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Objective: To compare the severity of maternal infection and perinatal outcomes during periods in which wildtype, alpha variant, and delta variant of SARS-CoV-2 were dominant in the UK. Design Prospective: cohort study. Setting: 194 obstetric units across the UK, during the following periods: between 1 March and 30 November 2020 (wildtype dominance), between 1 December 2020 and 15 May 2021 (alpha variant dominance), and between 16 May and 31 October 2021 (delta variant dominance). Participants: 4436 pregnant women admitted to hospital with covid-19 related symptoms. Main outcome measures: Moderate to severe maternal SARS-CoV-2 infection (indicated by any of the following: oxygen saturation Results: 1387, 1613, and 1436 pregnant women were admitted to hospital with covid-19 related symptoms during the wildtype, alpha, and delta dominance periods, respectively; of these women, 340, 585, and 614 had moderate to severe infection, respectively. The proportion of pregnant women admitted with moderate to severe infection increased during the subsequent alpha and delta dominance periods, compared with the wildtype dominance period (wildtype 24.5% v alpha 36.2% (adjusted odds ratio 1.98, 95% confidence interval 1.66% to 2.37%); wildtype 24.5% v delta 42.8% (2.66, 2.21 to 3.20)). Compared with the wildtype dominance period, women admitted during the alpha dominance period were significantly more likely to have pneumonia, require respiratory support, and be admitted to intensive care; these three risks were even greater during the delta dominance period (wildtype v delta: pneumonia, adjusted odds ratio 2.52, 95% confidence interval 2.06 to 3.09; respiratory support, 1.90, 1.52 to 2.37; and intensive care, 2.71, 2.06 to 3.56). Of 1761 women whose vaccination status was known, 38 (2.2%) had one dose and 16 (1%) had two doses before their diagnosis (of whom 14 (88%) had mild infection). The proportion of women receiving drug treatment for SARS-CoV-2 management was low, but did increase between the wildtype dominance period and the alpha and delta dominance periods (10.4% wildtype v 14.9% alpha (2.74, 2.08 to 3.60); 10.4% wildtype v 13.6% delta (2.54, 1.90 to 3.38)). Conclusions: While limited by the absence of variant sequencing data, these findings suggest that during the periods when the alpha and delta variants of SARS-CoV-2 were dominant, covid-19 was associated with more severe maternal infection and worse pregnancy outcomes than during the wildtype dominance period. Most women admitted with SARS-CoV-2 related symptoms were unvaccinated. Urgent action to prioritise vaccine uptake in pregnancy is essential.

