrates of the IRE1 RNase domain. On a functional level, pharmacological inhibition of the IRE1 RNase domain curtailed IL-12 and TNF production by cDC1s upon stimulation with TLR agonists. Altogether, this work demonstrates that activation of the IRE1/XBP1s axis is a conserved feature of cDC1s across species and suggests that the UPR sensor may also play a relevant role in the biology of the human lineage.

Effect of Maternal and Fetal Characteristics in Feto-Placental Doppler and Impact of Using Adjusted Standards in the Definition of Fetal Growth Restriction at Term.

INTRODUCTION: This study aimed to determine the effect and clinical impact of physiological characteristics on the 95th/5th centile of the umbilical artery (UA) Doppler and the cerebroplacental ratio (CPR), at 36+ weeks. METHODS: From the multicenter randomized trial "Ratio37," we selected 4,505 low-risk pregnant women between June 2016 and January 2020. We registered physiological characteristics and the pulsatility indexes (PI) of the UA and middle cerebral artery (36-39 weeks). The 95th/5th centile of the UA PI and CPR was modeled by quantile regression. To evaluate the clinical impact of adjusting Doppler, we retrospectively applied gestational age (GA) and fully adjusted standards to 682 small for gestational age (SGA)-suspected fetuses (37 weeks) from a cohort of consecutive patients obtained between January 2010 and January 2020. RESULTS: Several physiological characteristics significantly influenced the 95th/5th centile of the UA and CPR PI. The fully adjusted 95th centile of the UA was higher, and the 5th centile of the CPR was lower than GA-only-adjusted standards. Of the 682 SGA fetuses, 150 (22%) were classified as late fetal growth restricted only by GA and 112 (16.4%) when we adjusted Doppler. These 38 fetuses had similar perinatal outcome than the SGA group. DISCUSSION: The 95th/5th centile of the UA and CPR PI is significantly influenced by physiological characteristics. Adjusting Doppler standards could differentiate better between FGR and SGA.

The Novel Ultrasonographic Marker of Uterocervical Angle for Prediction of Spontaneous Preterm Birth in Singleton and Twin Pregnancies: A Systematic Review and Meta-Analysis.

The alteration of the uterocervical angle (UCA) has been proposed to play an important role in spontaneous preterm birth (sPTB). The aim of this systematic review and meta-analysis was to evaluate the evidence on the UCA predictive role in sPTB. In this study, PubMed, Web of Science, Scopus, and Google scholar were systematically searched from inception up to June 2020. Inter-study heterogeneity was also assessed using Cochrane's Q test and the I2 statistic. Afterward, the random-effects model was used to pool the weighted mean differences (WMDs) and the corresponding 95% confidence intervals (CIs). Eleven articles that reported second-trimester UCA of 5,061 pregnancies were included in this study. Our meta-analysis results indicate that a wider UCA significantly increases the risk of sPTB in following cases: all pregnancies (WMD = 15.25, 95% CI: 11.78-18.72, p < 0.001; I2 = 75.9%, p < 0.001), singleton (WMD = 14.43, 95% CI: 8.79-20.06, p < 0.001; I2 = 82.4%, p < 0.001), and twin pregnancies (WMD = 15.14, 95% CI: 13.42-16.87, p < 0.001; I2 = 0.0%, p = 0.464). A wider ultrasound-measured UCA in the second trimester seems to be associated with the increased risk of sPTB in both singleton and twin pregnancies, which reinforces the clinical evidence that UCA has the potential to be used as a predictive marker of sPTB.

Prescriptive Reference Standards of Third-Trimester Cerebroplacental Ratio and Its Physiological Determinants.

OBJECTIVE: To construct valid reference standards reflecting optimal cerebroplacental ratio and to explore its physiological determinants. METHODS: A cohort of 391 low-risk pregnancies of singleton pregnancies of nonmalformed fetuses without maternal medical conditions and with normal perinatal outcomes was created. Doppler measurements of the middle cerebral artery and umbilical artery were performed at 24-42 weeks. Reference standards were produced, and the influence of physiological determinants was explored by nonparametric quantile regression. The derived standards were validated in a cohort of 200 low-risk pregnancies. RESULTS: Maternal body mass index was significantly associated with the 5th centile of the cerebroplacental ratio. For each additional unit of body mass index, the 5th centile was on average 0.014 lower. The derived 5th, 10th, and 50th centiles selected in the validation cohort were 5, 9.5, and 51% of the measurements. CONCLUSIONS: This study provides methodologically sound prescriptive standards and suggests that maternal body mass index is a determinant of a cutoff commonly used for decision-making.

