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.

Death and severe morbidity in isolated periviable small-for-gestational-age fetuses.

OBJECTIVE: This study aims to predict perinatal death or severe sequelae in isolated small-for-gestational-age fetuses, diagnosed at a periviable gestational age, based on ultrasound and Doppler parameters at diagnosis. DESIGN: Observational study. SETTING: A tertiary perinatal centre. POPULATION: A cohort of singleton non-malformed fetuses suspected to be small for gestational age (estimated fetal weight, EFW, <10th centile) diagnosed at 22.0-25.6 weeks of gestation. The following parameters were recorded at diagnosis: severe smallness (<3rd centile); absent or reversed end-diastolic velocity in umbilical artery; abnormal middle cerebral artery Doppler; abnormal cerebroplacental ratio; abnormal uterine artery Doppler; and absent or reversed end-diastolic velocity in the ductus venosus. METHODS: Logistic regression analysis. MAIN OUTCOME MEASURES: Predictive performance of EFW and Doppler parameters for short-term adverse outcome of perinatal morbimortality and composite serious adverse outcomes (death, neurological impairment or severe bronchopulmonary dysplasia). RESULTS: A total of 155 pregnancies were included. There were 13 (8.4%) intrauterine and 11 (7.7%) neonatal deaths. A short-term adverse perinatal outcome occurred in 40 (25.8%) pregnancies. There were 31 (20%) cases of serious adverse outcomes. For the prediction of serious adverse outcomes, the combination of absent or reversed end-diastolic velocity in the umbilical artery and impaired middle cerebral artery detected by Doppler evaluation achieved a detection rate of 87%, with a false-positive rate of 14% (accuracy 86%). CONCLUSION: In periviable isolated small-for-gestational-age fetuses, a Doppler evaluation of the umbilical and fetal brain circulation can accurately predict short-term adverse perinatal complications and serious adverse outcomes.

Perinatal outcomes in 13,626 singleton pregnancies after autologous IVF across three continents over 7 years.

PURPOSE: Are trends in singleton autologous IVF perinatal outcomes consistent over time among five international infertility centers? METHODS: This was a retrospective cohort study from January 1, 2012, to December 31, 2018. This study was performed through a large infertility network at five international infertility centers in which patients who had a singleton live birth resulting from fresh and frozen autologous IVF cycles were included. The primary outcome was live birth weight (BW) with secondary outcomes of preterm birth (PTB), large for gestational age (LGA), small for gestational age (SGA), and gestational age at delivery. RESULTS: The entire cohort (n = 13,626) consisted of 6941 fresh and 6685 frozen autologous IVF cycles leading to singleton deliveries. Maternal age, parity, body mass index, neonatal sex, and GA at delivery were similar for fresh and frozen IVF cycles in the entire cohort and within each infertility center. Four centers had a trend of decreased BW and three centers had decreased rates of PTB before 32 and 28 weeks and LGA newborns annually, although significance was not reached. Three IVF centers had annual increased trends of PTB before 37 weeks and four centers had increased rates of SGA newborns, although significance was not reached. CONCLUSION: Similar trends in perinatal outcomes were present across five international infertility centers over 7 years. Additional studies are crucial to further assess and optimize perinatal outcomes at an international level.

Perinatal outcomes in 6640 singleton pregnancies after donor oocyte IVF across three continents over 7 years.

