Guidelines for NGS procedures applied to prenatal diagnosis by the Spanish Society of Gynecology and Obstetrics and the Spanish Association of Prenatal Diagnosis.

OBJECTIVE: This document addresses the clinical application of next-generation sequencing (NGS) technologies for prenatal genetic diagnosis and aims to establish clinical practice recommendations in Spain to ensure uniformity in implementing these technologies into prenatal care. METHODS: A joint committee of expert obstetricians and geneticists was created to review the existing literature on fetal NGS for genetic diagnosis and to make recommendations for Spanish healthcare professionals. RESULTS: This guideline summarises technical aspects of NGS technologies, clinical indications in prenatal setting, considerations regarding findings to be reported, genetic counselling considerations as well as data storage and protection policies. CONCLUSIONS: This document provides updated recommendations for the use of NGS diagnostic tests in prenatal diagnosis. These recommendations should be periodically reviewed as our knowledge of the clinical utility of NGS technologies, applied during pregnancy, may advance.

Pregnancy outcomes and vaccine effectiveness during the period of omicron as the variant of concern, INTERCOVID-2022: a multinational, observational study.

BACKGROUND: In 2021, we showed an increased risk associated with COVID-19 in pregnancy. Since then, the SARS-CoV-2 virus has undergone genetic mutations. We aimed to examine the effects on maternal and perinatal outcomes of COVID-19 during pregnancy, and evaluate vaccine effectiveness, when omicron (B.1.1.529) was the variant of concern. METHODS: INTERCOVID-2022 is a large, prospective, observational study, involving 41 hospitals across 18 countries. Each woman with real-time PCR or rapid test, laboratory-confirmed COVID-19 in pregnancy was compared with two unmatched women without a COVID-19 diagnosis who were recruited concomitantly and consecutively in pregnancy or at delivery. Mother and neonate dyads were followed until hospital discharge. Primary outcomes were maternal morbidity and mortality index (MMMI), severe neonatal morbidity index (SNMI), and severe perinatal morbidity and mortality index (SPMMI). Vaccine effectiveness was estimated, adjusted by maternal risk profile. FINDINGS: We enrolled 4618 pregnant women from Nov 27, 2021 (the day after WHO declared omicron a variant of concern), to June 30, 2022: 1545 (33%) women had a COVID-19 diagnosis (median gestation 36·7 weeks [IQR 29·0-38·9]) and 3073 (67%) women, with similar demographic characteristics, did not have a COVID-19 diagnosis. Overall, women with a diagnosis had an increased risk for MMMI (relative risk [RR] 1·16 [95% CI 1·03-1·31]) and SPMMI (RR 1·21 [95% CI 1·00-1·46]). Women with a diagnosis, compared with those without a diagnosis, also had increased risks of SNMI (RR 1·23 [95% CI 0·88-1·71]), although the lower bounds of the 95% CI crossed unity. Unvaccinated women with a COVID-19 diagnosis had a greater risk of MMMI (RR 1·36 [95% CI 1·12-1·65]). Severe COVID-19 symptoms in the total sample increased the risk of severe maternal complications (RR 2·51 [95% CI 1·84-3·43]), perinatal complications (RR 1·84 [95% CI 1·02-3·34]), and referral, intensive care unit (ICU) admission, or death (RR 11·83 [95% CI 6·67-20·97]). Severe COVID-19 symptoms in unvaccinated women increased the risk of MMMI (RR 2·88 [95% CI 2·02-4·12]) and referral, ICU admission, or death (RR 20·82 [95% CI 10·44-41·54]). 2886 (63%) of 4618 total participants had at least a single dose of any vaccine, and 2476 (54%) of 4618 had either complete or booster doses. Vaccine effectiveness (all vaccines combined) for severe complications of COVID-19 for all women with a complete regimen was 48% (95% CI 22-65) and 76% (47-89) after a booster dose. For women with a COVID-19 diagnosis, vaccine effectiveness of all vaccines combined for women with a complete regimen was 74% (95% CI 48-87) and 91% (65-98) after a booster dose. INTERPRETATION: COVID-19 in pregnancy, during the first 6 months of omicron as the variant of concern, was associated with increased risk of severe maternal morbidity and mortality, especially among symptomatic and unvaccinated women. Women with complete or boosted vaccine doses had reduced risk for severe symptoms, complications, and death. Vaccination coverage among pregnant women remains a priority. FUNDING: None.

Real-time ultrasound demonstration of uterine isthmus contractions during pregnancy.

