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Objective: To assess the reproducibility of a standardized method of measuring the Cesarean section (CS) scar, CS scar niche and their position relative to the internal os of the uterine cervix by transvaginal ultrasound in pregnant women with a previous full-dilatation CS., Methods: This was a prospective, single-center reproducibility study on women with a singleton pregnancy and a previous full-dilatation CS who underwent transvaginal ultrasound assessment of cervical length and CS scar characteristics at 14-24 weeks' gestation. The CS scar was identified as a hypoechogenic linear discontinuity of the myometrium at the anterior wall of the lower uterine segment or cervix. The CS scar niche was identified as an indentation at the site of the scar with a depth of at least 2 mm. The CS scar position was evaluated by measuring the distance to the internal cervical os. CS scar niche parameters, including its length, depth, width, and residual and adjacent myometrial thickness, were assessed in the sagittal and transverse planes. Qualitative reproducibility was assessed by agreement regarding visibility of the CS scar and niche. Quantitative reproducibility of CS scar measurements was assessed using three sets of images: (1) real-time two-dimensional (2D) images (real-time acquisition and caliper placement on 2D images by two operators), (2) offline 2D still images (offline caliper placement by two operators on stored 2D images acquired by one operator) and (3) three-dimensional (3D) volume images (volume manipulation and caliper placement on 2D images extracted by two operators). Agreement on CS scar visibility and the presence of a niche was analyzed using kappa coefficients. Intraobserver and interobserver reproducibility of quantitative measurements was assessed using Bland-Altman plots., Results: To achieve the desired statistical power, 72 women were recruited. The CS scar was visualized in > 80% of images. Interobserver agreement for scar visualization and presence of a niche in real-time 2D images was excellent (kappa coefficients of 0.84 and 0.85, respectively). Overall, reproducibility was higher for real-time 2D and offline 2D still images than for 3D volume images. The 95% limits of agreement (LOA) for intraobserver reproducibility were between ± 1.1 and ± 3.6 mm for all sets of images; the 95% LOA for interobserver reproducibility were between ± 2.0 and ± 6.3 mm. Measurement of the distance from the CS scar to the internal cervical os was the most reproducible 2D measurement (intraobserver and interobserver 95% LOA within ± 1.6 and ± 2.7 mm, respectively). Overall, niche measurements were the least reproducible measurements (intraobserver 95% LOA between ± 1.6 and ± 3.6 mm; interobserver 95% LOA between ± 3.1 and ± 6.3 mm). There was no consistent difference between measurements obtained by reacquisition of 2D images (planes obtained twice and caliper placed), caliper placement on 2D stored images or volume manipulation (planes obtained twice and caliper placed)., Conclusions: The CS scar position and scar niche in pregnant women with a previous full-dilatation CS can be assessed in the second trimester of a subsequent pregnancy using either 2D or 3D volume ultrasound imaging with a high level of reproducibility. Overall, the most reproducible CS scar parameter is the distance from the CS scar to the internal cervical os. The method proposed in this study should enable clinicians to assess the CS scar reliably and may help predict pregnancy outcome. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

This two-paper Series focuses on recent advances and applications of regenerative medicine that could benefit paediatric patients. Innovations in genomic, stem-cell, and tissue-based technologies have created progress in disease modelling and new therapies for congenital and incurable paediatric diseases. Prenatal approaches present unique opportunities associated with substantial biotechnical, medical, and ethical obstacles. Maternal plasma fetal DNA analysis is increasingly adopted as a noninvasive prenatal screening or diagnostic test for chromosomal and monogenic disorders. The molecular basis for cell-free DNA detection stimulated the development of circulating tumour DNA testing for adult cancers. In-utero stem-cell, gene, gene-modified cell (and to a lesser extent, tissue-based) therapies have shown early clinical promise in a wide range of paediatric disorders. Fetal cells for postnatal treatment and artificial placenta for ex-utero fetal therapies are new frontiers in this exciting field., Competing Interests: Declaration of interests PKHT reports fee from BlueRock Therapeutics and Xellera Therapeutics., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Delivering safe clinical trials of novel therapeutics is central to enable pregnant women and their babies to access medicines for better outcomes. This review describes clinical monitoring of fetal well-being and safety. Current pregnancy surveillance includes regular antenatal checks of blood pressure and urine for signs of gestational hypertension. Fetal and placental development is assessed routinely using the first-trimester "dating" and mid-trimester "anomaly" ultrasound scans, but the detection of fetal anomalies can continue throughout pregnancy using targeted sonography or magnetic resonance imaging (MRI). Serial sonography can be used to assess fetal size, well-being, and placental function. Carefully defined reproducible imaging parameters, such as the head circumference (HC), abdominal circumference (AC), and femur length (FL), are combined to calculate an estimate of the fetal weight. Doppler analysis of maternal uterine blood flow predicts placental insufficiency, which is associated with poor fetal growth. Fetal doppler analysis can indicate circulatory decompensation and fetal hypoxia, requiring delivery to be expedited. Novel ways to assess fetal well-being and placental function using MRI, computerized cardiotocography (CTG), serum circulating fetoplacental proteins, and mRNA may improve the assessment of the safety and efficacy of maternal and fetal interventions. Progress has been made in how to define and grade clinical trial safety in pregnant women, the fetus, and neonate. A new system for improved safety monitoring for clinical trials in pregnancy, Maternal and Fetal Adverse Event Terminology (MFAET), describes 12 maternal and 18 fetal adverse event (AE) definitions and severity grading criteria developed through an international modified Delphi consensus process. This fills a vital gap in maternal and fetal translational medicine research., (© 2022 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

We are living in a golden age of medicine in which the availability of prenatal diagnosis, fetal therapy, and gene therapy/editing make it theoretically possible to repair almost any defect in the genetic code. Furthermore, the ability to diagnose genetic disorders before birth and the presence of established surgical techniques enable these therapies to be delivered safely to the fetus. Prenatal therapies are generally used in the second or early third trimester for severe, life-threatening disorders for which there is a clear rationale for intervening before birth. While there has been promising work for prenatal gene therapy in preclinical models, the path to a clinical prenatal gene therapy approach is complex. We recently held a conference with the University of California, San Francisco-Stanford Center of Excellence in Regulatory Science and Innovation, researchers, patient advocates, regulatory (members of the Food and Drug Administration), and other stakeholders to review the scientific background and rationale for prenatal somatic cell gene therapy for severe monogenic diseases and initiate a dialogue toward a safe regulatory path for phase 1 clinical trials. This review represents a summary of the considerations and discussions from these conversations., (© 2022, The American College of Clinical Pharmacology.)

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., (Copyright © 2022. Published by Elsevier Inc.)

Background: Preterm birth is associated with adverse health and developmental sequelae that impose a burden on finite resources and significant challenges for individuals, families and societies., Objectives: To estimate economic outcomes at age 11 associated with extremely preterm birth using evidence from a whole population study (EPICure2 study)., Methods: The study population comprised a sample of children born at ≤26 completed weeks of gestation during 2006 in England (n = 200) and a comparison group of classmates born at term (n = 143). Societal costs were estimated using parent and teacher reports of service utilisation, and valuations of work losses and additional care costs to families. Utility scores for the Health Utilities Index Mark 2 (HUI2) and Mark 3 (HUI3) were generated using UK and Canadian value sets. Generalised linear regression was used to estimate the impact of extremely preterm birth on societal costs and utility scores., Results: Unadjusted mean societal costs that excluded provision of special educational support in mainstream schools during the 11th year after birth were £6536 for the extremely preterm group and £3275 for their classmates, generating a difference of £3262 (95% confidence interval [CI] £1912, £5543). The mean adjusted cost difference was £2916 (95% CI £1609, £4224), including special educational needs provision in mainstream schools increased the adjusted cost difference to £4772 (95% CI £3166, £6378). Compared with birth at term, extremely preterm birth generated mean-adjusted utility decrements ranging from 0.13 (95% CI 0.09, 0.18) based on the UK HUI2 statistical inference tariff to 0.28 (95% CI 0.18, 0.37) based on the Canadian HUI3 tariff., Conclusions: The adverse economic impact of extremely preterm birth persists into late childhood. Further longitudinal studies conducted from multiple perspectives are needed to understand the magnitude, trajectory and underpinning mechanisms of economic outcomes following extremely preterm birth., (© 2022 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.)

Background: Spina bifida aperta (SBA) is a birth defect associated with severe anatomical changes in the developing fetal brain. Brain magnetic resonance imaging (MRI) atlases are popular tools for studying neuropathology in the brain anatomy, but previous fetal brain MRI atlases have focused on the normal fetal brain. We aimed to develop a spatio-temporal fetal brain MRI atlas for SBA. Methods: We developed a semi-automatic computational method to compute the first spatio-temporal fetal brain MRI atlas for SBA. We used 90 MRIs of fetuses with SBA with gestational ages ranging from 21 to 35 weeks. Isotropic and motion-free 3D reconstructed MRIs were obtained for all the examinations. We propose a protocol for the annotation of anatomical landmarks in brain 3D MRI of fetuses with SBA with the aim of making spatial alignment of abnormal fetal brain MRIs more robust. In addition, we propose a weighted generalized Procrustes method based on the anatomical landmarks for the initialization of the atlas. The proposed weighted generalized Procrustes can handle temporal regularization and missing annotations. After initialization, the atlas is refined iteratively using non-linear image registration based on the image intensity and the anatomical land-marks. A semi-automatic method is used to obtain a parcellation of our fetal brain atlas into eight tissue types: white matter, ventricular system, cerebellum, extra-axial cerebrospinal fluid, cortical gray matter, deep gray matter, brainstem, and corpus callosum. Results: An intra-rater variability analysis suggests that the seven anatomical land-marks are sufficiently reliable. We find that the proposed atlas outperforms a normal fetal brain atlas for the automatic segmentation of brain 3D MRI of fetuses with SBA. Conclusions: We make publicly available a spatio-temporal fetal brain MRI atlas for SBA, available here:  https://doi.org/10.7303/syn25887675. This atlas can support future research on automatic segmentation methods for brain 3D MRI of fetuses with SBA., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Fidon L et al.)