PURPOSE: Are trends in singleton donor oocyte IVF perinatal outcomes consistent over time among four international ethnically diverse infertility centers? METHODS: This retrospective cohort consisted of an infertility network of four international IVF centers across three continents. Singleton live births resulting from fresh and frozen donor oocyte embryo transfers from January 1, 2012 to December 31, 2018 were included. The main outcome measures were birth weight (BW), preterm birth (PTB), large for gestational age (LGA), small for gestational age (SGA) and gestational age (GA) at delivery. RESULTS: The entire cohort (n = 6640) consisted of 4753 fresh and 1887 frozen donor oocyte embryo transfers. Maternal age, parity, body mass index, neonatal sex and GA at delivery were similar for fresh and frozen donor oocyte embryo transfers in the entire cohort and within each infertility center. All four centers had a trend of decreased BW and rates of PTB before 32 weeks annually, although significance was not reached. Three of the four centers had annual increased trends of PTB before 37 weeks and LGA newborns, although significance was not reached. BWs for the entire cohort for fresh and frozen donor embryo transfers were 3166 g ± 601 g and 3137 g ± 626 g, respectively. CONCLUSION: Similar trends in perinatal outcomes were present across four international infertility centers over 7 years. The overall perinatal trends in donor oocyte IVF may be applicable to centers worldwide, but further studies in more geographic regions are needed.

Fetal Growth Velocity according to the Mode of Assisted Conception.

INTRODUCTION: Pregnancies conceived through assisted reproductive techniques (ARTs) are on the rise worldwide and have been associated with a higher risk of placental-related disease in the third trimester. METHODS: A cohort was created of singleton pregnancies after assisted reproduction, admitted at our institution for delivery, between January 2020 and August 2022. Fetal growth velocity from the second trimester to delivery was compared against a gestational-age-matched group of pregnancies spontaneously conceived according to the origin of the selected oocyte (i.e., autologous vs. donated). RESULTS: 125 singleton pregnancies conceived through ART were compared to 315 singleton spontaneous conceptions. Overall, after adjusting for possible confounders, multivariate analysis demonstrated that ART pregnancies had a significantly lower estimated fetal weight (EFW) z-velocity from the second trimester to delivery (adjusted mean difference = -0.002; p = 0.035) and a higher frequency of EFW z-velocity in the lowest decile (adjusted OR = 2.32 [95% CI, 1.15-4.68]). Also, when ART pregnancies were compared according to the type of oocyte, those conceived with donated oocytes showed a significantly lower EFW z-velocity from the second trimester to delivery (adjusted mean difference = -0.008; p = 0.001) and a higher frequency of EFW z-velocity in the lowest decile (adjusted OR = 5.33 [95% CI, 1.34-21.5]). CONCLUSIONS: Pregnancies achieved through ART exhibit a pattern of lower growth velocity across the third trimester, especially those conceived with donated oocytes. The former represents a sub-group at the highest risk of placental dysfunction that may warrant closer follow-up.

Clinical Opinion: The diagnosis and management of suspected fetal growth restriction: an evidence-based approach.

This study reviewed the literature about the diagnosis, antepartum surveillance, and time of delivery of fetuses suspected to be small for gestational age or growth restricted. Several guidelines have been issued by major professional organizations, including the International Society of Ultrasound in Obstetrics and Gynecology and the Society for Maternal-Fetal Medicine. The differences in recommendations, in particular about Doppler velocimetry of the ductus venosus and middle cerebral artery, have created confusion among clinicians, and this review has intended to clarify and highlight the available evidence that is pertinent to clinical management. A fetus who is small for gestational age is frequently defined as one with an estimated fetal weight of <10th percentile. This condition has been considered syndromic and has been frequently attributed to fetal growth restriction, a constitutionally small fetus, congenital infections, chromosomal abnormalities, or genetic conditions. Small for gestational age is not synonymous with fetal growth restriction, which is defined by deceleration of fetal growth determined by a change in fetal growth velocity. An abnormal umbilical artery Doppler pulsatility index reflects an increased impedance to flow in the umbilical circulation and is considered to be an indicator of placental disease. The combined finding of an estimated fetal weight of <10th percentile and abnormal umbilical artery Doppler velocimetry has been widely accepted as indicative of fetal growth restriction. Clinical studies have shown that the gestational age at diagnosis can be used to subclassify suspected fetal growth restriction into early and late, depending on whether the condition is diagnosed before or after 32 weeks of gestation. The early type is associated with umbilical artery Doppler abnormalities, whereas the late type is often associated with a low pulsatility index in the middle cerebral artery. A large randomized clinical trial indicated that in the context of early suspected fetal growth restriction, the combination of computerized cardiotocography and fetal ductus venosus Doppler improves outcomes, such that 95% of surviving infants have a normal neurodevelopmental outcome at 2 years of age. A low middle cerebral artery pulsatility index is associated with an adverse perinatal outcome in late fetal growth restriction; however, there is no evidence supporting its use to determine the time of delivery. Nonetheless, an abnormality in middle cerebral artery Doppler could be valuable to increase the surveillance of the fetus at risk. We propose that fetal size, growth rate, uteroplacental Doppler indices, cardiotocography, and maternal conditions (ie, hypertension) according to gestational age are important factors in optimizing the outcome of suspected fetal growth restriction.

