Perinatal outcomes in women with sickle cell disease: a matched cohort study from London, UK.

There are limited data on contemporary outcomes for women with sickle cell disease (SCD) in pregnancy. We conducted a single-site matched cohort study, comparing 131 pregnancies to women with SCD between 2007 and 2017 to a comparison group of 1310 pregnancies unaffected by SCD. Restricting our analysis to singleton pregnancies that reached 24 weeks of gestation, we used conditional Poisson regression to estimate adjusted risk ratios (aRRs) for perinatal outcomes. Infants born to mothers with SCD were more likely to be small for gestational age [aRR 1·69, 95% confidence interval (CI) 1·13-2·48], preterm (aRR 2·62, 95% CI 1·82-3·78) and require Neonatal Unit (NNU) admission (aRR 3·59, 95% CI 2·18-5·90). Pregnant women with SCD were at higher risk of pre-eclampsia/eclampsia (aRR 3·53, 95% CI 2·00-6·24), more likely to receive induction of labour (aRR 2·50, 95% CI 1·82-1·76) and caesarean birth (aRR 1·44, 95% CI 1·18-1·76). In analysis stratified by genotype, the risk of adverse outcomes was highest in haemoglobin SS (HbSS) pregnancies (n = 80). There was no strong evidence that haemoglobin SC (HbSC) pregnancies (n = 46) were at higher risk of preterm birth, caesarean delivery, or NNU admission. Pre-eclampsia/eclampsia was more frequently observed in HbSC pregnancies. Despite improvements in the care of pregnant women with SCD, the increased risk of adverse perinatal outcomes remains.

Preterm birth after the introduction of COVID-19 mitigation measures in Norway, Sweden, and Denmark: a registry-based difference-in-differences study.

BACKGROUND: Although some studies have reported a decrease in preterm birth following the start of the COVID-19 pandemic, the findings are inconsistent. OBJECTIVE: This study aimed to compare the incidences of preterm birth before and after the introduction of COVID-19 mitigation measures in Scandinavian countries using robust population-based registry data. STUDY DESIGN: This was a registry-based difference-in-differences study using births from January 2014 through December 2020 in Norway, Sweden, and Denmark. The changes in the preterm birth (<37 weeks) rates before and after the introduction of COVID-19 mitigation measures (set to March 12, 2020) were compared with the changes in preterm birth before and after March 12 from 2014 to 2019. The differences per 1000 births were calculated for 2-, 4-, 8-, 12-, and 16-week intervals before and after March 12. The secondary analyses included medically indicated preterm birth, spontaneous preterm birth, and very preterm (<32 weeks) birth. RESULTS: A total of 1,519,521 births were included in this study. During the study period, 5.6% of the births were preterm in Norway and Sweden, and 5.7% were preterm in Denmark. There was a seasonal variation in the incidence of preterm birth, with the highest incidence during winter. In all the 3 countries, there was a slight overall decline in preterm births from 2014 to 2020. There was no consistent evidence of a change in the preterm birth rates following the introduction of COVID-19 mitigation measures, with difference-in-differences estimates ranging from 3.7 per 1000 births (95% confidence interval, -3.8 to 11.1) for the first 2 weeks after March 12, 2020, to -1.8 per 1000 births (95% confidence interval, -4.6 to 1.1) in the 16 weeks after March 12, 2020. Similarly, there was no evidence of an impact on medically indicated preterm birth, spontaneous preterm birth, or very preterm birth. CONCLUSION: Using high-quality national data on births in 3 Scandinavian countries, each of which implemented different approaches to address the pandemic, there was no evidence of a decline in preterm births following the introduction of COVID-19 mitigation measures.

Association of SARS-CoV-2 Vaccination During Pregnancy With Pregnancy Outcomes.

