Risk factors associated with stillbirth and adverse perinatal outcomes in dichorionic twin pregnancies complicated by selective fetal growth restriction: a cohort study.

OBJECTIVE: The main aim of this study was to investigate the perinatal outcomes of dichorionic twin pregnancies complicated by selective fetal growth restriction (sFGR). DESIGN: Retrospective cohort study. SETTING: Tertiary reference centre. POPULATION: Dichorionic twin pregnancies complicated by sFGR between 2000 and 2019 in St George's University Hospital. METHODS: Regression analyses were performed using generalised linear models and mixed-effects generalised linear models where appropriate to account for pregnancy level dependency in variables. Time to event analyses were performed with mixed-effects Cox regression models. MAIN OUTCOME MEASURES: Stillbirth, neonatal death or neonatal unit admission with morbidity in one or both twins. RESULTS: A total of 102 (of 2431 dichorionic twin pregnancies) pregnancies complicated by sFGR were included in the study. The Cochrane-Armitage test revealed a significant trend for increased adverse perinatal outcome rates with more severe forms of umbilical artery flow impedance, i.e. reversed, absent, positive with resistant flow and positive flow without resistance. A multivariable model including maternal and conception characteristics had poor predictive accuracy for stillbirth (area under the curve: 0.68, 95% confidence interval [CI] 0.55-0.81) and composite adverse perinatal outcomes (area under the curve: 0.58, 95% CI 0.47-0.70). When umbilical artery Doppler parameters were added to the models, the area under the curve values improved to 0.95 (95% CI 0.89-0.99) and 0.83 (95% CI 0.73-0.92) for stillbirth and composite adverse perinatal outcomes, respectively. CONCLUSION: In dichorionic twin pregnancies complicated by sFGR, the umbilical artery Z-scores were associated with both intrauterine death and adverse perinatal outcomes.

Feasibility of antenatal ambulatory fetal electrocardiography: a systematic review.

BACKGROUND: Antenatal fetal heart rate (FHR) monitoring is currently limited by hospital-based accessibility as well as the availability of relevant equipment and expertise required to position device electrodes. Ambulatory FHR monitoring in the form of noninvasive fetal electrocardiography (NIFECG) is currently an area of research interest, particularly during the era of the COVID-19 pandemic, and the potential to improve maternity care and reduce hospital attendances need to be evaluated. OBJECTIVES: To assess the feasibility, acceptability, and signal success of ambulatory NIFECG monitoring and identify research areas required to facilitate clinical utilization of this method of monitoring. METHODS: Medline, EMBASE, and PubMed databases were searched from January 2005 to April 2021 using terms relevant to antenatal ambulatory or home NIFECG. The search was compliant with PRISMA guidelines, and was registered with the PROSPERO database (CRD42020195809). All studies reporting the clinical utilization of NIFECG inclusive of its use in the ambulatory setting performed in the antenatal period, human studies, and those in the English language were included. Those reporting novel technological methods and electrophysiological algorithms, satisfaction surveys, intrapartum studies, case reports and reviews, and animal studies were excluded. Study screening and data extraction were conducted in duplicate. Risk of bias was appraised using the Modified Downs and Black tool. Due to the heterogeneity of the reported findings, a meta-analysis was not feasible. RESULTS: The search identified 193 citations, where 11 studies were deemed eligible for inclusion. All studies used a single NIFECG system with a duration of monitoring ranging from 5.6 to 21.4 h. Predefined signal acceptance threshold ranged from 34.0-80.0%. Signal success in the study populations was 48.6-95.0% and was not affected by maternal BMI. Good signals were achieved in the 2nd trimester, but less so in the early 3rd trimester. NIFECG was a well-accepted method of FHR monitoring, with up to 90.0% of women's satisfaction levels when worn during outpatient induction of labor. Placement of the acquisition device needed input from healthcare staff in every report. CONCLUSIONS: Although there is evidence for the clinical feasibility of ambulatory NIFECG, the disparity in the literature limits the ability to draw firm conclusions. Further studies to establish repeatability and device validity, whilst developing standardized FHR parameters and set evidence-based standards for signal success for NIFECG are required to ascertain the clinical benefit and potential limitations of ambulatory outpatient FHR monitoring.