BACKGROUND: Asymptomatic isthmic contractions are a frequent physiological phenomenon in pregnancy, sometimes triggered by bladder voiding. They can interfere with proper cervical length assessment and may lead to false images of placenta previa. However, there is limited research on the prevalence and characteristics of these contractions. OBJECTIVE: This study aimed to determine the prevalence and characteristics of isthmic contractions after bladder voiding in the second trimester of pregnancy, to evaluate their effect on cervical length assessment, and to propose a new method for the objective assessment of the presence and intensity of isthmic contractions. STUDY DESIGN: In this prospective observational study, long videos of the uterine cervix were recorded in 30 singleton pregnancies during the second trimester of pregnancy after bladder voiding. Isthmic length and cervicoisthmic length changes were assessed over time. The isthmic length was measured using a new approach, which involved calculating the distance from the base of the cervix to the internal os, including the isthmus. RESULTS: Isthmic contractions were observed in 43% of pregnant women (95% confidence interval, 26%-62%) after bladder voiding. The median time for complete isthmus relaxation was 19.7 minutes (95% confidence interval, 15.0 to not available). No substantial differences in maternal characteristics were found between individuals with and without contractions. The proposed method for measuring isthmic length provided an objective assessment of the presence and intensity of isthmic contractions. A cutoff of 18 mm in isthmic length allowed for the distinction of pregnant women presenting a contraction. In addition, the study identified a characteristic undulatory pattern in the relaxation of the isthmus in half of the cases with contractions. CONCLUSION: Isthmic contractions are a common occurrence after bladder voiding in the second trimester of pregnancy and may interfere with proper cervical length assessment. We recommend performing cervical assessment at least 20 minutes after bladder voiding to reduce the risk of bias in cervical length measurement and to avoid false images of placenta previa. The new method for measuring isthmic length provides an objective way to assess the presence and intensity of isthmic contractions. Further research is needed to understand the role of isthmic contractions in the physiology of pregnancy and birth.

Maternal vaccination against COVID-19 and neonatal outcomes during Omicron: INTERCOVID-2022 study.

BACKGROUND: In early 2023, when Omicron was the variant of concern, we showed that vaccinating pregnant women decreased the risk for severe COVID-19-related complications and maternal morbidity and mortality. OBJECTIVE: This study aimed to analyze the impact of COVID-19 during pregnancy on newborns and the effects of maternal COVID-19 vaccination on neonatal outcomes when Omicron was the variant of concern. STUDY DESIGN: INTERCOVID-2022 was a large, prospective, observational study, conducted in 40 hospitals across 18 countries, from November 27, 2021 (the day after the World Health Organization declared Omicron the variant of concern) to June 30, 2022, to assess the effect of COVID-19 in pregnancy on maternal and neonatal outcomes and to assess vaccine effectiveness. Women diagnosed with laboratory-confirmed COVID-19 during pregnancy were compared with 2 nondiagnosed, unmatched women recruited concomitantly and consecutively during pregnancy or at delivery. Mother-newborn dyads were followed until hospital discharge. The primary outcomes were a neonatal positive test for COVID-19, severe neonatal morbidity index, severe perinatal morbidity and mortality index, preterm birth, neonatal death, referral to neonatal intensive care unit, and diseases during the neonatal period. Vaccine effectiveness was estimated with adjustment for maternal risk profile. RESULTS: We enrolled 4707 neonates born to 1577 (33.5%) mothers diagnosed with COVID-19 and 3130 (66.5%) nondiagnosed mothers. Among the diagnosed mothers, 642 (40.7%) were not vaccinated, 147 (9.3%) were partially vaccinated, 551 (34.9%) were completely vaccinated, and 237 (15.0%) also had a booster vaccine. Neonates of booster-vaccinated mothers had less than half (relative risk, 0.46; 95% confidence interval, 0.23-0.91) the risk of being diagnosed with COVID-19 when compared with those of unvaccinated mothers; they also had the lowest rates of preterm birth, medically indicated preterm birth, respiratory distress syndrome, and number of days in the neonatal intensive care unit. Newborns of unvaccinated mothers had double the risk for neonatal death (relative risk, 2.06; 95% confidence interval, 1.06-4.00) when compared with those of nondiagnosed mothers. Vaccination was not associated with any congenital malformations. Although all vaccines provided protection against neonatal test positivity, newborns of booster-vaccinated mothers had the highest vaccine effectiveness (64%; 95% confidence interval, 10%-86%). Vaccine effectiveness was not as high for messenger RNA vaccines only. Vaccine effectiveness against moderate or severe neonatal outcomes was much lower, namely 13% in the booster-vaccinated group (all vaccines) and 25% and 28% in the completely and booster-vaccinated groups, respectively (messenger RNA vaccines only). Vaccines were fairly effective in protecting neonates when given to pregnant women ≤100 days (14 weeks) before birth; thereafter, the risk increased and was much higher after 200 days (29 weeks). Finally, none of the neonatal practices studied, including skin-to-skin contact and direct breastfeeding, increased the risk for infecting newborns. CONCLUSION: When Omicron was the variant of concern, newborns of unvaccinated mothers had an increased risk for neonatal death. Neonates of vaccinated mothers had a decreased risk for preterm birth and adverse neonatal outcomes. Because the protective effect of COVID-19 vaccination decreases with time, to ensure that newborns are maximally protected against COVID-19, mothers should receive a vaccine or booster dose no more than 14 weeks before the expected date of delivery.

Mid-trimester uterine artery Doppler for aspirin discontinuation in pregnancies at high risk for preterm pre-eclampsia: Post-hoc analysis of StopPRE trial.