STUDY QUESTION: Does a policy of elective freezing of embryos, followed by frozen embryo transfer result in a higher healthy baby rate, after first embryo transfer, when compared with the current policy of transferring fresh embryos? SUMMARY ANSWER: This study, although limited by sample size, provides no evidence to support the adoption of a routine policy of elective freeze in preference to fresh embryo transfer in order to improve IVF effectiveness in obtaining a healthy baby. WHAT IS KNOWN ALREADY: The policy of freezing all embryos followed by frozen embryo transfer is associated with a higher live birth rate for high responders but a similar/lower live birth after first embryo transfer and cumulative live birth rate for normal responders. Frozen embryo transfer is associated with a lower risk of ovarian hyperstimulation syndrome (OHSS), preterm delivery and low birthweight babies but a higher risk of large babies and pre-eclampsia. There is also uncertainty about long-term outcomes, hence shifting to a policy of elective freezing for all remains controversial given the delay in treatment and extra costs involved in freezing all embryos. STUDY DESIGN, SIZE, DURATION: A pragmatic two-arm parallel randomized controlled trial (E-Freeze) was conducted across 18 clinics in the UK from 2016 to 2019. A total of 619 couples were randomized (309 to elective freeze/310 to fresh). The primary outcome was a healthy baby after first embryo transfer (term, singleton live birth with appropriate weight for gestation); secondary outcomes included OHSS, live birth, clinical pregnancy, pregnancy complications and cost-effectiveness. PARTICIPANTS/MATERIALS, SETTING, METHODS: Couples undergoing their first, second or third cycle of IVF/ICSI treatment, with at least three good quality embryos on Day 3 where the female partner was ≥18 and MAIN RESULTS AND THE ROLE OF CHANCE: Of the 619 couples randomized, 307 and 309 couples in the elective freeze and fresh transfer arms, respectively, were included in the primary analysis. There was no evidence of a statistically significant difference in outcomes in the elective freeze group compared to the fresh embryo transfer group: healthy baby rate {20.3% (62/307) versus 24.4% (75/309); risk ratio (RR), 95% CI: 0.84, 0.62 to 1.15}; OHSS (3.6% versus 8.1%; RR, 99% CI: 0.44, 0.15 to 1.30); live birth rate (28.3% versus 34.3%; RR, 99% CI 0.83, 0.65 to 1.06); and miscarriage (14.3% versus 12.9%; RR, 99% CI: 1.09, 0.72 to 1.66). Adherence to allocation was poor in the elective freeze group. The elective freeze approach was more costly and was unlikely to be cost-effective in a UK National Health Service context. LIMITATIONS, REASONS FOR CAUTION: We have only reported on first embryo transfer after randomization; data on the cumulative live birth rate requires further follow-up. Planned target sample size was not obtained and the non-adherence to allocation rate was high among couples in the elective freeze arm owing to patient preference for fresh embryo transfer, but an analysis which took non-adherence into account showed similar results. WIDER IMPLICATIONS OF THE FINDINGS: Results from the E-Freeze trial do not lend support to the policy of electively freezing all for everyone, taking both efficacy, safety and costs considerations into account. This method should only be adopted if there is a definite clinical indication. STUDY FUNDING/COMPETING INTEREST(S): NIHR Health Technology Assessment programme (13/115/82). This research was funded by the National Institute for Health Research (NIHR) (NIHR unique award identifier) using UK aid from the UK Government to support global health research. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR or the UK Department of Health and Social Care. J.L.B., C.C., E.J., P.H., J.J.K., L.L. and G.S. report receipt of funding from NIHR, during the conduct of the study. J.L.B., E.J., P.H., K.S. and L.L. report receipt of funding from NIHR, during the conduct of the study and outside the submitted work. A.M. reports grants from NIHR personal fees from Merck Serono, personal fees for lectures from Merck Serono, Ferring and Cooks outside the submitted work; travel/meeting support from Ferring and Pharmasure and participation in a Ferring advisory board. S.B. reports receipt of royalties and licenses from Cambridge University Press, a board membership role for NHS Grampian and other financial or non-financial interests related to his roles as Editor-in-Chief of Human Reproduction Open and Editor and Contributing Author of Reproductive Medicine for the MRCOG, Cambridge University Press. D.B. reports grants from NIHR, during the conduct of the study; grants from European Commission, grants from Diabetes UK, grants from NIHR, grants from ESHRE, grants from MRC, outside the submitted work. Y.C. reports speaker fees from Merck Serono, and advisory board role for Merck Serono and shares in Complete Fertility. P.H. reports membership of the HTA Commissioning Committee. E.J. reports membership of the NHS England and NIHR Partnership Programme, membership of five Data Monitoring Committees (Chair of two), membership of six Trial Steering Committees (Chair of four), membership of the Northern Ireland Clinical Trials Unit Advisory Group and Chair of the board of Oxford Brain Health Clinical Trials Unit. R.M. reports consulting fees from Gedeon Richter, honorarium from Merck, support fees for attendance at educational events and conferences for Merck, Ferring, Bessins and Gedeon Richter, payments for participation on a Merck Safety or Advisory Board, Chair of the British Fertility Society and payments for an advisory role to the Human Fertilisation and Embryology Authority. G.S. reports travel and accommodation fees for attendance at a health economic advisory board from Merck KGaA, Darmstadt, Germany. N.R.-F. reports shares in Nurture Fertility. Other authors’ competing interests: none declared. TRIAL REGISTRATION NUMBER: ISRCTN: 61225414. TRIAL REGISTRATION DATE: 29 December 2015. DATE OF FIRST PATIENT’S ENROLMENT: 16 February 2016.

Aim:To describe the birth prevalence, temporal trends, and clinical outcomes of twins, triplets, or quadruplets with cerebral palsy (CP).Method:This was a cross-sectional study using data for twins, triplets, and quadruplets with prenatally or perinatally acquired CP and pooled from the Surveillance of Cerebral Palsy in Europe network (born 1992–2009) and Australian Cerebral Palsy Register (born 1993–2009). Children were at least 4 years old at time of registration. Children born in regions with population ascertainment and available denominator data were included in prevalence calculations (n=1033 twins, 81 triplets, and 11 quadruplets). Clinical data from children registered in all participating registers were described, including 2163 twins (56% male), 187 triplets (59% male), and 20 quadruplets (45% male).Results:The birth prevalence of CP was higher with increasing plurality (twins 6.5 per 1000 live births [95% confidence interval {CI} 6.1–6.9], triplets 17.1 [95% CI 13.6–21.2], quadruplets 50.7 [95% CI 25.6–88.9]); however, prevalence by gestational age was similar across all pluralities. Between 1992–1994 and 2007–2009, prevalence of CP among twins declined (p=0.001) but prevalence of CP among triplets did not change significantly over time (p=0.55). The distributions of Gross Motor Function Classification System, epilepsy, and impairments of intellect, vision, and hearing were similar regardless of plurality.Interpretation:The data combined from two CP register networks indicated that triplets and quadruplets had increased risk of CP compared to twins. The higher prevalence of CP in triplets and quadruplets is due to their higher risk of preterm birth. Prevalence of CP among twins significantly declined in Europe and Australia. Clinical outcomes were similar for all multiple births.

