Showing papers in "Ultrasound in Obstetrics & Gynecology in 2021"

Pregnancy and neonatal outcomes of COVID-19: coreporting of common outcomes from PAN-COVID and AAP-SONPM registries.

Abstract: Objective Few large cohort studies have reported data on maternal, fetal, perinatal and neonatal outcomes associated with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection in pregnancy. We report the outcome of infected pregnancies from a collaboration formed early during the pandemic between the investigators of two registries, the UK and Global Pregnancy and Neonatal outcomes in COVID‐19 (PAN‐COVID) study and the American Academy of Pediatrics (AAP) Section on Neonatal–Perinatal Medicine (SONPM) National Perinatal COVID‐19 Registry. Methods This was an analysis of data from the PAN‐COVID registry (1 January to 25 July 2020), which includes pregnancies with suspected or confirmed maternal SARS‐CoV‐2 infection at any stage in pregnancy, and the AAP‐SONPM National Perinatal COVID‐19 registry (4 April to 8 August 2020), which includes pregnancies with positive maternal testing for SARS‐CoV‐2 from 14 days before delivery to 3 days after delivery. The registries collected data on maternal, fetal, perinatal and neonatal outcomes. The PAN‐COVID results are presented overall for pregnancies with suspected or confirmed SARS‐CoV‐2 infection and separately in those with confirmed infection. Results We report on 4005 pregnant women with suspected or confirmed SARS‐CoV‐2 infection (1606 from PAN‐COVID and 2399 from AAP‐SONPM). For obstetric outcomes, in PAN‐COVID overall and in those with confirmed infection in PAN‐COVID and AAP‐SONPM, respectively, maternal death occurred in 0.5%, 0.5% and 0.2% of cases, early neonatal death in 0.2%, 0.3% and 0.3% of cases and stillbirth in 0.5%, 0.6% and 0.4% of cases. Delivery was preterm (< 37 weeks' gestation) in 12.0% of all women in PAN‐COVID, in 16.1% of those women with confirmed infection in PAN‐COVID and in 15.7% of women in AAP‐SONPM. Extreme preterm delivery (< 27 weeks' gestation) occurred in 0.5% of cases in PAN‐COVID and 0.3% in AAP‐SONPM. Neonatal SARS‐CoV‐2 infection was reported in 0.9% of all deliveries in PAN‐COVID overall, in 2.0% in those with confirmed infection in PAN‐COVID and in 1.8% in AAP‐SONPM; the proportions of neonates tested were 9.5%, 20.7% and 87.2%, respectively. The rates of a small‐for‐gestational‐age (SGA) neonate were 8.2% in PAN‐COVID overall, 9.7% in those with confirmed infection and 9.6% in AAP‐SONPM. Mean gestational‐age‐adjusted birth‐weight Z‐scores were −0.03 in PAN‐COVID and −0.18 in AAP‐SONPM. Conclusions The findings from the UK and USA registries of pregnancies with SARS‐CoV‐2 infection were remarkably concordant. Preterm delivery affected a higher proportion of women than expected based on historical and contemporaneous national data. The proportions of pregnancies affected by stillbirth, a SGA infant or early neonatal death were comparable to those in historical and contemporaneous UK and USA data. Although maternal death was uncommon, the rate was higher than expected based on UK and USA population data, which is likely explained by underascertainment of women affected by milder or asymptomatic infection in pregnancy in the PAN‐COVID study, although not in the AAP‐SONPM study. The data presented support strong guidance for enhanced precautions to prevent SARS‐CoV‐2 infection in pregnancy, particularly in the context of increased risks of preterm delivery and maternal mortality, and for priority vaccination of pregnant women and women planning pregnancy. Copyright © 2021 ISUOG. Published by John Wiley & Sons Ltd.

Pregnant women with SARS-CoV-2 infection are at higher risk of death and pneumonia: propensity score matched analysis of a nationwide prospective cohort (COV19Mx).

Abstract: Objective There are limited, unmatched data reporting low complication rates in pregnant women with coronavirus disease 2019 (COVID-19). The aim of this study was to compare COVID-19-related outcomes between pregnant and non-pregnant women after adjusting for potential risk factors for severe outcomes. Methods Data were obtained from the COVID-19 National Data Registry of Mexico, which is an ongoing prospective cohort of people of any age with clinically suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and admitted to 475 monitoring hospitals. This study included pregnant and non-pregnant women of reproductive age (15-45 years) with COVID-19 confirmed by reverse transcription polymerase chain reaction. To adjust for underlying risk factors, propensity score matching was conducted for chronic obstructive pulmonary disease, asthma, smoking, hypertension, cardiovascular disease, obesity, diabetes, chronic renal disease, immunosuppression, age, language, nationality and level of health insurance. The primary outcome was death. Secondary outcomes were pneumonia, intubation and intensive care unit (ICU) admission. Results The cohort comprised 5183 pregnant and 175 905 non-pregnant women with COVID-19. The crude (unmatched) rates of death, pneumonia, intubation and ICU admission in pregnant compared with non-pregnant women were 1.5% vs 1.5%, 9.9% vs 6.5%, 8.1% vs 9.9% and 13.0% vs 6.9%, respectively. After propensity score matching (5183 pregnant and 5183 non-pregnant matched women), pregnant women had a higher odds of death (odds ratio (OR), 1.84; 95% CI, 1.26-2.69), pneumonia (OR, 1.86; 95% CI, 1.60-2.16) and ICU admission (OR, 1.86; 95% CI, 1.41-2.45) than non-pregnant women, but similar odds of intubation (OR, 0.93; 95% CI, 0.70-1.25). Conclusion After adjusting for background demographic and medical factors, pregnancy is a risk factor for death, pneumonia and ICU admission in SARS-CoV-2-infected women of reproductive age. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Maternal and Perinatal Outcomes of Pregnant Women with SARS-COV-2 infection.

Abstract: OBJECTIVES: To evaluate maternal and perinatal outcomes of pregnant women affected by SARS-COV-2. METHODS: This was a multinational retrospective cohort study including women with laboratory-confirmed SARS-COV-2 from 73 centers from 22 different countries in Europe, United States, South America, Asia and Australia from February 1, 2020 to April 30, 2020. Confirmed SARS-COV-2 infection was defined as a positive result on real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens. The primary outcome was a composite measure of maternal mortality and morbidity including admission to intensive care unit (ICU), use of mechanical ventilation, or death. RESULTS: 388 singleton pregnancies tested positive to SARS-COV-2 at RT-PCR nasal and pharyngeal swab were included in the study. The primary outcome was observed in 47/388 women (12.1%). 43/388 women (11.1%) were admitted to ICU, 36/388 (9.3%) required mechanical ventilation, and 3/388 women deceased (0.8%). Of the 388 women included in the study, 122 (31.4%) were still pregnant at the time of the study. Among the other 266 women, 6 had spontaneous first-trimester abortion, 3 had elective termination of pregnancy, 6 had stillbirth, and 251 delivered a live-born infant. The rate of preterm birth less than 37 weeks of gestation was 26.3% (70/266). Of the 251 live-born infants, 69/251 (27.5%) were admitted to NICU, with 5 neonatal deaths (2.0%). The overall rate of perinatal death was 4.1% (11/266). Only one infant (1/251, 0.4%) born from a mother tested positive during the third trimester, was found positive to SARS-COV-2 at RT-PCR. CONCLUSIONS: SARS-COV-2 in pregnant women is associated with 0.8% rate of maternal mortality, but 11.1% rate of admission to ICU. The risk of vertical transmission seems to be negligible. This article is protected by copyright. All rights reserved.

Short-term outcome of pregnant women vaccinated with BNT162b2 mRNA COVID-19 vaccine.