OBJECTIVE: To assess whether aspirin treatment can be discontinued in pregnancies with normal uterine artery pulsatility index (≤90th percentile) at 24-28 weeks. DESIGN: Post-hoc analysis of a clinical trial. SETTING: Nine maternity hospitals in Spain. POPULATION OR SAMPLE: Pregnant individuals at high risk of pre-eclampsia at 11-13 weeks and normal uterine artery Doppler at 24-28 weeks. METHODS: All participants received treatment with daily aspirin at a dose of 150 mg. Participants were randomly assigned, in a 1:1 ratio, either to continue aspirin treatment until 36 weeks (control group) or to discontinue aspirin treatment (intervention group), between September 2019 and September 2021. In this secondary analysis, women with a UtAPI >90th percentile at 24-28 weeks were excluded. The non-inferiority margin was set at a difference of 1.9% for the incidence of preterm pre-eclampsia. MAIN OUTCOME MEASURES: Incidence of preterm pre-eclampsia. RESULTS: Of the 1611 eligible women, 139 were excluded for UtAPI >90th percentile or if UtAPI was not available. Finally, 804 were included in this post-hoc analysis. Preterm pre-eclampsia occurred in three of 409 (0.7%) women in the aspirin discontinuation group and five of 395 (1.3%) women in the continuation group (-0.53; 95% CI -1.91 to 0.85), indicating non-inferiority of aspirin discontinuation. CONCLUSIONS: Discontinuing aspirin treatment at 24-28 weeks in women with a UtAPI ≤90th percentile was non-inferior to continuing aspirin treatment until 36 weeks for preventing preterm pre-eclampsia.

Proposal for standardized prenatal assessment of fetal open dysraphisms by the European reference network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies (ITHACA) and eUROGEN.

Open dysraphisms, that is, myelomeningocele and myeloschisis, are rare diseases associated with a risk of severe disability, including lower limb motor and sensory deficiency, sphincter deficiency, and potential intellectual deficiency. Open dysraphism is diagnosed in Europe in 93.5% of cases. In case of suspicion of fetal open dysraphism, a detailed fetal morphologic assessment is required to confirm the diagnosis and exclude associated structural anomalies, as well as genetic assessment. In case of isolated fetal open dysraphism, assessment of prognosis is based on fetal imaging including the level of the lesion, the presence or not of a sac, the presence and nature of intra cranial anomalies, and the anatomical and functional evaluation of the lower extremities. Based on these biomarkers, a personalized prognosis as well as comprehensive information about prenatal management alternatives will allow parents to decide on further management options. Standardization of prenatal assessment is essential to compare outcomes with benchmark data and make assessment of surgical innovation possible. Herein, we propose a protocol for the standardized ultrasound assessment of fetuses with isolated open dysraphism.

Cannabis exposure during pregnancy and perinatal outcomes: A cohort study.

INTRODUCTION: Cannabis potency and its use during pregnancy have increased in the last decade. The aim of this study was to investigate the impact of antenatal cannabis use on fetal growth, preterm birth and other perinatal outcomes. MATERIAL AND METHODS: A propensity score-matched analysis was performed in women with singleton pregnancies attending a tertiary care site in Barcelona. Women in the cannabis group were selected based on the results of a detection test. Primary outcomes were small for gestational age at birth (SGA), low birthweight and preterm birth. Secondary outcomes were other biometric parameters (neonatal length and head circumference), respiratory distress, admission to the neonatal intensive care unit and breastfeeding at discharge. A second propensity score-matched analysis excluding other confounders (use of other recreational drugs and discontinuation of cannabis use during pregnancy) was performed. RESULTS: Antenatal cannabis was associated with a higher odds ratio of SGA (OR 3.60, 95% CI: 1.68-7.69), low birthweight (OR 3.94, 95% CI: 2.17-7.13), preterm birth at 37 weeks (OR 2.07, 95% CI: 1.12-3.84) and 32 weeks of gestation (OR 4.13, 95% CI: 1.06-16.11), admission to the neonatal intensive care unit (OR 1.95, 95% CI: 1.03-3.71), respiratory distress (OR 2.77, 95% CI: 1.26-6.34), and lower breastfeeding rates at discharge (OR 0.10, 95% CI: 0.05-0.18). When excluding other confounders, no significant association between antenatal cannabis use and SGA was found. CONCLUSIONS: Antenatal cannabis use increases the risk of SGA, low birthweight, preterm birth and other adverse perinatal outcomes. However, when isolating the impact of cannabis use by excluding women who use other recreational drugs and those who discontinue cannabis during pregnancy, no significant association between antenatal cannabis use and SGA birth was found.

The Arabin cervical pessary for the prevention of preterm birth in twin-to-twin transfusion syndrome treated by fetoscopic laser coagulation: a multicenter randomized controlled trial.

BACKGROUND: Miscarriage and preterm birth are leading causes of loss and disability in monochorionic twins after laser treatment of twin-twin transfusion syndrome. OBJECTIVE: This study aimed to investigate the use of cervical pessary to reduce preterm birth before 32 weeks of gestation in monochorionic diamniotic twin pregnancies after fetal surgery for twin-twin transfusion syndrome. STUDY DESIGN: In this open-label multicenter randomized trial, pregnant women carrying monochorionic diamniotic twins requiring fetoscopic laser coagulation for twin-twin transfusion syndrome were randomly assigned in a 1:1 ratio to pessary placement or conservative management. The primary outcome was birth before 32 weeks of gestation. The secondary outcomes were birth before 28, 30, 34, or 37 weeks of gestation; preterm premature rupture of membranes; fetal and neonatal survival; and a composite of maternal and neonatal complications. The estimated sample size was 364 patients, with 182 cases in each arm of the study. The analysis was performed according to the intention-to-treat principle. Moreover, 2 interim analyses were planned. RESULTS: The trial was stopped prematurely after the first planned interim analysis for futility. Overall, 137 women were included in the analysis, 67 in the pessary group and 70 in the conservative management group. Preterm birth before 32 weeks of gestation occurred in 27 of 67 women (40.3%) in the pessary group and in 25 of 70 women (35.7%) in the conservative management group (adjusted odds ratio, 1.19; 95% confidence interval, 0.58-2.47; P=.63). No differences between groups was observed in the rate of deliveries before 28, 30, 34, and 37 weeks of gestation. Overall survival to delivery was 91.2% (125/137) for at least 1 twin, and 70.8% (97/137) for both twins, with no difference between groups. Neonatal survival at 30 days was 76.5% (208/272). There was no difference between the groups in maternal or neonatal morbidity. CONCLUSION: In monochorionic diamniotic twin pregnancies requiring fetal therapy for twin-twin transfusion syndrome, routine use of cervical pessary did not reduce the rate of preterm birth before 32 weeks of gestation.