Importance: Data about the safety of vaccines against SARS-CoV-2 during pregnancy are limited. Objective: To examine the risk of adverse pregnancy outcomes after vaccination against SARS-CoV-2 during pregnancy. Design, Setting, and Participants: This registry-based retrospective cohort study included 157 521 singleton pregnancies ending after 22 gestational weeks from January 1, 2021, until January 12, 2022 (Sweden), or January 15, 2022 (Norway). The Pregnancy Register in Sweden and the Medical Birth Registry of Norway were linked to vaccination and other registries for identification of exposure and background characteristics. Exposures: Data on mRNA vaccines-BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)-and 1 viral vector vaccine-AZD1222 (AstraZeneca)-were collected from national vaccination registries. Main Outcomes and Measures: The risk of preterm birth and stillbirth was evaluated using Cox regression models, with gestational day as the time metric and vaccination as a time-dependent exposure variable. The risk of small for gestational age, low Apgar score, and neonatal care admission was evaluated using logistic regression. Random-effects meta-analysis was used to combine results between countries. Results: Among the 157 521 singleton births included in the study (103 409 in Sweden and 54 112 in Norway), the mean maternal age at the time of delivery was 31 years, and 28 506 (18%) were vaccinated against SARS-CoV-2 (12.9% with BNT162b2, 4.8% with mRNA-1273, and 0.3% with AZD1222) while pregnant. A total of 0.7%, 8.3%, and 9.1% of individuals delivering were vaccinated during the first, second, and third trimester, respectively. Vaccination against SARS-CoV-2 was not significantly associated with increased risk of preterm birth (6.2 vs 4.9 per 10 000 pregnancy days; adjusted hazard ratio [aHR], 0.98 [95% CI, 0.91 to 1.05]; I2 = 0%; P for heterogeneity = .60), stillbirth (2.1 vs 2.4 per 100 000 pregnancy days; aHR, 0.86 [95% CI, 0.63 to 1.17]), small for gestational age (7.8% vs 8.5%; difference, -0.6% [95% CI, -1.3% to 0.2%]; adjusted OR [aOR], 0.97 [95% CI, 0.90 to 1.04]), low Apgar score (1.5% vs 1.6%; difference, -0.05% [95% CI, -0.3% to 0.1%]; aOR, 0.97 [95% CI, 0.87 to 1.08]), or neonatal care admission (8.5% vs 8.5%; difference, 0.003% [95% CI, -0.9% to 0.9%]; aOR, 0.97 [95% CI, 0.86 to 1.10]). Conclusions and Relevance: In this population-based study conducted in Sweden and Norway, vaccination against SARS-CoV-2 during pregnancy, compared with no SARS-CoV-2 vaccination during pregnancy, was not significantly associated with an increased risk of adverse pregnancy outcomes. The majority of the vaccinations were with mRNA vaccines during the second and third trimesters of pregnancy, which should be considered in interpreting the findings.

Health care professionals' perspectives on screening and management of gestational diabetes mellitus in public hospitals of South India - a qualitative study.

BACKGROUND: Women developing Gestational Diabetes Mellitus (GDM) are subsequently at a higher risk of developing Type 2 Diabetes later in life. Screening and effective management of women with GDM are essential in preventing progression to type 2 diabetes mellitus. We aimed to explore the perspectives of healthcare providers regarding the barriers from the health system context that restrict the timely screening and effective management of GDM. METHODS: We conducted six in-depth interviews of health care providers- four with nurses and two with obstetricians in the public hospitals in India's major city (Bengaluru). The interviews were conducted in the preferred language of the participants (Kannada for nurses, English for the obstetricians) and audio-recorded. All Kannada interviews were transcribed and translated into English for analysis. The primary data were analyzed using the grounded theory approach by NVivo 12 plus. The findings are put into perspective using the socio-ecological model. RESULTS: Health care providers identified delayed visits to public hospitals and stress on household-level responsibilities as barriers at the individual level for GDM screening. Also, migration of pregnant women to their natal homes during first pregnancy is a cultural barrier in addition to health system barriers such as unmet nurse training needs, long waiting hours, uneven power dynamics, lack of follow-up, resource scarcity, and lack of supportive oversight. The barriers for GDM management included non-reporting women to follow - up visits, irregular self-monitoring of drug and blood sugar, trained staff shortage, ineffective tracking, and lack of standardized protocol. CONCLUSION: There is a pressing need to develop and improve existing GDM Screening and Management services to tackle the growing burden of GDM in public hospitals of India.