Abstract: OBJECTIVES: To determine the immunogenicity and reactogenicity of the Pfizer/BioNTech BNT162b2 mRNA coronavirus disease 2019 (COVID-19) vaccine among pregnant women compared with non-pregnant women, and to evaluate obstetric outcome following vaccination. METHODS: This was an observational case-control study of pregnant women who were vaccinated with a two-dose regimen of BNT162b2 vaccine during gestation between January and February 2021 (study group) and age-matched non-pregnant women who received the vaccine during the same time period (control group). Participants received a digital questionnaire 1-4 weeks after the second dose and were asked to provide information regarding demographics, medication, medical history, history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, timing of COVID-19 vaccine doses and side effects after each vaccine dose. A second digital questionnaire, regarding current pregnancy and delivery outcomes, was sent to patients in the study group after the calculated due date. All recruited women were offered a serology blood test for SARS-CoV-2 immunoglobulin G (IgG) following the second vaccination dose and SARS-CoV-2 IgG levels were compared between the two groups. RESULTS: Of 539 pregnant women who were recruited after completion of the two-dose regimen of the vaccine, 390 returned the digital questionnaire and were included in the study group and compared to 260 age-matched non-pregnant vaccinated women. The rates of rash, fever and severe fatigue following vaccination among pregnant women were comparable to those in non-pregnant women. Myalgia, arthralgia and headache were significantly less common among pregnant women after each dose, local pain or swelling and axillary lymphadenopathy were significantly less common among pregnant women after the first and second doses, respectively, while paresthesia was significantly more common among the pregnant population after the second dose. Among pregnant women, there were no significant differences in the rates of side effects according to whether the vaccine was administered during the first, second or third trimester of pregnancy, except for local pain/swelling, which was significantly less common after the first dose when administered during the third trimester, and uterine contractions, which were significantly more common after the second dose when administered during the third trimester. The rates of obstetric complications, including uterine contractions (1.3% after the first dose and 6.4% after the second dose), vaginal bleeding (0.3% after the first dose and 1.5% after the second dose) and prelabor rupture of membranes (0% after the first dose and 0.8% after the second dose) were very low following vaccination. All maternal sera samples in both groups were positive for SARS-CoV-2 IgG. However, pregnant women had significantly lower serum SARS-CoV-2 IgG levels compared to those of non-pregnant women (signal-to-cut-off ratio, 27.03 vs 34.35, respectively; P < 0.001). Among the 57 pregnant women who delivered during the study period and who completed the second questionnaire, median gestational age at delivery was 39.5 (interquartile range, 38.7-40.0) weeks, with no cases of preterm birth < 37 weeks, no cases of fetal or neonatal death and two (3.5%) cases of admission to the neonatal intensive care unit for respiratory support. CONCLUSIONS: The adverse-effect profile and short-term obstetric and neonatal outcomes among pregnant women who were vaccinated with the BNT162b2 vaccine at any stage of pregnancy do not indicate any safety concerns. The vaccine is effective in generating a humoral immune response in pregnant women, although SARS-CoV-2 IgG levels were lower than those observed in non-pregnant vaccinated women. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Pregnancy and COVID-19: Pharmacologic Considerations.

Abstract: The Severe Acute Respiratory Syndrome-related Coronavirus-2 (SARS-CoV2) pandemic has sparked controversy regarding the use of certain routine and investigational pharmacologic interventions during pregnancy and the postpartum period. In this review, we critically appraise guidance in regard to pharmacologic considerations unique to pregnant and lactating women with coronavirus disease (COVID-19). We summarize the evidence, which supports the routine use of antenatal corticosteroids, magnesium sulfate and low-dose aspirin where clinically indicated, and if not contraindicated for medical reasons. We highlight that decision-making about initiation, dose and duration of prophylactic anticoagulation for pregnant patients with COVID-19 should be made by a multidisciplinary team and must consider disease severity, timing of delivery in relation to disease onset, inpatient versus outpatient status, underlying comorbidities, and contraindications to the use of anticoagulation. We discuss the rationale behind suggested modifications to the use of peripartum analgesia and anaesthesia at the time of the pandemic, as well as considerations specific to mechanically-ventilated pregnant patients. Finally, we discuss emerging evidence supporting the reduction in mortality in patients with COVID-19 with the use of corticosteroids, while tabulating up-to-date information on the safety of various investigational therapies for COVID-19. It is hoped that this comprehensive review while providing guidance to clinicians caring for pregnant and postpartum women during the COVID-19 pandemic will also encourage researchers to consider their inclusion in clinical trials of therapeutic interventions for COVID-19. This article is protected by copyright. All rights reserved.

Single-cell RNA expression profiling of SARS-CoV-2-related ACE2 and TMPRSS2 in human trophectoderm and placenta.

Abstract: Objectives To examine the characteristics and distribution of possible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) target cells in the human trophectoderm (TE) and placenta. Methods Bioinformatics analysis was performed based on published single-cell transcriptomic datasets of early TE and first- and second-trimester human placentae. We conducted the transcriptomic analysis of 4198 early TE cells, 1260 first-trimester placental cells and 189 extravillous trophoblast cells (EVTs) from 24-week placentae (EVT_24W) using the SMART-Seq2 method. In addition, to confirm the bioinformatic results, we performed immunohistochemical staining of three first-trimester, three second-trimester and three third-trimester placentae from nine women recruited prospectively to this study. We evaluated the expression of the SARS-CoV-2-related molecules angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). Results Via bioinformatic analysis, we identified the existence of ACE2 and TMPRSS2 expression in human TE as well as in first- and second-trimester placentae. In the human TE, 54.4% of TE1 cells, 9.0% of cytotrophoblasts (CTBs), 3.2% of EVTs and 29.5% of syncytiotrophoblasts (STBs) were ACE2-positive. In addition, 90.7% of TE1 cells, 31.5% of CTBs, 22.1% of EVTs and 70.8% of STBs were TMPRSS2-positive. In placental cells, 20.4% of CTBs, 44.1% of STBs, 3.4% of EVTs from 8-week placentae (EVT_8W) and 63% of EVT_24W were ACE2-positive, while 1.6% of CTBs, 26.5% of STBs, 1.9% of EVT_8W and 20.1% of EVT_24W were TMPRSS2-positive. Pathway analysis revealed that EVT_24W cells that were positive for both ACE2 and TMPRSS2 (ACE2 + TMPRSS2-positive) were associated with morphogenesis of branching structure, extracellular matrix interaction, oxygen binding and antioxidant activity. The ACE2 + TMPRSS2-positive TE1 cells were correlated with an increased capacity for viral invasion, epithelial-cell proliferation and cell adhesion. Expression of ACE2 and TMPRSS2 was observed on immunohistochemical staining in first-, second- and third-trimester placentae. Conclusions ACE2- and TMPRSS2-positive cells are present in the human TE and placenta in all three trimesters of pregnancy, which indicates the possibility that SARS-CoV-2 could spread via the placenta and cause intrauterine fetal infection. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Consensus on revised definitions of morphological uterus sonographic assessment (MUSA) features of adenomyosis: results of a modified Delphi procedure

Abstract: Objective To update the Morphological Uterus Sonographic Assessment (MUSA) definitions of adenomyosis if deemed necessary, and to reach consensus on the updated definitions METHODS: A modified Delphi procedure among European gynecologists with expertise in ultrasound diagnosis of adenomyosis was performed. To identify MUSA features that might need revision, 15 two-dimensional (2D) video recordings (four recordings including also three-dimensional (3D) still images) of transvaginal ultrasound (TVUS) examinations of the uterus were presented in an online survey in the first Delphi round. Experts were asked to confirm or refute the presence of each of nine MUSA features of adenomyosis in each of the 15 videoclips and to give comments. In the second round, the results of the first round and suggestions for revision of MUSA features were shared with the experts before they were asked to assess a new set of 2D and 3D still images of TVUS examinations and to provide feedback on the proposed revisions. A third round, an on-line face-to-face meeting, was used to discuss and reach final consensus on revised definitions of MUSA features. Consensus was predefined as at least 66.7% agreement between experts. Results Sixteen of eighteen invited experts agreed to participate. Eleven experts completed and four experts partly finished the first assessment round. The experts identified a need for more detailed definitions of some MUSA features. They recommended to use 3D ultrasound to optimize visualization of the junctional zone. Fifteen experts joined the second round and reached consensus on the presence or absence of ultrasound features of adenomyosis in most still images. Consensus was reached for all revised definitions except those for subendometrial lines and buds and interrupted junctional zone. Thirteen experts joined the on-line meeting, discussed, and agreed on final revisions of the MUSA definitions. There was consensus on the need to distinguish between direct features, i.e. features indicating presence of ectopic endometrial tissue in the myometrium, and indirect features, i.e. features reflecting changes in the myometrium secondary to presence of endometrial tissue in the myometrium. Myometrial cysts, hyperechogenic islands and subendometrial lines and buds were unanimously classified as direct features of adenomyosis, all others were classified as indirect features. Conclusions Consensus between gynecologists with expertise in ultrasound diagnosis of adenomyosis was achieved regarding revised definitions of the MUSA features of adenomyosis and on the classification of MUSA features as direct or indirect features of adenomyosis. This article is protected by copyright. All rights reserved.

