Diagnosis and management of selective fetal growth restriction in monochorionic twin pregnancies: A cross-sectional international survey.

OBJECTIVE: To identify current practices in the management of selective fetal growth restriction (sFGR) in monochorionic diamniotic (MCDA) twin pregnancies. DESIGN: Cross-sectional survey. SETTING: International. POPULATION: Clinicians involved in the management of MCDA twin pregnancies with sFGR. METHODS: A structured, self-administered survey. MAIN OUTCOME MEASURES: Clinical practices and attitudes to diagnostic criteria and management strategies. RESULTS: Overall, 62.8% (113/180) of clinicians completed the survey; of which, 66.4% (75/113) of the respondents reported that they would use an estimated fetal weight (EFW) of <10th centile for the smaller twin and an inter-twin EFW discordance of >25% for the diagnosis of sFGR. For early-onset type I sFGR, 79.8% (75/94) of respondents expressed that expectant management would be their routine practice. On the other hand, for early-onset type II and type III sFGR, 19.3% (17/88) and 35.7% (30/84) of respondents would manage these pregnancies expectantly, whereas 71.6% (63/88) and 57.1% (48/84) would refer these pregnancies to a fetal intervention centre or would offer fetal intervention for type II and type III cases, respectively. Moreover, 39.0% (16/41) of the respondents would consider fetoscopic laser surgery (FLS) for early-onset type I sFGR, whereas 41.5% (17/41) would offer either FLS or selective feticide, and 12.2% (5/41) would exclusively offer selective feticide. For early-onset type II and type III sFGR cases, 25.9% (21/81) and 31.4% (22/70) would exclusively offer FLS, respectively, whereas 33.3% (27/81) and 32.9% (23/70) would exclusively offer selective feticide. CONCLUSIONS: There is significant variation in clinician practices and attitudes towards the management of early-onset sFGR in MCDA twin pregnancies, especially for type II and type III cases, highlighting the need for high-level evidence to guide management.

Evidence-based surgical procedures to optimize caesarean outcomes: an overview of systematic reviews.

Background: Caesarean section (CS) is the most performed major surgery worldwide. Surgical techniques used for CS vary widely and there is no internationally accepted standardization. We conducted an overview of systematic reviews (SR) of randomized controlled trials (RCT) to summarize the evidence on surgical techniques or procedures related to CS. Methods: Searches were conducted from database inception to 31 January 2024 in Cochrane Database of Systematic Reviews, PubMed, EMBASE, Lilacs and CINAHL without date or language restrictions. AMSTAR 2 and GRADE were used to assess the methodological quality of the SRs and the certainty of evidence at outcome level, respectively. We classified each procedure-outcome pair into one of eight categories according to effect estimates and certainty of evidence. The overview was registered at PROSPERO (CRD 42023208306). Findings: The analysis included 38 SRs (16 Cochrane and 22 non-Cochrane) published between 2004-2024 involving 628 RCT with a total of 190,349 participants. Most reviews were of low or critically low quality (AMSTAR 2). The SRs presented 345 procedure-outcome comparisons (237 procedure versus procedure, 108 procedure versus no treatment/placebo). There was insufficient or inconclusive evidence for 256 comparisons, clear evidence of benefit for 40, possible benefit for 17, no difference of effect for 13, clear evidence of harm for 14, and possible harm for 5. We found no SRs for 7 pre-defined procedures. Skin cleansing with chlorhexidine, Joel-Cohen-based abdominal incision, uterine incision with blunt dissection and cephalad-caudal expansion, cord traction for placental extraction, manual cervical dilatation in pre-labour CS, changing gloves, chromic catgut suture for uterine closure, non-closure of the peritoneum, closure of subcutaneous tissue, and negative pressure wound therapy are procedures associated with benefits for relevant outcomes. Interpretation: Current evidence suggests that several CS surgical procedures improve outcomes but also reveals a lack of or inconclusive evidence for many commonly used procedures. There is an urgent need for evidence-based guidelines standardizing techniques for CS, and trials to fill existing knowledge gaps. Funding: UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), a cosponsored programme executed by the World Health Organization (WHO).

Association between pregnancy-related complications and development of type 2 diabetes and hypertension in women: an umbrella review.