Fetal abdominal cysts: Predicting adverse outcomes.

INTRODUCTION: The primary aim of the study was to identify risk factors associated with fetal or neonatal loss, neonatal morbidity, and the need for surgery in fetuses diagnosed with an abdominal cyst. The secondary aim was to compare the characteristics of the cyst according to trimester at diagnosis. MATERIAL AND METHODS: This was an observational retrospective study performed at Vall d'Hebron University Hospital. The study included pregnant women aged 18 years or older with diagnosis of a fetal abdominal cyst from 2008 to 2021. RESULTS: A total of 82 women with a median gestational age of 31+1 weeks (12+0-39+4) were included in the analysis. Seven (8.5%) cases were diagnosed in the first trimester, 28 (34.1%) in the second trimester, and 47 (57.3%) in the third trimester. Fetal or neonatal loss occurred in 10 (12.2%) cases; significant predictors were diagnosis in the first trimester (OR 36.67, 95% CI: 4.89-274.79), male gender (OR 4.75, 95% CI: 1.13-19.9), and associated abnormalities (OR 15.2, 95% CI: 2.92-79.19). A total of 10 of 75 (13.3%) neonates showed at least one neonatal complication, and the only predictor was occurrence of associated abnormalities (OR 7.36, 95% CI: 1.78-30.51). A total of 16 of 75 (21.3%) neonates required postnatal surgery, and the predictors were second-trimester diagnosis (OR 3.92, 95% CI: 1.23-12.51), associated abnormalities (OR 3.81, 95% CI: 1.15-12.64), and bowel location (OR 10.0, 95% CI: 1.48-67.55). CONCLUSIONS: Factors associated with adverse outcomes in fetuses diagnosed with abdominal cysts are first-trimester diagnosis and associated abnormalities. Cysts detected in the second trimester and those of intestinal origin are more likely to require surgery.

Reference values for interleukin-6 in the amniotic fluid of asymptomatic pregnant women.

INTRODUCTION: Nowadays, proinflammatory factors are considered to play an important role in the pathophysiology of threatened preterm labor or chorioamnionitis. The aim of this study was to establish the normal reference range for interleukin-6 (IL-6) levels in the amniotic fluid and to identify factors which may alter this value. MATERIAL AND METHODS: Prospective study in a tertiary-level center including asymptomatic pregnant women undergoing amniocentesis for genetic studies from October 2016 to September 2019. IL-6 measurements in amniotic fluid were performed using a fluorescence immunoassay with microfluidic technology (ELLA Proteinsimple, Bio Techne). Maternal history and pregnancy data were also recorded. RESULTS: This study included 140 pregnant women. Of those, women who underwent termination of pregnancy were excluded. Therefore, a total of 98 pregnancies were included in the final statistical analysis. The mean gestational age was 21.86 weeks (range: 15-38.7) at the time of amniocentesis, and 38.6 weeks (range: 30.9-41.4) at delivery. No cases of chorioamnionitis were reported. The log10 IL-6 values follow a normal distribution (W = 0.990, p = 0.692). The median, and the 5th, 10th, 90th, and 95th percentiles for IL-6 levels were 573, 105, 130, 1645, and 2260 pg/mL, respectively. The log10 IL-6 values were not affected by gestational age (p = 0.395), maternal age (p = 0.376), body mass index (p = 0.551), ethnicity (p = 0.467), smoking status (p = 0.933), parity (p = 0.557), method of conception (p = 0.322), or diabetes mellitus (p = 0.381). CONCLUSIONS: The log10 IL-6 values follow a normal distribution. IL-6 values are independent of gestational age, maternal age, body mass index, ethnicity, smoking status, parity and method of conception. Our study provides a normal reference range for IL-6 levels in the amniotic fluid that can be used in future studies. We also observed that normal IL-6 values were higher in the amniotic fluid than in serum.

Fetal PR Interval in Pregnancies with Intrahepatic Cholestasis of Pregnancy: A Case-Control Study.