Cardiovascular events following pregnancy complicated by pre-eclampsia with emphasis on comparison between early- and late-onset forms: systematic review and meta-analysis.

Abstract: OBJECTIVE To elucidate whether pre-eclampsia (PE) and the gestational age at onset of the disease (early- vs late-onset PE) have an impact on the risk of long-term maternal cardiovascular complications. METHODS MEDLINE, EMBASE and Scopus databases were searched until 15 April 2020 for studies evaluating the incidence of cardiovascular events in women with a history of PE, utilizing combinations of the relevant MeSH terms, keywords and word variants for 'pre-eclampsia', 'cardiovascular disease' and 'outcome'. Inclusion criteria were cohort or case-control design, inclusion of women with a diagnosis of PE at the time of the first pregnancy, and sufficient data to compare each outcome in women with a history of PE vs women with previous normal pregnancy and/or in women with a history of early- vs late-onset PE. The primary outcome was a composite score of maternal cardiovascular morbidity and mortality, including cardiovascular death, major cardiovascular and cerebrovascular events, hypertension, need for antihypertensive therapy, Type-2 diabetes mellitus, dyslipidemia and metabolic syndrome. Secondary outcomes were the individual components of the primary outcome analyzed separately. Data were combined using a random-effects generic inverse variance approach. MOOSE guidelines and the PRISMA statement were followed. RESULTS Seventy-three studies were included. Women with a history of PE, compared to those with previous normotensive pregnancy, had a higher risk of composite adverse cardiovascular outcome (odds ratio (OR), 2.05 (95% CI, 1.9-2.3)), cardiovascular death (OR, 2.18 (95% CI, 1.8-2.7)), major cardiovascular events (OR, 1.80 (95% CI, 1.6-2.0)), hypertension (OR, 3.93 (95% CI, 3.1-5.0)), need for antihypertensive medication (OR, 4.44 (95% CI, 2.4-8.2)), dyslipidemia (OR, 1.32 (95% CI, 1.3-1.4)), Type-2 diabetes (OR, 2.14 (95% CI, 1.5-3.0)), abnormal renal function (OR, 3.37 (95% CI, 2.3-5.0)) and metabolic syndrome (OR, 4.30 (95% CI, 2.6-7.1)). Importantly, the strength of the associations persisted when considering the interval ( 10 years) from PE to the occurrence of these outcomes. When stratifying the analysis according to gestational age at onset of PE, women with previous early-onset PE, compared to those with previous late-onset PE, were at higher risk of composite adverse cardiovascular outcome (OR, 1.75 (95% CI, 1.0-3.0)), major cardiovascular events (OR, 5.63 (95% CI, 1.5-21.4)), hypertension (OR, 1.48 (95% CI, 1.3-1.7)), dyslipidemia (OR, 1.51 (95% CI, 1.3-1.8)), abnormal renal function (OR, 1.52 (95% CI, 1.1-2.2)) and metabolic syndrome (OR, 1.66 (95% CI, 1.1-2.5). CONCLUSIONS Both early- and late-onset PE represent risk factors for maternal adverse cardiovascular events later in life. Early-onset PE is associated with a higher burden of cardiovascular morbidity and mortality compared to late-onset PE. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

COngenital heart disease and the Diagnostic yield with Exome sequencing (CODE) study: prospective cohort study and systematic review.

Abstract: OBJECTIVE To determine the incremental yield of antenatal exome sequencing (ES) over chromosomal microarray analysis (CMA) or conventional karyotyping in prenatally diagnosed congenital heart disease (CHD). METHODS A prospective cohort study of 197 trios undergoing ES following CMA or karyotyping owing to CHD identified prenatally and a systematic review of the literature were performed. MEDLINE, EMBASE, CINAHL and ClinicalTrials.gov (January 2000 to October 2019) databases were searched electronically for studies reporting on the diagnostic yield of ES in prenatally diagnosed CHD. Selected studies included those with more than three cases, with initiation of testing based upon prenatal phenotype only and that included cases in which CMA or karyotyping was negative. The incremental diagnostic yield of ES was assessed in: (1) all cases of CHD; (2) isolated CHD; (3) CHD associated with extracardiac anomaly (ECA); and (4) CHD according to phenotypic subgroup. RESULTS In our cohort, ES had an additional diagnostic yield in all CHD, isolated CHD and CHD associated with ECA of 12.7% (25/197), 11.5% (14/122) and 14.7% (11/75), respectively (P = 0.81). The corresponding pooled incremental yields from 18 studies (encompassing 636 CHD cases) included in the systematic review were 21% (95% CI, 15-27%), 11% (95% CI, 7-15%) and 37% (95% CI, 18-56%), respectively. The results did not differ significantly when subanalysis was limited to studies including more than 20 cases, except for CHD associated with ECA, in which the incremental yield was greater (49% (95% CI, 17-80%)). In cases of CHD associated with ECA in the primary analysis, the most common extracardiac anomalies associated with a pathogenic variant were those affecting the genitourinary system (23/52 (44.2%)). The greatest incremental yield was in cardiac shunt lesions (41% (95% CI, 19-63%)), followed by right-sided lesions (26% (95% CI, 9-43%)). In the majority (68/96 (70.8%)) of instances, pathogenic variants occurred de novo and in autosomal dominant (monoallelic) disease genes. The most common (19/96 (19.8%)) monogenic syndrome identified was Kabuki syndrome. CONCLUSIONS There is an apparent incremental yield of prenatal ES in CHD. While the greatest yield is in CHD associated with ECA, consideration could also be given to performing ES in the presence of an isolated cardiac abnormality. A policy of routine application of ES would require the adoption of robust bioinformatic, clinical and ethical pathways. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Protein expression of angiotensin-converting enzyme 2, a SARS-CoV-2-specific receptor, in fetal and placental tissues throughout gestation: new insight for perinatal counseling

Abstract: Infection with SARS-CoV2 does not spare pregnant women and the possibility of vertical transmission which might lead to fetal damages is pending. OBJECTIVE: We hypothesized that the observed low incidence of perinatal infection could be related to a low expression of the membrane receptor for SARS-CoV2, ACE2, in the fetal-placental unit. We evaluated protein expression of ACE2 both in placentas and fetal organs from non-infected pregnancies across gestation. METHODS: Discovery study. Immunocytochemistry analysis for ACE2 in organs and placentas were performed in May 2020, in samples from a registered biobank. Five cases of medical termination of pregnancy performed at between 15 and 38 weeks' in healthy women. Paraffin-embedded tissues (kidneys, brain, lungs, intestinal tract, heart). Matching tissues from 8-year-old children (N=4) were tested as controls. Seven placentas including those of the 5 cases, 1 of a 7-week miscarriage and 1 of a symptomatic SARS-COV2 pregnancy at 34 weeks. Tissues' sections were incubated with rabbit monoclonal anti-ACE2. Protein expression of ACE2 was detected by immunochemistry. RESULTS: ACE2 expression was detected in fetal kidneys, rectum and ileum across gestation and similarly in the pediatric control. It was barely detectable in lungs at 15 weeks' and not found thereafter. In the pediatric control, ACE2 was only detectable in type 2 pneumocytes. No ACE2 expression was found in the cerebral ependymal, parenchyma nor in cardiac tissues ACE2 was expressed in syncitiotrophoblast and cytotrophoblast from 7th weeks' onwards and across gestation but not in the amnion. Similar intensity and distribution of ACE2 staining were identified in the mother's SARS-CoV2 placenta. CONCLUSIONS: Marked placental expression of ACE2 provides a rationale for vertical transmission at cellular level. Absence of ACE2 expression in the fetal brain and heart is reassuring on the risk of congenital malformation. Clinical follow-up of infected pregnant women and their children are needed to validate these observations. This article is protected by copyright. All rights reserved.

Effect of maternal diabetes on fetal heart function on echocardiography: systematic review and meta-analysis.