Cumulative outcome of pre-implantation genetic diagnosis for sickle cell disease: a 5-year review.

To review the cumulative outcome of pre-implantation genetic diagnosis (PGD) cycles performed for prevention of sickle cell disease (SCD). Couples referred for PGD for SCD between April 2012 and October 2017 were included. Ovarian stimulation was performed using a short gonadotrophin-releasing hormone (GnRH) antagonist protocol and follicle-stimulating hormone injections. The GnRH agonist was used to trigger oocyte maturation. Oocytes were fertilised using intracytoplasmic sperm injection. Trophectoderm biopsy was performed on day 5 or 6 followed by vitrification. Genetic testing was done using pre-implantation genetic haplotyping. A total of 60 couples started 70 fresh PGD cycles (mean 1·2 cycles/couple) and underwent a total of 74 frozen-embryo-transfer (FET) cycles (mean 1·3 FET/couple). The mean (SD) female age was 33 (4·4) years and the mean (SD) anti-müllerian hormone level was 22·9 (2·8) pmol/l. The cumulative live-birth rate was 54%/PGD cycle started and 63%/couple embarking on PGD. The rate of multiple births was 8%. The cumulative outcome of PGD treatment for prevention of SCD transmission is high and PGD treatment should be offered to all at-risk couples.

Pulmonary complications for women with sickle cell disease in pregnancy: systematic review and meta-analysis.

BACKGROUND: Sickle cell disease (SCD) is a multisystem disease characterised by vaso-occlusive crisis, chronic anaemia and a shorter lifespan. More patients with SCD are living till reproductive age and contemplating pregnancy. Pulmonary complications in pregnancy are significant causes of maternal morbidity and mortality but yet this has not been systematically quantified. A systematic review and meta-analysis were conducted to quantify the association between SCD and pulmonary complications in pregnancy. METHODS: MEDLINE, EMBASE, Web of Science, Cochrane and Maternity and Infant Care databases were searched for publications between January 1998 and April 2019. Observational studies involving at least 30 participants were included. Random-effects models were used for statistical meta-analysis. FINDINGS: Twenty-two studies were included in the systematic review and 18 in the quantitative analysis. The meta-analysis included 3964 pregnancies with SCD and 336 559 controls. Compared with women without SCD, pregnancies complicated by SCD were at increased risk of pulmonary thromboembolism (relative risk (RR) 7.74; 95% CI 4.65 to 12.89). The estimated prevalence of acute chest syndrome and pneumonia was 6.46% (95% CI 4.66% to 8.25%), with no significant difference between the HbSS and HbSC genotypes (RR 1.42; 95% CI 0.90 to 2.23). INTERPRETATION: This meta-analysis highlighted a strong association between SCD and maternal pulmonary complications. Understanding the risks of and the factors associated with pulmonary complications would aid preconceptual counselling and optimal management of the condition in pregnancy, thereby reducing associated maternal morbidity and mortality. PROSPERO REGISTRATION NUMBER: CRD42019124708.

Does first-trimester serum pregnancy-associated plasma protein A differ in pregnant women with sickle cell disease?

OBJECTIVE: To assess whether levels of first-trimester pregnancy-associated plasma protein A (PAPP-A) differ between women with and without sickle cell disease (SCD). METHODS: Retrospective study of 101 singleton pregnancies in women with SCD (including 55 with genotype HbSS, 37 with genotype HbSC, and nine with other genotypes). Measured levels of PAPP-A were converted to multiple of the median (MoM) values corrected for gestational age and maternal characteristics. Median PAPP-A MoM in the SCD group was compared with that of 1010 controls. RESULTS: In the SCD group median, PAPP-A MoM was lower than in the non-SCD group (0.72, interquartile range [IQR] = 0.54-1.14 versus 1.09, IQR = 0.74-1.49; P < .001). Within the SCD group median PAPP-A MoM was lower for those with genotype HbSS than HbSC (0.62, IQR = 0.44-1.14 versus 0.94, IQR = 0.72-1.25; .006). In 7.3% (4/55) of the HbSS group, there was stillbirth, and in these cases, PAPP-A was less than or equal to 0.5 MoM; in the control group, the incidence of stillbirth was lower (1%; P < .001). In HbSS disease, the incidence of small for gestational age (SGA) neonates was increased. CONCLUSION: Pregnancies with HbSS have lower PAPP-A MoM values and higher incidence of stillbirth and birth of SGA neonates than in non-SCD controls.