OBJECTIVE: This study had three purposes: first, to explore differences in fetal cardiac function in patients with and without intrahepatic cholestasis of pregnancy (ICP) based on PR interval (the interval between the beginning of the atrial contraction and the beginning of the ventricular contraction). Second, to explore a potential correlation between PR interval and bile acid levels in pregnant women with ICP. Third, to study changes in PR interval of fetuses from pregnant women with ICP after administration of ursodeoxycholic acid (UDCA). STUDY DESIGN: This was a prospective observational case-control study. ICP was defined as palmar plantar pruritus of nocturnal predominance for more than 1 week associated with a total bile acid level >10 µmol/L. Control cases were women with pregnancies scheduled for induction or elective cesarean section at term. RESULTS: One hundred and ten women with ICP and 72 controls were included in the study. Median gestational age at inclusion was 35.9 weeks. Median PR interval was significantly longer in fetuses of women with ICP (122 vs. 102 ms, p < 0.001). There was a significant correlation between bile acid levels and PR interval (rho = 0.723, p < 0.001). In 22 fetuses, the median PR interval decreased significantly following UDCA administration (134 vs. 118 ms, p = 0.004). CONCLUSION: PR interval is longer in fetuses of women with ICP. PR interval was significantly correlated with bile acid levels, and administration of UDCA significantly reduced PR interval. KEY POINTS: · Differences in fetal cardiac function in patients with and without intrahepatic cholestasis.. · PR interval and bile acid levels in pregnant women with intrahepatic cholestasis.. · Changes in PR interval of fetuses from pregnant women with ICP after use of UDCA..

Usefulness of angiogenic factors in prenatal counseling of late-onset fetal growth-restricted and small-for-gestational-age gestations: a prospective observational study.

OBJECTIVES: To create a predictive model including biomarkers and evaluate its ability to predict adverse perinatal outcomes in late-onset small fetuses, ultimately helping to provide individualized counseling at the time of diagnosis. METHODS: This was a prospective observational study, including singleton pregnancies with an estimated fetal weight (EFW) below the 10th percentile, at a gestational age between 32 + 0 and 36 + 6 weeks of gestation (WG). Variables recorded at diagnosis to predict adverse pregnancy outcomes were: soluble fms-like tyrosine-kinase-1 to placental growth factor ratio (sFlt-1/PlGF), fetal Doppler (umbilical artery and middle cerebral artery), uterine artery pulsatility index (UtAPI), EFW percentile, gestational age, and the presence of maternal risk factors for placental insufficiency. Logistic regression models were developed for the prediction of three co-primary outcomes: composite adverse perinatal outcomes (APO), and the need for elective delivery before 35 or 37 WG. RESULTS: Sixty (52.2%) fetal growth restricted (FGR) and 55 (47.8%) small for gestational age (SGA) were enrolled. Thirteen (11.3%) women needed elective delivery before 35 WG and 27 (23.5%) women before 37 WG. At least one APO occurred in 43 (37.4%) pregnancies. The best marker in univariate analyses was the sFlt-1/PlGF ratio [AUC = 0.932 (95% CI, 0.864-0.999)]. The multivariate model including sFlt-1/PlGF showed a better predictive performance for APO than the multivariate model without sFlt-1/PlGF (P < 0.024). CONCLUSIONS: sFlt-1/PlGF is a good predictor of APO at the time of late-onset FGR/SGA diagnosis. Our predictive models may be useful to provide early individualized prenatal counseling in this group of women. Further studies are needed to validate these preliminary findings in a larger cohort.

Array study in fetuses with nuchal translucency above the 95th percentile: a 4-year observational single-centre study.

PURPOSE: To evaluate the performance of chromosomal microarray analysis (CMA) in fetuses with nuchal translucency (NT) > 95th percentile. Secondary objectives were to analyze these results according to NT thickness, below or above 3.5 mm, and those without associated anomalies. METHODS: This observational single-cohort study was conducted between 2015 and 2018 in fetuses with NT > 95th percentile. Following an invasive test, quantitative fluorescence-polymerase chain reaction (QF-PCR) was performed, and if normal, CMA was performed. Pathogenic copy number variants (CNVs), non-reported pathogenic CNV, pathogenic autosomal recessive variants and variants of unknown significance (VUS) were analysed. RESULTS: One-hundred and sixty-two fetuses with NT > 95th percentile, normal QF-PCR and CMA were included. Amongst 128 fetuses with NT between the 95th percentile and 3.5 mm, one (0.8%) had a pathogenic CNV, four (3.1%) had non-reported pathogenic CNV, one (0.8%) had pathogenic autosomal recessive variant and 13 (10.2%) had VUS. Amongst 34 fetuses with NT ≥ 3.5 mm, four (11.8%) had pathogenic CNV, one (2.9%) had non-reported pathogenic CNV, one (2.9%) had pathogenic autosomal recessive variant and four (11.8%) had VUS. Four in 162 (2.5%) fetuses had CNVs at the chromosome 16p13.11 region. Amongst 154 fetuses without structural abnormalities and normal QF-PCR, three (1.9%) had a pathogenic CNV, 5 (3.2%) had non-reported pathogenic CNV, one (0.6%) autosomal recessive pathogenic CNV and 16 (10.4%) had VUS. CONCLUSION: Pathogenic CNVs were found in 1% of fetuses with an NT thickness between the 95th percentile and 3.5 mm and in 12% of fetuses with NT ≥ 3.5 mm. CNVs were found at the 16p13.11 region in 2.5% of cases.

Aspirin Discontinuation at 24 to 28 Weeks' Gestation in Pregnancies at High Risk of Preterm Preeclampsia: A Randomized Clinical Trial.