BACKGROUND: Despite many systematic reviews and meta-analyses examining the associations of pregnancy complications with risk of type 2 diabetes mellitus (T2DM) and hypertension, previous umbrella reviews have only examined a single pregnancy complication. Here we have synthesised evidence from systematic reviews and meta-analyses on the associations of a wide range of pregnancy-related complications with risk of developing T2DM and hypertension. METHODS: Medline, Embase and Cochrane Database of Systematic Reviews were searched from inception until 26 September 2022 for systematic reviews and meta-analysis examining the association between pregnancy complications and risk of T2DM and hypertension. Screening of articles, data extraction and quality appraisal (AMSTAR2) were conducted independently by two reviewers using Covidence software. Data were extracted for studies that examined the risk of T2DM and hypertension in pregnant women with the pregnancy complication compared to pregnant women without the pregnancy complication. Summary estimates of each review were presented using tables, forest plots and narrative synthesis and reported following Preferred Reporting Items for Overviews of Reviews (PRIOR) guidelines. RESULTS: Ten systematic reviews were included. Two pregnancy complications were identified. Gestational diabetes mellitus (GDM): One review showed GDM was associated with a 10-fold higher risk of T2DM at least 1 year after pregnancy (relative risk (RR) 9.51 (95% confidence interval (CI) 7.14 to 12.67) and although the association differed by ethnicity (white: RR 16.28 (95% CI 15.01 to 17.66), non-white: RR 10.38 (95% CI 4.61 to 23.39), mixed: RR 8.31 (95% CI 5.44 to 12.69)), the between subgroups difference were not statistically significant at 5% significance level. Another review showed GDM was associated with higher mean blood pressure at least 3 months postpartum (mean difference in systolic blood pressure: 2.57 (95% CI 1.74 to 3.40) mmHg and mean difference in diastolic blood pressure: 1.89 (95% CI 1.32 to 2.46) mmHg). Hypertensive disorders of pregnancy (HDP): Three reviews showed women with a history of HDP were 3 to 6 times more likely to develop hypertension at least 6 weeks after pregnancy compared to women without HDP (meta-analysis with largest number of studies: odds ratio (OR) 4.33 (3.51 to 5.33)) and one review reported a higher rate of T2DM after HDP (hazard ratio (HR) 2.24 (1.95 to 2.58)) at least a year after pregnancy. One of the three reviews and five other reviews reported women with a history of preeclampsia were 3 to 7 times more likely to develop hypertension at least 6 weeks postpartum (meta-analysis with the largest number of studies: OR 3.90 (3.16 to 4.82) with one of these reviews reporting the association was greatest in women from Asia (Asia: OR 7.54 (95% CI 2.49 to 22.81), Europe: OR 2.19 (95% CI 0.30 to 16.02), North and South America: OR 3.32 (95% CI 1.26 to 8.74)). CONCLUSIONS: GDM and HDP are associated with a greater risk of developing T2DM and hypertension. Common confounders adjusted for across the included studies in the reviews were maternal age, body mass index (BMI), socioeconomic status, smoking status, pre-pregnancy and current BMI, parity, family history of T2DM or cardiovascular disease, ethnicity, and time of delivery. Further research is needed to evaluate the value of embedding these pregnancy complications as part of assessment for future risk of T2DM and chronic hypertension.

Polypharmacy during pregnancy and associated risk factors: a retrospective analysis of 577 medication exposures among 1.5 million pregnancies in the UK, 2000-2019.

BACKGROUND: The number of medications prescribed during pregnancy has increased over the past few decades. Few studies have described the prevalence of multiple medication use among pregnant women. This study aims to describe the overall prevalence over the last two decades among all pregnant women and those with multimorbidity and to identify risk factors for polypharmacy in pregnancy. METHODS: A retrospective cohort study was conducted between 2000 and 2019 using the Clinical Practice Research Datalink (CPRD) pregnancy register. Prescription records for 577 medication categories were obtained. Prevalence estimates for polypharmacy (ranging from 2+ to 11+ medications) were presented along with the medications commonly prescribed individually and in pairs during the first trimester and the entire pregnancy period. Logistic regression models were performed to identify risk factors for polypharmacy. RESULTS: During the first trimester (812,354 pregnancies), the prevalence of polypharmacy ranged from 24.6% (2+ medications) to 0.1% (11+ medications). During the entire pregnancy period (774,247 pregnancies), the prevalence ranged from 58.7 to 1.4%. Broad-spectrum penicillin (6.6%), compound analgesics (4.5%) and treatment of candidiasis (4.3%) were commonly prescribed. Pairs of medication prescribed to manage different long-term conditions commonly included selective beta 2 agonists or selective serotonin re-uptake inhibitors (SSRIs). Risk factors for being prescribed 2+ medications during the first trimester of pregnancy include being overweight or obese [aOR: 1.16 (1.14-1.18) and 1.55 (1.53-1.57)], belonging to an ethnic minority group [aOR: 2.40 (2.33-2.47), 1.71 (1.65-1.76), 1.41 (1.35-1.47) and 1.39 (1.30-1.49) among women from South Asian, Black, other and mixed ethnicities compared to white women] and smoking or previously smoking [aOR: 1.19 (1.18-1.20) and 1.05 (1.03-1.06)]. Higher and lower age, higher gravidity, increasing number of comorbidities and increasing level of deprivation were also associated with increased odds of polypharmacy. CONCLUSIONS: The prevalence of polypharmacy during pregnancy has increased over the past two decades and is particularly high in younger and older women; women with high BMI, smokers and ex-smokers; and women with multimorbidity, higher gravidity and higher levels of deprivation. Well-conducted pharmaco-epidemiological research is needed to understand the effects of multiple medication use on the developing foetus.

Association of pregnancy complications/risk factors with the development of future long-term health conditions in women: overarching protocol for umbrella reviews.

INTRODUCTION: With good medical care, most pregnancy complications like pre-eclampsia, gestational diabetes, etc resolve after childbirth. However, pregnancy complications are known to be associated with an increased risk of new long-term health conditions for women later in life, such as cardiovascular disease. These umbrella reviews aim to summarise systematic reviews evaluating the association between pregnancy complications and five groups of long-term health conditions: autoimmune conditions, cancers, functional disorders, mental health conditions and metabolic health conditions (diabetes and hypertension). METHODS AND ANALYSIS: We will conduct searches in Medline, Embase and the Cochrane database of systematic reviews without any language restrictions. We will include systematic reviews with or without meta-analyses that studied the association between pregnancy complications and the future risk of the five groups of long-term health conditions in women. Pregnancy complications were identified from existing core outcome sets for pregnancy and after consultation with experts. Two reviewers will independently screen the articles. Data will be synthesised with both narrative and quantitative methods. Where a meta-analysis has been carried out, we will report the combined effect size from individual studies. For binary data, pooled ORs with 95% CIs will be presented. For continuous data, we will use the mean difference with 95% CIs. The findings will be presented in forest plots to assess heterogeneity. The methodological quality of the studies will be evaluated with the AMSTAR 2 tool or the Cochrane risk of bias tool. The corrected covered area method will be used to assess the impact of overlap in reviews. The findings will be used to inform the design of prediction models, which will predict the risk of women developing these five group of health conditions following a pregnancy complication. ETHICS AND DISSEMINATION: No ethical approvals required. Findings will be disseminated through publications in peer-reviewed journals and conference presentations.