Ambulatory antenatal fetal electrocardiography in high-risk pregnancies (AMBER): protocol for a pilot prospective cohort study.

INTRODUCTION: Fetal heart rate (FHR) monitoring is a vital aspect of fetal well-being assessment, and the current method of computerised cardiotocography (cCTG) is limited to the hospital setting. Non-invasive fetal ECG (NIFECG) has the ability to produce FHR patterns through R wave detection while eliminating confusion with maternal heart rate, but is presently limited to research use. Femom is a novel wireless NIFECG device that is designed to be placed without professional assistance, while connecting to mobile applications. It has the ability to achieve home FHR monitoring thereby allowing more frequent monitoring, earlier detection of deterioration, while reducing hospital attendances. This study aims to assess the feasibility, reliability, and accuracy of femom (NIFECG) by comparing its outputs to cCTG monitoring. METHODS AND ANALYSIS: This is a single-centred, prospective pilot study, taking place in a tertiary maternity unit. Women with a singleton pregnancy over 28+0 weeks' gestation who require antenatal cCTG monitoring for any clinical indication are eligible for recruitment. Concurrent NIFECG and cCTG monitoring will take place for up to 60 min. NIFECG signals will be postprocessed to produce FHR outputs such as baseline FHR and short-term variation (STV). Signal acceptance criteria is set as <50% of signal loss for the trace duration. Correlation, precision and accuracy studies will be performed to compare the STV and baseline FHR values produced by both devices. The impact of maternal and fetal characteristics on the effectiveness of both devices will be investigated. Other non-invasive electrophysiological assessment parameters will be assessed for its correlation with the STV, ultrasound assessments and maternal and fetal risk factors. ETHICS AND DISSEMINATION: Approval has been obtained from South-East Scotland Research Ethics Committee 02 and MHRA. The results of this study will be published in peer-reviewed journals, and presented at international conferences. TRIAL REGISTRATION NUMBER: NCT04941534.

Effectiveness of ambulatory non-invasive fetal electrocardiography: impact of maternal and fetal characteristics.

INTRODUCTION: Non-invasive fetal electrocardiography (NIFECG) has potential benefits over the computerized cardiotocography (cCTG) that may permit its development in remote fetal heart-rate monitoring. Our study aims to compare signal quality and heart-rate detection from a novel self-applicable NIFECG monitor against the cCTG, and evaluate the impact of maternal and fetal characteristics on both devices. MATERIAL AND METHODS: This prospective observational study took place in a university hospital in London. Women with a singleton pregnancy from 28 + 0 weeks' gestation presenting for cCTG were eligible. Concurrent monitoring with both NIFECG and cCTG were performed for up to 60 minutes. Post-processing of NIFECG produced signal loss, computed in both 0.25 (E240)- and 3.75 (E16)-second epochs, and fetal heart-rate and maternal heart-rate values. cCTG signal loss was calculated in 3.75-second epochs. Accuracy and precision analysis of 0.25-second epochal fetal heart-rate and maternal heart-rate were compared between the two devices. Multiple regression analyses were performed to assess the impact of maternal and fetal characteristics on signal loss. CLINICALTRIALS: gov Identifier: NCT04941534. RESULTS: 285 women underwent concurrent monitoring. For fetal heart-rate, mean bias, precision and 95% limits of agreement were 0.1 beats per minute (bpm), 4.5 bpm and -8.7 bpm to 8.8 bpm, respectively. For maternal heart-rate, these results were -0.4 bpm, 3.3 bpm and -7.0 to 6.2 bpm, respectively. Median NIFECG E240 and E16 signal loss was 32.0% (interquartile range [IQR] 6.5%-68.5%) and 17.3% (IQR 1.8%-49.0%), respectively. E16 cCTG signal loss was 1.0% (IQR 0.0%-3.0%). For NIFECG, gestational age was negatively associated with signal loss (beta = -2.91, 95% CI -3.69 to -2.12, P < 0.001). Increased body mass index, fetal movements and lower gestational age were all associated with cCTG signal loss (beta = 0.30, 95% CI 0.17-0.43, P < 0.001; beta = 0.03, 95% CI 0.01-0.05, P = 0.014; and beta = -0.28, 95% CI -0.51 to -0.05, P = 0.017, respectively). CONCLUSIONS: Although NIFECG is complicated by higher signal loss, it does not appear to be influenced by increased body mass index or fetal movement. NIFECG signal loss varies according to method of computation, and standards of signal acceptability need to be defined according to the ability of the device to produce clinically reliable physiological indices. The high accuracy of heart-rate indices is promising for NIFECG usage in the remote setting.