Purpose: The Measure of Ovarian Symptoms and Treatment (MOST) concerns is a validated patient-reported symptom assessment tool for assessing symptom benefit and adverse effects of palliative chemotherapy in women with recurrent ovarian cancer (ROC). We aimed to examine (i) how symptoms within MOST symptom indexes track together (i.e. co-occur) and (ii) the association between MOST symptom indexes and key aspects of health-related quality of life (HRQL)., Method: A prospective cohort of women with ROC completed the MOST-T35, EORTC QLQ-C30 and EORTC QLQ-OV28 at baseline and before each cycle of chemotherapy. Analyses were conducted on baseline and end-of-treatment data. Exploratory factor analysis and hierarchical cluster analysis identified groups of co-occurring symptoms. Path models examined associations between MOST symptom indexes and HRQL., Results: Data from 762 women at baseline and 681 at treatment-end who completed all 22 symptom-specific MOST items and at least one HRQL measure were analysed. Four symptom clusters emerged at baseline and treatment-end: abdominal symptoms, symptoms associated with peripheral neuropathy, nausea and vomiting, and psychological symptoms. Psychological symptoms (MOST-Psych) and symptoms due to disease (ovarian cancer) or treatment (MOST-DorT) were associated with poorer scores on QLQ-C30 and OV28 functioning domains and worse overall health at both time points., Conclusion: Four MOST symptom clusters were consistent across statistical methods and time points. These findings suggest that routine standardized assessment of psychological and physical symptoms in clinical practice with MOST plus appropriate symptom management referral pathways is an intervention for improving HRQL that warrants further research., Competing Interests: Declaration of Competing Interest YCL has received honoraria from GSK for participation on Advisory Board. FJ has received honoraria for educational events and consulting fees from AstraZeneca, Clovis, GSK, MSD, and Seagen. JS has received honoraria and fees from PharmaMar, Roche, Astra, GSK, Clovis, NovoCure, MSD, Tesaro. AO acknowledges institutional research grants from MSD K.K., Fuji Pharma Co., Kissei Pharmaceutical Co., Meiji Holdings Co., Taiho Pharmaceutical Co., Kaken Pharmaceutical Co., Chugai Pharmaceutical Co., Tsumura & Co, Daiichi Sankyo Co., Mochida Pharmaceutical Co., ASKA Pharmaceutical CO., Takeda, Pfizer, AstraZeneca, and Terumo Co.; and has received honoraria for educational events from Takeda, Eisai Co., AstraZeneca, Chugai Pharmaceutical Co, Kaken Pharmaceutical Co., MSD K.K. and Zeria Pharmaceutical. JAL acknowledges institutional research grants from AstraZeneca and MSD/Merck; has received honoraria for educational events from AstraZeneca, Neopharm, GSK and Pfizer; and participate on data safety monitoring board of Regeneron. EAL has received honoraria from Roche. MRS acknowledges institutional research grants from Amgen, Astellas, Astra Zeneca, Bayer, Beigene, BMS, Celgene, Medivation, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi and Tilray. MF acknowledges institutional research grants from AstraZeneca, Novartis, and Beigene; has received honoraria (consultancy/educational events) from AstraZeneca, Novartis, GSK, MSD, Takeda, Lily, and ACT-Genomics; and participate on data safety monitoring board for AGITG. RC, MTK, RO, AL, FH, FR, JB, AMO, JSB, DB, AF, MK and KD have declared no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To study the time course of retinopathy of prematurity (ROP) regression and reactivation after treatment with intravitreal ranibizumab or laser in the ranibizumab compared with laser therapy for the treatment of infants born prematurely with ROP trial., Design: Post hoc analysis of a randomized, clinical trial., Subjects: A total of 225 infants (448 eyes) were randomized to ranibizumab 0.2 mg (n = 74, 148 eyes), ranibizumab 0.1 mg (n = 77, 152 eyes), and laser (n = 74, 148 eyes)., Methods: Features of disease regression were measured using time-to-event analysis per eye, corrected for within-subject association. Analyses of disease reactivation and additional treatments were descriptive., Main Outcome Measures: Median time to regression of plus disease, stage 3 ROP, aggressive posterior (AP)-ROP to 24-week follow-up and disease reactivation and first additional treatment to 2-year follow-up., Results: The median times to regression after ranibizumab 0.2 mg vs. laser were as follows: plus disease, 4 vs. 16 days (P < 0.001); stage 3 ROP, 8 vs. 16 days (P = 0.004); and AP-ROP, 7.3 vs. 22 days (P = 0.03). Results for ranibizumab 0.1 mg were similar to those for 0.2 mg, with a median of 4, 9, and 8 days, respectively. Additional treatments were given in 34 (25%) of 138 eyes after laser and 40 (27%) of 146 and 42 (28%) of 152 eyes after 0.2 mg and 0.1 mg ranibizumab, respectively. Incomplete disease regression requiring additional treatment occurred in 30 (22%) of 138 eyes after laser after a median interval of 15 days compared with 11 (8%) of 146 and 9 (6%) of 152 after 0.2 mg and 0.1 mg ranibizumab after a median interval of 21 and 13 days, respectively. Retinopathy of prematurity reactivation requiring additional treatment occurred in 3 (2%) of 138 eyes after laser after a median interval of 43 days compared with 22 (15%) of 146 and 26 (17%) of 152 after 0.2 and 0.1 mg ranibizumab after a median interval of 53.5 (maximum, 105) and 54.5 days (maximum, 128), respectively., Conclusions: Intravitreal 0.2 or 0.1 mg ranibizumab induced a faster regression of plus disease, stage 3 ROP, and AP-ROP than laser did. Ranibizumab was associated with fewer additional treatments for incomplete disease regression but more for disease reactivation., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

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/m 2 ), 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., (Copyright © 2021. Published by Elsevier Inc.)

