Background Pregnant women with epilepsy on antiepileptic drugs (AEDs) may experience a reduction in serum AED levels. This has the potential to worsen seizure control. Objective To determine if, in pregnant women with epilepsy on AEDs, additional therapeutic drug monitoring reduces seizure deterioration compared with clinical features monitoring after a reduction in serum AED levels. Design A double-blind, randomised trial nested within a cohort study was conducted and a qualitative study of acceptability of the two strategies was undertaken. Stratified block randomisation with a 1 : 1 allocation method was carried out. Setting Fifty obstetric and epilepsy clinics in secondary and tertiary care units in the UK. Participants Pregnant women with epilepsy on one or more of the following AEDs: lamotrigine, carbamazepine, phenytoin or levetiracetam. Women with a ≥ 25% decrease in serum AED level from baseline were randomised to therapeutic drug monitoring or clinical features monitoring strategies. Interventions In the therapeutic drug monitoring group, clinicians had access to clinical findings and monthly serum AED levels to guide AED dosage adjustment for seizure control. In the clinical features monitoring group, AED dosage adjustment was based only on clinical features. Main outcome measures Primary outcome – seizure deterioration, defined as time to first seizure and to all seizures after randomisation per woman until 6 weeks post partum. Secondary outcomes – pregnancy complications in mother and offspring, maternal quality of life, seizure rates in cohorts with stable serum AED level, AED dose exposure and adverse events related to AEDs. Analysis Analysis of time to first and to all seizures after randomisation was performed using a Cox proportional hazards model, and multivariate failure time analysis by the Andersen–Gill model. The effects were reported as hazard ratios (HRs) with 95% confidence intervals (CIs). Secondary outcomes were reported as mean differences (MDs) or odds ratios. Results A total of 130 women were randomised to the therapeutic drug monitoring group and 133 to the clinical features monitoring group; 294 women did not have a reduction in serum AED level. A total of 127 women in the therapeutic drug monitoring group and 130 women in the clinical features monitoring group (98% of complete data) were included in the primary analysis. There were no significant differences in the time to first seizure (HR 0.82, 95% CI 0.55 to 1.2) or timing of all seizures after randomisation (HR 1.3, 95% CI 0.7 to 2.5) between both trial groups. In comparison with the group with stable serum AED levels, there were no significant increases in seizures in the clinical features monitoring (odds ratio 0.93, 95% CI 0.56 to 1.5) or therapeutic drug monitoring group (odds ratio 0.93, 95% CI 0.56 to 1.5) associated with a reduction in serum AED levels. Maternal and neonatal outcomes were similar in both groups, except for higher cord blood levels of lamotrigine (MD 0.55 mg/l, 95% CI 0.11 to 1 mg/l) or levetiracetam (MD 7.8 mg/l, 95% CI 0.86 to 14.8 mg/l) in the therapeutic drug monitoring group than in the clinical features monitoring group. There were no differences between the groups on daily AED exposure or quality of life. An increase in exposure to lamotrigine, levetiracetam and carbamazepine significantly increased the cord blood levels of the AEDs, but not maternal or fetal complications. Women with epilepsy perceived the need for weighing up their increased vulnerability to seizures during pregnancy against the side effects of AEDs. Limitations Fewer women than the original target were recruited. Conclusion There is no evidence to suggest that regular monitoring of serum AED levels in pregnancy improves seizure control or affects maternal or fetal outcomes. Future work recommendations Further evaluation of the risks of seizure deterioration for various threshold levels of reduction in AEDs and the long-term neurodevelopment of infants born to mothers in both randomised groups is needed. An individualised prediction model will help to identify those women who need close monitoring in pregnancy. Trial registration Current Controlled Trials ISRCTN01253916. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 23. See the NIHR Journals Library website for further project information.

Background Previous reviews examining the effect of participation in trials on outcomes have not consistently shown benefit. Obstetrics and gynaecology is a unique disease area posing challenges for both researchers and patients.Objectives To determine whether participation in randomised controlled trials (RCTs), compared with non-participation, has a beneficial effect on women's health.Search strategy Medline, Embase, the Cochrane Library, and PsycInfo were searched up to December 2015.Selection criteria We selected studies that reported the same clinical outcomes for participants in a women's health RCT and a comparable non-participant cohort.Data collection and analysis Data were extracted on quality, characteristics and study results. Outcomes were compared using logistic regression.Main results There were 21 relevant studies (20 160 women, 4759 outcome events). Trial participants, compared with nonparticipants, had 25% better odds of improved outcomes on average (OR 0.75; 95% CI 0.64-0.87; I 2 = 64.3%). The beneficial effect of participating in a trial was larger in comparisons where: RCTs were of high quality (OR 0.62; 95% CI 0.50-0.76) versus low (OR 0.92; 95% CI 0.74-1.16); and RCT intervention was not available to non-participants (OR 0.57; 95% CI 0.47-0.69) versus when it was (OR 1.13; 95% CI 0.89-1.44). The effect of trial participation was not influenced by effect size within the RCT (P = 0.48), whether funding was received or not (P = 0.13), whether non-participants received any treatment or not (P = 0.49), and the quality of the comparison of RCT participants with non-participants (P = 0.88).Conclusions Women participating in RCTs on average experienced better outcomes compared with those outside trials.Keywords Neonate, randomised, systematic review, trial participation, women's health.Tweetable abstract Participants in obstetric and gynaecology RCTs experience better outcomes compared with nonparticipants.Please cite this paper as: Nijjar SK, D'Amico MI, Wimalaweera NA, Cooper NAM, Zamora J, Khan KS. Participation in clinical trials improves outcomes in women's health: a systematic review and meta-analysis.