Timing of Delivery for Twins With Growth Discordance and Growth Restriction: An Individual Participant Data Meta-analysis.

OBJECTIVE: First, to evaluate the risks of stillbirth and neonatal death by gestational age in twin pregnancies with different levels of growth discordance and in relation to small for gestational age (SGA), and on this basis to establish optimal gestational ages for delivery. Second, to compare these optimal gestational ages with previously established optimal delivery timing for twin pregnancies not complicated by fetal growth restriction, which, in a previous individual patient meta-analysis, was calculated at 37 0/7 weeks of gestation for dichorionic pregnancies and 36 0/7 weeks for monochorionic pregnancies. DATA SOURCES: A search of MEDLINE, EMBASE, ClinicalTrials.gov, and Ovid between 2015 and 2018 was performed of cohort studies reporting risks of stillbirth and neonatal death in twin pregnancies from 32 to 41 weeks of gestation. Studies from a previous meta-analysis using a similar search strategy (from inception to 2015) were combined. Women with monoamniotic twin pregnancies were excluded. METHODS OF STUDY SELECTION: Overall, of 57 eligible studies, 20 cohort studies that contributed original data reporting on 7,474 dichorionic and 2,281 monochorionic twin pairs. TABULATION, INTEGRATION, AND RESULTS: We performed an individual participant data meta-analysis to calculate the risk of perinatal death (risk difference between prospective stillbirth and neonatal death) per gestational week. Analyses were stratified by chorionicity, levels of growth discordance, and presence of SGA in one or both twins. For both dichorionic and monochorionic twins, the absolute risks of stillbirth and neonatal death were higher when one or both twins were SGA and increased with greater levels of growth discordance. Regardless of level of growth discordance and birth weight, perinatal risk balanced between 36 0/7-6/7 and 37 0/7-6/7 weeks of gestation in both dichorionic and monochorionic twin pregnancies, with likely higher risk of stillbirth than neonatal death from 37 0/7-6/7 weeks onward. CONCLUSION: Growth discordance or SGA is associated with higher absolute risks of stillbirth and neonatal death. However, balancing these two risks, we did not find evidence that the optimal timing of delivery is changed by the presence of growth disorders alone. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42018090866.

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.

Reducing health inequality in Black, Asian and other minority ethnic pregnant women: impact of first trimester combined screening for placental dysfunction on perinatal mortality.

OBJECTIVE: To assess the impact of the Fetal Medicine Foundation (FMF) first trimester screening algorithm for pre-eclampsia on health disparities in perinatal death among minority ethnic groups. DESIGN: A retrospective cohort study from July 2016 to December 2020. SETTING: A large London teaching hospital. PATIENTS AND METHODS: All women who underwent first trimester pre-eclampsia risk assessment using either the NICE screening checklist or the FMF multimodal approach. Women considered at high-risk in the FMF cohort were offered 150 mg aspirin before 16 weeks' gestation, serial growth scans and elective birth at 40 weeks. MAIN OUTCOME MEASURES: Stillbirth, neonatal death and perinatal death rates stratified by screening method and maternal ethnicity. RESULTS: In the NICE cohort, the perinatal death rate was significantly higher in non-white than white women (7.95 versus 2.63/1000 births, OR 3.035, 95% CI 1.551-5.941). Following the introduction of FMF screening, the perinatal death rate in non-white women fell from 7.95 to 3.22/1000 births (OR 0.403, 95% CI 0.206-0.789), such that it was no longer significantly different from the perinatal mortality rate in white women (3.22 versus 2.55/1000 births, OR 1.261, 95% CI 0.641-2.483). CONCLUSIONS: First trimester combined screening for placental dysfunction is associated with a significant reduction in perinatal death in minority ethnic women. Health disparities in perinatal death among ethnic minority women demand urgent attention from both clinicians and health policy makers. The data of this study suggest that this ethnic health inequality may be avoidable. TWEETABLE ABSTRACT: Multimodal early pregnancy placental dysfunction screening can lead to a significant reduction in perinatal deaths in non-white women.