Development of standard definitions and grading for Maternal and Fetal Adverse Event Terminology.

OBJECTIVE: Adverse event (AE) monitoring is central to assessing therapeutic safety. The lack of a comprehensive framework to define and grade maternal and fetal AEs in pregnancy trials severely limits understanding risks in pregnant women. We created AE terminology to improve safety monitoring for developing pregnancy drugs, devices and interventions. METHOD: Existing severity grading for pregnant AEs and definitions/indicators of 'severe' and 'life-threatening' conditions relevant to maternal and fetal clinical trials were identified through a literature search. An international multidisciplinary group identified and filled gaps in definitions and severity grading using Medical Dictionary for Regulatory Activities (MedDRA) terms and severity grading criteria based on Common Terminology Criteria for Adverse Event (CTCAE) generic structure. The draft criteria underwent two rounds of a modified Delphi process with international fetal therapy, obstetric, neonatal, industry experts, patients and patient representatives. RESULTS: Fetal AEs were defined as being diagnosable in utero with potential to harm the fetus, and were integrated into MedDRA. AE severity was graded independently for the pregnant woman and her fetus. Maternal (n = 12) and fetal (n = 19) AE definitions and severity grading criteria were developed and ratified by consensus. CONCLUSIONS: This Maternal and Fetal AE Terminology version 1.0 allows systematic consistent AE assessment in pregnancy trials to improve safety.

INTERGROWTH-21st versus a customized method for the prediction of neonatal nutritional status in hypertensive disorders of pregnancy.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) generate complications and are one of the principal causes of maternal, foetal, and neonatal mortality worldwide. It has been observed that in pregnancies with HDP, the incidence of foetuses small for their gestational age (SGA) is twice as high as that in noncomplicated pregnancies. In women with HDP, the identification of foetuses (SGA) is substantially important, as management and follow-up are determined by this information. OBJECTIVE: The objective of this study was to evaluate whether the INTERGROWTH-21st method or customized birthweight references better identify newborns with an abnormal nutritional status resulting from HDP. METHOD: A comparative analysis study was designed with two diagnostic methods for the prediction of neonatal nutritional status in pregnancies with HDP. The performance of both methods in identifying neonatal malnutrition (defined by a neonatal body mass index < 10th centile or a ponderal index < 10th centile) was assessed by calculating sensitivity, specificity, positive predictive value, negative predictive value, diagnostic odds ratio, Youden's index and probability ratios. RESULTS: The study included 226 pregnant women diagnosed with HDP. The customized method identified 45 foetuses as small for gestational age (19.9%), while the INTERGROWTH-21st method identified 27 newborns with SGA (11.9%). The difference between proportions was statistically significant (p < 0.01). Using body mass index (< 10th centile) as a measure of nutritional status, newborns identified as SGA by the customized method showed a higher risk of malnutrition than those identified as SGA by INTERGROWTH-21st (RR: 4.87 (95% CI: 1.86-12.77) vs. 3.75 (95% CI: 1.49-9.43)) (DOR: 5.56 (95% CI: 1.82-16.98) vs. 4.84 (95% CI: 1.51-15.54)) Even when using Ponderal index (< 10th centile), newborns identified as SGA by the customized method showed a higher risk of malnutrition than those identified as SGA by INTERGROWTH-21st (RR 2.37 (95% CI: 1.11-5.05) vs. 1.68 (95% CI: 0.70-4.03))(DOR 2.62 (95% CI: 1.00-6.87) vs. 1.90 (95% CI: 0.61-5.92)). CONCLUSION: In pregnant women with HDP, the predictive ability of the customized foetal growth curves to identify neonatal malnutrition appears to surpass that of INTERGROWTH-21st.