Abstract: OBJECTIVE Maternal diabetes in pregnancy is associated with structural anomalies of the fetal heart, as well as hypertrophy and functional impairment. This systematic review and meta-analysis aimed to estimate the effect of maternal diabetes on fetal cardiac function as measured by prenatal echocardiography. METHODS We performed a search of the EMBASE, PubMed and The Cochrane Library databases, from inception to 4 July 2019, for studies evaluating fetal cardiac function using echocardiography in pregnancies affected by diabetes compared with uncomplicated pregnancies. Outcome measures were cardiac hypertrophy and diastolic, systolic and overall cardiac function as assessed by various ultrasound parameters. The quality of the studies was assessed using the Newcastle-Ottawa Scale. Data on interventricular septal (IVS) thickness, myocardial performance index (MPI) and E/A ratio were pooled for the meta-analysis using random-effects models. For pregnancies with diabetes, results were reported overall and according to whether diabetes was pregestational (PDM) or gestational (GDM). Results were also stratified according to the trimester in which fetal cardiac assessment was performed. RESULTS Thirty-nine studies were included, comprising data for 2276 controls and 1925 women with pregnancy affected by diabetes mellitus (DM). Of these, 1120 had GDM, 671 had PDM and in 134 cases diabetes type was not specified. Fetal cardiac hypertrophy was more prevalent in diabetic pregnancies than in non-diabetic controls in 21/26 studies, and impaired diastolic function was observed in diabetic pregnancies in 22/28 studies. The association between DM and systolic function was inconsistent, with 10/25 studies reporting no difference between cases and controls, although more recent studies measuring cardiac deformation, i.e. strain, did show decreased systolic function in diabetic pregnancies. Of the studies measuring overall fetal cardiac function, the majority (14/21) found significant impairment in diabetic pregnancies. Results were similar when stratified according to GDM or PDM. These effects were already present in the first trimester, but were most profound in the third trimester. Meta-analysis of studies performed in the third trimester showed, compared with controls, increased IVS thickness in both PDM (mean difference, 0.75 mm (95% CI, 0.56-0.94 mm)) and GDM (mean difference, 0.65 mm (95% CI, 0.39-0.91 mm)) pregnancies, decreased E/A ratio in PDM pregnancies (mean difference, -0.09 (95% CI, -0.15 to -0.03)), no difference in E/A ratio in GDM pregnancies (mean difference, -0.01 (95% CI, -0.02 to 0.01)) and no difference in MPI in either PDM (mean difference, 0.04 (95% CI, -0.01 to 0.09)) or GDM (mean difference, 0.03 (95% CI, -0.01 to 0.06)) pregnancies. CONCLUSIONS The findings of this review show that maternal diabetes is associated with fetal cardiac hypertrophy, diastolic dysfunction and overall impaired myocardial performance on prenatal ultrasound, irrespective of whether diabetes is pregestational or gestational. Further studies are needed to demonstrate the relationship with long-term outcomes. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Optimal imaging modality for detection of rectosigmoid deep endometriosis: systematic review and meta-analysis.

Abstract: OBJECTIVES To review the accuracy of different imaging modalities for the detection of rectosigmoid deep endometriosis (DE) in women with clinical suspicion of endometriosis, and to determine the optimal modality. METHODS A search was conducted using PubMed, MEDLINE, Scopus, EMBASE and Google Scholar to identify studies using imaging to evaluate women with suspected DE, published from inception to May 2020. Studies were considered eligible if they were prospective and used any imaging modality to assess preoperatively for the presence of DE in the rectum/rectosigmoid, which was then correlated with the surgical diagnosis as the reference standard. Eligibility was restricted to studies including at least 10 affected and 10 unaffected women. The QUADAS-2 tool was used to assess the quality of the included studies. Mixed-effects diagnostic meta-analysis was used to determine the overall pooled sensitivity and specificity of each imaging modality for rectal/rectosigmoid DE, which were used to calculate the likelihood ratio of a positive (LR+) and negative (LR-) test and diagnostic odds ratio (DOR). RESULTS Of the 1979 records identified, 30 studies (3374 women) were included in the analysis. The overall pooled sensitivity and specificity, LR+, LR- and DOR for the detection of rectal/rectosigmoid DE using transvaginal sonography (TVS) were, respectively, 89% (95% CI, 83-92%), 97% (95% CI, 95-98%), 30.8 (95% CI, 17.6-54.1), 0.12 (95% CI, 0.08-0.17) and 264 (95% CI, 113-614). For magnetic resonance imaging (MRI), the respective values were 86% (95% CI, 79-91%), 96% (95% CI, 94-97%), 21.0 (95% CI, 13.4-33.1), 0.15 (95% CI, 0.09-0.23) and 144 (95% CI, 70-297). For computed tomography, the respective values were 93% (95% CI, 84-97%), 95% (95% CI, 81-99%), 20.3 (95% CI, 4.3-94.9), 0.07 (95% CI, 0.03-0.19) and 280 (95% CI, 28-2826). For rectal endoscopic sonography (RES), the respective values were 92% (95% CI, 87-95%), 98% (95% CI, 96-99%), 37.1 (95% CI, 21.1-65.4), 0.08 (95% CI, 0.05-0.14) and 455 (95% CI, 196-1054). There was significant heterogeneity and the studies were considered methodologically poor according to the QUADAS-2 tool. CONCLUSIONS The sensitivity of TVS for the detection of rectal/rectosigmoid DE seems to be slightly better than that of MRI, although RES was superior to both. The specificity of both TVS and MRI was excellent. As TVS is simpler, faster and more readily available than the other methods, we believe that it should be the first-line diagnostic tool for women with suspected DE. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Ultrasound image analysis using deep neural networks for discriminating between benign and malignant ovarian tumors: comparison with expert subjective assessment.

Abstract: OBJECTIVES To develop and test the performance of computerized ultrasound image analysis using deep neural networks (DNNs) in discriminating between benign and malignant ovarian tumors and to compare its diagnostic accuracy with that of subjective assessment (SA) by an ultrasound expert. METHODS We included 3077 (grayscale, n = 1927; power Doppler, n = 1150) ultrasound images from 758 women with ovarian tumors, who were classified prospectively by expert ultrasound examiners according to IOTA (International Ovarian Tumor Analysis) terms and definitions. Histological outcome from surgery (n = 634) or long-term (≥ 3 years) follow-up (n = 124) served as the gold standard. The dataset was split into a training set (n = 508; 314 benign and 194 malignant), a validation set (n = 100; 60 benign and 40 malignant) and a test set (n = 150; 75 benign and 75 malignant). We used transfer learning on three pre-trained DNNs: VGG16, ResNet50 and MobileNet. Each model was trained, and the outputs calibrated, using temperature scaling. An ensemble of the three models was then used to estimate the probability of malignancy based on all images from a given case. The DNN ensemble classified the tumors as benign or malignant (Ovry-Dx1 model); or as benign, inconclusive or malignant (Ovry-Dx2 model). The diagnostic performance of the DNN models, in terms of sensitivity and specificity, was compared to that of SA for classifying ovarian tumors in the test set. RESULTS At a sensitivity of 96.0%, Ovry-Dx1 had a specificity similar to that of SA (86.7% vs 88.0%; P = 1.0). Ovry-Dx2 had a sensitivity of 97.1% and a specificity of 93.7%, when designating 12.7% of the lesions as inconclusive. By complimenting Ovry-Dx2 with SA in inconclusive cases, the overall sensitivity (96.0%) and specificity (89.3%) were not significantly different from using SA in all cases (P = 1.0). CONCLUSION Ultrasound image analysis using DNNs can predict ovarian malignancy with a diagnostic accuracy comparable to that of human expert examiners, indicating that these models may have a role in the triage of women with an ovarian tumor. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Counseling in maternal-fetal medicine: SARS-CoV-2 infection in pregnancy.