Polycystic ovary syndrome and risk of adverse obstetric outcomes: a retrospective population-based matched cohort study in England.

BACKGROUND: Polycystic ovary syndrome (PCOS) affects up to one in five women of childbearing age. Observational studies assessing the association between maternal PCOS and adverse obstetric outcomes have reported varying results, depending on patient population, diagnostic criteria for PCOS and covariates accounted for in their analyses. We aimed to assess the risk of obstetric outcomes among a population-based representative cohort of women with PCOS compared to an age-matched cohort of women without PCOS. METHODS: A retrospective cohort study was conducted of pregnancies of women in England aged 15-49 years identified from the Clinical Practice Research Datalink (CPRD) GOLD pregnancy register and linked Hospital Episodes Statistic (HES) data between March 1997 and March 2020. Pregnancies from the register that had a linked HES delivery record were included. Linked CPRD primary care data was used to ascertain maternal PCOS exposure prior to pregnancy. To improve detection of PCOS, in addition to PCOS diagnostic codes, codes for (1) polycystic ovaries or (2) hyperandrogenism and anovulation together were also considered. Sensitivity analysis was limited to only pregnant women with a diagnostic code for PCOS. Primary outcomes ascertained from linked HES data were (1) preterm delivery (gestation < 37 weeks), (2) mode of delivery, (3) high (> 4000 g) or low birthweight (< 2500 g) and (4) stillbirth. Secondary outcomes were (1) very preterm delivery (< 32 weeks), (2) extremely preterm delivery (< 28 weeks), (3) small and (4) large for gestational age. Conditional logistic regression models were performed adjusting for age, ethnicity, deprivation, dysglycaemia, hypertension, thyroid disorders, number of babies born at index pregnancy, and pre-gravid BMI. Multiple imputation was performed for missing outcome data. RESULTS: 27,586 deliveries with maternal PCOS were matched for age (± 1 year) to 110,344 deliveries without PCOS. In the fully adjusted models, maternal PCOS was associated with an increased risk of (1) preterm birth [aOR: 1.11 (95% CI 1.06-1.17)], and (2) emergency caesarean, elective caesarean and instrumental vaginal compared to spontaneous delivery [aOR: 1.10 (1.05-1.15), 1.07 (1.03-1.12) and 1.04 (1.00-1.09), respectively]. There was absence of association with low birthweight, high birthweight and stillbirth. In the sensitivity analysis, the association with preterm birth [aOR: 1.31 (95% CI 1.13-1.52)], emergency caesarean [aOR: 1.15 (95% CI 1.02-1.30)], and elective caesarean [aOR: 1.03 (95% CI 1.02-1.03)] remained. While there was no significant association with any of the secondary outcomes in the primary analysis, in the sensitivity analysis maternal PCOS was associated with increased risk of extremely preterm delivery [aOR: 1.86 (95% CI 1.31-2.65)], and lower risk of small for gestational age babies [aOR: 0.74 (95% CI 0.59-0.94)]. CONCLUSIONS: Maternal PCOS was associated with increased risk of preterm and caesarean delivery. Association with low birthweight may be largely mediated by lower gestational age at birth.

Epidemiology of pre-existing multimorbidity in pregnant women in the UK in 2018: a population-based cross-sectional study.

BACKGROUND: Although maternal death is rare in the United Kingdom, 90% of these women had multiple health/social problems. This study aims to estimate the prevalence of pre-existing multimorbidity (two or more long-term physical or mental health conditions) in pregnant women in the United Kingdom (England, Northern Ireland, Wales and Scotland). STUDY DESIGN: Pregnant women aged 15-49 years with a conception date 1/1/2018 to 31/12/2018 were included in this population-based cross-sectional study, using routine healthcare datasets from primary care: Clinical Practice Research Datalink (CPRD, United Kingdom, n = 37,641) and Secure Anonymized Information Linkage databank (SAIL, Wales, n = 27,782), and secondary care: Scottish Morbidity Records with linked community prescribing data (SMR, Tayside and Fife, n = 6099). Pre-existing multimorbidity preconception was defined from 79 long-term health conditions prioritised through a workshop with patient representatives and clinicians. RESULTS: The prevalence of multimorbidity was 44.2% (95% CI 43.7-44.7%), 46.2% (45.6-46.8%) and 19.8% (18.8-20.8%) in CPRD, SAIL and SMR respectively. When limited to health conditions that were active in the year before pregnancy, the prevalence of multimorbidity was still high (24.2% [23.8-24.6%], 23.5% [23.0-24.0%] and 17.0% [16.0 to 17.9%] in the respective datasets). Mental health conditions were highly prevalent and involved 70% of multimorbidity CPRD: multimorbidity with ≥one mental health condition/s 31.3% [30.8-31.8%]). After adjusting for age, ethnicity, gravidity, index of multiple deprivation, body mass index and smoking, logistic regression showed that pregnant women with multimorbidity were more likely to be older (CPRD England, adjusted OR 1.81 [95% CI 1.04-3.17] 45-49 years vs 15-19 years), multigravid (1.68 [1.50-1.89] gravidity ≥ five vs one), have raised body mass index (1.59 [1.44-1.76], body mass index 30+ vs body mass index 18.5-24.9) and smoked preconception (1.61 [1.46-1.77) vs non-smoker). CONCLUSION: Multimorbidity is prevalent in pregnant women in the United Kingdom, they are more likely to be older, multigravid, have raised body mass index and smoked preconception. Secondary care and community prescribing dataset may only capture the severe spectrum of health conditions. Research is needed urgently to quantify the consequences of maternal multimorbidity for both mothers and children.