Congenital Cytomegalovirus Awareness and Knowledge among Health Professionals and Pregnant Women: An Action towards Prevention.

INTRODUCTION: Cytomegalovirus (CMV) is a major cause of childhood disabilities, and consensus recommendations emphasize the importance of hygienic measures to reduce perinatal infection. Our study aimed to evaluate the level of awareness about CMV among health professionals and pregnant women. METHODS: We submitted a 20-item online survey regarding CMV perinatal infection to all obstetricians and midwives in Catalonia (Spain) and a 7-item lay version of the questionnaire to 700 pregnant women. Levels of knowledge were compared among groups. RESULTS: Of the 1,449 health professionals approached, 338 surveys were answered. 72% of professionals considered CMV a relevant problem. 47% of obstetricians and 28% of midwives (p ≤ 0.001) routinely informed pregnant women, and less than half knew the risk of fetal transmission. We observed significant differences in knowledge between obstetricians and midwives concerning the risks of recurrent infections, risk of transmission, and risk of severe infection (60.7% vs. 45.6%, p = 0.006 and 50.6% vs. 22.5%, p ≤ 0.001); and regarding maternal and neonatal symptoms and newborn sequelae (23% vs. 8.8%, p ≤ 0.001). Of the 700 women approached, we obtained a response rate of 72%. Only 23% had previously heard about CMV, 22% identified transmission routes, and 15% preventive measures. Compared to women without risk factors for CMV infection, women at greater risk had heard more about CMV (mothers of children <3 years: 36% vs. 20%, p < 0.001; occupational exposure: 43% vs. 20%, p ≤ 0.001) and had received more information (mothers of children <3 years: 18% vs. 9.5%, p ≤ 0.001; occupational exposure: 23% vs. 9.3%, p = 0.001). CONCLUSION: Health care professionals have limited knowledge about CMV and may fail to enforce preventive measures. While pregnant women have limited awareness about CMV infection, they recognize the need for information. Health campaigns should be promoted to enhance awareness about this perinatal infection.

Impact of Severe Acute Respiratory Syndrome Coronavirus 2 Infection on Pregnancy Outcomes: A Population-based Study.

BACKGROUND: We performed a population-based study to describe the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on pregnancy outcomes. METHODS: This prospective, population-based study included pregnant women who consecutively presented at first/second trimester visits or at delivery at 3 hospitals in Barcelona, Spain. SARS-CoV-2 antibodies (immunoglobulin [Ig] G and IgM/IgA) were measured in all participants, and nasopharyngeal real-time polymerase chain reaction (RT-PCR) was performed at delivery. The primary outcome was a composite of pregnancy complications in SARS-CoV-2-positive vs negative women that included miscarriage, preeclampsia, preterm delivery, perinatal death, small-for-gestational-age newborn, or neonatal admission. Secondary outcomes were components of the primary outcome plus abnormal fetal growth, malformation, or intrapartum fetal distress. Outcomes were also compared between positive symptomatic and positive asymptomatic SARS-CoV-2 women. RESULTS: Of 2225 pregnant women, 317 (14.2%) were positive for SARS-CoV-2 antibodies (n = 314, 99.1%) and/or RT-PCR (n = 36, 11.4%). Among positive women, 217 (68.5%) were asymptomatic, 93 (29.3%) had mild coronavirus disease 2019 (COVID-19), and 7 (2.2%) had pneumonia, of whom 3 required intensive care unit admission. In women with and without SARS-CoV-2 infection, the primary outcome occurred in 43 (13.6%) and 268 (14%), respectively (risk difference, -0.4%; 95% confidence interval, -4.1% to 4.1). Compared with noninfected women, those with symptomatic COVID-19 had increased rates of preterm delivery (7.2% vs 16.9%, P = .003) and intrapartum fetal distress (9.1% vs 19.2%, P = .004), while asymptomatic women had rates that were similar to those of noninfected cases. Among 143 fetuses from infected mothers, none had anti-SARS-CoV-2 IgM/IgA in cord blood. CONCLUSIONS: The overall rate of pregnancy complications in women with SARS-CoV-2 infection was similar to that of noninfected women. However, symptomatic COVID-19 was associated with modest increases in preterm delivery and intrapartum fetal distress.