Importance: Aspirin reduces the incidence of preterm preeclampsia by 62% in pregnant individuals at high risk of preeclampsia. However, aspirin might be associated with an increased risk of peripartum bleeding, which could be mitigated by discontinuing aspirin before term (37 weeks of gestation) and by an accurate selection of individuals at higher risk of preeclampsia in the first trimester of pregnancy. Objective: To determine whether aspirin discontinuation in pregnant individuals with normal soluble fms-like tyrosine kinase-1 to placental growth factor (sFlt-1:PlGF) ratio between 24 and 28 weeks of gestation was noninferior to aspirin continuation to prevent preterm preeclampsia. Design, Setting, and Participants: Multicenter, open-label, randomized, phase 3, noninferiority trial conducted in 9 maternity hospitals across Spain. Pregnant individuals (n = 968) at high risk of preeclampsia during the first-trimester screening and an sFlt-1:PlGF ratio of 38 or less at 24 to 28 weeks of gestation were recruited between August 20, 2019, and September 15, 2021; of those, 936 were analyzed (intervention: n = 473; control: n = 463). Follow-up was until delivery for all participants. Interventions: Enrolled patients were randomly assigned in a 1:1 ratio to aspirin discontinuation (intervention group) or aspirin continuation until 36 weeks of gestation (control group). Main Outcomes and Measures: Noninferiority was met if the higher 95% CI for the difference in preterm preeclampsia incidences between groups was less than 1.9%. Results: Among the 936 participants, the mean (SD) age was 32.4 (5.8) years; 3.4% were Black and 93% were White. The incidence of preterm preeclampsia was 1.48% (7/473) in the intervention group and 1.73% (8/463) in the control group (absolute difference, -0.25% [95% CI, -1.86% to 1.36%]), indicating noninferiority. Conclusions and Relevance: Aspirin discontinuation at 24 to 28 weeks of gestation was noninferior to aspirin continuation for preventing preterm preeclampsia in pregnant individuals at high risk of preeclampsia and a normal sFlt-1:PlGF ratio. Trial Registration: ClinicalTrials.gov Identifier: NCT03741179 and ClinicalTrialsRegister.eu Identifier: 2018-000811-26.

Effects of prenatal exposure to maternal COVID-19 and perinatal care on neonatal outcome: results from the INTERCOVID Multinational Cohort Study.

BACKGROUND: The effect of COVID-19 in pregnancy on maternal outcomes and its association with preeclampsia and gestational diabetes mellitus have been reported; however, a detailed understanding of the effects of maternal positivity, delivery mode, and perinatal practices on fetal and neonatal outcomes is urgently needed. OBJECTIVE: To evaluate the impact of COVID-19 on fetal and neonatal outcomes and the role of mode of delivery, breastfeeding, and early neonatal care practices on the risk of mother-to-child transmission. STUDY DESIGN: In this cohort study that took place from March 2020 to March 2021, involving 43 institutions in 18 countries, 2 unmatched, consecutive, unexposed women were concomitantly enrolled immediately after each infected woman was identified, at any stage of pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed up until hospital discharge. COVID-19 in pregnancy was determined by laboratory confirmation and/or radiological pulmonary findings or ≥2 predefined COVID-19 symptoms. The outcome measures were indices of neonatal and perinatal morbidity and mortality, neonatal positivity and its correlation with mode of delivery, breastfeeding, and hospital neonatal care practices. RESULTS: A total of 586 neonates born to women with COVID-19 diagnosis and 1535 neonates born to women without COVID-19 diagnosis were enrolled. Women with COVID-19 diagnosis had a higher rate of cesarean delivery (52.8% vs 38.5% for those without COVID-19 diagnosis, P<.01) and pregnancy-related complications, such as hypertensive disorders of pregnancy and fetal distress (all with P<.001), than women without COVID-19 diagnosis. Maternal diagnosis of COVID-19 carried an increased rate of preterm birth (P≤.001) and lower neonatal weight (P≤.001), length, and head circumference at birth. In mothers with COVID-19 diagnosis, the length of in utero exposure was significantly correlated to the risk of the neonate testing positive (odds ratio, 4.5; 95% confidence interval, 2.2-9.4 for length of in utero exposure >14 days). Among neonates born to mothers with COVID-19 diagnosis, birth via cesarean delivery was a risk factor for testing positive for COVID-19 (odds ratio, 2.4; 95% confidence interval, 1.2-4.7), even when severity of maternal conditions was considered and after multivariable logistic analysis. In the subgroup of neonates born to women with COVID-19 diagnosis, the outcomes worsened when the neonate also tested positive, with higher rates of neonatal intensive care unit admission, fever, gastrointestinal and respiratory symptoms, and death, even after adjusting for prematurity. Breastfeeding by mothers with COVID-19 diagnosis and hospital neonatal care practices, including immediate skin-to-skin contact and rooming-in, were not associated with an increased risk of newborn positivity. CONCLUSION: In this multinational cohort study, COVID-19 in pregnancy was associated with increased maternal and neonatal complications. Cesarean delivery was significantly associated with newborn COVID-19 diagnosis. Vaginal delivery should be considered the safest mode of delivery if obstetrical and health conditions allow it. Mother-to-child skin-to-skin contact, rooming-in, and direct breastfeeding were not risk factors for newborn COVID-19 diagnosis, thus well-established best practices can be continued among women with COVID-19 diagnosis.