Diabetes mellitus, maternal adiposity, and insulin-dependent gestational diabetes are associated with COVID-19 in pregnancy: the INTERCOVID study.

BACKGROUND: Among nonpregnant individuals, diabetes mellitus and high body mass index increase the risk of COVID-19 and its severity. OBJECTIVE: This study aimed to determine whether diabetes mellitus and high body mass index are risk factors for COVID-19 in pregnancy and whether gestational diabetes mellitus is associated with COVID-19 diagnosis. STUDY DESIGN: INTERCOVID was a multinational study conducted between March 2020 and February 2021 in 43 institutions from 18 countries, enrolling 2184 pregnant women aged ≥18 years; a total of 2071 women were included in the analyses. For each woman diagnosed with COVID-19, 2 nondiagnosed women delivering or initiating antenatal care at the same institution were also enrolled. The main exposures were preexisting diabetes mellitus, high body mass index (overweight or obesity was defined as a body mass index ≥25 kg/m2), and gestational diabetes mellitus in pregnancy. The main outcome was a confirmed diagnosis of COVID-19 based on a real-time polymerase chain reaction test, antigen test, antibody test, radiological pulmonary findings, or ≥2 predefined COVID-19 symptoms at any time during pregnancy or delivery. Relationships of exposures and COVID-19 diagnosis were assessed using generalized linear models with a Poisson distribution and log link function, with robust standard errors to account for model misspecification. Furthermore, we conducted sensitivity analyses: (1) restricted to those with a real-time polymerase chain reaction test or an antigen test in the last week of pregnancy, (2) restricted to those with a real-time polymerase chain reaction test or an antigen test during the entire pregnancy, (3) generating values for missing data using multiple imputation, and (4) analyses controlling for month of enrollment. In addition, among women who were diagnosed with COVID-19, we examined whether having gestational diabetes mellitus, diabetes mellitus, or high body mass index increased the risk of having symptomatic vs asymptomatic COVID-19. RESULTS: COVID-19 was associated with preexisting diabetes mellitus (risk ratio, 1.94; 95% confidence interval, 1.55-2.42), overweight or obesity (risk ratio, 1.20; 95% confidence interval, 1.06-1.37), and gestational diabetes mellitus (risk ratio, 1.21; 95% confidence interval, 0.99-1.46). The gestational diabetes mellitus association was specifically among women requiring insulin, whether they were of normal weight (risk ratio, 1.79; 95% confidence interval, 1.06-3.01) or overweight or obese (risk ratio, 1.77; 95% confidence interval, 1.28-2.45). A somewhat stronger association with COVID-19 diagnosis was observed among women with preexisting diabetes mellitus, whether they were of normal weight (risk ratio, 1.93; 95% confidence interval, 1.18-3.17) or overweight or obese (risk ratio, 2.32; 95% confidence interval, 1.82-2.97). When the sample was restricted to those with a real-time polymerase chain reaction test or an antigen test in the week before delivery or during the entire pregnancy, including missing variables using imputation or controlling for month of enrollment, the observed associations were comparable. CONCLUSION: Diabetes mellitus and overweight or obesity were risk factors for COVID-19 diagnosis in pregnancy, and insulin-dependent gestational diabetes mellitus was associated with the disease. Therefore, it is essential that women with these comorbidities are vaccinated.

Preeclampsia and COVID-19: results from the INTERCOVID prospective longitudinal study.