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a zoonotic coronavirus that crossed species to infect humans, causing coronavirus disease 2019 (COVID-19). Despite a potentially higher risk of pregnant women acquiring SARS-CoV-2 infection compared with the non-pregnant population (particularly in some ethnic minorities), no additional specific recommendations to avoid exposure are needed in pregnancy. The most common clinical symptoms and laboratory signs of SARS-CoV-2 infection in pregnancy are fever, cough, lymphopenia and elevated C-reactive protein levels. Pregnancy is associated with a higher risk of severe SARS-CoV-2 infection compared with the non-pregnant population, including pneumonia, admission to the intensive care unit and death, even after adjusting for potential risk factors for severe outcomes. The risk of miscarriage does not appear to be increased in women with SARS-CoV-2 infection. Evidence with regards to preterm birth and perinatal mortality is conflicting, but these risks are generally higher only in symptomatic, hospitalized women. The risk of vertical transmission, defined as the transmission of SARS-CoV-2 from the mother to the fetus or the newborn, is generally low. Fetal invasive procedures are considered to be generally safe in pregnant women with SARS-CoV-2 infection, although the evidence is still limited. In pregnant women with COVID-19, use of steroids should not be avoided if clinically indicated; the preferred regimen is a 2-day course of dexamethasone followed by an 8-day course of methylprednisolone. Non-steroidal anti-inflammatory drugs may be used if there are no contraindications. Hospitalized pregnant women with severe COVID-19 should undergo thromboprophylaxis throughout the duration of hospitalization and at least until discharge, preferably with low molecular weight heparin. Hospitalized women who have recovered from a period of serious or critical illness with COVID-19 should be offered a fetal growth scan about 14 days after recovery from their illness. In asymptomatic or mildly symptomatic women who have tested positive for SARS-CoV-2 infection at full term (i.e. ≥ 39 weeks of gestation), induction of labor might be reasonable. To date, there is no clear consensus on the optimal timing of delivery for critically ill women. In women with no or few symptoms, management of labor should follow routine evidence-based guidelines. Regardless of COVID-19 status, mothers and their infants should remain together and breastfeeding, skin-to-skin contact, kangaroo mother care and rooming-in throughout the day and night should be practiced, while applying necessary infection prevention and control measures. Many pregnant women have already undergone vaccination, mostly in the USA where the first reports show no significant difference in pregnancy outcomes in pregnant women receiving SARS-CoV-2 vaccination during pregnancy compared with the background risk. Vaccine-generated antibodies were present in the umbilical cord blood and breast milk samples of pregnant and lactating women who received the mRNA COVID-19 vaccine. Based on the available limited data on the safety of the COVID-19 vaccine in pregnancy, it seems reasonable to offer the option of vaccination to pregnant women after accurate counseling on the potential risk of a severe course of the disease and the unknown risk of fetal exposure to the vaccine. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Risk factors, histopathology and diagnostic accuracy in posterior placenta accreta spectrum disorders: systematic review and meta-analysis.

Abstract: OBJECTIVE To elucidate the risk factors, histopathological correlations and diagnostic accuracy of prenatal imaging in pregnancies complicated by posterior placenta accreta spectrum (PAS) disorders. METHODS MEDLINE, EMBASE and CINAHL were searched for studies reporting on women with posterior PAS. Inclusion criteria were women with posterior PAS confirmed either at surgery or on histopathological analysis. The outcomes explored were risk factors for posterior PAS, histopathological correlation and the diagnostic accuracy of ultrasound and magnetic resonance imaging (MRI) in detecting posterior PAS. Random-effects meta-analysis of proportions was used to analyze the data. RESULTS Twenty studies were included. Placenta previa was present in 92.8% (107/114; 17 studies) of pregnancies complicated by posterior PAS, while 76.1% (53/88; 11 studies) of women had had prior uterine surgery, mainly a Cesarean section (CS) or curettage and 82.5% (66/77; 10 studies) were multiparous. When considering histopathological analysis in women affected by posterior PAS, 77.5% (34/44; 11 studies) had placenta accreta, 19.5% (8/44; 11 studies) had placenta increta and 9.3% (2/44; 11 studies) had placenta percreta. Of the cases of posterior PAS disorder, 52.4% (31/63; 12 studies) were detected prenatally on ultrasound, while 46.7% (32/63; 12 studies) were diagnosed only at birth. When exploring the distribution of the classic ultrasound signs of PAS, placental lacunae were present in 39.0% (12/30; seven studies), loss of the clear zone in 41.1% (13/30; seven studies) and bladder-wall interruption in 16.6% (4/30; seven studies) of women, while none of the included cases showed hypervascularization at the bladder-wall interface. When assessing the role of MRI in detecting posterior PAS, 73.5% (26/32; 11 studies) of cases were detected on prenatal MRI, while 26.5% (6/32; 11 studies) were discovered only at the time of CS. CONCLUSIONS Placenta previa, prior uterine surgery and multiparity represent the most commonly reported risk factors for posterior PAS. Ultrasound had a very low diagnostic accuracy in detecting these disorders prenatally. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Typical ultrasound features of various endometrial pathologies described using International Endometrial Tumor Analysis (IETA) terminology in women with abnormal uterine bleeding.

Abstract: OBJECTIVE To describe the ultrasound features of different endometrial and other intracavitary pathologies inpre- and postmenopausal women presenting with abnormal uterine bleeding, using the International Endometrial Tumor Analysis (IETA) terminology. METHODS This was a prospective observational multicenter study of consecutive women presenting with abnormal uterine bleeding. Unenhanced sonography with color Doppler and fluid-instillation sonography were performed. Endometrial sampling was performed according to each center's local protocol. The histological endpoints were cancer, atypical endometrial hyperplasia/endometrioid intraepithelial neoplasia (EIN), endometrial atrophy, proliferative or secretory endometrium, endometrial hyperplasia without atypia, endometrial polyp, intracavitary leiomyoma and other. For fluid-instillation sonography, the histological endpoints were endometrial polyp, intracavitary leiomyoma and cancer. For each histological endpoint, we report typical ultrasound features using the IETA terminology. RESULTS The database consisted of 2856 consecutive women presenting with abnormal uterine bleeding. Unenhanced sonography with color Doppler was performed in all cases and fluid-instillation sonography in 1857. In 2216 women, endometrial histology was available, and these comprised the study population. Median age was 49 years (range, 19-92 years), median parity was 2 (range, 0-10) and median body mass index was 24.9 kg/m2 (range, 16.0-72.1 kg/m2 ). Of the study population, 843 (38.0%) women were postmenopausal. Endometrial polyps were diagnosed in 751 (33.9%) women, intracavitary leiomyomas in 223 (10.1%) and endometrial cancer in 137 (6.2%). None (0% (95% CI, 0.0-5.5%)) of the 66 women with endometrial thickness < 3 mm had endometrial cancer or atypical hyperplasia/EIN. Endometrial cancer or atypical hyperplasia/EIN was found in three of 283 (1.1% (95% CI, 0.4-3.1%)) endometria with a three-layer pattern, in three of 459 (0.7% (95% CI, 0.2-1.9%)) endometria with a linear endometrial midline and in five of 337 (1.5% (95% CI, 0.6-3.4%)) cases with a single vessel without branching on unenhanced ultrasound. CONCLUSIONS The typical ultrasound features of endometrial cancer, polyps, hyperplasia and atrophy and intracavitary leiomyomas, are described using the IETA terminology. The detection of some easy-to-assess IETA features (i.e. endometrial thickness < 3 mm, three-layer pattern, linear midline and single vessel without branching) makes endometrial cancer unlikely. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Outcome of fetuses with congenital cytomegalovirus infection and normal ultrasound at diagnosis: systematic review and meta-analysis