Early breastfeeding practices: Descriptive analysis of recent Demographic and Health Surveys.

The aim of this study was to describe early breastfeeding practices (initiation within 1 hr of birth, no prelacteal feeding, and a combination of both-"optimal" early breastfeeding) according to childbirth location in low- and middle-income countries. Using data from the most recent Demographic and Health Survey (2000-2013) for 57 countries, we extracted information on the most recent birth for women aged 15-49 with a live birth in the preceding 24 months. Childbirth setting was self-reported by location (home or facility) and subtype (home delivery with or without a skilled birth attendant; public or private facility). We produced overall world and four region-level summary statistics by applying national population adjusted survey weights. Overall, 39% of children were breastfed within 1 hr of birth (region range 31-60%), 49% received no prelacteal feeding (41-65%), and 28% benefited from optimal early breastfeeding (21-46%). In South/Southeast Asia and Sub-Saharan Africa, early breastfeeding outcomes were more favourable for facility births compared to home births; trends were less consistent in Latin America and Middle East/Europe. Among home deliveries, there was a higher prevalence of positive breastfeeding practices for births with a skilled birth attendant across all regions other than Latin America. For facility births, breastfeeding practices were more favourable among those taking place in the public sector. This study is the most comprehensive assessment to date of early breastfeeding practices by childbirth location. Our results suggest that skilled delivery care-particularly care delivered in public sector facilities-appears positively correlated with favourable breastfeeding practices.

Breastfeeding in England: time trends 2005-2006 to 2012-2013 and inequalities by area profile.

Breastfeeding rates in England have risen steadily since the 1970s, but rates remain low and little is known about area-based trends. We report an ecological analysis of time trends in area breastfeeding rates in England using annual data on breastfeeding initiation (2005-2006 to 2012-2013) and any breastfeeding at 6-8 weeks (2008-2009 to 2012-2013) for 151 primary care trusts (PCTs). Overall, breastfeeding initiation rose from 65.5% in 2005-2006 to 72.4% in 2012-2013 (average annual absolute increase 0.9%). There was a statistically significantly higher (interaction P < 0.001) annual increase in initiation in PCTs in the most deprived (1.2%) compared with the least deprived tertile (0.7%), and in PCTs with low baseline breastfeeding initiation (2005-2006; 1.4%) compared with high baseline initiation (0.6%). Similar trends were observed when PCTs were stratified by the proportion of teenage mothers and maternal smoking, but not when stratified by ethnicity. Although breastfeeding prevalence at 6-8 weeks also increased significantly over the observed time period (41.2% in 2008-2009, 43.7% in 2012-2013; annual increase 0.7%), there was no difference in the average increase by deprivation profile, ethnicity, teenage mothers and maternal smoking. However, PCTs with low baseline prevalence in 2008-2009 saw a significantly larger annual increase (0.8%) compared with PCTs with high baseline prevalence (0.07%). In conclusion, breastfeeding initiation and prevalence have seen higher increases in areas with low initial breastfeeding, and for initiation, more disadvantaged areas. Although these results suggest that inequalities in breastfeeding have narrowed, rates have plateaued since 2010-2011. Sustained efforts are needed to address breastfeeding inequalities.

Ethnic variation in stillbirth risk and the role of maternal obesity: analysis of routine data from a London maternity unit.