Placental growth factor testing in the management of late preterm preeclampsia without severe features: a multicenter, randomized, controlled trial.

BACKGROUND: In women with late preterm preeclampsia, the optimal time for delivery remains a controversial topic, because of the fine balance between the maternal benefits from early delivery and the risks for prematurity. It remains challenging to define prognostic markers to identify women at highest risk for complications, in which case a selective, planned delivery may reduce the adverse maternal and perinatal outcomes. OBJECTIVE: This trial aimed to determine whether using an algorithm based on the maternal levels of placental growth factor in women with late preterm preeclampsia to evaluate the best time for delivery reduced the progression to preeclampsia with severe features without increasing the adverse perinatal outcomes. STUDY DESIGN: This parallel-group, open-label, multicenter, randomized controlled trial was conducted at 7 maternity units across Spain. We compared selective planned deliveries based on maternal levels of placental growth factor at admission (revealed group) and expectant management under usual care (concealed group) with individual randomization in singleton pregnancies with late preterm preeclampsia from 34 to 36+6 weeks' gestation. The coprimary maternal outcome was the progression to preeclampsia with severe features. The coprimary neonatal outcome was morbidity at infant hospital discharge with a noninferiority hypothesis (noninferiority margin of 10% difference in incidence). Analyses were conducted according to intention-to-treat. RESULTS: Between January 1, 2016, and December 31, 2019, 178 women were recruited. Of those women, 88 were assigned to the revealed group and 90 were assigned to the concealed group. The data analysis was performed before the completion of the required sample size. The proportion of women with progression to preeclampsia with severe features was significantly lower in the revealed group than in the concealed group (adjusted relative risk, 0.5; 95% confidence interval, 0.33-0.76; P=.001). The proportion of infants with neonatal morbidity was not significantly different between groups (adjusted relative risk, 0.77; 95% confidence interval, 0.39-1.53; P=.45). CONCLUSION: There is evidence to suggest that the use of an algorithm based on placental growth factor levels in women with late preterm preeclampsia leads to a lower rate of progression to preeclampsia with severe features and reduces maternal complications without worsening the neonatal outcomes. This trade-off should be discussed with women with late preterm preeclampsia to allow shared decision making about the timing of delivery.

Prescriptive standards of echocardiographic morphometric and functional parameters in uncomplicated monochorionic diamniotic fetuses.

OBJECTIVE: To create prescriptive standards of cardiac morphometric and functional parameters in a cohort of uncomplicated monochorionic diamniotic (MCDA) twins. METHOD: Fetal echocardiography was performed in a cohort of uncomplicated monochorionic twin fetuses scanned longitudinally, including comprehensive morphometric and functional parameters, using 2-D imaging, M-mode and conventional Doppler. A multilevel polynomial hierarchical model adjusted by gestational age and estimated fetal weight was used to fit each cardiac parameter. RESULTS: The global heart dimensions including the atrial and ventricular areas, the ventricles dimensions and myocardial wall thicknesses and most of the functional parameters, such as the longitudinal myocardial motion and the biventricular cardiac output showed a positive quadratic increment throughout pregnancy. On the other hand, the left ejection fraction, shortening fraction and right fractional area change decreased with gestational age. Scatterplots for the main structural and functional parameters and ratios by gestational age, with mean, 5th, 10th, 90th, and 95th percentiles are provided. Regression equations by estimated fetal weight are also created. CONCLUSION: We provide specific comprehensive echocardiographic prescriptive standards for uncomplicated MCDA twin fetuses following current standardized methodology. The implementation of these charts will potentially help to better identify abnormal cardiovascular parameters associated to monochorionic complications.