Intrauterine cannabis exposure and fetal and maternal blood flow: a case-control study.

INTRODUCTION: Cannabis consumption during pregnancy increases the risk of pregnancy and neonatal complications. Since the underlying mechanism is unknown, the purpose of this study is to evaluate the changes in maternal and fetal blood flow in pregnancies exposed to cannabis, Δ9-tetrahydrocannabinol (THC). MATERIAL AND METHODS: A case-control study between 2013 and 2020, included women with continued cannabis exposure during the pregnancies, defined by qualitative detection of THC in urine (Cannabis Group), and low-risk pregnancy women divided into tobacco smokers (Tobacco Group), and non-tobacco smokers (Control Group). We evaluated the association between cannabis consumption and maternal and fetal blood flow parameters measured by Doppler ultrasound: uterine artery at 11-14, 20-22 and 33-35 weeks, umbilical artery and middle cerebral artery at 33-35 weeks. Cerebral-placental ratio was calculated. RESULTS: Overall, 275 participants were included, 60 in the Cannabis Group, 17 in the Tobacco Group and 198 in the Control Group. At 33-35 weeks, differences were found in the umbilical artery pulsatility index (PI) (1.05 ± 0.23, 1.06 ± 0.19, 0.93 ± 0.15, P < 0.01), middle cerebral artery PI (1.75 ± 0.35, 1.90 ± 0.45, 1.88 ± 0.34, P < 0.05), cerebral-placental ratio (1.69 ± 0.40, 1.85 ± 0.53, 2.07 ± 0.47, P < 0.05) and mean uterine artery PI (0.89 ± 0.26, 0.73 ± 0.19, 0.74 ± 0.20, P < 0.01), respectively. On logistic regression analysis, adjusted for maternal age, maternal body mass index, maternal weight and white ethnicity, both cannabis and tobacco were predictors for increased umbilical artery PI, but only cannabis was a predictor for a decreased cerebral-placental ratio and an increased uterine artery PI at 33-35 weeks. CONCLUSIONS: Data from a large cohort of continuous cannabis exposure pregnancies show that cannabis is associated with maternal and fetal blood flow changes. However, it is not possible to disentangle the association of the tobacco and cannabis.

Gestational age-based reference ranges for cervical length and preterm birth prediction in triplet pregnancies: an observational retrospective study.

OBJECTIVES: To develop gestational age-based reference ranges for cervical length in triplet pregnancies. The secondary objective was to assess the performance of cervical length measured between 18 and 20 + 6 days for the prediction of preterm delivery before 28 and 32 weeks, respectively. METHODS: Observational retrospective study of triplet pregnancies in three Spanish tertiary-care hospitals between 2001 and 2019. Cervical length measurements were consecutively obtained between 15 and 34 weeks of gestation. Pregnancies undergoing multifetal reduction or fetal surgery were excluded. RESULTS: Two hundred and six triplet pregnancies were included in the final analysis. There was a quadratic decrease in cervical length with gestational age. The median and fifth centiles for cervical length at 20 weeks were 35 and 13 mm. In the prediction of preterm birth < 28 weeks, for a false positive rate of 5%, and 10%, the detection rates were 40.9%, and 40.9%, respectively, and the prediction of preterm birth < 32 weeks, 22.0% and 26.0%, respectively. CONCLUSIONS: In triplet pregnancies, cervical length decreases with gestational age. The performance of cervical length at 18-20 + 6 in screening for preterm birth before 28 and 32 weeks is poor.

Shared risk factors for COVID-19 and preeclampsia in the first trimester: An observational study.

INTRODUCTION: The association between preeclampsia and coronavirus disease 2019 (COVID-19) is under study. Previous publications have hypothesized the existence of shared risk factors for both conditions or a deficient trophoblastic invasion as possible explanations for this association. The primary aim of this study was to examine baseline risk factors measured in the first-trimester combined screening for preeclampsia in pregnant women with COVID-19 compared with the general population. A secondary aim of this study was to compare risk factors among patients with mild and severe COVID-19. MATERIAL AND METHODS: This was an observational retrospective study conducted at Vall d'Hebron Hospital Campus (Catalonia, Spain). Study patients were 231 pregnant women undergoing the first-trimester screening for preeclampsia and positive for severe acute respiratory syndrome coronavirus 2 between February 2020 and September 2021. The reference cohort were 13 033 women of the general population from six centers across Catalonia from May 2019 to June 2021. Based on the need for hospitalization, patients were classified in two groups: mild and severe COVID-19. First-trimester screening for preeclampsia included maternal history, mean arterial blood pressure, mean uterine artery pulsatility index (UtAPI), placental growth factor (PlGF), and pregnancy-associated plasma protein-A (PAPP-A). RESULTS: The proportion of cases at high risk for preeclampsia was significantly higher among the COVID-19 group compared with the general population (19.0% and 13.2%, respectively; p = 0.012). When analyzing risk factors for preeclampsia individually, women with COVID-19 had higher median body mass index (25.2 vs 24.5, p = 0.041), higher UtAPI multiple of the median (MoM) (1.08 vs 1.00, p < 0.001), higher incidence of chronic hypertension (2.8% vs 0.9%, p = 0.015), and there were fewer smokers (5.7% vs 11.6%, p = 0.007). The MoMs of PlGF and PAPP-A did not differ significantly between both groups (0.96 vs 0.97, p = 0.760 and 1.00 vs 1.01, p = 0.432; respectively). CONCLUSIONS: In patients with COVID-19, there was a higher proportion of women at high risk for preeclampsia at the first-trimester screening than in the general population, mainly because of maternal risk factors, rather than placental signs of a deficient trophoblastic invasion.