Background: Several interventions and techniques are suggested to improve the outcome of embryo transfer (ET) in assisted conception. However, there remains no consensus on the optimal practice, with high variations among fertility specialists., Objective and Rationale: We conducted a comprehensive systematic review and meta-analyses of randomized controlled trials (RCTs) aiming to identify effective interventions that could be introduced around the time of ET to improve reproductive outcomes., Search Methods: We searched the electronic databases (MEDLINE, EMBASE and Cochrane CENTRAL) from inception until March 2021 using a multi-stage search strategy of MeSH terms and keywords, and included all RCTs that evaluated an intervention in the 24-h period before/after ET in women undergoing IVF/ICSI. Our primary outcome was clinical pregnancy rate post-ET confirmed as viable pregnancy on ultrasound scan. We assessed the risk of bias in included trials and extracted data in duplicate. We pooled data using a random-effect meta-analysis and reported using risk ratio (RR) with 95% CI. We explored publication bias and effect modifiers using subgroup analyses., Outcomes: Our search yielded 3685 citations of which we included 188 RCTs (38 interventions, 59 530 participants) with a median sample size of 200 (range 26-1761). The quality of included RCTs was moderate with most showing a low risk of bias for randomization (118/188, 62.8%) and attrition (105/188, 55.8%) but there was a significant risk of publication bias (Egger's test P = 0.001). Performing ET with ultrasound guidance versus clinical touch (n = 24, RR 1.265, 95% CI 1.151-1.391, I2 = 38.53%), hyaluronic acid versus routine care (n = 9, RR 1.457, 95% CI 1.197-1.261, I2 = 46.48%) and the use of a soft versus hard catheter (n = 27, RR 1.122, 95% CI 1.028-1.224, I2 = 57.66%) led to higher clinical pregnancy rates. Other pharmacological add-ons also showed a beneficial effect including granulocyte colony-stimulating factor (G-CSF: n = 4, RR 1.774, 95% CI 1.252-2.512, I2 = 0), Atosiban (n = 7, RR 1.493, 95% CI 1.184-1.882, I2 = 68.27%) and hCG (n = 17, RR 1.232, 95% CI 1.099-1.382, I2 = 57.76%). Bed rest following ET was associated with a reduction in clinical pregnancy (n = 6, RR 0.857, 95% CI 0.741-0.991, I2 = 0.01%). Other commonly used interventions, such as non-steroidal anti-inflammatory drugs, prophylactic antibiotics, acupuncture and cervical mucus removal, did not show a significant benefit on reproductive outcomes. Our effect estimates for other important outcomes, including miscarriage and live birth, were limited by the varied reporting across included RCTs., Wider Implications: Using ultrasound guidance, soft catheters and hyaluronic acid at the time of ET appears to increase clinical pregnancy rates. The use of Atosiban, G-CSF and hCG showed a trend towards increased clinical pregnancy rate, but larger trials are required before adopting these interventions in clinical practice. Bed rest post-ET was associated with a reduction in clinical pregnancy and should not be recommended., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: The Gynecologic Cancer InterGroup (GCIG)-Symptom Benefit Study was designed to evaluate the effects of chemotherapy on symptoms and health-related quality of life (HRQL) in women having chemotherapy for platinum resistant/refractory recurrent ovarian cancer (PRR-ROC) and potentially platinum sensitive with ≥3 lines of chemotherapy (PPS-ROC ≥3)., Methods: Participants completed the Measure of Ovarian Cancer Symptoms and Treatment (MOST) and European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-C30 questionnaires at baseline and every 3-4 weeks until progression. Participants were classified symptomatic if they rated ≥4 of 10 in at least one-third of symptoms in the MOST index. Improvement in MOST was defined as two consecutive scores of ≤3 in at least half of the symptomatic items at baseline. Improvement in HRQL was defined as two consecutive scores ≥10 points above baseline in the QLQ-C30 summary score scale (range 0-100)., Results: Of 948 participants enrolled, 910 (96%) completed baseline questionnaires: 546 with PRR-ROC and 364 with PPS-ROC ≥3. The proportions of participants symptomatic at baseline as per MOST indexes were: abdominal 54%, psychological 53%, and disease- or treatment-related 35%. Improvement was reported in MOST indexes: abdominal 40%, psychological 35%, and disease- or treatment-related 38%. Median time to improvement in abdominal symptoms occurred earlier for PRR-ROC than for PPS-ROC ≥3 (4 vs 6 weeks, p=0.044); median duration of improvement was also similar (9.0 vs 11.7 weeks, p=0.65). Progression-free survival was longer among those with improvement in abdominal symptoms than in those without (median 7.2 vs 2.5 months, p<0.0001). Improvements in HRQL were reported by 77/448 (17%) with PRR-ROC and 61/301 (20%) with PPS-ROC ≥3 (p=0.29), and 102/481 (21%) of those with abdominal symptoms at baseline., Conclusion: Over 50% of participants reported abdominal and psychological symptoms at baseline. Of those, 40% reported an improvement within 2 months of starting chemotherapy. Approximately one in six participants reported an improvement in HRQL. Symptom monitoring and supportive care is important as chemotherapy palliated less than half of symptomatic participants., Competing Interests: Competing interests: YCL has received honoraria from GSK for participation on the Advisory Board. FJ acknowledges institutional research grants from GSK and has received honoraria for educational events from AstraZeneca, Astellas, Amgen, BMS, Bayer, Clovis, GSK, Ipsen, MSD, Janssen, Pfizer, and Sanofi. AO acknowledges institutional research grants from MSD K.K., Fuji Pharma, Kissei Pharmaceutical, Meiji Holdings, Taiho Pharmaceutical, Kaken Pharmaceutical, Chugai Pharmaceutical, Tsumura, Daiichi Sankyo, Shinnihonseiyaku, Mochida Pharmaceutical, CMIC Holdings, CMIC Holdings, ASKA Pharmaceutical, Takeda, Pfizer, AstraZeneca, and Terumo; and has received honoraria for educational events from Takeda and AstraZeneca. JL acknowledges institutional research grants from AstraZeneca and MSD/Merck and has received honoraria for educational events from AstraZeneca, Neopharm, GSK and Pfizer and participated on the data safety monitoring board of Regeneron. JS has received honoraria (educational events/travel) from AstraZeneca, Clovis, Clovis and Roche; and has participated on the data safety monitoring board or advisory board for AstraZeneca, Clovis, Eisei, GSK, Novocure, Pfizer, Roche, and Tesaro. MLF acknowledges institutional research grants from AstraZeneca, Novartis, and Beigene; has received honoraria (consultancy/educational events) from AstraZeneca, Novartis, GSK, MSD, Takeda, Lily, and ACT-Genomics; and participated on the data safety monitoring board for AGITG. MTK, RO, AL, FH, AD, FTR, JB, PD, AMO, EA-L, JSB, DB, AF, M-CK, KD and MRS declare no conflict of interest., (© IGCS and ESGO 2022. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Purpose: Fetoscopic laser photocoagulation is a minimally invasive procedure to treat twin-to-twin transfusion syndrome during pregnancy by stopping irregular blood flow in the placenta. Building an image mosaic of the placenta and its network of vessels could assist surgeons to navigate in the challenging fetoscopic environment during the procedure., Methodology: We propose a fetoscopic mosaicking approach by combining deep learning-based optical flow with robust estimation for filtering inconsistent motions that occurs due to floating particles and specularities. While the current state of the art for fetoscopic mosaicking relies on clearly visible vessels for registration, our approach overcomes this limitation by considering the motion of all consistent pixels within consecutive frames. We also overcome the challenges in applying off-the-shelf optical flow to fetoscopic mosaicking through the use of robust estimation and local refinement., Results: We compare our proposed method against the state-of-the-art vessel-based and optical flow-based image registration methods, and robust estimation alternatives. We also compare our proposed pipeline using different optical flow and robust estimation alternatives., Conclusions: Through analysis of our results, we show that our method outperforms both the vessel-based state of the art and LK, noticeably when vessels are either poorly visible or too thin to be reliably identified. Our approach is thus able to build consistent placental vessel mosaics in challenging cases where currently available alternatives fail., (© 2022. The Author(s).)

Objective: To examine changes in lung function over time in extremely prematurely born adolescents., Working Hypothesis: Changes in lung function during adolescence would vary by ventilation mode immediately after birth., Study Design: Longitudinal follow-up study., Patient Subject Selection: Participants from the United Kingdom Oscillation Study who were randomized at birth to high-frequency oscillation (HFO) or conventional ventilation (CV) were assessed at 11-14 years (n = 319) and at 16-19 years (n = 159)., Methodology: Forced expiratory flow (FEF), forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and lung volumes including functional residual capacity (FRC) were reported as z-scores. The diffusion capacity of the lungs for carbon monoxide (DLCO) was measured. Lung function trajectories were compared by mode of ventilation using mixed models. Changes in z-scores were scaled to 5-year average follow-up., Results: There were significant changes in the mean FEF75, FEF50, FEF25, FEV1, FVC, and DLCO z-scores within the CV and HFO cohorts, but no significant differences in the changes between the two groups. The mean FRC z-score increased in both groups, with an average change of greater than one z-score. The mean FEV1/FVC z-score increased significantly in the CV group, but not in the HFO group (difference in slopes: p = 0.02). Across the population, deterioration in lung function was associated with male sex, white ethnicity, lower gestational age at birth, postnatal corticosteroids, oxygen dependency at 36 weeks postmenstrual age, and lower birth weight, but not ventilation mode., Conclusions: There was little evidence that the mode of ventilation affected changes in lung function over time., (© 2022 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Study Question: Does maternal infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the first trimester affect the risk of miscarriage before 13 week's gestation?, Summary Answer: Pregnant women with self-reported diagnosis of SARS-CoV-2 in the first trimester had a higher risk of early miscarriage., What Is Known Already: Viral infections during pregnancy have a broad spectrum of placental and neonatal pathology. Data on the effects of the SARS-CoV-2 infection in pregnancy are still emerging. Two systematic reviews and meta-analyses reported an increased risk of preterm birth, caesarean delivery, maternal morbidity and stillbirth. Data on the impact of first trimester infection on early pregnancy outcomes are scarce. This is the first study, to our knowledge, to investigate the rates of early pregnancy loss during the SARS-CoV-2 outbreak among women with self-reported infection., Study Design, Size, Duration: This was a nationwide prospective cohort study of pregnant women in the community recruited using social media between 21 May and 31 December 2020. We recruited 3545 women who conceived during the SARS-CoV-2 pandemic who were <13 week's gestation at the time of recruitment., Participants/materials, Setting, Methods: The COVID-19 Contraception and Pregnancy Study (CAP-COVID) was an on-line survey study collecting longitudinal data from pregnant women in the UK aged 18 years or older. Women who were pregnant during the pandemic were asked to complete on-line surveys at the end of each trimester. We collected data on current and past pregnancy complications, their medical history and whether they or anyone in their household had symptoms or been diagnosed with SARS-CoV-2 infection during each trimester of their pregnancy. RT-PCR-based SARS-CoV-2 RNA detection from respiratory samples (e.g. nasopharynx) is the standard practice for diagnosis of SARS-CoV-2 in the UK. We compared rate of self-reported miscarriage in three groups: 'presumed infected', i.e. those who reported a diagnosis with SARS-CoV-2 infection in the first trimester; 'uncertain', i.e. those who did not report a diagnosis but had symptoms/household contacts with symptoms/diagnosis; and 'presumed uninfected', i.e. those who did not report any symptoms/diagnosis and had no household contacts with symptoms/diagnosis of SARS-CoV-2., Main Results and the Role of Chance: A total of 3545 women registered for the CAP-COVID study at <13 weeks gestation and were eligible for this analysis. Data for the primary outcome were available from 3041 women (86%). In the overall sample, the rate of self-reported miscarriage was 7.8% (238/3041 [95% CI, 7-9]). The median gestational age (GA) at miscarriage was 9 weeks (interquartile range 8-11). Seventy-seven women were in the 'presumed infected' group (77/3041, 2.5% [95% CI 2-3]), 295/3041 were in the uncertain group (9.7% [95% CI 9-11]) and the rest in the 'presumed uninfected' (87.8%, 2669/3041 [95% CI 87-89]). The rate of early miscarriage was 14% in the 'presumed infected' group, 5% in the 'uncertain' and 8% in the 'presumed uninfected' (11/77 [95% CI 6-22] versus 15/295 [95% CI 3-8] versus 212/2669 [95% CI 7-9], P = 0.02). After adjusting for age, BMI, ethnicity, smoking status, GA at registration and the number of previous miscarriages, the risk of early miscarriage appears to be higher in the 'presumed infected' group (relative rate 1.7, 95% CI 1.0-3.0, P = 0.06)., Limitations, Reasons for Caution: We relied on self-reported data on early pregnancy loss and SARS-CoV-2 infection without any means of checking validity. Some women in the 'presumed uninfected' and 'uncertain' groups may have had asymptomatic infections. The number of 'presumed infected' in our study was low and therefore the study was relatively underpowered., Wider Implications of the Findings: This was a national study from the UK, where infection rates were one of the highest in the world. Based on the evidence presented here, women who are infected with SARS-CoV-2 in their first trimester may be at an increased risk of a miscarriage. However, the overall rate of miscarriage in our study population was 8%. This is reassuring and suggests that if there is an effect of SARS-CoV-2 on the risk of miscarriage, this may be limited to those with symptoms substantial enough to lead to a diagnostic test. Further studies are warranted to evaluate a causal association between SARS-CoV-2 infection in early pregnancy and miscarriage risk. Although we did not see an overall increase in the risk of miscarriage, the observed comparative increase in the presumed infected group reinforces the message that pregnant women should continue to exercise social distancing measures and good hygiene throughout their pregnancy to limit their risk of infection., Study Funding/competing Interest(s): This study was supported by a grant from the Elizabeth Garrett Anderson Hospital Charity (G13-559194). The funders of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. J.A.H. is supported by an NIHR Advanced Fellowship. A.L.D. is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi&#95;disclosure.pdf and declare: support to J.A.H. and A.L.D. as above; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work., Trial Registration Number: N/A., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Introduction: To develop an attribute-based method for assessing patient contraceptive preferences in Botswana and pilot its use to explore the relationship between patient contraceptive preferences and the contraceptive methods provided or recommended to patients by clinicians., Methods: A list of contraceptive attributes was developed with input from patients, clinicians, and other stakeholders. We assessed patient preferences for attributes of contraceptives using a discrete choice "best-worst scaling" approach and a multi-attribute decision-making method that linked patient attribute preferences to actual contraceptive method characteristics. Attribute-based patient method preferences and clinician recommendations were compared in 100 women seeking contraceptive services, and 19 clinicians who provided their care. For 41 of the patients, the short-term reliability of their preference scores was also examined., Results: For 57 patients who wanted more children in the future, the degree of concordance between patients and clinicians was 7% when comparing the top attribute-based contraceptive preference for each woman with the clinician-provided/recommended method. When the top two model-based preferred contraceptive methods were considered, concordance was 28%. For 43 women who did not want more children, concordance was 0% when using the patient's model-based "most-preferred" method, and 14% when considering the top two methods. Assessment of the short-term reliability of preference scores yielded an intraclass correlation coefficient of 0.93., Conclusions: A best-worst scaling assessment of attributes of contraceptives was designed and piloted in Botswana as a Contraceptive Preference Assessment Tool. The preference assessment was found to have high short-term reliability, which supports its potential use as a measurement tool. There was very low concordance between women's attribute-based contraceptive preferences and their clinician's provision/recommendations of contraceptive methods. Using such a preference assessment tool could encourage greater patient involvement and more tailored discussion in contraceptive consultations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gertz, Soffi, Mompe, Sickboy, Gaines, Ryan, Mussa, Bawn, Gallop, Morroni and Crits-Christoph.)