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 Preeclamptic Environment Promotes the Activation of Transcription Factor Kappa B by P53/RSK1 Complex in a HTR8/SVneo Trophoblastic Cell Line.

Preeclampsia is a pregnancy disorder associated with shallow placentation, forcing placental cells to live in hypoxic conditions. This activates the transcription factor kappa B (NFκB) in maternal and placental cells. Although the role of NFκB in preeclampsia is well documented, its mechanism of activation in trophoblastic cells has been never studied. This study investigates the mechanism of NFκB activation in a first trimester trophoblastic cell line (HTR8/SVneo) stimulated by a medium containing serum from preeclamptic (PE) or normotensive (C) women in hypoxic (2% O2) or normoxic (8% O2) conditions. The results indicate that in HTR8/SVneo cells, the most widely studied NFκB pathways, i.e., canonical, non-canonical and atypical, are downregulated in environment PE 2% O2 in comparison to C 8% O2. Therefore, other pathways may be responsible for NFκB activation. One such pathway depends on the activation of NFκB by the p53/RSK1 complex through its phosphorylation at Serine 536 (pNFκB Ser536). The data generated by our study show that inhibition of the p53/RSK1 pathway by p53-targeted siRNA results in a depletion of pNFκB Ser536 in the nucleus, but only in cells incubated with PE serum at 2% O2. Thus, the p53/RSK1 complex might play a critical role in the activation of NFκB in trophoblastic cells and preeclamptic placentas.

Development and validation of a multivariable prediction model of spontaneous preterm delivery and microbial invasion of the amniotic cavity in women with preterm labor.

BACKGROUND: Early spontaneous preterm delivery is often associated with microbial invasion of the amniotic cavity and/or intraamniotic inflammation. OBJECTIVE: The objective of the study was to develop and validate clinically feasible multivariable prediction models of spontaneous delivery within 7 days and microbial invasion of the amniotic cavity in women admitted with diagnose of preterm labor and intact membranes below 34 weeks. STUDY DESIGN: We used data from a cohort of women admitted from 2012 to 2018 with diagnosis of preterm labor below 34 weeks who had undergone amniocentesis to rule out microbial invasion of the amniotic cavity. The main outcome was spontaneous delivery within 7 days from admission. The secondary outcome was microbial invasion of the amniotic cavity, defined by a positive culture and/or 16S ribosomal RNA gene in the amniotic fluid. The sample (n = 358) was divided into derivation (2012-2016) and validation cohorts (2017-2018). Logistic regression models using a stepwise selection of variables were developed for the outcomes evaluated. We explored as predictive variables ultrasound cervical length measurement at admission, maternal C-reactive protein, gestational age, amniotic fluid glucose, and interleukin-6 (expressed as log units). Models were developed in the derivation cohort and applied to the validation cohort and diagnostic performance was calculated. RESULTS: The derivation cohort included 263 women and the validation cohort 95 women. One hundred five of the women (39%, 105 of 268) spontaneously delivered in the following 7 days and 68 (19%, 68 of 358) had microbial invasion of the amniotic cavity. For spontaneous delivery within 7 days after admission, 4 predictors were identified: cervical length at admission, gestational age, amniotic fluid glucose, and interleukin-6. The diagnostic performance of the model was assessed in the validation cohort using the receiver operating characteristic curve and showed an area under curve of 0.86 (95% confidence interval, 0.77-0.95) with a detection rate of spontaneous delivery within 7 days of 87%, a false-positive rate of 33%, a negative predictive value of 80%, and a negative likelihood ratio of 0.1908. For microbial invasion of the amniotic cavity, 2 independent predictors of the amniotic cavity were identified: amniotic fluid glucose and maternal C-reactive protein. The receiver operating characteristic curve and an area under curve in the validation cohort was 0.83 (95% confidence interval, 0.70-0.96) with a detection rate of 76%, a false-positive rate of 8%, a negative predictive value of 93%, and a negative likelihood ratio of 0.2591. CONCLUSION: In women with preterm labor, we propose 2 clinically feasible prediction models to classify as low vs high risk of spontaneous delivery within 7 days and of microbial invasion of the amniotic cavity. The models showed a high diagnostic performance and could be of value to optimize clinical management.