BACKGROUND: It is unclear whether the suggested link between COVID-19 during pregnancy and preeclampsia is an independent association or if these are caused by common risk factors. OBJECTIVE: This study aimed to quantify any independent association between COVID-19 during pregnancy and preeclampsia and to determine the effect of these variables on maternal and neonatal morbidity and mortality. STUDY DESIGN: This was a large, longitudinal, prospective, unmatched diagnosed and not-diagnosed observational study assessing the effect of COVID-19 during pregnancy on mothers and neonates. Two consecutive not-diagnosed women were concomitantly enrolled immediately after each diagnosed woman was identified, at any stage during pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed until hospital discharge using the standardized INTERGROWTH-21st protocols and electronic data management system. A total of 43 institutions in 18 countries contributed to the study sample. The independent association between the 2 entities was quantified with the risk factors known to be associated with preeclampsia analyzed in each group. The outcomes were compared among women with COVID-19 alone, preeclampsia alone, both conditions, and those without either of the 2 conditions. RESULTS: We enrolled 2184 pregnant women; of these, 725 (33.2%) were enrolled in the COVID-19 diagnosed and 1459 (66.8%) in the COVID-19 not-diagnosed groups. Of these women, 123 had preeclampsia of which 59 of 725 (8.1%) were in the COVID-19 diagnosed group and 64 of 1459 (4.4%) were in the not-diagnosed group (risk ratio, 1.86; 95% confidence interval, 1.32-2.61). After adjustment for sociodemographic factors and conditions associated with both COVID-19 and preeclampsia, the risk ratio for preeclampsia remained significant among all women (risk ratio, 1.77; 95% confidence interval, 1.25-2.52) and nulliparous women specifically (risk ratio, 1.89; 95% confidence interval, 1.17-3.05). There was a trend but no statistical significance among parous women (risk ratio, 1.64; 95% confidence interval, 0.99-2.73). The risk ratio for preterm birth for all women diagnosed with COVID-19 and preeclampsia was 4.05 (95% confidence interval, 2.99-5.49) and 6.26 (95% confidence interval, 4.35-9.00) for nulliparous women. Compared with women with neither condition diagnosed, the composite adverse perinatal outcome showed a stepwise increase in the risk ratio for COVID-19 without preeclampsia, preeclampsia without COVID-19, and COVID-19 with preeclampsia (risk ratio, 2.16; 95% confidence interval, 1.63-2.86; risk ratio, 2.53; 95% confidence interval, 1.44-4.45; and risk ratio, 2.84; 95% confidence interval, 1.67-4.82, respectively). Similar findings were found for the composite adverse maternal outcome with risk ratios of 1.76 (95% confidence interval, 1.32-2.35), 2.07 (95% confidence interval, 1.20-3.57), and 2.77 (95% confidence interval, 1.66-4.63). The association between COVID-19 and gestational hypertension and the direction of the effects on preterm birth and adverse perinatal and maternal outcomes, were similar to preeclampsia, but confined to nulliparous women with lower risk ratios. CONCLUSION: COVID-19 during pregnancy is strongly associated with preeclampsia, especially among nulliparous women. This association is independent of any risk factors and preexisting conditions. COVID-19 severity does not seem to be a factor in this association. Both conditions are associated independently of and in an additive fashion with preterm birth, severe perinatal morbidity and mortality, and adverse maternal outcomes. Women with preeclampsia should be considered a particularly vulnerable group with regard to the risks posed by COVID-19.

Maternal and Neonatal Morbidity and Mortality Among Pregnant Women With and Without COVID-19 Infection: The INTERCOVID Multinational Cohort Study.

