The roll of placental growth in the prediction of preeclampsia in asymptomatic women:systematic review of the literature and meta-analysis. Hierarchical models for meta-analysis of diagnostic test accuracy

Depto. de Estadística y Ciencia de los DatosFac. de Estudios EstadísticosFALSEsubmitte

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Implementation of maternal blood cell-free DNA testing in early screening for aneuploidies.

Several externally blinded validation and implementation studies in the last 9 years have shown that it is now possible, through analysis of cell-free (cf) DNA in maternal blood, to effectively detect a high proportion of fetuses affected by trisomies 21, 18, and 13 at a much lower false-positive rate (FPR) than all other existing screening methods. This article is aimed at reviewing technical and clinical considerations for implementing cfDNA testing in routine practice, including methods of analysis, performance of the test, models for clinical implementation, and interpretation of results.post-print305 K

The Fetal Growth Restriction at Term Managed by Angiogenic Factors Versus Feto-Maternal Doppler (GRAFD) Trial to Avoid Adverse Perinatal Outcomes: Protocol for a Multicenter, Open-Label, Randomized Controlled Trial.

Background: Fetal smallness affects 10% of pregnancies. Small fetuses are at a higher risk of adverse outcomes. Their management using estimated fetal weight and feto-maternal Doppler has a high sensitivity for adverse outcomes; however, more than 60% of fetuses are electively delivered at 37 to 38 weeks. On the other hand, classification using angiogenic factors seems to have a lower false-positive rate. Here, we present a protocol for the Fetal Growth Restriction at Term Managed by Angiogenic Factors Versus Feto-Maternal Doppler (GRAFD) trial, which compares the use of angiogenic factors and Doppler to manage small fetuses at term. Objective: The primary objective is to demonstrate that classification based on angiogenic factors is not inferior to estimated fetal weight and Doppler at detecting fetuses at risk of adverse perinatal outcomes. Methods: This is a multicenter, open-label, randomized controlled trial conducted in 20 hospitals across Spain. A total of 1030 singleton pregnancies with an estimated fetal weight ≤10th percentile at 36+0 to 37+6 weeks+days 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 ≥38 will be classified as having fetal growth restriction; otherwise, they will be classified as being small for gestational age. In both arms, the fetal growth restriction group will be delivered at ≥37 weeks and the small for gestational age group at ≥40 weeks. We will assess differences between the groups by calculating the relative risk, the absolute difference between incidences, and their 95% CIs. Results: Recruitment for this study started on September 28, 2020. The study results are expected to be published in peer-reviewed journals and disseminated at international conferences in early 2023. Conclusions: The angiogenic factor–based protocol may reduce the number of pregnancies classified as having fetal growth restriction 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.post-print467 K

Genome-Wide Cell-Free DNA Test for Fetal Chromosomal Abnormalities and Variants: Unrestricted Versus Restricted Reporting.

This study aimed to compare the screening performance of genome-wide cfDNA testing for chromosomal abnormalities between two periods where additional findings were reported and not reported. Data were obtained from consecutive pregnant women with a singleton pregnancy at ≥10 weeks who requested cfDNA testing during 2015–2019. The performance of screening of the cfDNA test was determined by calculating the concordance rate, detection rate, and false-positive rate. Data from 3981 women were included. The no-result rates were similar between the two reporting periods (2.04% vs. 2.08%). Concordance rates for trisomy 21 and 18 were 100% and 100%, respectively. There were two cases tested high risk for trisomy 13, with a concordance rate of 0%. In total, 12 cases were high risk for any sex chromosome aneuploidy with an overall concordance of 75%, and 15 cases tested high risk for any rare autosomal trisomy, with a 13.3% concordance rate. The detection rates for trisomy 21 and 18 were 100% and 100%, respectively. For any SCA, the detection rate was 90%. For the two reporting periods, the combined false-positive rates were 0.93% and 0.17%, which were significantly different (p = 0.002). Restricting the reporting of additional findings from genome-wide cfDNA analysis has reduced the false-positive rate but without a reduction in the no-result rate.post-print474 K

First-trimester screening for trisomies by cfDNA testing of maternal blood in singleton and twin pregnancies: factors affecting test failure.