Objective: To assess the impact of public health measures taken during the COVID-19 pandemic on perinatal health indicators., Design: Interrupted time series analysis comparing periods of the pandemic with the previous 5 years., Setting: Yorkshire and the Humber region, England (2015-2020)., Main Outcome Measures: Relative risk (RR) of stillbirth, extreme preterm (EPT, <27 weeks' gestational age) delivery, hypoxic ischaemic encephalopathy (HIE) and meconium aspiration syndrome (MAS), antenatal transfer for threatened EPT delivery and postnatal transfer for EPT birth, HIE or MAS., Results: Stillbirths fell from 3.7/1000 deliveries prepandemic to 2.9/1000 afterwards; EPT births decreased from 2.5/1000 to 1.8/1000 live births. Following adjustment, during the first lockdown there were decreased antenatal transfers (RR 0.74, 95% CI 0.57 to 0.94) with non-statistically significant increased stillbirth (RR 1.08, 95% CI 0.78 to 1.51) and decreased EPT admissions (RR 0.88, 95% CI 0.60 to 1.29). Over the entire pandemic period, antenatal transfer (RR 0.64, 95% CI 0.55 to 0.76) and EPT birth (RR 0.73, 95% CI 0.56 to 0.94) decreased; stillbirths showed non-statistically significant increases overall (RR 1.21, 95% CI 0.98 to 1.49) but with increasing trend through the pandemic (RR 1.11, 95% CI 1.00 to 1.22). No changes were seen for HIE, MAS, postnatal transfers or in subgroup analyses by ethnicity., Conclusions: Lower rates of antenatal transfer and extreme preterm birth were identified, alongside an apparent increase in stillbirth over time. The findings provide evidence that effects on perinatal activity related to the pandemic changed over time., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: In obstetric ultrasound (US) scanning, the learner's ability to mentally build a three-dimensional (3D) map of the fetus from a two-dimensional (2D) US image represents a major challenge in skill acquisition. We aim to build a US plane localisation system for 3D visualisation, training, and guidance without integrating additional sensors., Methods: We propose a regression convolutional neural network (CNN) using image features to estimate the six-dimensional pose of arbitrarily oriented US planes relative to the fetal brain centre. The network was trained on synthetic images acquired from phantom 3D US volumes and fine-tuned on real scans. Training data was generated by slicing US volumes into imaging planes in Unity at random coordinates and more densely around the standard transventricular (TV) plane., Results: With phantom data, the median errors are 0.90 mm/1.17[Formula: see text] and 0.44 mm/1.21[Formula: see text] for random planes and planes close to the TV one, respectively. With real data, using a different fetus with the same gestational age (GA), these errors are 11.84 mm/25.17[Formula: see text]. The average inference time is 2.97 ms per plane., Conclusion: The proposed network reliably localises US planes within the fetal brain in phantom data and successfully generalises pose regression for an unseen fetal brain from a similar GA as in training. Future development will expand the prediction to volumes of the whole fetus and assess its potential for vision-based, freehand US-assisted navigation when acquiring standard fetal planes., (© 2022. The Author(s).)

Objectives: To calculate 3D-segmented total lung volume (TLV) in fetuses with thoracic anomalies using deformable slice-to-volume registration (DSVR) with comparison to 2D-manual segmentation. To establish a normogram of TLV calculated by DSVR in healthy control fetuses., Methods: A pilot study at a single regional fetal medicine referral centre included 16 magnetic resonance imaging (MRI) datasets of fetuses (22-32 weeks gestational age). Diagnosis was CDH (n = 6), CPAM (n = 2), and healthy controls (n = 8). Deformable slice-to-volume registration was used for reconstruction of 3D isotropic (0.85 mm) volumes of the fetal body followed by semi-automated lung segmentation. 3D TLV were compared to traditional 2D-based volumetry. Abnormal cases referenced to a normogram produced from 100 normal fetuses whose TLV was calculated by DSVR only., Results: Deformable slice-to-volume registration-derived TLV values have high correlation with the 2D-based measurements but with a consistently lower volume; bias -1.44 cm 3 [95% limits: -2.6 to -0.3] with improved resolution to exclude hilar structures even in cases of motion corruption or very low lung volumes., Conclusions: Deformable slice-to-volume registration for fetal lung MRI aids analysis of motion corrupted scans and does not suffer from the interpolation error inherent to 2D-segmentation. It increases information content of acquired data in terms of visualising organs in 3D space and quantification of volumes, which may improve counselling and surgical planning., (© 2022 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Background: Laboratory data suggest that insufficient circulating levels of the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1ra) are associated with intrapartum inflammation and epidural-related maternal fever, both of which increase the rate of obstetric interventions and antibiotic use during labour. Genetic polymorphisms strongly influence IL-1ra levels in the general population. We aim to examine the association between IL-1ra polymorphisms and epidural-related maternal fever using Mendelian randomization analysis., Methods: EPIFEVER-2 is a multicentre UK trial enrolling 637 women receiving epidural analgesia for labour. Blood samples obtained no later than four hours after epidural insertion will provide deoxyribonucleic acid for Taqman single-nucleotide polymorphism genotyping for presence/absence of rs6743376, rs1542176 alleles for IL-1ra, to establish the genetic score. The absence of both alleles is associated with the lowest IL-1ra levels. The primary outcome is pyrexia (>38°C) or intrapartum antibiotic administration. Secondary outcomes include mode of delivery, maternal and neonatal healthcare interventions., Results: The EPIFEVER-2 study was prospectively registered (ISRCTN99641204) following ethical approval. Participant recruitment began in May 2021, with 221 women recruited across three centres as of November 21, 2021., Conclusions: EPIFEVER-2 will generate the largest prospective dataset detailing the incidence and consequences of epidural-related maternal fever. Using Mendelian randomisation analysis, a causative role for lower IL1-ra levels in determining the risk of epidural-related maternal fever and/or antibiotic administration before delivery will be examined., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: Prenatal exome sequencing (pES) for the diagnosis of fetal abnormalities is being introduced more widely in clinical practice. Here we explore parents' and professionals' views and experiences of pES, to identify perceived benefits, concerns, and support needs., Methods: Semi-structured interviews were conducted with 11 parents and 20 health professionals (fetal medicine and clinical genetics) with experience of rapid pES prior to implementation in the English National Health Service. Interviews were transcribed verbatim and analysed thematically., Results: Parents and professionals were largely positive about pES, emphasising clinical and psychosocial benefits of a timely, definitive diagnosis in pregnancy. Concerns included parental anxiety related to the timing of pES results or uncertain findings, a need for guidelines for case selection and reporting, and ensuring sufficient capacity for counselling, phenotyping and variant interpretation. Professionals were concerned non-genetics professionals may not be equipped to counsel parents on the complexities of pES., Conclusion: These findings highlight important issues for clinical implementation of pES. Expert counselling is required to enable parents to make informed decisions during a stressful time. To achieve this, professionals need further education and training, and fetal medicine and genetics services must work closely together to ensure parental understanding and appropriate support., (© 2022 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Topographic cortical maps are essential for spatial localisation of sensory stimulation and generation of appropriate task-related motor responses. Somatosensation and nociception are finely mapped and aligned in the adult somatosensory (S1) cortex, but in infancy, when pain behaviour is disorganised and poorly directed, nociceptive maps may be less refined. We compared the topographic pattern of S1 activation following noxious (clinically required heel lance) and innocuous (touch) mechanical stimulation of the same skin region in newborn infants ( n = 32) using multioptode functional near-infrared spectroscopy (fNIRS). Within S1 cortex, touch and lance of the heel elicit localised, partially overlapping increases in oxygenated haemoglobin concentration (Δ[HbO]), but while touch activation was restricted to the heel area, lance activation extended into cortical hand regions. The data reveals a widespread cortical nociceptive map in infant S1, consistent with their poorly directed pain behaviour., Competing Interests: LJ, MV, RC, ML, MR, JM, LF, MF No competing interests declared, (© 2022, Jones et al.)