BACKGROUND: Approximately 5 in 1,000 deliveries in England and Wales result in stillbirth, with little improvement in figures over the last few decades. The aim of this study was to investigate the association between clinical and socio-demographic factors and stillbirth, with a particular focus on ethnicity and obesity. METHODS: Analysis of routine maternity data on 53,293 singleton births occurring in a large London teaching hospital between 2004 and 2012. Logistic regression was used to investigate risk factors for stillbirth and to explore potential effect modification. RESULTS: 53,293 deliveries occurred during the time period, of which 329 resulted in a stillbirth (6.2 per 1,000 births). Compared to White women, non-White ethnicity was associated with a doubling of the odds of stillbirth (aOR for Black women 2.15, 95% CI 1.56-2.97; aOR for South Asian women 2.33, 95% CI 1.42-3.83). Obese women had a trend towards higher odds of stillbirth compared to women of recommended BMI (aOR 1.38, 95% CI 0.98-1.96), though this was not significant (p 0.07). Both higher parity (≥2 compared to para 1) and hypertension were associated with a higher odds of stillbirth (parity ≥2 aOR 1.65, 95% CI 1.13-2.39; hypertension aOR 1.84, 95% CI 1.22-2.78) but there was no evidence that area deprivation or maternal age were independently associated with stillbirth in this population. There was some evidence of effect modification between ethnicity and obesity (p value for interaction 0.06), with obesity a particularly strong risk factor for stillbirth in South Asian women (aOR 4.64, 95% CI 1.84-11.70). CONCLUSIONS: There was a high prevalence of stillbirth in this multi-ethnic urban population. The increased risk of stillbirth observed in non-White women remains after adjusting for other factors. Our finding of possible effect modification between ethnicity and obesity suggests that further research should be conducted in order to improve understanding of the interplay between ethnicity, obesity and stillbirth.

The role of support and other factors in early breastfeeding cessation: an analysis of data from a maternity survey in England.

BACKGROUND: Although the majority of women in England initiate breastfeeding, approximately one third cease breastfeeding by six weeks and many of these women report they would like to have breastfed for longer. METHODS: Data from a survey of women ≥16 years who gave birth to singleton term infants in 2009 in England; questionnaires were completed approximately three months postnatally. Logistic regression was used to investigate the association between postnatal support and other factors, and breastfeeding cessation at 10 days and six weeks. Population attributable fractions (PAFs) were calculated to estimate the relative contribution of breastfeeding support factors to overall breastfeeding cessation at these two time points. RESULTS: Of the 3840 women who initiated breastfeeding and reported timing of breastfeeding cessation, 13% had stopped by 10 days; and of the 3354 women who were breastfeeding at 10 days, 17% had stopped by six weeks. Socio-demographic factors (maternal age, ethnicity, country of birth, deprivation, education) and antenatal feeding intention were all independently associated with breastfeeding cessation at 10 days and six weeks. Women who did not receive feeding advice or support from a parent or peer support group, voluntary organisation, or breastfeeding clinic were more likely to stop breastfeeding by 10 days. Perceived active support and encouragement from midwives was associated with a lower odds of breastfeeding cessation at both 10 days and six weeks. Estimated PAFs suggest that 34-59% of breastfeeding cessations by 10 days could be avoided if more women in the study population received breastfeeding support. CONCLUSION: Although multiple factors influence a mother's likelihood of continuing breastfeeding, it is clear that socio-demographic factors are strongly associated with breastfeeding continuation. However, there is evidence that breastfeeding support, including that delivered by peer or lay support workers, may have an important role in preventing cessations in the first few weeks.

Association between breastfeeding duration and educational attainment in rural Southwest Uganda: a population-based cohort study.

BACKGROUND: Breastfeeding is important for early childhood nutrition and health. The positive effects on educational outcomes may be attributed to socioeconomic factors. Socioeconomic status is not a strong predictor of breastfeeding in sub-Saharan African countries. Yet, few studies have investigated the association between breastfeeding and educational outcomes in these countries. OBJECTIVE: This study investigated the association between breastfeeding duration and children's educational attainment in rural Southwest Uganda. METHODS: We analysed longitudinal data on 3018 children who had information on breastfeeding and were followed for at least 5 years, with at least one primary school grade recorded by 2005. Data on breastfeeding duration were collected from mothers. The highest school grade was recorded repeatedly between ages 6 and 12 years. We calculated age-for-grade based on whether a child was on, over, or under the official age for a grade. Generalised estimating equations and binary logistic regression estimated the effect of breastfeeding duration on being 2 years, 3 or more years, or any years over-age for grade in primary school, adjusting for socioeconomic status and maternal-child characteristics. RESULTS: Most mothers breastfed for more than a year. Just over one-third breastfed for 18-23 months, and 30% breastfed for longer. By age eight, 42% of the children were two years over-age for their grade. Three or more years over-age for grade increased from 19% at age nine to 56% at age 12. Both adjusted and unadjusted estimates were consistent in showing reduced odds for children being 2 years, 3 or more years, or any years over-age for grade among children breastfed for 7-12, 13-17, 18-23, and > 23 months compared to those breastfed for 0-6 months. There was no evidence to support an overall association between breastfeeding duration and being over-age for grade. There was no evidence of association in the sex and age sub-group analyses. CONCLUSION: Although we found no association between breastfeeding duration and educational attainment, breastfeeding remains important for children's health and nutrition, and mothers should be encouraged and supported to breastfeed for the recommended duration.