A Comparison of the Cost-Effectiveness of Lifestyle Interventions in Pregnancy.

OBJECTIVES: Lifestyle interventions during pregnancy improve maternal and infant outcomes. We aimed to compare the cost-effectiveness of 4 antenatal lifestyle intervention types with standard care. METHODS: A decision tree model was constructed to compare lifestyle intervention effects from a novel meta-analysis. The target population was women with singleton pregnancies and births at more than 20 weeks' gestation. Interventions were categorized as diet, diet with physical activity, physical activity, and mixed (lacking structured diet and, or, physical activity components). The outcome of interest was cost per case prevented (gestational diabetes, hypertensive disorders in pregnancy, cesarean birth) expressed as an incremental cost-effectiveness ratio (ICER) from the Australian public healthcare perspective. Scenario analyses were included for all structured interventions combined and by adding neonatal intensive care unit costs. Costs were estimated from published data and consultations with experts and updated to 2019 values. Discounting was not applied owing to the short time horizon. RESULTS: Physical activity interventions reduced adverse maternal events by 4.2% in the intervention group compared with standard care and could be cost saving. Diet and diet with physical activity interventions reduced events by 3.5% (ICER = A$4882) and 2.9% (ICER = A$2020), respectively. Mixed interventions did not reduce events and were dominated by standard care. In scenario analysis, all structured interventions combined and all interventions when including neonatal intensive care unit costs (except mixed) may be cost saving. Probabilistic sensitivity analysis showed that for physical activity and all structured interventions combined, the probability of being cost saving was 58% and 41%, respectively. CONCLUSIONS: Governments can expect a good return on investment and cost savings when implementing effective lifestyle interventions population-wide.

Association of Antenatal Diet and Physical Activity-Based Interventions With Gestational Weight Gain and Pregnancy Outcomes: A Systematic Review and Meta-analysis.

IMPORTANCE: Excessive gestational weight gain (GWG) is common and associated with adverse pregnancy outcomes. Antenatal lifestyle interventions limit GWG; yet benefits of different intervention types and specific maternal and neonatal outcomes are unclear. OBJECTIVE: To evaluate the association of different types of diet and physical activity-based antenatal lifestyle interventions with GWG and maternal and neonatal outcomes. DATA SOURCES: A 2-stage systematic literature search of MEDLINE, Embase, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, and Health Technology Assessment Database was conducted from February 1, 2017, to May 31, 2020. Search results from the present study were integrated with those from a previous systematic review from 1990 to February 2017. STUDY SELECTION: Randomized trials reporting GWG and maternal and neonatal outcomes. DATA EXTRACTION AND SYNTHESIS: Data were extracted for random-effects meta-analyses to calculate the summary effect estimates and 95% CIs. MAIN OUTCOMES AND MEASURES: Outcomes were clinically prioritized, with mean GWG as the primary outcome. Secondary outcomes included gestational diabetes, hypertensive disorders of pregnancy, cesarean section, preterm delivery, large or small for gestational age neonates, neonatal intensive care unit admission, or fetal death. RESULTS: A total of 117 randomized clinical trials of antenatal lifestyle interventions (involving 34 546 women) were included. Overall lifestyle intervention was associated with reduced GWG (-1.15 kg; 95% CI, -1.40 to -0.91), risk of gestational diabetes (odds ratio [OR], 0.79; 95% CI, 0.70-0.89), and total adverse maternal outcomes (OR, 0.89; 95% CI, 0.84-0.94) vs routine care. Compared with routine care, diet was associated with less GWG (-2.63 kg; 95% CI, -3.87 to -1.40) than physical activity (-1.04 kg; 95% CI, -1.33 to -0.74) or mixed interventions (eg, unstructured lifestyle support, written information with weight monitoring, or behavioral support alone) (-0.74 kg; 95% CI, -1.06 to -0.43). Diet was associated with reduced risk of gestational diabetes (OR, 0.61; 95% CI, 0.45-0.82), preterm delivery (OR, 0.43; 95% CI, 0.22-0.84), large for gestational age neonate (OR, 0.19; 95% CI, 0.08-0.47), neonatal intensive care admission (OR, 0.68; 95% CI, 0.48-0.95), and total adverse maternal (OR, 0.75; 95% CI, 0.61-0.92) and neonatal outcomes (OR, 0.44; 95% CI, 0.26-0.72). Physical activity was associated with reduced GWG and reduced risk of gestational diabetes (OR, 0.60; 95% CI, 0.47-0.75), hypertensive disorders (OR, 0.66; 95% CI, 0.48-0.90), cesarean section (OR, 0.85; 95% CI, 0.75-0.95), and total adverse maternal outcomes (OR, 0.78; 95% CI, 0.71-0.86). Diet with physical activity was associated with reduced GWG (-1.35 kg; 95% CI, -1.95 to -0.75) and reduced risk of gestational diabetes (OR, 0.72; 95% CI, 0.54-0.96) and total adverse maternal outcomes (OR, 0.81; 95% CI, 0.69-0.95). Mixed interventions were associated with reduced GWG only. CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis found level 1 evidence that antenatal structured diet and physical activity-based lifestyle interventions were associated with reduced GWG and lower risk of adverse maternal and neonatal outcomes. The findings support the implementation of such interventions in routine antenatal care and policy around the world.