Chronic inflammatory placental disorders are a group of rare but devastating gestational syndromes associated with adverse pregnancy outcome. This review focuses on three related conditions: villitis of unknown etiology (VUE), chronic histiocytic intervillositis (CHI) and massive perivillous fibrin deposition (MPFD). The hallmark of these disorders is infiltration of the placental architecture by maternal immune cells and disruption of the intervillous space, where gas exchange between the mother and fetus occurs. Currently, they can only be detected through histopathological examination of the placenta after a pregnancy has ended. All three are associated with a significant risk of recurrence in subsequent pregnancies. Villitis of unknown etiology is characterised by a destructive infiltrate of maternal CD8+ T lymphocytes invading into the chorionic villi, combined with activation of fetal villous macrophages. The diagnosis can only be made when an infectious aetiology has been excluded. VUE becomes more common as pregnancy progresses and is frequently seen with normal pregnancy outcome. However, severe early-onset villitis is usually associated with fetal growth restriction and recurrent pregnancy loss. Chronic histiocytic intervillositis is characterised by excessive accumulation of maternal CD68+ histiocytes in the intervillous space. It is associated with a wide spectrum of adverse pregnancy outcomes including high rates of first-trimester miscarriage, severe fetal growth restriction and late intrauterine fetal death. Intervillous histiocytes can also accumulate due to infection, including SARS-CoV-2, although this infection-induced intervillositis does not appear to recur. As with VUE, the diagnosis of CHI requires exclusion of an infectious cause. Women with recurrent CHI and their families are predisposed to autoimmune diseases, suggesting CHI may have an alloimmune pathology. This observation has driven attempts to prevent CHI with a wide range of maternal immunosuppression. Massive perivillous fibrin deposition is diagnosed when >25% of the intervillous space is occupied by fibrin, and is associated with fetal growth restriction and late intrauterine fetal death. Although not an inflammatory disorder per se, MPFD is frequently seen in association with both VUE and CHI. This review summarises current understanding of the prevalence, diagnostic features, clinical consequences, immune pathology and potential prophylaxis against recurrence in these three chronic inflammatory placental syndromes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cornish, McDonnell and Williams.)

Introduction: Children born very preterm have an immature sucking reflex at birth and are exposed to neonatal care that can impede proper palate growth., Objectives: We aimed to describe the frequency of high-arched palate and posterior crossbite at the age of 5 in children born very preterm and to identify their respective risk factors., Methods: Our study was based on the data from EPIPAGE-2, a French national prospective cohort study, and included 2,594 children born between 24- and 31-week gestation. Outcomes were high-arched palate and posterior crossbite. Multivariable models estimated by generalized estimation equations with multiple imputation were used to study the association between the potential risk factors studied and each outcome., Results: Overall, 8% of children born very preterm had a high-arched palate and 15% posterior crossbite. The odds of high-arched palate were increased for children with low gestational age (24-29 vs. 30-31 weeks of gestation) [adjusted odds ratio (aOR) 1.76, 95% confidence interval (CI) 1.17, 2.66], thumb-sucking habits at the age of 2 (aOR 1.53, 95% CI 1.03, 2.28), and cerebral palsy (aOR 2.18, 95% CI 1.28, 3.69). The odds of posterior crossbite were increased for children with pacifier-sucking habits at the age of 2 (aOR 1.75, 95% CI 1.30, 2.36)., Conclusions: Among very preterm children, low gestational age and cerebral palsy are the specific risk factors for a high-arched palate. High-arched palate and posterior crossbite share non-nutritive sucking habits as a common risk factor. The oro-facial growth of these children should be monitored., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Herrera, Pierrat, Kaminski, Benhammou, Marchand-Martin, Morgan, Le Norcy, Ancel and Germa.)

Introduction: Following the detection of fetal growth restriction, there is no consensus about the criteria that should trigger delivery in the late preterm period. The consequences of inappropriate early or late delivery are potentially important yet practice varies widely around the world, with abnormal findings from fetal heart rate monitoring invariably leading to delivery. Indices derived from fetal cerebral Doppler examination may guide such decisions although there are few studies in this area. We propose a randomised, controlled trial to establish the optimum method of timing delivery between 32 weeks and 36 weeks 6 days of gestation. We hypothesise that delivery on evidence of cerebral blood flow redistribution reduces a composite of perinatal poor outcome, death and short-term hypoxia-related morbidity, with no worsening of neurodevelopmental outcome at 2 years., Methods and Analysis: Women with non-anomalous singleton pregnancies 32+0 to 36+6 weeks of gestation in whom the estimated fetal weight or abdominal circumference is <10th percentile or has decreased by 50 percentiles since 18-32 weeks will be included for observational data collection. Participants will be randomised if cerebral blood flow redistribution is identified, based on umbilical to middle cerebral artery pulsatility index ratio values. Computerised cardiotocography (cCTG) must show normal fetal heart rate short term variation (≥4.5 msec) and absence of decelerations at randomisation. Randomisation will be 1:1 to immediate delivery or delayed delivery (based on cCTG abnormalities or other worsening fetal condition). The primary outcome is poor condition at birth and/or fetal or neonatal death and/or major neonatal morbidity, the secondary non-inferiority outcome is 2-year infant general health and neurodevelopmental outcome based on the Parent Report of Children's Abilities-Revised questionnaire., Ethics and Dissemination: The Study Coordination Centre has obtained approval from London-Riverside Research Ethics Committee (REC) and Health Regulatory Authority (HRA). Publication will be in line with NIHR Open Access policy., Trial Registration Number: Main sponsor: Imperial College London, Reference: 19QC5491. Funders: NIHR HTA, Reference: 127 976. Study coordination centre: Imperial College Healthcare NHS Trust, Du Cane Road, London, W12 0HS with Centre for Trials Research, College of Biomedical & Life Sciences, Cardiff University. IRAS Project ID: 266 400. REC reference: 20/LO/0031. ISRCTN registry: 76 016 200., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coidisclosure.pdfanddeclare: no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Initiatives to optimise preconception health are emerging following growing recognition that this may improve the health and well-being of women and men of reproductive age and optimise health in their children. To inform and evaluate such initiatives, guidance is required on indicators that describe and monitor population-level preconception health. We searched relevant databases and websites (March 2021) to identify national and international preconception guidelines, recommendations and policy reports. These were reviewed to identify preconception indicators. Indicators were aligned with a measure describing the prevalence of the indicator as recorded in national population-based data sources in England. From 22 documents reviewed, we identified 66 indicators across 12 domains. Domains included wider (social/economic) determinants of health; health care; reproductive health and family planning; health behaviours; environmental exposures; cervical screening; immunisation and infections; mental health, physical health; medication and genetic risk. Sixty-five of the 66 indicators were reported in at least one national routine health data set, survey or cohort study. A measure of preconception health assessment and care was not identified in any current national data source. Perspectives from three (healthcare) professionals described how indicator assessment and monitoring may influence patient care and inform awareness campaign development. This review forms the foundation for developing a national surveillance system for preconception health in England. The identified indicators can be assessed using national data sources to determine the population's preconception needs, improve patient care, inform and evaluate new campaigns and interventions and enhance accountability from responsible agencies to improve preconception health.

Simulation training provides a safe, non-judgmental environment where members of the multi-professional team can practice both their technical and non-technical skills. Poor teamwork and communication are recurring contributing factors to adverse maternal and neonatal outcomes. Simulation can improve outcomes and is now a compulsory part of the national training matrix. Components of successful training include involving the multi-professional team, high fidelity models, keeping training on-site, and focussing on human factors training; a key factor in adverse patient outcomes. The future of simulation training is an exciting field, with the advent of augmented reality devices and the use of artificial intelligence., Competing Interests: Declaration of competing interest There are no known conflicts of interests to declare., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: To investigate whether ovarian fragmentation for follicular activation (OFFA) improves ovarian reserve markers and in vitro fertilization (IVF) outcomes in women with poor ovarian response (POR)., Design: Randomized, controlled trial, with parallel assignment., Setting: University hospital., Patient(s): Thirty-four women with POR according to the European Society of Human Reproduction and Embryology criteria., Intervention(s): Women with POR were randomly allocated to receive ovarian fragmentation in 1 ovary or to no intervention (control group). Ovarian reserve markers were followed at 2-week intervals for 6 months. In vitro fertilization cycles were initiated when the antral follicle count (AFC) doubled or at the end of follow-up., Main Outcome Measure(s): The primary outcome was the number of metaphase II (MII) oocytes obtained. Antral follicle count, antimüllerian hormone level, and reproductive outcomes were recorded as secondary outcomes. Exploratory outcomes included surgical results and analysis of protein and gene expression., Result(s): Ovarian fragmentation for follicular activation resulted in an increase in AFC in the intervention ovary compared with the control ovary and an increase in total AFC in the OFFA group compared with controls. Serum antimüllerian hormone and follicle-stimulating-hormone levels did not improve in the OFFA group throughout the follow-up period. Fifteen patients from each arm underwent IVF. In the control group, 33 MII oocytes were retrieved and 18 embryo transfers were performed, with a 20% pregnancy rate and an 18.7% live birth rate per cycle. In the OFFA group, 23 MII oocytes were retrieved and 11 embryo transfers were performed, with a 13.3% pregnancy rate and a 6.7% live birth rate per cycle. Reproductive outcomes did not significantly differ between the groups. Hippo pathway inhibition was confirmed by an 18.8% reduction in the phospho-YAP/YAP (Yes-associated protein 1) ratio and BIRC and CCN overexpression after fragmentation., Conclusion(s): Ovarian fragmentation for follicular activation in women with POR resulted in an increase in AFC but did not modify IVF outcomes when compared with controls., Clinical Trial Registration Number: NCT02354963., (Copyright © 2021 American Society for Reproductive Medicine. All rights reserved.)