OBJECTIVES:Following a perinatal death, a standardised multidisciplinary review should take place. Learning from these deaths and engaging parents in this process could help prevent future perinatal deaths in line with United Kingdom (UK) national and international targets to reduce the number of such deaths by 2020. Moreover, it would support parents in understanding events around the death of their baby. An earlier study (Parents' Active Role and ENgagement in The review of their Stillbirth/perinatal death - PARENTS 1 study) found that parents would endorse the opportunity to give feedback into the perinatal mortality review process (PNMR). In subsequent focus groups, healthcare professionals were positive about parental engagement, although they considered there may be significant challenges. The objective of this study was to develop core principles and recommendations for parental engagement in PNMR in the UK.METHODS:We followed a two-round Delphi technique to reach a consensus on core principles; including a national consensus workshop and an online questionnaire. The consensus meeting was attended by a national panel of stakeholders (clinical and academic experts, parent support groups, managers and commissioners) in stillbirth, neonatal and bereavement care (n=22). To develop recommendations for parental engagement, participants discussed four key areas including: receiving feedback from parents; format of the PNMR meeting; the parental pathway; and challenging aspects of engaging with parents in reviews. Content analysis was conducted to generate recommendations from the meeting for a subsequent, anonymous web-based survey. Attendees of the consensus workshop and members of the PARENTS 2 Project Advisory Board were asked to rank recommendations using a 9-point Likert scale from 1 (not important) to 9 (critical). It had been agreed a priori, in compliance with established Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria, that 'Consensus' would be achieved if over 70% scored the principle as 'critical' (score 7 to 9) and less than 15% scored the principle as 'not important' (score 1 to 3). Principles where Consensus was achieved would be included in the core recommendations.RESULTS:Twenty-five of the 29 invited stakeholders participated in the consensus meeting and the subsequent online questionnaire in June 2017 (86.2% response rate). Consensus was agreed on 12 core principles. Ninety-six percent agreed that it was of critical importance that there should be a face-to-face explanation of the PNMR process; 72% considered parents should be offered the opportunity to nominate a suitable advocate; 92% believed responses to parents' comments should be formally documented; 96% indicated that it was vital for action plans to be translated into lessons learnt and that this process is monitored; and 100% of stakeholders voted that a plain English summary should be produced for the parents following the meeting. There was good agreement on a further seven principles.CONCLUSIONS:Key national stakeholders were unanimously supportive of parental engagement and agreed on core principles to make it feasible, meaningful and robust process. A six-month pilot of parental engagement in the perinatal mortality review process (PARENTS 2 Study) in two UK units took place after the consensus on core principles. In collaboration with the National Perinatal Epidemiology Unit, findings will inform the national standardised perinatal mortality review tool (PMRT).

Background Public health organisations use public health indicators to guide health policy. Joint analysis of multiple public health indicators can provide a more comprehensive understanding of what they are intended to evaluate. Objective To analyse variaitons in the prevalence of congenital anomaly‐related perinatal mortality attributable to termination of pregnancy for foetal anomaly (TOPFA) and prenatal diagnosis of congenital anomaly prevalence. Methods We included 55 363 cases of congenital anomalies notified to 18 EUROCAT registers in 10 countries during 2008‐12. Incidence rate ratios (IRR) representing the risk of congenital anomaly‐related perinatal mortality according to TOPFA and prenatal diagnosis prevalence were estimated using multilevel Poisson regression with country as a random effect. Between‐country variation in congenital anomaly‐related perinatal mortality was measured using random effects and compared between the null and adjusted models to estimate the percentage of variation in congenital anomaly‐related perinatal mortality accounted for by TOPFA and prenatal diagnosis. Results The risk of congenital anomaly‐related perinatal mortality decreased as TOPFA and prenatal diagnosis prevalence increased (IRR 0.79, 95% confidence interval [CI] 0.72, 0.86; and IRR 0.88, 95% CI 0.79, 0.97). Modelling TOPFA and prenatal diagnosis together, the association between congenital anomaly‐related perinatal mortality and TOPFA prevalence became stronger (RR 0.70, 95% CI 0.61, 0.81). The prevalence of TOPFA and prenatal diagnosis accounted for 75.5% and 37.7% of the between‐country variation in perinatal mortality, respectively. Conclusion We demonstrated an approach for analysing inter‐linked public health indicators. In this example, as TOPFA and prenatal diagnosis of congenital anomaly prevalence decreased, the risk of congenital anomaly‐related perinatal mortality increased. Much of the between‐country variation in congenital anomaly‐related perinatal mortality was accounted for by TOPFA, with a smaller proportion accounted for by prenatal diagnosis.