Abstract: OBJECTIVE To report the outcome of fetuses with congenital cytomegalovirus (CMV) infection and normal ultrasound at the time of diagnosis, and to evaluate the rate of an additional anomaly detected only on magnetic resonance imaging (MRI). METHODS Medline, EMBASE, CINAHL and Cochrane databases were searched for studies reporting on the outcome of fetuses with congenital CMV infection. Inclusion criteria were fetuses with confirmed CMV infection and normal ultrasound assessment at the time of the initial evaluation. The outcomes observed were an anomaly detected on a follow-up ultrasound scan, an anomaly detected on prenatal MRI but missed on ultrasound, an anomaly detected on postnatal assessment but missed prenatally, perinatal mortality, symptomatic infection at birth, neurodevelopmental outcome and hearing and visual deficits. Neurodevelopmental outcome was assessed only in cases of isolated CMV infection confirmed at birth. Subgroup analysis was performed according to the trimester in which maternal infection occurred. Random-effects meta-analysis of proportions was used to analyze the data. RESULTS Twenty-six studies were included, comprising 2603 fetuses with congenital CMV infection, of which 1178 (45.3%) had normal ultrasound at the time of diagnosis and were included in the analysis. The overall rate of an associated central nervous system (CNS) anomaly detected on a follow-up ultrasound scan was 4.4% (95% CI, 1.4-8.8%) (32/523; 15 studies), while the rates of those detected exclusively on prenatal MRI or on postnatal imaging were 5.8% (95% CI, 1.9-11.5%) (19/357; 11 studies) and 3.2% (95% CI, 0.3-9.0%) (50/660; 17 studies), respectively. The rate of an associated extra-CNS anomaly detected on a follow-up ultrasound scan was 2.9% (95% CI, 0.8-6.3%) (19/523; 15 studies), while the rates of those detected exclusively on MRI or on postnatal imaging were 0% (95% CI, 0.0-1.7%) (0/357; 11 studies) and 0.9% (95% CI, 0.3-1.8%) (4/660; 17 studies), respectively. Intrauterine death and perinatal death each occurred in 0.7% (95% CI, 0.3-1.4%) (2/824; 23 studies) of cases. In cases without an associated anomaly detected pre- or postnatally, symptomatic infection was found in 1.5% (95% CI, 0.7-2.7%) (6/548; 19 studies) of infants, the overall rate of a neurodevelopmental anomaly was 3.1% (95% CI, 1.6-5.1%) (16/550; 19 studies), and hearing problems affected 6.5% (95% CI, 3.8-10.0%) (36/550; 19 studies) of children. Subanalyses according to the trimester in which maternal infection occurred were affected by the very small number of included cases and lack of comparison of the observed outcomes in the original studies. Compared with fetuses infected in the second or third trimester, those infected in the first trimester had a relatively higher risk of having an additional anomaly detected on follow-up ultrasound or MRI, abnormal neurodevelopmental outcome and hearing problems. CONCLUSIONS In fetuses with congenital CMV infection in which no anomalies are detected on prenatal ultrasound or MRI, the risk of adverse postnatal outcome is lower than that reported previously in the published literature when not considering the role of antenatal imaging assessment. The results from this review also highlight the potential role of MRI, even in fetuses with no anomalies detected on ultrasound, as an anomaly can be detected exclusively on MRI in about 6% of cases. The findings from this study could enhance prenatal counseling of pregnancies with congenital CMV infection with normal prenatal imaging. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

First trimester ultrasound for the detection of fetal heart anomalies: A systematic review and meta-analysis

Abstract: OBJECTIVES To determine the diagnostic accuracy of ultrasound at 11-14 weeks gestational age in the detection of fetal cardiac abnormalities, and to evaluate factors that impact detection rates. METHODS A systematic review of studies evaluating the diagnostic accuracy of ultrasound in the detection of fetal cardiac anomalies at 11-14 weeks gestational age was undertaken by two independent reviewers. Prospective and retrospective studies evaluating pregnancies at all levels of prior risk and in any healthcare setting were eligible for inclusion. The reference standard used was the detection of a major cardiac abnormality on postnatal or post-mortem examination. Data were extracted from included studies to populate 2 x 2 tables. Meta-analysis was performed using a random-effects model in order to determine the overall performance of first trimester ultrasound in the detection of major cardiac abnormalities overall and in addition, for individual types of cardiac abnormalities. Data were analysed separately for high-risk populations vs. non-high risk populations. Pre-planned secondary analyses were conducted in order to assess factors which may impact screening performance including: the imaging protocol used for cardiac assessment (including use of Colour Doppler), mode of ultrasound, publication year of study, and the index of sonographer suspicion at the time of scan. A risk of bias and quality assessment was undertaken for all included studies using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). RESULTS An electronic search of four databases (Medline, Embase, Web of Science Core Collection and Cochrane Library) was conducted from January 1998 until July 2020 and identified 4108 citations. This led to 223 full text reviews from which a total of 63 studies were selected for inclusion. Data from a total of 328,214 screened fetuses were included. In non-high risk populations (45 studies, 306,872 fetuses), 1,445 major cardiac anomalies were identified (prevalence 0.41 (95% C.I. 0.39 - 0.43)). Of these, 767 were correctly detected by first trimester examination of the heart and 678 were not detected. Pooled sensitivity was 55.80% (95% CI 45.87- 65.50%,), specificity 99.98% (95% CI 99.97 - 99.99%) and positive predictive value 94.85% (95% CI 91.63- 97.32%). The cases diagnosed in the first trimester represent 63.67% (95% CI 54.35 - 72.49%) of all antenatally diagnosed major cardiac abnormalities. In high risk populations (18 studies, 21,342 fetuses) 480 major cardiac anomalies were identified (prevalence 1.36 (95% C.I. 1.20 - 1.52)). Of these, 338 were correctly detected in the first trimester, and 142 were not detected. The sensitivity was 67.74% (95% CI 55.25 - 79.06%), specificity 99.75% (95% CI 99.47 - 99.92%) and positive predictive value 94.22% (95% CI 90.22 - 97.22%). The cases diagnosed in the first trimester represent 79.86% (95% CI 69.89 - 88.25%) of all antenatally diagnosed major cardiac abnormalities in high risk populations. The imaging protocol used for examination was found to have an important impact on screening performance in all populations (p<0.0001), with significantly higher detection rates in those studies using outflow tract views and colour-flow Doppler imaging (both p<0.0001). Results showed that individual cardiac anomalies are not equally amenable to first trimester detection. CONCLUSIONS First trimester examination of the heart allows identification of over half of fetuses who are highly likely to be affected by major cardiac pathology. Future first-trimester screening programmes should follow structured anatomical assessment protocols, and introduction of outflow tract views and colour Doppler would be expected to improve detection rates. This article is protected by copyright. All rights reserved.

Ophthalmic artery Doppler in combination with other biomarkers in prediction of pre-eclampsia at 19–23 weeks' gestation

Abstract: OBJECTIVE To examine the potential value of maternal ophthalmic artery Doppler at 19-23 weeks' gestation on its own and in combination with the established biomarkers of pre-eclampsia (PE), including uterine artery (UtA) pulsatility index (PI), mean arterial pressure (MAP), serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1), in the prediction of subsequent development of PE. METHODS This was a prospective observational study of women attending for a routine hospital visit at 19 + 1 to 23 + 3 weeks' gestation. This visit included recording of maternal demographic characteristics and medical history, ultrasound examination for fetal anatomy and growth, assessment of flow velocity waveforms from the maternal ophthalmic arteries, and measurement of MAP, UtA-PI, serum PlGF and serum sFlt-1. Waveforms were obtained from the ophthalmic arteries in sequence from the right eye, left eye and again from the right and then left eye. We recorded the average of the four measurements, two from each eye, for the following four indices: first peak of systolic velocity; second peak of systolic velocity; PI; and the ratio of the second to first peak of systolic velocity (PSV ratio). The measurements of the four indices were standardized to remove the effects of maternal characteristics and elements from the medical history. The competing-risks model was used to estimate the individual patient-specific risks of delivery with PE at < 37 and ≥ 37 weeks' gestation and to determine the area under the receiver-operating-characteristics curve (AUC) and detection rate (DR), at a 10% false-positive rate (FPR), in screening by a combination of maternal demographic characteristics and medical history with biomarkers. The modeled performance of screening for PE was also estimated. RESULTS The study population of 2853 pregnancies contained 76 (2.7%) that developed PE, including 18 (0.6%) that delivered with PE at < 37 weeks' gestation. The ophthalmic artery PSV ratio was significantly increased in PE pregnancies, and the PE effect depended on gestational age at delivery; the deviation from normal was greater for early than late PE. The second peak of systolic velocity was also increased in PE pregnancies, but the effect did not depend on gestational age at delivery. The other two ophthalmic artery indices of first peak of systolic velocity and PI were not significantly affected by PE. The PSV ratio improved the prediction of preterm PE provided by maternal factors alone (from 56.1% to 80.2%), maternal factors, MAP and UtA-PI (80.7% to 87.9%), maternal factors, MAP, UtA-PI and PlGF (85.5% to 90.3%) and maternal factors, MAP, UtA-PI, PlGF and sFlt-1 (84.9% to 89.8%), at a FPR of 10%. The PSV ratio also improved the prediction of term PE provided by maternal factors alone (from 33.8% to 46.0%), maternal factors, MAP and UtA-PI (46.6% to 54.2%), maternal factors, MAP, UtA-PI and PlGF (45.2% to 53.4%) and maternal factors, MAP, UtA-PI, PlGF and sFlt-1 (43.0% to 51.2%), at a FPR of 10%. The empirical results for DR at a 10% FPR were consistent with the modeled results. The second peak of systolic velocity did not improve the prediction of either preterm or term PE provided by maternal factors alone. CONCLUSION Ophthalmic artery PSV ratio at 19-23 weeks' gestation, both on its own and in combination with other biomarkers, is potentially useful for prediction of subsequent development of PE, especially preterm PE, but larger studies are needed to validate this finding. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Secondary prevention of congenital cytomegalovirus infection with valacyclovir following maternal primary infection in early pregnancy.