Heparin therapy in placental insufficiency: Systematic review and meta-analysis.

INTRODUCTION: The objective of this study was to establish whether heparin improves the neonatal outcome of fetuses with suspected placental insufficiency. MATERIAL AND METHODS: Before data extraction, the project was registered in the PROSPERO International Prospective Register of Systematic Reviews (registration number: CRD42019117627). A systematic search was performed to identify relevant studies, using PubMed, SCOPUS, ISI Web of Knowledge, and PROSPERO database for meta-analysis. Suspected placental insufficiency was defined as either an estimated fetal weight or abdominal circumference below the 10th centile or when at least 2 of the following criteria were met: (1) abnormal biochemical markers, (2) sonographic evidence of abnormal placental morphology, or (3) abnormal uterine artery Doppler. Heparin in any commercial presentation was defined as the intervention. Mean difference (MD) by random effects model was used. Heterogeneity between studies was assessed using Cochran's Q, H, and I2 statistics. RESULTS: From 1159 assessed studies, two were retained for analysis. The results showed a significantly higher birthweight (MD 365; 95% CI 236 to 494; P < 0.001) and a significant increase of gestational age at birth by 1 week in those women treated with heparin (MD 0.806; 95% CI 0.354 to 1.258; P < 0.001). However, there were no significant differences in Apgar scores, neonatal admission, neonatal mortality, or composite neonatal morbidity. CONCLUSIONS: In women with very high suspicion of placental insufficiency, heparin may increase fetal growth and prolong pregnancy. There is no evidence for a beneficial effect of heparin in reducing neonatal adverse outcomes.

Cytogenetic Investigation in 136 Consecutive Stillbirths: Does the Tissue Type Affect the Success Rate of Chromosomal Microarray Analysis and Karyotype?

BACKGROUND: Chromosomal anomalies are a recognized cause of stillbirth, accounting for 6-17% of the cases. As a diagnostic laboratory method in this setting, conventional karyotyping has two main drawbacks: the need for viable fetal cells in a dead fetus and its limited resolution as compared to alternative techniques. OBJECTIVE: To assess the effectiveness of cytogenetic analysis in stillbirths between different testing methods and different sampled tissues. METHODS: From 2011 to 2017, 145 stillborn fetuses (defined as fetal losses after 22 weeks) were delivered in our center. The stillbirth protocol includes genetic testing by means of a karyotype, QF-PCR, or chromosomal microarray analysis (CMA), depending on the presence of fetal structural anomalies and the study time period. The success rates were compared between tests and between different sampled tissues. RESULTS: Consent was granted for cytogenetic analysis in 136 stillbirths. Test success rate was 100% (38/38) for CMA independent of the sampled tissue, 99% (65/66) for QF-PCR, and 66% (65/98) for karyotyping. The success rate for karyotyping was 48% (69/145) of the total tissues samples, showing great variation according to the tissue sampled: 83% (40/48) in amniotic fluid, 78% (21/27) in the placenta, 13% (7/54) in fetal skin, and 6.3% (1/16) in fetal blood. Four full or partial aneuploidies (trisomy 9, trisomy 22, tetrasomy 18p, and monosomy X) and 2 microdeletions (del2p16.3 and del1q13.2q13.4) were found, resulting in a 3.9% (4/103) prevalence for full or partial aneuploidy and a 5.3% prevalence (2/38) for submicroscopic abnormalities. CONCLUSIONS: Amniotic fluid should be the preferred tissue source in the cytogenetic analysis of stillbirth due to its high success rate. Between tests, CMA is a preferable method because of its higher test success rate, independent of the sampled tissue, and higher diagnostic yield including chromosomal and submicroscopic anomalies.