Background: Disparities have been documented in maternal mortality rates between women from different ethnic, age and socio-economic groups in the UK. It is unclear whether there are differential changes in these rates amongst women from different groups over time. The objectives of this analysis were to describe UK maternal mortality rates in different age, ethnic and socio-economic groups between 2009 and 2017, and to identify whether there were changes in the observed inequalities, or different trends amongst population subgroups. Methods: Maternal mortality rates with 95% confidence intervals (CI) in specific age, deprivation and ethnic groups were calculated using numbers of maternal deaths as numerator and total maternities as denominator. Relative risks (RR) with 95% CI were calculated and compared using ratios of relative risk. Change over time was investigated using non-parametric tests for trend across ordered groups. Results: Women from black and Asian groups had a higher mortality rate than white women in most time periods, as did women aged 35 and over and women from the most deprived quintile areas of residence. There was evidence of an increasing trend in maternal mortality amongst black women and a decrease in mortality amongst women from the least deprived areas, but no trends over time in any of the other ethnic, age or IMD groups were seen. There was a widening of the disparity between black and white women (RR 2.59 in 2009-11 compared with 5.27 in 2015-17, ratio of the relative risks 2.03, 95% CI 1.11, 3.72). Conclusions: The clear differences in the patterns of maternal mortality amongst different ethnic, age and socio-economic groups emphasise the importance of research and policies focussed specifically on women from black and minority ethnic groups, together with other disadvantaged groups, to begin to reduce maternal mortality in the UK.

© 2019 McCall et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Objective: To examine the association between maternal BMI>50kg/m 2 during pregnancy and maternal and perinatal outcomes. Materials and methods: An international cohort study was conducted using data from separate national studies in the UK and Australia. Outcomes of pregnant women with BMI>50 were compared to those of pregnant women with BMI50 and perinatal and maternal outcomes. Results: 932 pregnant women with BMI>50 were compared with 1232 pregnant women with BMI50 were slightly older, more likely to be multiparous, and have pre-existing comorbidities. There were no maternal deaths, however, extremely obese women had a nine-fold increase in the odds of thrombotic events compared to those with a BMI50 during pregnancy had significantly raised odds of preeclampsia/eclampsia (aOR:4.88(95%CI: 3.11-7.65)), caesarean delivery (aOR: 2.77 (95%CI: 2.31-3.32)), induction of labour (aOR: 2.45 (95% CI:2.00-2.99)) post caesarean wound infection (aOR:7.25(95%CI: 3.28-16.07)), macrosomia (aOR: 8.05(95%CI: 4.70-13.78)) compared a BMI50 have a high risk of inferior maternal and perinatal outcomes.

Background Neonatal encephalopathy (NE) is a leading cause of global child mortality. Survivor outcomes in low-resource settings are poorly described. We present early childhood outcomes after NE in Uganda. Methods We conducted a prospective cohort study of term-born infants with NE (n = 210) and a comparison group of term non-encephalopathic (non-NE) infants (n = 409), assessing neurodevelopmental impairment (NDI) and growth at 27–30 months. Relationships between early clinical parameters and later outcomes were summarised using risk ratios (RR). Findings Mortality by 27–30 months was 40·3% after NE and 3·8% in non-NE infants. Impairment-free survival occurred in 41·6% after NE and 98·7% of non-NE infants. Amongst NE survivors, 29·3% had NDI including 19·0% with cerebral palsy (CP), commonly bilateral spastic CP (64%); 10·3% had global developmental delay (GDD) without CP. CP was frequently associated with childhood seizures, vision and hearing loss and mortality. NDI was commonly associated with undernutrition (44·1% Z-score, Highlights • This is, to our knowledge, the largest published cohort describing childhood outcomes after neonatal encephalopathy (NE) in sub-Saharan Africa • Children with NE are at high-risk of multidomain neurodevelopmental impairment in a setting where access to supportive services are often lacking. • Mortality is highest in the early neonatal period and in those with severe neurodevelopmental impairment • Simple early clinical predictors may support a targeted approach to follow-up of particularly high-risk children Outstanding Questions • What is the contribution of NE to cerebral palsy and other developmental disorders in low resource African settings? • What strategies are effective to improve childhood outcomes in NE in way of prevention and intervention? • What are the school-age outcomes after NE and later impacts across the life course?