Iron preparations for women of reproductive age with iron deficiency anaemia in pregnancy (FRIDA): a systematic review and network meta-analysis.

BACKGROUND: Numerous iron preparations are available for the treatment of iron deficiency anaemia in pregnancy. We aimed to provide a summary of the effectiveness and safety of iron preparations used in this setting. METHODS: We did a systematic review and network meta-analysis of randomised trials. We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, trial registers, and grey literature for trials published in any language from Jan 1, 2011, to Feb 28, 2021. We included trials including pregnant women with iron deficiency anaemia and evaluating iron preparations, irrespective of administration route, with at least 60 mg of elemental iron, in comparison with another iron or non-iron preparation. Three authors independently selected studies, extracted data, and did a risk of bias assessment using the Cochrane tool (version 1.0). The primary outcome was the effectiveness of iron preparations, evaluated by changes in haemoglobin concentration at 4 weeks from baseline. The secondary outcomes were change in serum ferritin concentration at 4 weeks from baseline and treatment-related severe and non-severe adverse events. We did random-effects pairwise and network meta-analyses. Side-effects were reported descriptively for each trial. This study is registered with PROSPERO, CRD42018100822. FINDINGS: Among 3037 records screened, 128 full-text articles were further assessed for eligibility. Of the 53 eligible trials (reporting on 9145 women), 30 (15 interventions; 3243 women) contributed data to the network meta-analysis for haemoglobin and 15 (nine interventions; 1396 women) for serum ferritin. The risk of bias varied across the trials contributing to network meta-analysis, with 22 of 30 trials in the network meta-analysis for haemoglobin judged to have a high or medium global risk of bias. Compared with oral ferrous sulfate, intravenous iron sucrose improved both haemoglobin (mean difference 7·17 g/L, 95% CI 2·62-11·73; seven trials) and serum ferritin (mean difference 49·66 µg/L, 13·63-85·69; four trials), and intravenous ferric carboxymaltose improved haemoglobin (mean difference 8·52 g/L, 0·51-16·53; one trial). The evidence for other interventions compared with ferrous sulfate was insufficient. The most common side-effects with oral iron preparations were gastrointestinal effects (nausea, vomiting, and altered bowel movements). Side-effects were less common with parenteral iron preparations, although these included local pain, skin irratation, and, on rare occasions, allergic reactions. INTERPRETATION: Iron preparations for treatment of iron deficiency anaemia in pregnancy vary in effectiveness, with good evidence of benefit for intravenous iron sucrose and some evidence for intravenous ferric carboxymaltose. Clinicians and policy makers should consider the effectiveness of individual preparations before administration, to ensure effective treatment. FUNDING: None.

Diet and physical activity in pregnancy to prevent gestational diabetes: a protocol for an individual participant data (IPD) meta-analysis on the differential effects of interventions with economic evaluation.

INTRODUCTION: Mothers with gestational diabetes mellitus (GDM) are at increased risk of pregnancy-related complications and developing type 2 diabetes after delivery. Diet and physical activity-based interventions may prevent GDM, but variations in populations, interventions and outcomes in primary trials have limited the translation of available evidence into practice. We plan to undertake an individual participant data (IPD) meta-analysis of randomised trials to assess the differential effects and cost-effectiveness of diet and physical activity-based interventions in preventing GDM and its complications. METHODS: The International Weight Management in Pregnancy Collaborative Network database is a living repository of IPD from randomised trials on diet and physical activity in pregnancy identified through a systematic literature search. We shall update our existing search on MEDLINE, Embase, BIOSIS, LILACS, Pascal, Science Citation Index, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects and Health Technology Assessment Database without language restriction to identify relevant trials until March 2021. Primary researchers will be invited to join the Network and share their IPD. Trials including women with GDM at baseline will be excluded. We shall perform a one and two stage random-effect meta-analysis for each intervention type (all interventions, diet-based, physical activity-based and mixed approach) to obtain summary intervention effects on GDM with 95% CIs and summary treatment-covariate interactions. Heterogeneity will be summarised using I2 and tau2 statistics with 95% prediction intervals. Publication and availability bias will be assessed by examining small study effects. Study quality of included trials will be assessed by the Cochrane Risk of Bias tool, and the Grading of Recommendations, Assessment, Development and Evaluations approach will be used to grade the evidence in the results. A model-based economic analysis will be carried out to assess the cost-effectiveness of interventions to prevent GDM and its complications compared with usual care. ETHICS AND DISSEMINATION: Ethics approval is not required. The study is registered on the International Prospective Register of Systematic Reviews (CRD42020212884). Results will be submitted for publication in peer-reviewed journals.

Prognostic indicators of severe disease in late preterm pre-eclampsia to guide decision making on timing of delivery: The PEACOCK study.