First trimester screening for preterm and term pre-eclampsia by maternal characteristics and biophysical markers in a low-risk population.

AIM: To develop a combined predictive model for preterm and term pre-eclampsia (PE) during the first trimester of pregnancy. METHODS: This investigation was a nested case-control study in singleton pregnancies at the Maternal-Fetal Medicine Unit, University of Chile Hospital. A priori risks for preterm and term PE were calculated by multivariate logistic regression analyses. Biophysical markers were log10 -transformed and expressed as multiples of the median. A multivariate logistic regression analysis was used to estimate a combined predictive model of preterm and term PE. Detection rates at different cut-off points were determined by a receiver operator curve analysis of a posteriori risks. RESULTS: First trimester mean arterial pressure and uterine artery Doppler pulsatility index were significantly higher in women who develop PE than in the unaffected group. The detection rate of preterm PE based on maternal characteristics and biophysical markers was 72% at a 10% false-positive rate, corresponding to a cut-off risk of 1 in 50. The detection rate for term PE was 30% at a 10% false-positive rate. CONCLUSION: Preterm PE can be predicted by a combination of maternal characteristics and biophysical markers. However, first trimester screening is less valuable for term PE.

Chorionic Bump: An Early Ultrasound Marker for Adverse Obstetric Outcome.

BACKGROUNDS/AIMS: To assess the perinatal outcome of pregnancies with chorionic bump detected at the first trimester of pregnancy. METHODS: This was a nested case-control study of pregnancies with chorionic bump identified at the first trimester ultrasound that was performed from October 2014 and October 2016. The control group consisted of the following 5 unaffected pregnancies after each case. From the first trimester ultrasound, maternal and perinatal characteristics were obtained and stored in a dedicated database. The primary outcome was defined as the presence of an alive new-born. Secondary outcome was defined as the presence of a composite adverse obstetric outcome. RESULTS: Eleven first trimester pregnancies affected by a chorionic bump and 55 controls were identified. The primary outcome was observed in 72.7 and 89.1% of chorionic bump and controls respectively (p = 0.2). The secondary outcome was observed in 45.5% of pregnancies with a chorionic bump versus 12.7% in the unaffected group (p = 0.01). First trimester uterine artery Doppler demonstrated a non-significant trend to be higher in the chorionic bump group. CONCLUSIONS: The presence of a chorionic bump is associated with a significant higher risk of adverse perinatal outcome.

Prediction of neonatal respiratory morbidity by quantitative ultrasound lung texture analysis: a multicenter study.

BACKGROUND: Prediction of neonatal respiratory morbidity may be useful to plan delivery in complicated pregnancies. The limited predictive performance of the current diagnostic tests together with the risks of an invasive procedure restricts the use of fetal lung maturity assessment. OBJECTIVE: The objective of the study was to evaluate the performance of quantitative ultrasound texture analysis of the fetal lung (quantusFLM) to predict neonatal respiratory morbidity in preterm and early-term (<39.0 weeks) deliveries. STUDY DESIGN: This was a prospective multicenter study conducted in 20 centers worldwide. Fetal lung ultrasound images were obtained at 25.0-38.6 weeks of gestation within 48 hours of delivery, stored in Digital Imaging and Communication in Medicine format, and analyzed with quantusFLM. Physicians were blinded to the analysis. At delivery, perinatal outcomes and the occurrence of neonatal respiratory morbidity, defined as either respiratory distress syndrome or transient tachypnea of the newborn, were registered. The performance of the ultrasound texture analysis test to predict neonatal respiratory morbidity was evaluated. RESULTS: A total of 883 images were collected, but 17.3% were discarded because of poor image quality or exclusion criteria, leaving 730 observations for the final analysis. The prevalence of neonatal respiratory morbidity was 13.8% (101 of 730). The quantusFLM predicted neonatal respiratory morbidity with a sensitivity, specificity, positive and negative predictive values of 74.3% (75 of 101), 88.6% (557 of 629), 51.0% (75 of 147), and 95.5% (557 of 583), respectively. Accuracy was 86.5% (632 of 730) and positive and negative likelihood ratios were 6.5 and 0.3, respectively. CONCLUSION: The quantusFLM predicted neonatal respiratory morbidity with an accuracy similar to that previously reported for other tests with the advantage of being a noninvasive technique.

Second-Trimester Anterior Cervical Angle in a Low-Risk Population as a Marker for Spontaneous Preterm Delivery.