Main findings: We found no clear evidence of an association between breastfeeding duration and educational attainment in rural Uganda.Added knowledge: The findings of this study contribute to a better understanding of the relationship between breastfeeding and educational outcomes in sub-Saharan African countries, where evidence on this topic is limited.Global health impact for policy and action: Our findings should not discourage breastfeeding, as it is essential for infant health and nutrition.

Trial to assess the tolerability of using felodipine to upregulate autophagy as a treatment of Huntington's disease (FELL-HD): a phase II, single-centre, open-label, dose-finding trial protocol.

INTRODUCTION: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that presents with a progressive movement disorder along with cognitive and psychiatric problems. It is caused by a Cytosine-adenin-guanine (CAG) expansion in exon 1 of the huntingtin gene which codes for mutant huntingtin (mHTT) that over time accumulates in cells, causing dysfunction and then death through new toxic gain-of-function mechanisms. Autophagy has been shown to be critical for the degradation of diverse intracytoplasmic aggregate-prone proteins that cause neurodegenerative disease, including mHTT. From a screen of a library enriched in approved drugs, felodipine was selected as the most suitable candidate showing strong autophagy-inducing effects in preclinical models of HD. We are, therefore, conducting a trial to assess the safety and tolerability of felodipine in people with early HD. METHODS AND ANALYSIS: FELL-HD is a phase II, single-centre, open-label, dose-finding trial in people with early HD. 18 participants with early clinical features of the disease will be treated with felodipine for 58 weeks, with a further 4-week follow-up. The primary outcome measure is the number of adverse events attributable to felodipine. Exploratory outcomes include additional measures of motor and cognitive function, non-motor symptoms and quality of life scales, as well as peripheral and central disease biomarkers assessed through brain MRI. Analysis of blood and cerebrospinal fluid will also be performed through an associated sample study, FELL HD-s. ETHICS AND DISSEMINATION: The study was approved by the London-Brent Research Ethics Committee (reference 22/LO/0387) and has been accepted by the Medicines and Healthcare products Regulatory Agency for clinical trials authorisation (reference CTA 12854/0256/001-0001). A lay summary of the results of the trial will be uploaded to our research group website which is publicly accessible. A webinar or in-person open day, to present results of the trial to participants and our wider cohort of patients who attend our centre, will be held once the trial is completed. The results of the trial will also be published in scientific journals and presented at national and international conferences. TRIAL REGISTRATION NUMBERS: EudraCT-2021-000897-27, ISRCTN56240656.

Prophylactic exchange transfusion in sickle cell disease pregnancy: a TAPS2 feasibility randomized controlled trial.