OBJECTIVE: To assess the diagnostic performance of angiogenic biomarkers in determining need for delivery in seven days in women with late preterm preeclampsia. STUDY DESIGN: In a prospective observational cohort study in 36 maternity units across England and Wales, we studied the diagnostic accuracy of placental growth factor (PlGF) and sFlt-1 in determining the risk of complications requiring delivery in late preterm (34+0 to 36+6 weeks' gestation) preeclampsia. Angiogenic biomarkers were measured using the Quidel (PlGF) and Roche (sFlt-1:PlGF ratio) assays. Additional clinical data was obtained for use within the established 'Prediction of complications in early-onset pre-eclampsia' (PREP)-S prognostic model. Biomarkers were assessed using standard methods (sensitivity, specificity, Receiver Operator Curve areas). Estimated probability of early delivery from PREP-S was compared to actual event rates. MAIN OUTCOME MEASURES: Clinically indicated need for delivery for pre-eclampsia within seven days. RESULTS: PlGF (Quidel) testing had high sensitivity (97.9%) for delivery within seven days, but negative predictive value was only 71.4%, with low specificity (8.4%), with similar results from sFlt-1/PlGF assay. The area under the curve for PlGF was 0.60 (SE 0.03), and 0.65 (0.03), and 0.64 (0.03) for PREP-S in combination with PlGF, and sFlt-1:PlGF, respectively. CONCLUSIONS: Angiogenic biomarkers do not add to clinical assessment to help determine need for delivery for women with late preterm pre-eclampsia. Existing models developed in women with early-onset pre-eclampsia to predict complications cannot be used to predict clinically indicated need for delivery in women with late preterm pre-eclampsia.

Harmonizing research outcomes for polycystic ovary syndrome (HARP), a marathon not a sprint: current challenges and future research need.

Investing in clinical research and evidence-based medicine has helped to improve the care for women with polycystic ovary syndrome (PCOS). However, several important questions remain unanswered on the optimal prevention and management strategies for PCOS. Addressing this uncertainty is often hindered by suboptimal research conduct leading to inefficient evidence synthesis and research wastage. PCOS research is often practised by varied specialized teams in silo leading to disharmonious and fragmented efforts neglecting the lifelong impact of PCOS on women's wellbeing. Poor engagement among key stakeholders and lay consumers continues to limit the impact and benefits of research to society. Selective reporting on surrogate outcomes with a 'significant' P-value is a common malpractice in PCOS outputs. Effective adoption of the harmonizing research outcomes for PCOS (HARP) core outcome set is needed to minimize heterogeneity in reporting and promote research excellence. Small single-centre studies offer limited value to assess the varied PCOS phenotypes. Efficient large scale data-sharing is needed to address complex research questions and glean the benefits of big data research. We propose a roadmap to address these challenges and remedy future research need by promoting patient and public involvement in PCOS research to guide research efforts and address real patients' needs; engaging all key stakeholder groups to promote a multi-disciplinary lifelong approach to new research; continuously refining research needs and priorities to revise the knowledge gap and allocate resources judiciously; standardizing outcomes definitions and measurement tools to harmonize reporting and promote excellence in research; and by investing in large data-sharing infrastructure to facilitate big data research and govern ethical data sharing.

Risk of foetal harm with letrozole use in fertility treatment: a systematic review and meta-analysis.

BACKGROUND: The aromatase inhibitor letrozole is increasingly recommended for ovulation induction, as it is more effective with fewer side-effects than other agents. But many clinicians are reluctant to use the drug for fertility treatment due to a strong-label warning against its use, which warns about congenital malformation risk to the foetus in women seeking pregnancy. OBJECTIVE AND RATIONALE: The aim of this study was to determine the risks of congenital malformations and pregnancy loss with letrozole compared with clomiphene primarily, and with other fertility drugs and natural conception. SEARCH METHODS: A systematic review and meta-analysis using PRISMA harms guidelines. We searched MEDLINE, EMBASE and other sources from inception until January 2020, with the MeSH words for 'letrozole' and pregnancy OR foetal/neonatal outcome. We included studies reported on congenital malformations in foetuses born to mothers conceived after fertility treatment, with letrozole versus clomiphene, placebo, gonadotrophins, metformin, natural conception or other agents, from randomised trials, comparative cohort studies and non-comparative observational cohorts. Quality of the studies was assessed using Cochrane risk of bias tool and Newcastle Ottawa Scale. The McMaster tool was used to assess the quality of reported harm for foetal congenital malformations in the studies. We compared the absolute risk of events using risk difference measures and pooled the findings using a fixed-effect model. We evaluated the statistical heterogeneity using forest plots and the I2 statistic and funnel plot to assess publication bias. We assessed the strength of evidence for congenital malformation and pregnancy loss as per the GRADE recommendations and with the Fragility index. OUTCOMES: We included 46 studies (18 randomised trials; 21 comparative cohorts; 7 non-comparative cohorts). Overall 2.15% (101/4697; 95% CI 1.7 to 2.5) of babies conceived on letrozole for fertility treatment had congenital foetal malformations. We did not observe a significant increase in congenital malformations with letrozole versus clomiphene in the randomised trials (risk difference (RD) 0.01, 95% CI -0.02, 0.03; I2 = 0%; 14 studies) and found a significant reduction in the cohort studies (RD -0.02, 95% CI -0.04, -0.01; I2 = 0%, 11 studies). The fragility index was 44% (7/16) (either an increase in the intervention arm or a decrease in control arm was needed to alter the results). The risks of pregnancy loss were not increased with letrozole versus clomiphene in the 14 randomised trials (RD -0.01, 95% CI -0.06, 0.04; I2 = 0%), and the risks were reduced in the six cohort studies (RD -0.09, 95% CI -0.17, -0.00; I2 = 68%). The GRADE quality of evidence was low to moderate for congenital malformations and pregnancy loss. We did not find any increased congenital malformation risk with letrozole versus gonadotrophins, natural conception or natural cycle ART, but the number of studies was small. WIDER IMPLICATIONS: There is no evidence that letrozole increases the risk of congenital foetal malformation or pregnancy loss compared with clomiphene, natural conception or other fertility agents, to warrant warning against its use. Given its therapeutic benefits and lack of evidence of harm to the foetus, clinicians should consider letrozole as first-line agent for ovulation induction.