Background: The objective of this study was to assess the impact of consultant presence, volume of patients seen and weekend opening on the health and cost-related outcomes associated with different Early Pregnancy Assessment Unit (EPAU) configurations., Methods: This was an observational study with a prospective cohort design. Six thousand six hundred six pregnant women (16 years of age and over) attending EPAUs because of suspected early pregnancy complications were recruited from 44 EPAUs across the UK. The main outcome measures were quality of life, costs, and anxiety., Results: Costs, quality of life and anxiety scores were similar across configurations with little evidence to suggest an impact of consultant presence, weekend opening or volume of patients seen. Mean overall costs varied from £92 (95% CI £85 - £98) for a diagnosis of normally developing pregnancy to £1793 (95% CI £1346 - £2240) for a molar pregnancy. EQ-5D-5L score increased from 0.85 (95% CI 0.84-0.86) at baseline to 0.91 (95% CI 0.90-0.92) at 4 weeks for the 573 women who completed questionnaires at both time points, largely due to improvements in the pain/discomfort and anxiety/depression dimensions. 78% of women reported a decrease in their anxiety score immediately following their EPAU appointment., Conclusions: EPAU configuration, as specified in this study, had limited impact on any of the outcomes examined. However, it is clear that care provided in the EPAU has a positive overall effect on women's health and emotional wellbeing, with significant improvements in EQ-5D and anxiety shown following an EPAU visit., (© 2022. The Author(s).)

Care for pregnant women and their infants at extremely low gestational ages challenges clinical teams. The continuing rise in survival at gestational ages below 25 weeks has prompted re-evaluation of practice guidelines within the UK and other countries. This paper describes the background data that have guided our practice, the approach that has been taken to deliver optimal outcomes for pregnancies delivering at extremely low gestational age in the UK, mainly through centralising care, and discusses the research and audit data that support our practice. In particular, we emphasize the importance of a coordinated perinatal approach to both mother and infant, and careful assessment of the risks to both, to ensure that we develop the highest quality personalized care for each family, supported by national quality improvement and research evidence., Competing Interests: Declaration of Competing Interest NM declares consulting fees with Novartis and Takeda outside the published work; other authors declare no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To develop a consensus statement of recommended terminology to use for describing different aspects of hysteroscopic procedures that can be uniformly used in clinical practice and research., Design: Open forum discussion followed by online video meetings., Setting: International community of hysteroscopy experts PATIENTS: Not applicable., Interventions: Series of online video meetings to complete a previously established agenda until a final agreement for standardized nomenclature was obtained., Measurement and Main Results: The adoption and implementation of a common terminology to standardize reporting of hysteroscopic procedures was proposed to cover five domains: pain management, healthcare setting, model of care, type of hysteroscopic procedure and the hysteroscopic approach to the uterine cavity. A final agreement was obtained after 3 online video meetings., Conclusion: Hysteroscopy is the gold standard technique for the evaluation and management of uterine disorders. A clear definition and understanding of the terminology used to describe hysteroscopic procedures is lacking. The production of this international consensus statement for terminology to describe hysteroscopic procedures, covering pain management, setting, model of care, type of procedure and hysteroscopic approach, has the potential to enable more effective communication for both clinical and research purposes with the ultimate aim of improving patient care and clinical outcomes., (Copyright © 2021 AAGL. Published by Elsevier Inc. All rights reserved.)

Objective: To define the dimensions of patient-centeredness of prenatal care for parents who had a fetus with isolated congenital diaphragmatic hernia (CDH) by exploring their values, experiences, needs and preferences., Methods: In-depth interviews with parents who were faced with the prenatal diagnosis of isolated CDH., Results: Interviews (n = 18) identified seven dimensions of patient-centeredness. Parental preferences are respected by unconditional acceptance of parental choices and needs. After diagnosis access to care should occur by swift referral to a specialised centre to prevent parents receiving contradictory information. Information and education help parents to gain some sense of control and cope with the many uncertainties. A multidisciplinary team with a coordinating professional is perceived supportive (coordination and integration), and seamless referral between local and treatment centres reduces parental distress (continuity and transition). Family-centred emotional support helps parents to cope with emotions and distress. Informal support by involvement of family and friends and trusted peer-support is of added value., Conclusion: The impact of the uncertainty of outcome in this condition is tremendous and needs to be considered when providing prenatal care. After initial diagnosis, one should avoid speculation about the severity of the condition and outcome, and provide swift referral to a specialist centre expert in managing CDH. Provision of realistic and comprehensive information helps parents cope. Multidisciplinary and continuous support throughout the full trajectory, but also integrated psychosocial support should become standard-of-care., (© 2022 John Wiley & Sons Ltd.)

Study Question: How should endometriosis be diagnosed and managed based on the best available evidence from published literature?, Summary Answer: The current guideline provides 109 recommendations on diagnosis, treatments for pain and infertility, management of disease recurrence, asymptomatic or extrapelvic disease, endometriosis in adolescents and postmenopausal women, prevention and the association with cancer., What Is Known Already: Endometriosis is a chronic condition with a plethora of presentations in terms of not only the occurrence of lesions, but also the presence of signs and symptoms. The most important symptoms include pain and infertility., Study Design Size Duration: The guideline was developed according to the structured methodology for development of ESHRE guidelines. After formulation of key questions by a group of experts, literature searches and assessments were performed. Papers published up to 1 December 2020 and written in English were included in the literature review., Participants/materials Setting Methods: Based on the collected evidence, recommendations were formulated and discussed within specialist subgroups and then presented to the core guideline development group (GDG) until consensus was reached. A stakeholder review was organized after finalization of the draft. The final version was approved by the GDG and the ESHRE Executive Committee., Main Results and the Role of Chance: This guideline aims to help clinicians to apply best care for women with endometriosis. Although studies mostly focus on women of reproductive age, the guideline also addresses endometriosis in adolescents and postmenopausal women. The guideline outlines the diagnostic process for endometriosis, which challenges laparoscopy and histology as gold standard diagnostic tests. The options for treatment of endometriosis-associated pain symptoms include analgesics, medical treatments and surgery. Non-pharmacological treatments are also discussed. For management of endometriosis-associated infertility, surgical treatment and/or medically assisted reproduction are feasible. While most of the more recent studies confirm previous ESHRE recommendations, there are five topics in which significant changes to recommendations were required and changes in clinical practice are to be expected., Limitations Reasons for Caution: The guideline describes different management options but, based on existing evidence, no firm recommendations could be formulated on the most appropriate treatments. Also, for specific clinical issues, such as asymptomatic endometriosis or extrapelvic endometriosis, the evidence is too scarce to make evidence-based recommendations., Wider Implications of the Findings: The guideline provides clinicians with clear advice on best practice in endometriosis care, based on the best evidence currently available. In addition, a list of research recommendations is provided to stimulate further studies in endometriosis., Study Funding/competing Interests: The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the dissemination of the guideline. The guideline group members did not receive payments. C.M.B. reports grants from Bayer Healthcare and the European Commission; Participation on a Data Safety Monitoring Board or Advisory Board with ObsEva (Data Safety Monitoring Group) and Myovant (Scientific Advisory Group). A.B. reports grants from FEMaLE executive board member and European Commission Horizon 2020 grant; consulting fees from Ethicon Endo Surgery, Medtronic; honoraria for lectures from Ethicon; and support for meeting attendance from Gedeon Richter; A.H. reports grants from MRC, NIHR, CSO, Roche Diagnostics, Astra Zeneca, Ferring; Consulting fees from Roche Diagnostics, Nordic Pharma, Chugai and Benevolent Al Bio Limited all paid to the institution; a pending patent on Serum endometriosis biomarker; he is also Chair of TSC for STOP-OHSS and CERM trials. O.H. reports consulting fees and speaker's fees from Gedeon Richter and Bayer AG; support for attending meetings from Gedeon-Richter, and leadership roles at the Finnish Society for Obstetrics and Gynecology and the Nordic federation of the societies of obstetrics and gynecology. L.K. reports consulting fees from Gedeon Richter, AstraZeneca, Novartis, Dr KADE/Besins, Palleos Healthcare, Roche, Mithra; honoraria for lectures from Gedeon Richter, AstraZeneca, Novartis, Dr KADE/Besins, Palleos Healthcare, Roche, Mithra; support for attending meetings from Gedeon Richter, AstraZeneca, Novartis, Dr KADE/Besins, Palleos Healthcare, Roche, Mithra; he also has a leadership role in the German Society of Gynecological Endocrinology (DGGEF). M.K. reports grants from French Foundation for Medical Research (FRM), Australian Ministry of Health, Medical Research Future Fund and French National Cancer Institute; support for meeting attendance from European Society for Gynaecological Endoscopy (ESGE), European Congress on Endometriosis (EEC) and ESHRE; She is an advisory Board Member, FEMaLe Project (Finding Endometriosis Using Machine Learning), Scientific Committee Chair for the French Foundation for Research on Endometriosis and Scientific Committee Chair for the ComPaRe-Endometriosis cohort. A.N. reports grants from Merck SA and Ferring; speaker fees from Merck SA and Ferring; support for meeting attendance from Merck SA; Participation on a Data Safety Monitoring Board or Advisory Board with Nordic Pharma and Merck SA; she also is a board member of medical advisory board, Endometriosis Society, the Netherlands (patients advocacy group) and an executive board member of the World Endometriosis Society. E.S. reports grants from National Institute for Health Research UK, Rosetrees Trust, Barts and the London Charity; Royalties from De Gruyter (book editor); consulting fees from Hologic; speakers fees from Hologic, Johnson & Johnson, Medtronic, Intuitive, Olympus and Karl Storz; Participation in the Medicines for Women's Health Expert Advisory Group with Medicines and Healthcare Products Regulatory Agency (MHRA); he is also Ambassador for the World Endometriosis Society. C.T. reports grants from Merck SA; Consulting fees from Gedeon Richter, Nordic Pharma and Merck SA; speaker fees from Merck SA, all paid to the institution; and support for meeting attendance from Ferring, Gedeon Richter and Merck SA. The other authors have no conflicts of interest to declare., Disclaimer: This guideline represents the views of ESHRE, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant ESHRE stakeholders has been obtained. Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgement to each individual presentation, nor variations based on locality and facility type . ESHRE makes no warranty, express or implied, regarding the clinical practice guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose (Full disclaimer available at www.eshre.eu/guidelines.)., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Background: Legal and social changes mean that information sharing and consent in antenatal and intrapartum settings is contentious, poorly understood and uncertain for healthcare professionals. This study aimed to investigate healthcare professionals' views and experiences of the consent process in antenatal and intrapartum care., Methods: Qualitative research performed in a large urban teaching hospital in London. Fifteen healthcare professionals (obstetricians and midwives) participated in semi-structured in-depth interviews. Data were collectively analysed to identify themes in the experiences of the consent process., Results: Three themes were identified: (1) Shared decision-making and shared responsibility -engaging women in dialogue is often difficult and, even when achieved, women are not always able or do not wish to share responsibility for decisions (2) Second-guessing women - assessing what is important to a woman is inherently difficult so healthcare professionals sometimes feel forced to anticipate a woman's views (3) Challenging professional contexts - healthcare professionals are disquieted by consent practice in the Labour ward setting which is often at odds with legal and professional guidance., Conclusions: Results suggest that there is a mismatch between what is required of healthcare professionals to effect an antenatal or intrapartum consent process concordant with current legal and professional guidance and what can be achieved in practice. If consent, as currently articulated, is to remain the barometer for current practice, healthcare professionals need more support in ways of enabling women to make decisions which healthcare professionals feel confident are autonomous whatever the circumstances of the consultation., (© 2022. The Author(s).)