The Overlooked Impact of Lower Uterine Segment Contractions on Second Trimester Cervical Assessment.

INTRODUCTION: Asymptomatic contractions in the lower uterine segment (LUS) may affect uterocervical angle and cervical length (CL); however, this has never been investigated. Therefore, the aim of this study was to evaluate the effect of LUS contractions on uterocervical angle, CL, and LUS thickness. MATERIALS AND METHODS: This was a prospective, observational, single-cohort study conducted on 102 asymptomatic singleton pregnancies between 19.0 and 22.6 weeks of gestation. Uterocervical angle and CL were measured by transvaginal ultrasound at two different time points with an interval of at least 20 min. LUS thickness was also measured as an indirect marker of myometrial contraction. A linear and curvilinear regression were performed to explore a potential association between LUS contractions, measured as increments in LUS thickness, and changes in CL and uterocervical angle. RESULTS: The linear regression between changes in LUS thickness and changes in CL showed that LUS contractions impact CL; for every 1-mm increase in LUS thickness, CL increased by 0.909 mm, when the isthmus was included in the CL measurement (R2 = 0.358; ß = 0.909; p < 0.001). By contrast, when the isthmus was not included in the measurement, a curvilinear relation between changes in LUS thickness and changes in CL was found (R2 = 0.077; ß1 = 0.575, ß2 = 0.038; p = 0.018). The relation between changes in uterocervical angle and changes in LUS thickness was not significant. DISCUSSION/CONCLUSION: LUS contractions can be observed in many asymptomatic women during the second trimester of pregnancy. LUS contractions lead to an increase in CL and LUS thickness, thus impacting ultrasound cervical assessments. These contractions do not affect the uterocervical angle.

Experience of 300 cases of prenatal fetoscopic open spina bifida repair: report of the International Fetoscopic Neural Tube Defect Repair Consortium.

BACKGROUND: The multicenter randomized controlled trial Management of Myelomeningocele Study demonstrated that prenatal repair of open spina bifida by hysterotomy, compared with postnatal repair, decreases the need for ventriculoperitoneal shunting and increases the chances of independent ambulation. However, the hysterotomy approach is associated with risks that are inherent to the uterine incision. Fetal surgeons from around the world embarked on fetoscopic open spina bifida repair aiming to reduce maternal and fetal/neonatal risks while preserving the neurologic benefits of in utero surgery to the child. OBJECTIVE: This study aimed to report the main obstetrical, perinatal, and neurosurgical outcomes in the first 12 months of life of children undergoing prenatal fetoscopic repair of open spina bifida included in an international registry and to compare these with the results reported in the Management of Myelomeningocele Study and in a subsequent large cohort of patients who received an open fetal surgery repair. STUDY DESIGN: All known centers performing fetoscopic spina bifida repair were contacted and invited to participate in a Fetoscopic Myelomeningocele Repair Consortium and enroll their patients in a registry. Patient data entered into this fetoscopic registry were analyzed for this report. Fisher exact test was performed for comparison of categorical variables in the registry with both the Management of Myelomeningocele Study and a post-Management of Myelomeningocele Study cohort. Binary logistic regression analyses were used to assess the registry data for predictors of preterm birth at <30 weeks' gestation, preterm premature rupture of membranes, and need for postnatal cerebrospinal fluid diversion in the fetoscopic registry. RESULTS: There were 300 patients in the fetoscopic registry, 78 in the Management of Myelomeningocele Study, and 100 in the post-Management of Myelomeningocele Study cohort. The 3 data sets showed similar anatomic levels of the spinal lesion, mean gestational age at delivery, distribution of motor function compared with upper anatomic level of the lesion in the neonates, and perinatal death. In the Management of Myelomeningocele Study (26.16±1.6 weeks) and post-Management of Myelomeningocele Study cohort (23.3 [20.2-25.6] weeks), compared with the fetoscopic registry group (23.6±1.4 weeks), the gestational age at surgery was lower (comparing fetoscopic repair group with the Management of Myelomeningocele Study; P<.01). After open fetal surgery, all patients were delivered by cesarean delivery, whereas in the fetoscopic registry approximately one-third were delivered vaginally (P<.01). At cesarean delivery, areas of dehiscence or thinning in the scar were observed in 34% of cases in the Management of Myelomeningocele Study, in 49% in the post-Management of Myelomeningocele Study cohort, and in 0% in the fetoscopic registry (P<.01 for both comparisons). At 12 months of age, there was no significant difference in the number of patients requiring treatment for hydrocephalus between those in the fetoscopic registry and the Management of Myelomeningocele Study. CONCLUSION: Prenatal and postnatal outcomes up to 12 months of age after prenatal fetoscopic and open fetal surgery repair of open spina bifida are similar. Fetoscopic repair allows for having a vaginal delivery and eliminates the risk of uterine scar dehiscence, therefore protecting subsequent pregnancies of unnecessary maternal and fetal risks.