Harmonising research outcomes for polycystic ovary syndrome: an international multi-stakeholder core outcome set.

STUDY QUESTION: What are the key core outcomes to be reported in studies on polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: We identified 3 generic and 30 specific core outcomes in 6 specialist domains: metabolic (8), reproductive (7), pregnancy (10), oncological (1), psychological (1) and long-term outcomes (1). WHAT IS KNOWN ALREADY: Research reporting PCOS is heterogeneous with high variation in outcome selection, definition and quality. STUDY DESIGN, SIZE, DURATION: Evidence synthesis and a modified Delphi method with e-surveys were used as well as a consultation meeting. PARTICIPANTS/MATERIALS, SETTING, METHODS: Overall, 71 health professionals and 123 lay consumers (women with lived experience of PCOS and members of advocacy and peer support groups) from 17 high-, middle- and low-income countries were involved in this analysis. MAIN RESULTS AND THE ROLE OF CHANCE: The final core outcome set included 3 generic outcomes (BMI, quality of life, treatment satisfaction) that are applicable to all studies on women with PCOS and 30 specific outcomes that were categorised into six specialist domains: 8 metabolic outcomes (waist circumference, type 2 diabetes, insulin resistance, impaired glucose tolerance, hypertension, coronary heart disease, lipid profile, venous thromboembolic disease); 7 reproductive outcomes [viable pregnancy (confirmed by ultrasound including singleton, twins and higher multiples), clinical and biochemical hyperandrogenism, menstrual regularity, reproductive hormonal profile, chronic anovulation, ovulation stimulation success including the number of stimulated follicles ≥ 12 mm, incidence and severity of ovarian hyperstimulation syndrome]; 10 pregnancy outcomes (live birth, miscarriage, stillbirth, neonatal mortality, gestational weight gain, gestational diabetes, preterm birth, hypertensive disease in pregnancy, baby birth weight, major congenital abnormalities); 3 psychological outcomes (depression, anxiety, eating disorders); 1 oncological (abnormal endometrial proliferation including atypical endometrial hyperplasia and endometrial cancer); and 1 outcome in the long-term domain (long-term offspring metabolic and developmental outcomes). LIMITATIONS, REASONS FOR CAUTION: We involved lay consumers in all stages of study through e-surveys but not through focus groups, thereby limiting our understanding of their choices. We did not address the variations in the definitions and measurement tools for some of the core outcomes. WIDER IMPLICATIONS OF THE FINDINGS: Implementing this core outcome set in future studies on women with PCOS will improve the quality of reporting and aid evidence synthesis. STUDY FUNDING/COMPETING INTEREST(S): Evidence synthesis was funded through the Australian government, National Health and Medical Research Council (NHMRC) Centre for Research Excellence in PCOS, and H.T. is funded through an NHMRC fellowship. B.H.A. is funded through an NIHR lectureship. All authors have no competing interest to declare.

Are Lifestyle Interventions to Reduce Excessive Gestational Weight Gain Cost Effective? A Systematic Review.

PURPOSE OF REVIEW: Lifestyle interventions (such as diet and physical activity) successfully limit excessive gestational weight gain and can reduce some adverse maternal events; however, benefit is variable and cost-effectiveness remains unclear. We aimed to review published cost-effectiveness analyses of lifestyle interventions compared with usual care on clinically relevant outcome measures. Five international and six grey-literature databases were searched from 2007 to 2018. Articles were assessed for quality of reporting. Data were extracted from healthcare and societal perspectives. Costs were adapted to the common currencies of Australia and the United Kingdom by adjusting for resource utilization, healthcare purchase price and changes in costs over time. Included studies were economic analyses of lifestyle interventions aiming to limit weight-gain during pregnancy and/or reduce risk of gestational diabetes, for women with a BMI of 25 or greater in pre- or early-pregnancy. RECENT FINDINGS: Of the 538 articles identified, six were retained for review: one modelling study and five studies in which an economic analysis was performed alongside a randomized-controlled trial. Outcome measures included infant birth-weight, fasting glucose, insulin resistance, gestational weight-gain, infant respiratory distress syndrome, perceived health, cost per case of adverse outcome avoided and quality-adjusted life years (QALYs). Interventions were cost-effective in only one study. Although many studies have investigated the efficacy of lifestyle interventions in pregnancy, few have included cost-effectiveness analyses. Where cost-effectiveness studies were undertaken, results were inconsistent. Secondary meta-analysis, taxonomy and framework research is now required to determine the effective components of lifestyle interventions and to guide future cost-effectiveness analyses.

Metabolic inflexibility in women with polycystic ovary syndrome: a systematic review.