Importance: Detailed information about the association of COVID-19 with outcomes in pregnant individuals compared with not-infected pregnant individuals is much needed. Objective: To evaluate the risks associated with COVID-19 in pregnancy on maternal and neonatal outcomes compared with not-infected, concomitant pregnant individuals. Design, Setting, and Participants: In this cohort study that took place from March to October 2020, involving 43 institutions in 18 countries, 2 unmatched, consecutive, not-infected 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. Exposures: COVID-19 in pregnancy determined by laboratory confirmation of COVID-19 and/or radiological pulmonary findings or 2 or more predefined COVID-19 symptoms. Main Outcomes and Measures: The primary outcome measures were indices of (maternal and severe neonatal/perinatal) morbidity and mortality; the individual components of these indices were secondary outcomes. Models for these outcomes were adjusted for country, month entering study, maternal age, and history of morbidity. Results: A total of 706 pregnant women with COVID-19 diagnosis and 1424 pregnant women without COVID-19 diagnosis were enrolled, all with broadly similar demographic characteristics (mean [SD] age, 30.2 [6.1] years). Overweight early in pregnancy occurred in 323 women (48.6%) with COVID-19 diagnosis and 554 women (40.2%) without. Women with COVID-19 diagnosis were at higher risk for preeclampsia/eclampsia (relative risk [RR], 1.76; 95% CI, 1.27-2.43), severe infections (RR, 3.38; 95% CI, 1.63-7.01), intensive care unit admission (RR, 5.04; 95% CI, 3.13-8.10), maternal mortality (RR, 22.3; 95% CI, 2.88-172), preterm birth (RR, 1.59; 95% CI, 1.30-1.94), medically indicated preterm birth (RR, 1.97; 95% CI, 1.56-2.51), severe neonatal morbidity index (RR, 2.66; 95% CI, 1.69-4.18), and severe perinatal morbidity and mortality index (RR, 2.14; 95% CI, 1.66-2.75). Fever and shortness of breath for any duration was associated with increased risk of severe maternal complications (RR, 2.56; 95% CI, 1.92-3.40) and neonatal complications (RR, 4.97; 95% CI, 2.11-11.69). Asymptomatic women with COVID-19 diagnosis remained at higher risk only for maternal morbidity (RR, 1.24; 95% CI, 1.00-1.54) and preeclampsia (RR, 1.63; 95% CI, 1.01-2.63). Among women who tested positive (98.1% by real-time polymerase chain reaction), 54 (13%) of their neonates tested positive. Cesarean delivery (RR, 2.15; 95% CI, 1.18-3.91) but not breastfeeding (RR, 1.10; 95% CI, 0.66-1.85) was associated with increased risk for neonatal test positivity. Conclusions and Relevance: In this multinational cohort study, COVID-19 in pregnancy was associated with consistent and substantial increases in severe maternal morbidity and mortality and neonatal complications when pregnant women with and without COVID-19 diagnosis were compared. The findings should alert pregnant individuals and clinicians to implement strictly all the recommended COVID-19 preventive measures.

Early prenatal presentation of the cartilage-hair hypoplasia / anauxetic dysplasia spectrum of disorders mimicking recurrent thanatophoric dysplasia.

Three sibling fetuses identified with limb shortening and thoracic narrowing at twelve weeks' gestation on first trimester ultrasound examination are presented. The parents were non-consanguineous, Caucasian, healthy, of normal stature and had a healthy normal daughter. The radiographic abnormalities were highly suggestive of thanatophoric dysplasia, but molecular analysis failed to identify a pathogenic variant in FGFR3. The three fetuses were found to have identical compound heterozygous mutations in RMRP in trans, one inherited from the mother and one from the father. This represents the early prenatal presentation and fetal findings of metaphyseal dysplasia type McKusick (Cartilage-hair hypoplasia; CHH)/anauxetic dysplasia spectrum of disorders.

Performance of Antenatal Diagnostic Criteria of Twin-Anemia-Polycythemia Sequence.

This study aims to elicit the validation performance of different diagnostic criteria and to evaluate the disease course and perinatal outcomes of pregnancies complicated by twin anemia polycythemia sequence (TAPS). Monochorionic diamniotic (MCDA) twin pregnancies who received serial middle cerebral artery (MCA) peak systolic velocity (PSV) measurements without non-TAPS-related demise or major anomalies were included. Course of disease, antenatal intervention, additional ultrasound features, and perinatal outcomes were compared between each criteria and onset. Forty-nine cases of TAPS and 203 non-TAPS controls were identified. The incidence of TAPS was 19.2%, 15.7%, 7.8%, and 6.3% for ΔPSV MoM > 0.373, ΔPSV MoM > 0.5, traditional, and Delphi consensus criteria, respectively (p < 0.001). The incidence of antenatal intervention was 55.1, 62.5, 75.0, and 87.5%, respectively. Furthermore, cases detected according to the Delphi consensus criteria had a higher rate of progression or intervention compared to cases detected with ΔPSV MoM > 0.373 (87.0 vs. 59.0%, p = 0.037). TAPS had a significantly higher birth weight discordance than uncomplicated MCDA twins (25.3 vs. 7.3%, p < 0.001). Application of four different diagnostic criteria for TAPS leads to significant differences in the incidence, severity, and antenatal intervention. The Delphi criteria identified more severe cases likely to require intervention, and the delta PSV > 0.373 criteria identified milder cases, without a significant impact on neonatal outcomes.