Abstract: Objective Cytomegalovirus (CMV) maternal primary infection (MPI) in early pregnancy is the main risk factor for congenital CMV (cCMV) infection with long-term sequelae. Our aim was to evaluate, in a single center offering CMV serology screening at 11-14 gestational weeks, secondary prevention of cCMV by administration of high-dosage maternal oral valacyclovir (VACV) in the first trimester of pregnancy. Methods This was a case-control study in a longitudinal cohort of pregnancies with CMV-MPI diagnosed prior to 14 weeks of gestation by serology screening (immunoglobulin (Ig) M and IgG measurement and IgG avidity) between 2009 and 2020. From October 2019 onwards, all women presenting at our center with MPI before 14 weeks' gestation were offered treatment with high-dosage oral VACV (8 g/day, 4 g twice/day). We used propensity score matching to compare fetal infection rates in cases treated with maternal oral VACV (8 g/day) with those in untreated controls. Fetal infection was assessed following amniocentesis at 17-22 weeks of gestation, by polymerase chain reaction (PCR) analysis of amniotic fluid for viral DNA. Results Of 310 cases of CMV-MPI identified, 269 underwent amniocentesis for PCR. Of these, 66 were offered, and 65 accepted, treatment with VACV. From the remaining untreated cases, we selected 65 controls, matched for proportion of periconceptional infections and gestational age at amniocentesis. VACV was initiated at a median gestational age of 12.71 (interquartile range (IQR), 10.00-13.86) weeks and the median duration of treatment was 35 (IQR, 26-54) days. On multivariate logistic regression, fetal infection was lower in the treated group (odds ratio, 0.318 (95% CI, 0.120-0.841); P = 0.021). One treated patient developed acute renal failure 4 weeks after initiation of VACV therapy, but this resolved within 5 days after treatment was stopped. Conclusion This study confirms the acceptability, tolerance and benefit of secondary prevention by VACV of cCMV infection in a clinical setting with a well-established routine maternal serum screening policy in the first trimester of pregnancy. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

The impact of COVID-19 pandemic restrictions on pregnancy duration and outcomes in Melbourne, Australia.

Abstract: OBJECTIVE: To investigate the effect of restriction measures implemented to mitigate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission during the coronavirus disease 2019 (COVID-19) pandemic on pregnancy duration and outcome. METHODS: A before-and-after study was conducted with cohort sampling in three maternity hospitals in Melbourne, Australia, including women who were pregnant when restriction measures were in place during the COVID-19 pandemic (estimated conception date between 1 November 2019 and 29 February 2020) and women who were pregnant before the restrictions (estimated conception date between 1 November 2018 and 28 February 2019). The primary outcome was delivery before 34 weeks' gestation or stillbirth. The main secondary outcome was a composite of adverse perinatal outcomes. Pregnancy outcomes were compared between women exposed to restriction measures and unexposed controls using the χ-square test and modified Poisson regression models, and duration of pregnancy was compared between the groups using survival analysis. RESULTS: In total, 3150 women who were exposed to restriction measures during pregnancy and 3175 unexposed controls were included. Preterm birth before 34 weeks or stillbirth occurred in 95 (3.0%) exposed pregnancies and in 130 (4.1%) controls (risk ratio (RR), 0.74 (95% CI, 0.57-0.96); P = 0.021). Preterm birth before 34 weeks occurred in 2.4% of women in the exposed group and in 3.4% of women in the control group (RR, 0.71 (95% CI, 0.53-0.95); P = 0.022), without evidence of an increase in the rate of stillbirth in the exposed group (0.7% vs 0.9%; RR, 0.83 (95% CI, 0.48-1.44); P = 0.515). Competing-risks regression analysis showed that the effect of the restriction measures on spontaneous preterm birth was stronger and started earlier (subdistribution hazard ratio (HR), 0.81 (95% CI, 0.64-1.03); P = 0.087) than the effect on medically indicated preterm birth (subdistribution HR, 0.89 (95% CI, 0.70-1.12); P = 0.305). The effect was stronger in women with a previous preterm birth (RR, 0.42 (95% CI, 0.21-0.82); P = 0.008) than in parous women without a previous preterm birth (RR, 0.93 (95% CI, 0.63-1.38); P = 0.714) (P for interaction = 0.044). Composite adverse perinatal outcome was less frequent in the exposed group than in controls (all women: 2.1% vs 2.9%; RR, 0.73 (95% CI, 0.54-0.99); P = 0.042); women with a previous preterm birth: 4.5% vs 8.4%; RR, 0.54 (95% CI, 0.25-1.18); P = 0.116). CONCLUSIONS: Restriction measures implemented to mitigate SARS-CoV-2 transmission during the COVID-19 pandemic were associated with a reduced rate of preterm birth before 34 weeks. This reduction was mainly due to a lower rate of spontaneous prematurity. The effect was more substantial in women with a previous preterm birth and was not associated with an increased stillbirth rate. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Fetal endoscopic tracheal occlusion reverses the natural history of right-sided congenital diaphragmatic hernia: European multicenter experience

Abstract: OBJECTIVE To evaluate the neonatal outcome of fetuses with isolated right-sided congenital diaphragmatic hernia (iRCDH) based on prenatal severity indicators and antenatal management. METHODS This was a retrospective review of prospectively collected data on consecutive cases diagnosed with iRCDH before 30 weeks' gestation in four fetal therapy centers, between January 2008 and December 2018. Data on prenatal severity assessment, antenatal management and perinatal outcome were retrieved. Univariate and multivariate logistic regression analysis were used to identify predictors of survival at discharge and early neonatal morbidity. RESULTS Of 265 patients assessed during the study period, we excluded 40 (15%) who underwent termination of pregnancy, two cases of unexplained fetal death, two that were lost to follow-up, one for which antenatal assessment of lung hypoplasia was not available and six cases which were found to have major associated anomalies or syndromes after birth. Of the 214 fetuses with iRCDH included in the neonatal outcome analysis, 86 were managed expectantly during pregnancy and 128 underwent fetal endoscopic tracheal occlusion (FETO) with a balloon. In the expectant-management group, lung size measured by ultrasound or by magnetic resonance imaging was the only independent predictor of survival (observed-to-expected lung-to-head ratio (o/e-LHR) odds ratio (OR), 1.06 (95% CI, 1.02-1.11); P = 0.003). Until now, stratification for severe lung hypoplasia has been based on an o/e-LHR cut-off of 45%. In cases managed expectantly, the survival rate was 15% (4/27) in those with o/e-LHR ≤ 45% and 61% (36/59) for o/e-LHR > 45% (P = 0.001). However, the best o/e-LHR cut-off for the prediction of survival at discharge was 50%, with a sensitivity of 78% and specificity of 72%. In the expectantly managed group, survivors with severe pulmonary hypoplasia stayed longer in the neonatal intensive care unit than did those with mildly hypoplastic lungs. In fetuses with an o/e-LHR ≤ 45% treated with FETO, survival rate was higher than in those with similar lung size managed expectantly (49/120 (41%) vs 4/27 (15%); P = 0.014), despite higher prematurity rates (gestational age at birth: 34.4 ± 2.7 weeks vs 36.8 ± 3.0 weeks; P < 0.0001). In fetuses treated with FETO, gestational age at birth was the only predictor of survival (OR, 1.25 (95% CI, 1.04-1.50); P = 0.02). CONCLUSIONS Antenatal measurement of lung size can predict survival in iRCDH. In fetuses with severe lung hypoplasia, FETO was associated with a significant increase in survival without an associated increase in neonatal morbidity. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Comprehensive evaluation of genetic variants using chromosomal microarray analysis and exome sequencing in fetuses with congenital heart defect.