Objective To develop maternal, fetal, and neonatal composite outcomes relevant to the evaluation of diet and lifestyle interventions in pregnancy by individual patient data (IPD) meta-analysis.Design Delphi survey.Setting The International Weight Management in Pregnancy (i-WIP) collaborative network. Sample Twenty-six researchers from the i-WIP collaborative network from 11 countries.Methods A two-generational Delphi survey involving members of the i-WIP collaborative network (26 members in 11 countries) was undertaken to prioritise the individual outcomes for their importance in clinical care. The final components of the composite outcomes were identified using pre-specified criteria. Results Of the 36 maternal outcomes, nine were prioritised and the following were included in the final composite: pre-eclampsia or pregnancy-induced hypertension, gestational diabetes mellitus (GDM), elective or emergency caesarean section, and preterm delivery. Of the 27 fetal and neonatal outcomes, nine were further evaluated, with the final composite consisting of intrauterine death, small for gestational age, large for gestational age, and admission to a neonatal intensive care unit (NICU).Conclusions Our work has identified the components of maternal, fetal, and neonatal composite outcomes required for the assessment of diet and lifestyle interventions in pregnancy by IPD meta-analysis.Keywords Composite outcome, Delphi survey, diet, fetal, lifestyle, maternal, neonatal.Tweetable abstract Composite outcomes in IPD meta-analysis on diet and lifestyle in pregnancy.

A walking programme, recipe ideas and weight monitoring may be useful components when designing a postpartum lifestyle intervention. Barriers to engagement are evident and the intervention should allow women to engage at a time that is appropriate for them.

This study aimed to comprehensively investigate the reliability of multiple heart rate variability (HRV) parameters, and to explore the influence of artefact removal and breathing condition on HRV reliability. Resting HRV was collected using Polar Team monitors on forty-one participants (age: 19.9±1.2 years; 28 females, 13 males) during two separate days. Within each session, participants performed 10 minutes each of spontaneous and controlled breathing (randomized order). Kubios HRV analysis software was used to analyze 180s data epochs using "low" or "strong" artefact removal. Relative reliability was assessed using intraclass correlation coefficients (ICC2,1) and absolute reliability was quantified using mean-normalized standard error of measurement (SEM%). Time domain and nonlinear parameters produced poor to good inter-session agreement (ICC:0.34-0.68; SEM%: 11.0-39.0) with "low" artefact removal, regardless of breathing condition. Frequency domain parameters demonstrated fair inter-session agreement during controlled breathing (ICC:0.40-0.45; SEM%: 26.0-70.0), but poor agreement during spontaneous breathing (ICC:0.07-0.13; SEM%: 32.0-81.0). Minimal differences in ICCs were observed between "low" and "strong" artefact removal. Thus, this study provides three practical applications: 1) HRV monitoring is most reliable when using time domain and nonlinear parameters, regardless of breathing or filtering condition, but no single parameter is especially reliable. The large variation and poor inter-session reliability of frequency indices during spontaneous breathing are improved by controlling breathing rate; 2) "Low" artefact removal appears superior to more aggressive artefact removal; and 3) Inter-session differences in HRV measurements <30% may be indicative of normal daily variation rather than true physiologic changes.

The severity and anatomical extent of mammary edema (edema) of 73 primigravid Holstein heifers was scored, and certain hormones in peripheral blood plasma were quantified. The objective was to obtain by least-squares analysis of covariance independent estimates of the association of each hormone and other factors with edema scores around first calving. Mammary edema prepartum increased with age of heifer and gestation length, decreased as calf birthweight increased, but was unrelated to seasonal fluctuations in temperature and photoperiod. The increase in edema during the last week of pregnancy was accounted for by associations with prepartum concentrations of hormones in plasma. The independent estimates of hormonal relationships to edema score prepartum were positive for plasma estrone and estradiol-17 alpha and were negative for plasma estradiol-17 beta and progesterone. Plasma prolactin was not related to edema score. After parturition, estradiol-17 beta was the only independent variable associated (negatively) with edema. The results indicate a complicated interaction among the sex steroids of late pregnancy wherein some steroids may promote edema and other steroids may inhibit edema in heifers.

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IntroductionUp to half of all women diagnosed with gestational diabetes mellitus develop type 2 diabetes within 5 years after delivery. Metformin is effective in preventing type 2 diabetes in high-risk non-pregnant individuals, but its effect when commenced in the postnatal period is not known. We plan to assess the feasibility of evaluating metformin versus placebo in minimising the risk of dysglycaemia including type 2 diabetes after delivery in postnatal women with a history of gestational diabetes through a randomised trial.Methods and analysisOptimising health outcomes with Metformin to prevent diAbetes After pregnancy (OMAhA) is a multicentre placebo-controlled double-blind randomised feasibility trial, where we will randomly allocate 160 postnatal women with gestational diabetes treated with medication to either metformin (intervention) or placebo (control) tablets to be taken until 1 year after delivery. The primary outcomes are rates of recruitment, randomisation, adherence and attrition. The secondary outcomes are maternal dysglycaemia, cost and quality of life outcomes in both arms, and acceptability of the study and intervention, which will be evaluated through a nested qualitative study. Feasibility outcomes will be summarised using descriptive statistics, point estimates and 95% CIs.Ethics and disseminationThe OMAhA study received ethics approval from the London-Brent Research Ethics Committee (18/LO/0505). Trial findings will be published in a peer-reviewed journal, disseminated at conferences, through our Patient and Public Involvement advisory group (Katie’s Team) and through social media platforms.Trial registration numberISRCTN20930880