Maternal and Perinatal Outcomes of White Coat Hypertension During Pregnancy: A Systematic Review and Meta-Analysis.

The aim of this meta-analysis is to investigate whether white-coat hypertension (WCH) has an adverse effect on maternal, fetal, and neonatal outcomes. Medline, EMBASE, www.Clinicaltrials.gov, and Cochrane Library databases were searched electronically in December 2019. The outcomes were compared between pregnant women with WCH and normotensive controls, women with chronic hypertension, gestational hypertension or any hypertensive disorder of pregnancy. Twelve studies were eligible for inclusion in the systematic review. Women with WCH enrolled below 20 weeks had a significantly increased risk of preeclampsia (pooled risk ratio [RR], 5.43 [95% CI, 2.00-14.71]). Furthermore, women with WCH had increased risk of delivering a small-for-gestational-age newborn (RR, 2.47 [95% CI, 1.21-5.05], P=0.013) and preterm birth (RR, 2.86 [95% CI, 1.44-5.68], P=0.002). The risk of preeclampsia (risk ratio, 0.43 [95% CI, 0.23-0.78], P=0.005), small-for-gestational-age (RR, 0.46 [95% CI, 0.26-0.82], P=0.008), preterm birth (RR, 0.47 [95% CI, 0.31-0.71], P<0.001) were significantly lower with WCH compared with women with gestational hypertension. Women with WCH delivered ≈1 week later compared with women with chronic hypertension (mean difference, 1.06 weeks [95% CI, 0.44-1.67 weeks]; P<0.001). WCH is associated with a worse perinatal and maternal outcome than normotension, but better outcomes than gestational hypertension and chronic hypertension. Therefore, diagnosis of WCH should be ascertained in pregnant women presenting with hypertension. When the diagnosis is confirmed, these women require monitoring for developing preeclampsia, small-for-gestational-age and preterm birth.

Selective Fetal Growth Restriction in Dichorionic Twin Pregnancies: Diagnosis, Natural History, and Perinatal Outcome.

This study aims to evaluate the natural history, disease progression, and outcomes in dichorionic twins with selective fetal growth restriction (sFGR) according to different diagnostic criteria and time of onset. Dichorionic twins seen from the first trimester were included. sFGR was classified according to the Delphi consensus, and was compared to the outcomes of those classified by the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) diagnostic criteria. Early sFGR occurred before 32-weeks, and late sFGR after 32-weeks. Disease progression, neonatal outcomes such as gestation at delivery, birthweight, neonatal unit (NNU) admission, and morbidities were compared. One-hundred twenty-three of 1053 dichorionic twins had sFGR, where 8.4% were classified as early sFGR, and 3.3% were late sFGR. Disease progression was seen in 36%, with a longer progression time (5 vs. 1 week) and higher progression rate (40% vs. 26%) in early sFGR. Perinatal death was significantly higher in the sFGR than the non-sFGR group (24 vs. 16 per 1000 births, p = 0.018), and those with early sFGR had more NNU admissions than late sFGR (p = 0.005). The ISUOG diagnostic criteria yielded a higher number of sFGR than the Delphi criteria, but similar outcomes. sFGR have worse perinatal outcomes, with early onset being more prevalent. Use of the Delphi diagnostic criteria can reduce over-diagnosis of sFGR and avoid unnecessary intervention.

Investigate the oral health impact and quality of life on patients with malocclusion of different treatment needs.