Objectives: To examine factors affecting the failure rate to obtain a result from (cf) DNA testing of maternal blood for fetal trisomies 21, 18 and 13 in singleton and twin pregnancies in the first trimester of pregnancy. Methods: This was a prospective study in 23,495 singleton and 928 twin pregnancies undergoing screening for fetal trisomies by targeted cfDNA testing at 10+0-14+1 weeks’ gestation. Multivariate regression analysis was used to determine significant predictors of failure to obtain a result after first sampling. Results: There was no result from cfDNA testing after first sampling in 3.4% (798/23,495) of singletons, 11.3% (91/806) of DC twins and in 4.9% (6/122) of MC twins. Multivariate logistic regression analysis demonstrated that the risk of test failure first, increased with increasing maternal age (odds ratio (OR) 1.02; 95% confidence interval (CI) 1.01, 1.04) and weight (OR 1.05; 95% CI 1.04, 1.05), decreasing gestational age (OR 0.85; 95% CI 0.79, 0.91) and serum PAPP-A (OR 0.56; 95% CI 0.49, 0.64) and free ß-hCG (OR 0.67; 95% CI 0.60, 0.74), second, was higher in women of Black (OR 1.72; 95% CI 1.33, 2.20) and South Asian (OR 1.99; 95% CI 1.56, 2.52) than White racial origin, in dichorionic twin (OR 1.75; 95% CI 1.34, 2.25) than singleton pregnancy and in in vitro fertilization (OR 3.82; 95% CI 3.19, 4.55) than natural conception and third, was lower in parous (OR 0.63; 95% CI 0.55, 0.74) than nulliparous women. Conclusions: Maternal age, weight, racial origin and parity, gestational age, dichorionicity, method of conception and serum levels of free ß-hCG and PAPP-A are independent predictors of cfDNA test failure. The risk of test failure is higher in dichorionic twin than in singleton pregnancies, mainly because a higher proportion of twins are conceived by in vitro fertilization and more of the women are nulliparous.pre-print429 K

Does low-dose aspirin initiated before 11 weeks' gestation reduce the rate of preeclampsia?

OBJECTIVE: DATA: Pre-conception or early administration of low-dose aspirin might improve endometrial growth, placental vascularization and organogenesis. Most studies have evaluated the potential benefit of pre-conception or early administration of low-dose aspirin in women with a history of recurrent pregnancy loss, women who have undergone in vitro fertilization or women with thrombophilia or antiphospholipid syndrome. These women are at an increased risk of placenta-associated complications of pregnancy, including preeclampsia, preterm delivery and fetal growth restriction. STUDY: We performed a systematic review and meta-analysis to evaluate the effect of low-dose aspirin initiated at <11 weeks' gestation on the risk of preeclampsia, gestational hypertension, or any hypertensive disorder of pregnancy. Secondary outcomes included preterm delivery at <37 weeks' gestation and fetal growth restriction. STUDY APPRAISAL AND SYNTHESIS METHODS: We searched in MEDLINE via PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.Gov and the World Health Organization International Clinical Trials Registry Platform (WHO-ICTRP) from 1985 to November 2018. Entry criteria were randomized controlled trials evaluating the effect of aspirin administered at 85% of the study population. Relative risks (RR) with 95% confidence intervals (CI) were calculated for each study and pooled for global analysis as the effect measure. We assessed statistical heterogeneity in each meta-analysis using the Chi2 statistics, I2 and Tau2. Heterogeneity was considered substantial if an I2 was greater than 50% and either the Tau2 was greater than zero, or there was a low P-value (<0.10) in the Chi2 test for heterogeneity. Random-effects meta-analysis, weighted by the size of the studies, was performed to produce an overall summary on aspirin effect for each outcome. Sensitivity analysis by sequential omission of each individual study and by fixed-effects model was performed. Publication bias was not assessed due to the small number of included studies. Statistical analysis was performed using Stata release 14.0 (StataCorp, College Station, TX). RESULTS: The entry criteria were fulfilled by eight randomized controlled trials on a combined total of 1,426 participants. Low-dose aspirin initiated at <11 weeks' gestation was associated with a non-significant reduction in the risk of preeclampsia (RR 0.52; 95% CI: 0.23-1.17, P=0.115), gestational hypertension (RR 0.49; 95% CI: 0.20-1.21; P=0.121) and any hypertensive disorder of pregnancy (RR 0.59; 95% CI 0.33-1.04, P=0.067). Early low-dose aspirin reduced the risk of preterm delivery (RR 0.52; 95% CI: 0.27-0.97, p=0.040) but had no impact on the risk of fetal growth restriction (RR 1.10; 95% CI 0.58-2.07, P=0.775). Except for preterm delivery and any hypertensive disorder of pregnancy, sensitivity analysis demonstrated similar observations; therefore confirming the robustness of the analysis. CONCLUSION: The administration of low-dose aspirin at <11 weeks' gestation in high risk women does not decrease the risk of preeclampsia, gestational hypertension, any hypertensive disorder of pregnancy and fetal growth restriction. However, it might reduce the risk of preterm delivery. Larger randomized controlled trials will be required to substantiate the findings.pre-print408 K

Protocol for a sequential, prospective metaanalysis to describe coronavirus disease 2019 (COVID-19) in the pregnancy and postpartum periods.