Polycystic ovary syndrome (PCOS) is a risk factor for dysglycemia, insulin resistance, and type 2 Diabetes Mellitus (T2DM). Inefficient energy oxidation, metabolic inflexibility, is a marker of blunted metabolism. We conducted a systematic review on metabolic inflexibility in women with PCOS. We searched MEDLINE, EMBASE and Cochrane central (inception-October 2018) for studies evaluating metabolic inflexibility and reporting on changes in Respiratory Quotient (ΔRQ). We extracted data and assessed quality using The Newcastle-Ottawa Scale. We included five prospective cohort studies (461 women). Three compared PCOS women to unaffected subjects, one to women with obesity or T2DM, and one to adolescent girls; all had medium quality. Three studies showed higher metabolic inflexibility in women with PCOS (ΔRQ range 0.05-0.098) compared to unaffected subjects. Women with PCOS had similar metabolic inflexibility compared to those with T2DM (ΔRQ 0.05 ± 0.03 vs 0.06 ± 0.04, p = .98) and obesity (p = .06). Inflexibility was higher in hyperandrogenemic women with PCOS (ΔRQ 0.091 ± 0.060 vs 0.120 ± 0.010, p = .014). ΔRQ was lower in PCOS women with insulin resistance vs those with normal insulin sensitivity (0.04 ± 0.02 vs. 0.07 ± 0.04, p = .007). In conclusion, women with polycystic ovary syndrome appear to have higher metabolic inflexibility associated with hyperandrogenemia and insulin resistance.

A brief update on the evidence supporting the treatment of infertility in polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is complex with reproductive, metabolic and psychological features. Infertility is a prevalent presenting feature of PCOS with approximately 75% of these women suffering infertility due to anovulation, making PCOS by far the most common cause of anovulatory infertility. Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. AIMS: This review paper aims to provide a brief update on the best available and most current research evidence supporting the treatment of PCOS which informed the recommendations in the assessment and treatment of infertility section of the international evidence-based guideline on PCOS 2018. MATERIALS AND METHODS: International evidence-based guideline development engaged professional societies and consumer organisations with multidisciplinary experts and women with PCOS directly involved at all stages. RESULTS: Lifestyle change alone is considered the first-line treatment for the management of infertile anovulatory PCOS women who are overweight or obese. Letrozole should now be considered first-line pharmacological treatment for ovulation induction to improve fertility outcomes. Clomiphene citrate alone and metformin alone could also be used as first-line pharmacological therapy, although both are less effective than letrozole and metformin is less effective than clomiphene citrate in obese women. Gonadotrophins or laparoscopic ovarian surgery are usually second-line ovulation induction therapies. In the absence of an absolute indication for in vitro fertilisation (IVF) / intracytoplasmic sperm injection, women with PCOS and anovulatory infertility could be offered IVF as third-line therapy where first- or second-line ovulation induction therapies have failed. CONCLUSION: This review provides the best available evidence informing recommendations (along with clinical expertise and consumer preference) which provide clinicians with clear advice on best practice for the management of infertile women with PCOS.

Impact of maternal education on response to lifestyle interventions to reduce gestational weight gain: individual participant data meta-analysis.

OBJECTIVES: To identify if maternal educational attainment is a prognostic factor for gestational weight gain (GWG), and to determine the differential effects of lifestyle interventions (diet based, physical activity based or mixed approach) on GWG, stratified by educational attainment. DESIGN: Individual participant data meta-analysis using the previously established International Weight Management in Pregnancy (i-WIP) Collaborative Group database (https://iwipgroup.wixsite.com/collaboration). Preferred Reporting Items for Systematic reviews and Meta-Analysis of Individual Participant Data Statement guidelines were followed. DATA SOURCES: Major electronic databases, from inception to February 2017. ELIGIBILITY CRITERIA: Randomised controlled trials on diet and physical activity-based interventions in pregnancy. Maternal educational attainment was required for inclusion and was categorised as higher education (≥tertiary) or lower education (≤secondary). RISK OF BIAS: Cochrane risk of bias tool was used. DATA SYNTHESIS: Principle measures of effect were OR and regression coefficient. RESULTS: Of the 36 randomised controlled trials in the i-WIP database, 21 trials and 5183 pregnant women were included. Women with lower educational attainment had an increased risk of excessive (OR 1.182; 95% CI 1.008 to 1.385, p =0.039) and inadequate weight gain (OR 1.284; 95% CI 1.045 to 1.577, p =0.017). Among women with lower education, diet basedinterventions reduced risk of excessive weight gain (OR 0.515; 95% CI 0.339 to 0.785, p = 0.002) and inadequate weight gain (OR 0.504; 95% CI 0.288 to 0.884, p=0.017), and reduced kg/week gain (B -0.055; 95% CI -0.098 to -0.012, p=0.012). Mixed interventions reduced risk of excessive weight gain for women with lower education (OR 0.735; 95% CI 0.561 to 0.963, p=0.026). Among women with high education, diet based interventions reduced risk of excessive weight gain (OR 0.609; 95% CI 0.437 to 0.849, p=0.003), and mixed interventions reduced kg/week gain (B -0.053; 95% CI -0.069 to -0.037,p<0.001). Physical activity based interventions did not impact GWG when stratified by education. CONCLUSIONS: Pregnant women with lower education are at an increased risk of excessive and inadequate GWG. Diet based interventions seem the most appropriate choice for these women, and additional support through mixed interventions may also be beneficial.