Background: Consent to episiotomy is subject to the same legal and professional requirements as consent to other interventions, yet is often neglected. This study explores how women experience and perceive the consent process., Methods: Qualitative research in a large urban teaching hospital in London. Fifteen women who had recently undergone episiotomy were interviewed using a semi-structured interview guide and data was analysed using thematic analysis., Results: Three themes captured women's experiences of the episiotomy consent process: 1) Missing information - "We knew what it was, so they didn't give us details," 2) Lived experience of contemporaneous, competing events - "There's no time to think about it," and 3) Compromised volitional consent - "You have no other option." Minimal information on episiotomy was shared with participants, particularly concerning risks and alternatives. Practical realities such as time pressure, women's physical exhaustion and their focus on the baby's safe delivery, constrained consent discussions. Participants consequently inferred that there was no choice but episiotomy; whilst some women were still happy to agree, others perceived the choice to be illusory and disempowering, and subsequently experienced episiotomy as a distressing event., Conclusions: Consent to episiotomy is not consistently informed and voluntary and more often takes the form of compliance. Information must be provided to women in a more timely fashion in order to fulfil legal requirements, and to facilitate a sense of genuine choice., (© 2022. The Author(s).)

There has been a surge in studies implicating a role of vaginal microbiota in spontaneous preterm birth (sPTB), but most are associative without mechanistic insight. Here we show a comprehensive approach to understand the causative factors of preterm birth, based on the integration of longitudinal vaginal microbiota and cervicovaginal fluid (CVF) immunophenotype data collected from 133 women at high-risk of sPTB. We show that vaginal depletion of Lactobacillus species and high bacterial diversity leads to increased mannose binding lectin (MBL), IgM, IgG, C3b, C5, IL-8, IL-6 and IL-1β and to increased risk of sPTB. Cervical shortening, which often precedes preterm birth, is associated with Lactobacillus iners and elevated levels of IgM, C3b, C5, C5a and IL-6. These data demonstrate a role for the complement system in microbial-driven sPTB and provide a scientific rationale for the development of live biotherapeutics and complement therapeutics to prevent sPTB., (© 2022. The Author(s).)

Objective: To present process evaluation results from the Bridge-it Study, a pragmatic cluster randomised cross-over trial to improve effective contraception uptake through provision of the progestogen only pill (POP) plus sexual and reproductive health (SRH) clinic rapid-access to women presenting to community pharmacies for emergency contraception (EC)., Research Design and Methods: A multimethod process evaluation was conducted to assess intervention implementation, mechanisms of change and contextual factors. Data were gathered from screening logs (n=599), observations of pharmacist training, analysis of data from 4-month follow-up questionnaires (n=406), monitoring of contemporaneous events and qualitative interviews with 22 pharmacists, 5 SRH clinical staff and 36 study participants in three participating UK sites in Lothian, Tayside and London., Results: The intervention was largely delivered as intended and was acceptable. Pharmacists', SRH clinical staff and participants' accounts highlighted that providing a supply of POP with EC from the pharmacy as routine practice may have positive impacts on contraceptive practices in the short term, and potentially longer term. Key mechanisms of change included ease of access, increased awareness of contraception and services, and greater motivation and perceptions of self-efficacy. Few participants took up the offer to attend an SRH service (rapid-access component), and existing barriers within the SRH context were apparent (eg, lack of staff). Participant accounts highlight persistent barriers to accessing and using routine effective contraception remain., Conclusions: Implementation appeared to be acceptable and feasible, highlighting the potential for provision of POP within EC consultations as routine practice in community pharmacies. However, lack of engagement with the rapid access component of the intervention and existing barriers within the SRH context suggest that signposting to SRH services may be sufficient. Wider implementation should consider ways to address key implementation challenges to increase effectiveness and sustainability, and to overcome persistent barriers to accessing and using effective contraception., Trial Registration Number: ISRCTN70616901., Competing Interests: Competing interests: STC reports grants from the National Institute for Health Research (Health Technology Assessment (NIHR HTA) Programme), during the conduct of the study. AG is a consultant to HRA Pharma. AR reports receiving research grants from Gilead Sciences, Bristol-Myers Squibb, AbbVie and Roche; honorariums from Gilead Sciences; and personal fees from AbbVie. AM reports grants from NIHR HTA during the conduct of this study. AM is a clinical support bank midwife for SH:24 and a research midwife at Oxford University. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Robust forms of measurement such as the London Measure of Unplanned Pregnancy (LMUP), which recognise the complexity of the construct of pregnancy planning/intention, are being adopted worldwide. The aim of this study was to evaluate the psychometric properties of the Mozambican Portuguese version of the LMUP. The Brazilian Portuguese interviewer-administered LMUP was culturally adapted for use in Mozambique and pre-tested with 28 women. Field testing included 524 women aged 16-42. Completion rates of LMUP items were 100%. LMUP scores 0-12 were captured. In terms of reliability (internal consistency), Cronbach's alpha was 0.90, item-rest correlations were <0.2, and all inter-item correlations were positive. In terms of construct validity, principal components analysis showed that measurement was unidimensional, confirmatory factor analysis showed good model fit, and all hypotheses were met. We conclude that the Mozambican Portuguese LMUP is reliable, valid and suitable to use in Mozambique.

Purpose: Open spina bifida (OSB) encompasses a wide spectrum of intracranial abnormalities. With foetal surgery as a new treatment option, robust intracranial imaging is important for comprehensive preoperative evaluation and prognostication. We aimed to determine the incidence of infratentorial and supratentorial findings detected by magnetic resonance imaging (MRI) alone and MRI compared to ultrasound., Methods: Two systematic reviews comparing MRI to ultrasound and MRI alone were conducted on MEDLINE, EMBASE, and Cochrane databases identifying studies of foetal OSB from 2000 to 2020. Intracranial imaging findings were analysed at ≤ 26 or > 26 weeks gestation and neonates (≤ 28 days). Data was independently extracted by two reviewers and meta-analysis was performed where possible., Results: Thirty-six studies reported brain abnormalities detected by MRI alone in patients who previously had an ultrasound. Callosal dysgenesis was identified in 4/29 cases (2 foetuses ≤ 26 weeks, 1 foetus under any gestation, and 1 neonate ≤ 28 days) (15.1%, CI:5.7-34.3%). Heterotopia was identified in 7/40 foetuses ≤ 26 weeks (19.8%, CI:7.7-42.2%), 9/36 foetuses > 26 weeks (25.3%, CI:13.7-41.9%), and 64/250 neonates ≤ 28 days (26.9%, CI:15.3-42.8%). Additional abnormalities included aberrant cortical folding and other Chiari II malformation findings such as lower cervicomedullary kink level, tectal beaking, and hypoplastic tentorium. Eight studies compared MRI directly to ultrasound, but due to reporting inconsistencies, it was not possible to meta-analyse., Conclusion: MRI is able to detect anomalies hitherto underestimated in foetal OSB which may be important for case selection. In view of increasing prenatal OSB surgery, further studies are required to assess developmental consequences of these findings., (© 2021. The Author(s).)

Competing Interests: Competing interests: We have read and understood The BMJ policy on declaration of interests and declare that we have no competing interests.