BACKGROUND: This study compared oral health impacts and QoL among patients with different malocclusion types and a normal population by using self-report questionnaires. METHODS: In this cross-sectional study, 214 healthy adults were divided into 3 groups: (1) Normal, control group; (2) ORTHO, patients who received orthodontic treatment; and (3) OGS group, patients who received orthognathic surgery (OGS). The timing of measurement were at the initial stage of the orthodontic therapy and before surgery. Two questionnaires and one additional item were used: the 36-item Short Form Health Survey (SF-36) for QoL, the 14-item Oral Health Impact Profile (OHIP-14) for oral health-related QoL (OHRQOL) and one additional item for aesthetic evaluation. Descriptive and inferential statistical analyses were used to compare the 3 groups. The effects of 3 malocclusion types, gender, age, and facial asymmetry in the OGS group were also evaluated. RESULTS: The ORTHO and OGS groups had higher negative impacts than did the Normal group in the OHIP-14, but not much difference in the SF-36. The item of aesthetics related to oral health impact was the lowest in the OGS group. The patients in the ORTHO group with a Class II malocclusion were most dissatisfied in the SF-36 and OHIP-14. In the OGS group, the women dissatisfied in the OHIP-14 and the aesthetic. The older patients had higher negative impacts in the OHIP-14 than the younger patients. The patients with facial asymmetry did not suffer higher negative impacts than did the patients with a symmetrical face in the SF-36 and OHIP-14. CONCLUSIONS: The majority of the patients who required orthodontics or OGS reported a higher negative impact in the OHIP-14 compared with the normal controls, but not in the SF-36. Class II malocclusion suffered from highest psychological stress and aesthetic sensitivity than the other two subgroups in the ORTHO group.

Human iPSC-derived trigeminal neurons lack constitutive TLR3-dependent immunity that protects cortical neurons from HSV-1 infection.

Herpes simplex virus type 1 (HSV-1) encephalitis (HSE) is the most common sporadic viral encephalitis in Western countries. Some HSE children carry inborn errors of the Toll-like receptor 3 (TLR3)-dependent IFN-α/ß- and -λ-inducing pathway. Induced pluripotent stem cell (iPSC)-derived cortical neurons with TLR3 pathway mutations are highly susceptible to HSV-1, due to impairment of cell-intrinsic TLR3-IFN immunity. In contrast, the contribution of cell-intrinsic immunity of human trigeminal ganglion (TG) neurons remains unclear. Here, we describe efficient in vitro derivation and purification of TG neurons from human iPSCs via a cranial placode intermediate. The resulting TG neurons are of sensory identity and exhibit robust responses to heat (capsaicin), cold (icilin), and inflammatory pain (ATP). Unlike control cortical neurons, both control and TLR3-deficient TG neurons were highly susceptible to HSV-1. However, pretreatment of control TG neurons with poly(I:C) induced the cells into an anti-HSV-1 state. Moreover, both control and TLR3-deficient TG neurons developed resistance to HSV-1 following pretreatment with IFN-ß but not IFN-λ. These data indicate that TG neurons are vulnerable to HSV-1 because they require preemptive stimulation of the TLR3 or IFN-α/ß receptors to induce antiviral immunity, whereas cortical neurons possess a TLR3-dependent constitutive resistance that is sufficient to block incoming HSV-1 in the absence of prior antiviral signals. The lack of constitutive resistance in TG neurons in vitro is consistent with their exploitation as a latent virus reservoir in vivo. Our results incriminate deficiencies in the constitutive TLR3-dependent response of cortical neurons in the pathogenesis of HSE.

Dynamin-related protein Drp1 is required for Bax translocation to mitochondria in response to irradiation-induced apoptosis.

Translocation of the pro-apoptotic protein Bax from the cytosol to the mitochondria is a crucial step in DNA damage-mediated apoptosis, and is also found to be involved in mitochondrial fragmentation. Irradiation-induced cytochrome c release and apoptosis was associated with Bax activation, but not mitochondrial fragmentation. Both Bax and Drp1 translocated from the cytosol to the mitochondria in response to irradiation. However, Drp1 mitochondrial translocation and oligomerization did not require Bax, and failed to induce apoptosis in Bax deficient diffuse large B-cell lymphoma (DLBCL) cells. Using fluorescent microscopy and the intensity correlation analysis, we demonstrated that Bax and Drp1 were colocalized and the levels of colocalization were increased by UV irradiation. Using co-immuno-precipitation, we confirmed that Bax and Drp1 were binding partners. Irradiation induced a time-associated increase in the interaction between active Bax and Drp1. Knocking down Drp1 using siRNA blocked UV irradiation-mediated Bax mitochondrial translocation. In conclusion, our findings demonstrate for the first time, that Drp1 is required for Bax mitochondrial translocation, but Drp1-induced mitochondrial fragmentation alone is not sufficient to induce apoptosis in DLBCL cells.