Coronavirus Disease 2019 in Pregnancy: A Clinical Management Protocol and Considerations for Practice.

The coronavirus disease 2019 (COVID-19) pandemic has represented a major impact to health systems and societies worldwide. The generation of knowledge about the disease has occurred almost as fast as its global expansion. The mother and fetus do not seem to be at particularly high risk. Nevertheless, obstetrics and maternal-fetal medicine practice have suffered profound changes to adapt to the pandemic. In addition, there are aspects specific to COVID-19 and gestation that should be known by specialists in order to correctly diagnose the disease, classify the severity, distinguish specific signs of COVID-19 from those of obstetric complications, and take the most appropriate management decisions. In this review we present in a highly concise manner an evidence-based protocol for the management of COVID-19 in pregnancy. We briefly contemplate all relevant aspects that we believe a specialist in obstetrics and maternal medicine should know, ranging from basic concepts about the disease and protection measures in the obstetric setting to more specific aspects related to maternal-fetal management and childbirth.

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.

Diagnostic performance of third-trimester ultrasound for the prediction of late-onset fetal growth restriction: a systematic review and meta-analysis.

OBJECTIVE: The objective of the study was to establish the diagnostic performance of ultrasound screening for predicting late smallness for gestational age and/or fetal growth restriction. DATA SOURCES: A systematic search was performed to identify relevant studies published since 2007 in English, Spanish, French, Italian, or German, using the databases PubMed, ISI Web of Science, and SCOPUS. STUDY ELIGIBILITY CRITERIA: We used rrospective and retrospective cohort studies in low-risk or nonselected singleton pregnancies with screening ultrasound performed at ≥32 weeks of gestation. STUDY APPRAISAL AND SYNTHESIS METHODS: The estimated fetal weight and fetal abdominal circumference were assessed as index tests for the prediction of birthweight <10th (i.e. smallness for gestational age), less than the fifth, and less than the third centile and fetal growth restriction (estimated fetal weight less than the third or estimated fetal weight <10th plus Doppler signs). Quality of the included studies was independently assessed by 2 reviewers, using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. For the meta-analysis, hierarchical summary receiver-operating characteristic curves were constructed, and quantitative data synthesis was performed using random-effects models. The sensitivity of the abdominal circumference <10th centile and estimated fetal weight <10th centile for a fixed 10% false-positive rate was derived from the corresponding hierarchical summary receiver-operating characteristic curves. Heterogeneity between studies was visually assessed using Galbraith plots, and publication bias was assessed by funnel plots and quantified by Deeks' method. RESULTS: A total of 21 studies were included. Observed pooled sensitivities of abdominal circumference and estimated fetal weight <10th centile for birthweight <10th centile were 35% (95% confidence interval, 20-52%) and 38% (95% confidence interval, 31-46%), respectively. Observed pooled specificities were 97% (95% confidence interval, 95-98%) and 95% (95% confidence interval, 93-97%), respectively. Modeled sensitivities of abdominal circumference and estimated fetal weight <10th centile for 10% false-positive rate were 78% (95% confidence interval, 61-95%) and 54% (95% confidence interval, 46-52%), respectively. The sensitivity of estimated fetal weight <10th centile was better when aimed to fetal growth restriction than to smallness for gestational age. Meta-regression analysis showed a significant increase in sensitivity when ultrasound evaluation was performed later in pregnancy (P = .001). CONCLUSION: Third-trimester abdominal circumference and estimated fetal weight perform similar in predicting smallness for gestational age. However, for a fixed 10% false-positive rate extrapolated sensitivity is higher for abdominal circumference. There is evidence of better performance when the scan is performed near term and when fetal growth restriction is the targeted condition.