OBJECTIVE: The aim of this article is to assess the use of the anterior cervical angle (ACA) as a predictor of spontaneous preterm delivery (sPTD) at 20+0-24+6 weeks of gestation in an unselected population. METHODS: We conducted a nested case-control study that included 93 women who later delivered spontaneously <34 weeks of gestation and 225 controls. The ACA was assessed retrospectively on all selected images using ImageJ® software. The concordance correlation coefficient was determined for the assessment of interobserver variability. Continuous variables were adjusted by maternal characteristics and expressed as the z-score or multiples of the expected normal median (MoM) of the unaffected group. Logistic regression analysis was used to evaluate whether any maternal characteristics and ultrasound variables were significantly associated with sPTD <34 weeks. RESULTS: ACA z-score values were significantly greater in women who later delivered <34 weeks compared to controls (ACA z-score = 1.32 ± 0.57 vs. -0.09 ± 0.35; p = 0.035). The best prediction of sPTD <34 weeks was provided by a model that combined cervical length (CL) MoM, ACA z-score and maternal characteristics. For a fixed false-positive rate of 10%, the detection rate for this model was 37.6%. CONCLUSION: A model combining maternal history, CL and ACA at 20+0-24+6 weeks of gestation can predict approximately 40% of the severe preterm births.

Maternal Plasma Nerve Growth Factor at the 11+0-13+6 Weeks' Scan as a Potential Angiogenic Marker of Preeclampsia: A Pilot Study.

OBJECTIVE: The aim of this study was to determine the role of nerve growth factor (NGF) in the first-trimester screening for preeclampsia (PE). METHODS: Uterine artery Doppler (UtAD) was determined transvaginally. Maternal concentrations of NGF were assessed in 42 patients who subsequently developed PE and in 95 controls. Quantile and multivariate regression analyses were performed for the NGF and UtAD adjustment and expressed as the multiple of the median (MoM) of the unaffected group. Logistic regression analysis was conducted to identify the best model for the prediction of PE. RESULTS: The maternal plasma concentration of NGF exhibited a trend towards lower values in patients who subsequently developed early-onset PE (e-PE) compared to controls (10.7 vs. 38.2 pg/ml, respectively; p = not significant). The median MoM NGF in the all-PE, e-PE and control groups was 0.97 (95% CI 0.13-3.36), 0.62 (95% CI 0.16-2.19) and 1.00 (95% CI 0.20-2.94), respectively (p = not significant). The best predictors of PE were previous PE, chronic hypertension and UtAD. With a false-positive rate of 10%, the detection rates (DRs) of all-PE and e-PE were 38 and 50%, respectively. The addition of MoM NGF did not improve the DR of PE. CONCLUSION: First-trimester NGF tends to be lower in patients who subsequently develop e-PE.

Serie guías clínicas: parto prematuro / Clinical guidelines series: preterm labor

Determinar factores de riesgo de parto prematuro espontáneo < 34 semanas.Determinar las medidas de prevención de parto prematuro espontáneo < 34 semanas.Conocer la alta tasa de falsos positivos del diagnóstico clínico de parto prematuro y el papel de la evaluación ecográfica del cérvix.Conocer el concepto del uso de tocolisis en parto prematuro.Valorar el papel de los corticoides y sulfato de magnesio en la reducción de morbi-mortalidad perinatal en el parto prematuro.Evaluar el papel de los antibióticos en el parto prematuro con membranas íntegras.

Increased PR Interval in Fetuses of Patients with Intrahepatic Cholestasis of Pregnancy.

OBJECTIVE: To evaluate the fetal mechanical PR interval in fetuses from pregnancies with intrahepatic cholestasis of pregnancy (ICP). METHODS: A case-control study was conducted in the Maternal-Fetal Medicine Unit at Hospital Carlos Van Buren between 2011 and 2013. Fetal echocardiography was performed in patients with ICP and normal pregnancies. Demographic and clinical characteristics were compared using the Mann-Whitney U test for continuous variables. A p value <0.05 was considered significant. RESULTS: 51 patients with ICP were compared with 51 unaffected pregnancies. There were no significant differences in neither demographic nor clinical characteristics between the two groups. The fetal PR interval was significantly longer in the ICP group when compared to the control group (134.6 ± 12 vs. 121.4 ± 10 ms, p < 0.001). Moreover, four fetuses from the ICP group had a mechanical PR interval >150 ms, which is compatible with a first-degree atrioventricular block. Two fetuses were identified in the neonatal period and were transferred to pediatric cardiology for follow-up, with a normal mechanical PR after the first month of life. CONCLUSIONS: We demonstrated that the fetal cardiac conduction system is altered in fetuses of patients with ICP. Further research is necessary to determine whether this alteration is related to stillbirths seen in ICP.