ABSTRACT: Serial prophylactic exchange blood transfusion (SPEBT) is increasingly used in sickle cell disease (SCD) pregnancy, despite a lack of robust evidence. The Transfusion Antenatally in Pregnant Women with Sickle Cell Disease (TAPS2) study assessed the feasibility and acceptability of conducting a definitive randomized controlled trial of SPEBT (intervention) vs standard care (control) in this population. Women aged ≥18 years with SCD, between 6+0 and 18+6 weeks of singleton gestation, were randomized 1:1 every 6 -10 weeks throughout pregnancy in 7 hospitals in England. The main outcomes were recruitment rate (primary outcome), acceptability, and retention. Secondary outcomes were safety and maternal/infant outcomes. In total, 194 women were screened over 42 months (extended because of the pandemic), 88 were eligible, and 35 (39.8%) consented to participate; 18 participants were randomized to intervention, and 17 to control. Follow-up data were collected on all participants. Twelve patients in the intervention group received at least 1 SPEBT, of these, 11 received ≥3. The remaining patient was withdrawn from SPEBT because of transfusion reaction. Sixteen control participants required at least 1 transfusion. There were no statistically significant differences in maternal, infant, and postnatal outcomes. A trend toward a lower incidence of vaso-occlusive crisis, preterm delivery, and improved birthweight was observed in the intervention. The study achieved satisfactory recruitment and retention, confirming its acceptability to participants. TAPS2 demonstrates that it is feasible to perform a definitive international trial of SPEBT in SCD pregnancy. These trials were registered at www.ClinicalTrials.gov as #NCT03975894 and International Standard Randomized Controlled Trial Number (www.isrctn.com; #ISRCTN52684446).

Serial prophylactic exchange blood transfusion in pregnant women with sickle cell disease (TAPS-2): statistical and qualitative analysis plan for a randomised controlled feasibility trial.

BACKGROUND: There are significant knowledge gaps regarding the effectiveness of serial prophylactic exchange blood transfusion (SPEBT) for pregnant women with sickle cell disease (SCD). The protocol for the randomised feasibility trial assessing SPEBT versus usual care in women with SCD (TAPS2 trial) has previously been published. This publication outlines the statistical and qualitative analysis plan for the study. METHODS AND DESIGN: TAPS2 is a randomised two-arm phase 2 feasibility trial with a nested qualitative study and health economic evaluation. Up to 50 pregnant women with SCD and a singleton pregnancy will be recruited and individually randomised to either SPEBT approximately every 6-10 weeks until delivery (intervention arm) or to usual care (control arm). Information will be collected on a range of feasibility and clinical outcomes. RESULTS: Due to the impact of COVID-19 on study recruitment, the initial study period of 24 months was extended to 48 months. Other protocol updates designed to mitigate the impact of COVID-19-related disruption included allowing for remote consent and conducting all qualitative interviews by telephone. The primary outcome for the trial is the overall recruitment rate. The number of women screened, eligible, consented, randomised and withdrawn will be summarised as a CONSORT flow diagram. Differences in clinical outcomes will additionally be presented as an initial assessment of efficacy and to inform sample size calculations for a future definitive trial. Qualitative interviews with trial participants and clinicians will be analysed using reflexive thematic analysis; data from interviews with participants who declined to participate in the trial will be extracted and incorporated into summary tables to report key findings. The health economic analysis plan is not covered by this update. CONCLUSION: The publication of this analysis plan is designed to aid transparency and to reduce the potential for reporting bias. TRIAL REGISTRATION: NIH registry ( www. CLINICALTRIALS: gov ), registration number NCT03975894 (registered 05/06/19); ISRCTN ( www.isrctn.com ), registration number ISRCTN52684446 (retrospectively registered 02/08/19).

Statistical analysis plan and protocol updates for Gestational diabetes in Uganda and India: Design and Evaluation of Educational Films for Improving Screening and Self-management (GUIDES) trial.

BACKGROUND: Timely detection and management of gestational diabetes mellitus (GDM) have been identified as a high priority for policymakers in low- and middle-income countries (LMICs). The GUIDES trial will evaluate a package of three interconnected film-based interventions aimed at improving the timely detection and management of GDM. The protocol for this trial has previously been published; this publication outlines the statistical analysis plan for the trial. METHODS AND DESIGN: The GUIDES study is a multi-country cluster-randomised controlled trial consisting of one trial conducted in Uganda and one in India (30 clusters in each country). Mixed effects models will be used to compare the primary study outcomes of the proportion of women who are tested for GDM between 24 and 32 weeks of pregnancy and the mean fasting blood sugar of women with GDM at 34-week follow-up while accounting for clustering. Secondary analyses will compare the proportion of women with self-reported GDM diagnosis at 32 weeks of pregnancy and the proportion of women with adverse perinatal outcomes related to GDM up to 4 weeks after birth in each trial arm. TRIAL STATUS AND DISCUSSION: Follow-up is expected to end in March 2023 in Uganda and in May 2023 in India. Analyses will be carried out following this statistical analysis plan in the month following trial completion. TRIAL REGISTRATION: ClinicalTrials.gov NCT03937050. Registered on 3 May 2019. Clinical Trials Registry India CTRI/2020/02/023605. Registered on 26 February 2020.