Abstract: OBJECTIVE To evaluate comprehensively, using chromosomal microarray analysis (CMA) and exome sequencing (ES), the prevalence of chromosomal abnormalities and sequence variants in unselected fetuses with congenital heart defect (CHD) and to evaluate the potential diagnostic yields of CMA and ES for different CHD subgroups. METHODS This was a study of 360 unselected singleton fetuses with CHD detected by echocardiography, referred to our department for genetic testing between February 2018 and December 2019. We performed CMA, as a routine test for aneuploidy and copy number variations (CNV), and then, in cases without aneuploidy or pathogenic CNV on CMA, we performed ES. RESULTS Overall, positive genetic diagnoses were made in 84 (23.3%) fetuses: chromosomal abnormalities were detected by CMA in 60 (16.7%) and sequence variants were detected by ES in a further 24 (6.7%) cases. The detection rate of pathogenic and likely pathogenic genetic variants in fetuses with non-isolated CHD (32/83, 38.6%) was significantly higher than that in fetuses with isolated CHD (52/277, 18.8%) (P C, p.Arg816Pro; c.1171C>T, p.Arg391Cys) and a new phenotype caused by variants in PLD1. CONCLUSIONS Chromosomal abnormalities were identified in 16.7% and sequence variants in a further 6.7% of fetuses with CHD. ES should be offered to all pregnant women with a CHD fetus without chromosomal abnormality or pathogenic CNV identified by CMA, regardless of whether the CHD is isolated. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Fetal hydrops and the Incremental yield of Next-generation sequencing over standard prenatal Diagnostic testing (FIND) study: prospective cohort study and meta-analysis.

Abstract: OBJECTIVE To determine the incremental yield of exome sequencing (ES) over chromosomal microarray analysis (CMA) or karyotyping in prenatally diagnosed non-immune hydrops fetalis (NIHF). METHODS A prospective cohort study (comprising an extended group of the Prenatal Assessment of Genomes and Exomes (PAGE) study) was performed which included 28 cases of prenatally diagnosed NIHF undergoing trio ES following negative CMA or karyotyping. These cases were combined with data from a systematic review of the literature. MEDLINE, EMBASE, CINAHL and ClinicalTrials.gov databases were searched electronically (January 2000 to October 2020) for studies reporting on the incremental yield of ES over CMA or karyotyping in fetuses with prenatally detected NIHF. Inclusion criteria for the systematic review were: (i) at least two cases of NIHF undergoing sequencing; (ii) testing initiated based on prenatal ultrasound-based phenotype; and (iii) negative CMA or karyotyping result. The incremental diagnostic yield of ES was assessed in: (i) all cases of NIHF; (ii) isolated NIHF; (iii) NIHF associated with an additional fetal structural anomaly; and (iv) NIHF according to severity (i.e. two vs three or more cavities affected). RESULTS In the extended PAGE study cohort, the additional diagnostic yield of ES over CMA or karyotyping was 25.0% (7/28) in all NIHF cases, 21.4% (3/14) in those with isolated NIHF and 28.6% (4/14) in those with non-isolated NIHF. In the meta-analysis, the pooled incremental yield based on 21 studies (306 cases) was 29% (95% CI, 24-34%; P < 0.00001; I2 = 0%) in all NIHF, 21% (95% CI, 13-30%; P < 0.00001; I2 = 0%) in isolated NIHF and 39% (95% CI, 30-49%; P < 0.00001; I2 = 1%) in NIHF associated with an additional fetal structural anomaly. In the latter group, congenital limb contractures were the most prevalent additional structural anomaly associated with a causative pathogenic variant, occurring in 17.3% (19/110) of cases. The incremental yield did not differ significantly according to hydrops severity. The most common genetic disorders identified were RASopathies, occurring in 30.3% (27/89) of cases with a causative pathogenic variant, most frequently due to a PTPN11 variant (44.4%; 12/27). The predominant inheritance pattern in causative pathogenic variants was autosomal dominant in monoallelic disease genes (57.3%; 51/89), with most being de novo (86.3%; 44/51). CONCLUSIONS Use of prenatal next-generation sequencing in both isolated and non-isolated NIHF should be considered in the development of clinical pathways. Given the wide range of potential syndromic diagnoses and heterogeneity in the prenatal phenotype of NIHF, exome or whole-genome sequencing may prove to be a more appropriate testing approach than a targeted gene panel testing strategy. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Clinical utility of expanded non-invasive prenatal screening and chromosomal microarray analysis in high-risk pregnancy.

Abstract: OBJECTIVE To evaluate the utility of expanded non-invasive prenatal screening (NIPS), compared with chromosomal microarray analysis (CMA), for the detection of chromosomal abnormalities in high-risk pregnancies. METHODS This was a multicenter retrospective study of singleton pregnancies at high risk for chromosomal abnormality. Patients who underwent expanded NIPS and CMA sequentially during pregnancy from 2015 to 2019 were included in the analysis. Pregnancies with a positive result for sex chromosome aneuploidy were excluded as the full details could not be retrieved. The utility of expanded NIPS and CMA for detection of chromosomal abnormalities in this cohort was compared by assessing the concordance between the results. RESULTS Of the 774 included high-risk pregnancies, 550 (71.1%) had a positive NIPS result, while a positive CMA result was detected in 308 (39.8%) cases. The rate of full or partial concordance between NIPS and CMA was 82.2%, 59.6% and 25.0% for trisomies 21, 18 and 13, respectively. For rare aneuploidies and segmental imbalances, NIPS and CMA results were fully or partially concordant in 7.5% and 33.3% of cases, respectively. Copy-number variants < 5 Mb were detected more often by CMA, with an incidence of 7.9% (61/774) compared with 3.1% (24/774) by NIPS. A genetic aberration was detected by CMA in 1 in 17 (5.8%) high-risk pregnancies that had a negative or non-reportable NIPS result. CONCLUSION CMA allows for comprehensive detection of genome-wide chromosomal abnormalities in high-risk pregnancies. CMA should be offered instead of expanded NIPS for high-risk pregnancies. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Position and integrity of uterine scar are determined by degree of cervical dilatation at time of Cesarean section.

Abstract: OBJECTIVE Abnormal placental invasion is more common after an elective Cesarean delivery, suggesting that prelabor Cesarean section (CS) increases the likelihood of the CS scar being above the internal cervical os and predisposing to a scar pregnancy in the future. The aim of this study was to assess the location and integrity of the CS scar in postpartum women delivered by CS at different stages of labor. METHODS This was a prospective cohort study of women at term who underwent a CS for the first time. In all women, cervical dilatation was determined by digital examination at the time of the CS. All patients had a transvaginal ultrasound examination to assess the location of the CS scar in relation to the internal cervical os, as well as the presence of a scar niche. RESULTS A total of 407 pregnant women were recruited into the study: 103 with cervical dilatation ≤ 2 cm, 261 with cervical dilatation 3-7 cm and 43 with cervical dilatation ≥ 8 cm at the time of the CS. A statistically significant correlation was observed between cervical dilatation at the time of the CS and the position of the CS scar. The scar was positioned in the uterus above the internal cervical os in 97.1% (100/103) of women delivered at a cervical dilatation of 0-2 cm, whereas the scar was located at or below the internal cervical os in 97.7% (42/43) of cases delivered at a cervical dilatation of 8-10 cm (P < 0.001). A uterine-scar defect (niche) was observed in 38.1% (64/168) of women with the scar located above, compared with 18.0% (43/239) of those with the scar situated at or below, the internal cervical os (P < 0.001). CONCLUSIONS Prelabor and early-labor Cesarean delivery are associated with an increased prevalence of a scar in the uterine cavity as well as a scar niche. CS in late labor is associated with the uterine scar being situated in the endocervical canal and with a lower incidence of a niche. The position and integrity of the CS scar after prelabor and early-labor Cesarean delivery explain the predisposition to abnormal placental invasion in subsequent pregnancy. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Controversies in the management of twin pregnancy.

Abstract: Despite many advances in antenatal care, twin pregnancies still experience more adverse outcomes, in particular perinatal morbidity and mortality. They also pose a multitude of challenges and controversies, as outlined in this Review. Moreover, they are less likely to be included in clinical trials. Many issues on classification and management remain under debate. Efforts at standardizing diagnostic criteria, monitoring protocols, management and outcome reporting are likely to reduce their perinatal risks. The top 10 most important research uncertainties related to multiple pregnancies have been identified by both clinicians and patients. More robust research in the form of randomized trials and large well-conducted prospective cohort studies is needed to address these controversies. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.