Background: Studies are sparse and inconclusive about the association between maternal education and cognitive development among children born very preterm (VPT). Although this association is well established in the general population, questions remain about its magnitude among children born VPT whose risks of medical and developmental complications are high. We investigated the association of maternal education with cognitive outcomes in European VPT birth cohorts., Methods: We used harmonized aggregated data from 15 population-based cohorts of children born at <32 weeks of gestational age (GA) or <1500 g from 1985 to 2013 in 13 countries with information on maternal education and assessments of general development at 2-3 years and/or intelligence quotients between 4 and 15 years. Term-born controls (≥37 weeks of GA) were available in eight cohorts. Maternal education was classified as: low (primary/lower secondary); medium (upper secondary/short tertiary); high (bachelor's/higher). Pooled standardized mean differences (SMDs) in cognitive scores were estimated (reference: high educational level) for children assessed at ages 2-3, 4-7 and 8-15 years., Results: The study included 10 145 VPT children from 12 cohorts at 2-3 years, 8829 from 12 cohorts at 4-7 years and 1865 children from 6 cohorts at 8-15 years. Children whose mothers had low, compared with high, educational attainment scored lower on cognitive measures [pooled unadjusted SMDs: 2-3 years = -0.32 (95% confidence intervals: -0.43 to -0.21); 4-7 years = -0.57 (-0.67; -0.47); 8-15 years = -0.54 (-0.72; -0.37)]. Analyses by GA subgroups (<27 vs ≥27 weeks) in children without severe neonatal morbidity and term controls yielded similar results., Conclusions: Across diverse settings and regardless of the degree of prematurity, low maternal education was associated with lower cognition., (© The Author(s) 2021; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Importance: Children born preterm (<37 weeks' gestation) have a higher risk of visual impairment and ocular morbidities compared peers born at full term. However, the long-term ocular sequelae in adulthood for those born extremely preterm (EP), who have the highest risk of neonatal retinopathy, are unknown., Objective: To evaluate visual function and ocular morbidity in young adults born EP compared with controls born full term., Design, Setting, and Participants: This prospective cohort study of a geographically based birth cohort in the UK and Ireland born from March 1 through December 31, 1995, included 128 participants aged 19 years (born at 22-25 weeks' gestation) and 65 age-matched controls born at full term. Statistical analysis was performed from March 1, 2020, to November 26, 2021., Exposures: Participants underwent eye examinations as part of a comprehensive outcome evaluation., Main Outcomes and Measures: Best-corrected visual acuity, refractive status, contrast sensitivity, color vision, prevalence of strabismus and nystagmus, and patient-reported visual function, measured using the Health Utilities Index Mark 3., Results: The study comprised 128 participants (256 eyes; 68 female participants [53%]; mean [SD] age, 19.3 [0.5] years) and 65 age-matched controls born at full term (130 eyes; 40 female participants [62%]; mean [SD] age, 19.2 [0.5] years). Compared with control eyes, the mean (SD) best-corrected visual acuity among eyes in the EP group was significantly worse (monocular vision: -0.06 [0.14] logMAR in the control group vs 0.14 [0.38] logMAR in the EP group; P < .001; binocular vision: -0.14 [0.15] logMAR in the control group vs 0.06 [0.37] logMAR in the EP group; P < .001). Participants in the EP group had a significantly higher prevalence of strabismus (36% [46 of 127] vs 0%; P < .001), abnormal ocular motility (15% [19 of 125] vs 0%; P < .001), and nystagmus (13% [16 of 127] vs 0%; P < .001) than the control group. No significant differences between participants in the EP group and controls were observed for refractive error, contrast sensitivity, color vision, or patient-reported visual function. Among the participants in the EP group, 48% of eyes (120 of 250) had no retinopathy of prematurity (ROP), 39% (98 of 250) had ROP not requiring neonatal treatment, and 13% (32 of 250) received cryotherapy or laser ablation for ROP. Within the EP group, there was no significant difference in binocular visual function parameters, prevalence of ocular morbidity, and patient-reported visual function by neonatal ROP status., Conclusions and Relevance: Extreme prematurity is associated with an increased prevalence of visual and ocular deficits in young adulthood; this study suggests that, for individuals born EP, visual and ocular deficits appear to be partially independent of ROP status in the neonatal period but reports similar overall visual function.

Objective: To assess the prevalence and morphological appearance of deep endometriosis and ovarian endometrioma using pelvic ultrasound examination in women attending for an early pregnancy assessment., Methods: This was a prospective observational study set within a dedicated early pregnancy unit. The study included 1341 consecutive women who attended for an early pregnancy assessment for reassurance or because of suspected early pregnancy complications. All women underwent a transvaginal scan to assess the location and viability of their pregnancy. In addition, a detailed examination of pelvic organs was carried out to detect the presence of endometriosis and other gynecological abnormalities. Data analysis was performed using logistic regression and multivariable analysis., Results: The prevalence of deep endometriosis and/or ovarian endometrioma in women attending our early pregnancy unit was 4.9% (95% CI, 3.8-6.2%). In 33/66 (50.0% (95% CI, 37.9-62.1%)) women with endometriosis, this was a new diagnosis that was made during their early pregnancy scan. On multivariable analysis, the presence of endometriosis was strongly associated with a history of subfertility (odds ratio (OR), 3.15 (95% CI, 1.63-6.07)) and presence of a congenital uterine anomaly (OR, 5.69 (95% CI, 2.17-14.9)) and uterine fibroids (OR, 2.37 (95% CI, 1.31-4.28)). Morphological changes typical of decidualization were seen in 11/33 (33.3% (95% CI, 17.2-49.4%)) women with ovarian endometrioma and 18/57 (31.6% (95% CI, 19.5-43.7%)) women with deep endometriotic nodules., Conclusions: Deep endometriosis and ovarian endometrioma were present in a significant proportion of women attending for early pregnancy assessment. The prevalence varied depending on a history of subfertility, and therefore is likely to differ significantly among populations, depending on their characteristics. Ultrasound is a useful tool for the detection of endometriosis in early pregnancy and the identification of women who may benefit from specialist antenatal care. © 2021 International Society of Ultrasound in Obstetrics and Gynecology., (© 2021 International Society of Ultrasound in Obstetrics and Gynecology.)

Aim: We investigated the timing of survival differences and effects on morbidity for foetuses alive at maternal admission to hospital delivered at 22 to 26 weeks' gestational age (GA)., Methods: Data from the EXPRESS (Sweden, 2004-07), EPICure-2 (England, 2006) and EPIPAGE-2 (France, 2011) cohorts were harmonised. Survival, stratified by GA, was analysed to 112 days using Kaplan-Meier analyses and Cox regression adjusted for population and pregnancy characteristics; neonatal morbidities, survival to discharge and follow-up and outcomes at 2-3 years of age were compared., Results: Among 769 EXPRESS, 2310 EPICure-2 and 1359 EPIPAGE-2 foetuses, 112-day survival was, respectively, 28.2%, 10.8% and 0.5% at 22-23 weeks' GA; 68.5%, 40.0% and 23.6% at 24 weeks; 80.5%, 64.8% and 56.9% at 25 weeks; and 86.6%, 77.1% and 74.4% at 26 weeks. Deaths were most marked in EPIPAGE-2 before 1 day at 22-23 and 24 weeks GA. At 25 weeks, survival varied before 28 days; differences at 26 weeks were minimal. Cox analyses were consistent with the Kaplan-Meier analyses. Variations in morbidities were not clearly associated with survival., Conclusion: Differences in survival and morbidity outcomes for extremely preterm births are evident despite adjustment for background characteristics. No clear relationship was identified between early mortality and later patterns of morbidity., (© 2021 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Objective: Adverse event (AE) monitoring is central to assessing therapeutic safety. The lack of a comprehensive framework to define and grade maternal and fetal AEs in pregnancy trials severely limits understanding risks in pregnant women. We created AE terminology to improve safety monitoring for developing pregnancy drugs, devices and interventions., Method: Existing severity grading for pregnant AEs and definitions/indicators of 'severe' and 'life-threatening' conditions relevant to maternal and fetal clinical trials were identified through a literature search. An international multidisciplinary group identified and filled gaps in definitions and severity grading using Medical Dictionary for Regulatory Activities (MedDRA) terms and severity grading criteria based on Common Terminology Criteria for Adverse Event (CTCAE) generic structure. The draft criteria underwent two rounds of a modified Delphi process with international fetal therapy, obstetric, neonatal, industry experts, patients and patient representatives., Results: Fetal AEs were defined as being diagnosable in utero with potential to harm the fetus, and were integrated into MedDRA. AE severity was graded independently for the pregnant woman and her fetus. Maternal (n = 12) and fetal (n = 19) AE definitions and severity grading criteria were developed and ratified by consensus., Conclusions: This Maternal and Fetal AE Terminology version 1.0 allows systematic consistent AE assessment in pregnancy trials to improve safety., (© 2021 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Objective: To explore the experiences of women who had used an Early Pregnancy Assessment Unit (EPAU) service in the UK and make recommendations for their improvement., Design: Qualitative interview study., Setting: Early Pregnancy Assessment Units in the UK., Sample: A maximum variation sample of women who had consented to be interviewed having attended one of 26 EPAUs involved in the VESPA study in 2018., Methods: In-depth telephone interviews with 38 women. A thematic framework analysis was conducted, with a focus on how experiences varied according to EPAU service configuration and clinical pathway., Main Outcome Measures: Women's experiences of EPAU services., Results: We found that EPAUs are highly valued, and women's experiences were generally positive. However, women reported a range of issues that negatively affected their experience. These included difficulties accessing the service, insensitive management of the investigation and treatment options of pregnancy loss, poor communication, insufficient information and a lack of support for their psychological health. These issues were not strongly associated with EPAU configuration or clinical pathway., Conclusions: Recommendations to improve women's experiences include the separation of EPAUs from general maternity services, and we make suggestions on how to remove barriers to access by reviewing opening hours, how to provide sensitive patient management, such as automatically cancelling appointments and scans following pregnancy loss, and how to improve communication, both with women and their partners as well as with other parts of the health service., Tweetable Abstract: Early Pregnancy Assessment Units are highly valued by women but aspects of their care experiences, particularly around sensitive management of pregnancy loss, could be improved., (© 2021 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)