Effects of exclusive breastfeeding on educational attainment and longitudinal trajectories of grade progression among children in a 13-year follow-up study in Malawi.

The benefits of exclusive breastfeeding (EBF) for infant health and survival are well documented. However, its impact on educational outcomes has been contested and poorly researched in Africa. It has been hypothesised that positive associations reported in high-income countries can be attributed to residual confounding by socioeconomic status (SES). Our study investigated whether EBF duration in infancy is associated with educational attainment and age-for-grade attainment trajectories at school-age in rural Malawi. Longitudinal data on 1021 children at the Karonga demographic surveillance site in Malawi were analysed. Breastfeeding data were collected 3 months after birth and again at age one. The school grade of each child was recorded each year from age 6 until age 13. We calculated age-for-grade based on whether a child was at, over, or under the official expected age for a grade. Generalised estimating equations estimated the average effect of breastfeeding on age-for-grade. Latent class growth analysis identified age-for-grade trajectories, and multinomial logistic regression examined their associations with EBF. Maternal-child characteristics, SES, and HIV status were controlled. Overall, 35.9% of the children were exclusively breastfed for 6 months. Over-age for grade steadily increased from 9.6% at age 8 to 41.9% at age 13. There was some evidence that EBF for 6 months was associated with lower odds of being over-age for grade than EBF for less than 3 months (aOR = 0.82, 95%CI = 0.64-1.06). In subgroup analyses, children exclusively breastfed for 6 months in infancy were less likely to be over-age for grades between ages 6-9 (aOR = 0.64, 95%CI = 0.43-0.94). Latent class growth analysis also provided some evidence that EBF reduced the odds of falling behind in the early school grades (aOR = 0.66, 95%CI = 0.41-1.08) but not later. Our study adds to the growing evidence that EBF for 6 months has benefits beyond infant health and survival, supporting the WHO's recommendation on EBF.

Contraceptive use and pregnancy planning in Britain during the first year of the COVID-19 pandemic: findings from a large, quasi-representative survey (Natsal-COVID).

BACKGROUND: Contraceptive services were significantly disrupted during the COVID-19 pandemic in Britain. We investigated contraception-related health inequalities in the first year of the pandemic. METHODS: Natsal-COVID Wave 2 surveyed 6658 adults aged 18-59 years between March and April 2021, using quotas and weighting to achieve quasi-representativeness. Our analysis included sexually active participants aged 18-44 years, described as female at birth. We analysed contraception use, contraceptive switching due to the pandemic, contraceptive service access, and pregnancy plannedness. RESULTS: Of 1488 participants, 1619 were at risk of unplanned pregnancy, of whom 54.1% (51.0%-57.1%) reported routinely using effective contraception in the past year. Among all participants, 14.3% (12.5%-16.3%) reported switching or stopping contraception due to the pandemic. 3.2% (2.0%-5.1%) of those using effective methods pre-pandemic switched to less effective methods, while 3.8% (2.5%-5.9%) stopped. 29.3% (26.9%-31.8%) of at-risk participants reported seeking contraceptive services, of whom 16.4% (13.0%-20.4%) reported difficulty accessing services. Clinic closures and cancelled appointments were commonly reported pandemic-related reasons for difficulty accessing services. This unmet need was associated with younger age, diverse sexual identities and anxiety symptoms. Of 199 pregnancies, 6.6% (3.9%-11.1%) scored as 'unplanned'; less planning was associated with younger age, lower social grade and unemployment. CONCLUSIONS: Just under a third of participants sought contraceptive services during the pandemic and most were successful, indicating resilience and adaptability of service delivery. However, one in six reported an unmet need due to the pandemic. COVID-induced inequalities in service access potentially exacerbated existing reproductive health inequalities. These should be addressed in the post-pandemic period and beyond.