We urgently need answers to basic epidemiological questions regarding SARS-CoV-2 infection in pregnant and postpartum women and its effect on their newborns. While many national registries, health facilities, and research groups are collecting relevant data, we need a collaborative and methodologically rigorous approach to better combine these data and address knowledge gaps, especially those related to rare outcomes. We propose that using a sequential, prospective meta-analysis (PMA) is the best approach to generate data for policy- and practice-oriented guidelines. As the pandemic evolves, additional studies identified retrospectively by the steering committee or through living systematic reviews will be invited to participate in this PMA. Investigators can contribute to the PMA by either submitting individual patient data or running standardized code to generate aggregate data estimates. For the primary analysis, we will pool data using two-stage meta-analysis methods. The meta-analyses will be updated as additional data accrue in each contributing study and as additional studies meet study-specific time or data accrual thresholds for sharing. At the time of publication, investigators of 25 studies, including more than 76,000 pregnancies, in 41 countries had agreed to share data for this analysis. Among the included studies, 12 have a contemporaneous comparison group of pregnancies without COVID-19, and four studies include a comparison group of non-pregnant women of reproductive age with COVID-19. Protocols and updates will be maintained publicly. Results will be shared with key stakeholders, including the World Health Organization (WHO) Maternal, Newborn, Child, and Adolescent Health (MNCAH) Research Working Group. Data contributors will share results with local stakeholders. Scientific publications will be published in open-access journals on an ongoing basis.post-print641 K

Application of a new protocol for providing obstetric care in an outpatient service during the COVID-19 pandemic in a public hospital in Madrid, Spain.

Objective: To evaluate the clinical implementation of a preventive COVID-19 protocol regarding re-organization of appointments and documented infections among health workers in an obstetric outpatient service. Methods: Descriptive analysis of the antenatal care at our obstetric outpatient service and infection rates among health care providers from March 19th to May 22nd, 2020. Appointments were divided into telephone calls or face-to-face examinations. A pre-consultation triage was implemented to identify suspected SARS-CoV2 infected women to reschedule them 14 days later or, if the consultation was non-delayable, to use complete Personal Protective Equipment (PPE). Firstly, the number of face-to-face appointments, telephone appointments, and COVID-19 diagnoses in pregnant women were analyzed. Secondly, the number of obstetricians and nurses diagnosed with SARS-CoV2 infection and their serologic status during universal screening in May 2020 were recorded. Results: One thousand eight hundred forty-two obstetric appointments were scheduled during this period, including 432 (23.5%) telephone appointments (96.53% according to clinical protocol, 1.62% symptomatic patients advised to stay at home, and 1.85% COVID-19 confirmed cases), and 1,410 (76.5%) face-to-face appointments (9.7% did not attend due to fear of getting the infection, 3.1% were lost-to-follow-up, 0.5% were rescheduled due to COVID-19 symptoms and 86.7% who did attend). Of the 1,223 women attending their hospital appointment, 3.6% screened positive at the triage (72.7% rescheduled and 27.3% seen with PPE). 43 rRT-PCR-SARS-CoV2 tests were performed, and two tested positive. No COVID-19 symptoms were reported among health workers at the outpatient obstetric service, and only one nurse presented immunoglobulin (Ig)G anti-SARS-CoV2. Conclusion: A prompt implementation of a preventive protocol in a hospital obstetric outpatient service, including triage, hygienic and preventive measurements, and rescheduling pregnancy appointments, reduces the percentage of health workers affected by SARS-CoV2.post-print369 K

Classification of uterine anomalies by three-dimensional ultrasonography using ESHRE/ESGE criteria: inter-observer variability.

Objective: To evaluate the interobserver repeatability of the coronal view measurements and classification of the uterine malformations (UM) according to the ESHRE/ESGE consensus by transvaginal three-dimensional ultrasound (3D US). Methods: 89 transvaginal 3D volumes acquired during the last two years at Delta Ecografía in Madrid, Spain, were selected from our archive by convenience sampling. Two expert operators blinded from each other, performed post-hoc analysis using render mode and multiplanar-VCI navigation. Uterine wall thickness at the fundus, indentation of the cavity and indentation of the fundus were measured, classified and sub-classified following the recommendations of the ESHRE/ESGE consensus. The reproducibility of interobserver measurements and classification was examined by calculating intraclass correlation coefficients (ICC) and their 95% confidence intervals (CI) and kappa statistic (k).pre-print261 K