John Allotey

Epilepsy in pregnancy and reproductive outcomes: a systematic review and meta-analysis

BACKGROUND Antenatal care of women with epilepsy is varied. The association of epilepsy and antiepileptic drug exposure with pregnancy outcomes needs to be quantified to guide management. We did a systematic review and meta-analysis to investigate the association between epilepsy and reproductive outcomes, with or without exposure to antiepileptic drugs. METHODS We searched MEDLINE, Embase, Cochrane, AMED, and CINAHL between Jan 1, 1990, and Jan 21, 2015, with no language or regional restrictions, for observational studies of pregnant women with epilepsy, which assessed the risk of obstetric complications in the antenatal, intrapartum, or postnatal period, and any neonatal complications. We used the Newcastle-Ottawa Scale to assess the methodological quality of the included studies, risk of bias in the selection and comparability of cohorts, and outcome. We assessed the odds of maternal and fetal complications (excluding congenital malformations) by comparing pregnant women with and without epilepsy and undertook subgroup analysis based on antiepileptic drug exposure in women with epilepsy. We summarised the association as odds ratio (OR; 95% CI) using random effects meta-analysis. The PROSPERO ID of this Systematic Reviews protocol is CRD42014007547. FINDINGS Of 7050 citations identified, 38 studies from low-income and high-income countries met our inclusion criteria (39 articles including 2,837,325 pregnancies). Women with epilepsy versus those without (2,809,984 pregnancies) had increased odds of spontaneous miscarriage (OR 1·54, 95% CI 1·02-2·32; I(2)=67%), antepartum haemorrhage (1·49, 1·01-2·20; I(2)=37%), post-partum haemorrhage (1·29, 1·13-1·49; I(2)=41%), hypertensive disorders (1·37, 1·21-1·55; I(2)=23%), induction of labour (1·67, 1·31-2·11; I(2)=64%), caesarean section (1·40, 1·23-1·58; I(2)=66%), any preterm birth (<37 weeks of gestation; 1·16, 1·01-1·34; I(2)=64%), and fetal growth restriction (1·26, 1·20-1·33; I(2)=1%). The odds of early preterm birth, gestational diabetes, fetal death or stillbirth, perinatal death, or admission to neonatal intensive care unit did not differ between women with epilepsy and those without the disorder. INTERPRETATION A small but significant association of epilepsy, exposure to antiepileptic drugs, and adverse outcomes exists in pregnancy. This increased risk should be taken into account when counselling women with epilepsy. FUNDING EBM CONNECT Collaboration.

Prediction models in obstetrics: understanding the treatment paradox and potential solutions to the threat it poses

the treatment paradox and potential solutions to the threat it poses F Cheong-See, J Allotey, N Marlin, BW Mol, E Schuit, G ter Riet, RD Riley, KGM Moons, KS Khan, S Thangaratinam a Women’s Health Research Unit, Barts and the London School of Medicine and Dentistry, Blizard Institute, Queen Mary University London, London, UK b Multidisciplinary Evidence Synthesis Hub (MESH), Queen Mary University of London, UK c Pragmatic Clinical Trials Unit, Barts and the London School of Medicine and Dentistry, Blizard Institute, Queen Mary University London, London, UK d Australian Research Centre for Health of Women and Babies, Robinson Institute, The University of Adelaide, Adelaide, SA, Australia e Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, the Netherlands f Stanford Prevention Research Center, Stanford University, Stanford, CA, USA g Department of General Practice, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands h Research Institute for Primary Care and Health Sciences, Keele University, Staffordshire, UK Correspondence: Prof S Thangaratinam, Women’s Health Research Unit, Barts and the London School of Medicine and Dentistry, Queen Mary University London, Yvonne Carter Building, 58 Turner Street, London E1 2AB, UK. Email s.thangaratinam@qmul.ac.uk

Cognitive, motor, behavioural and academic performances of children born preterm: a meta-analysis and systematic review involving 64 061 children

Preterm birth may leave the brain vulnerable to dysfunction. Knowledge of future neurodevelopmental delay in children born with various degrees of prematurity is needed to inform practice and policy.

Serum ferritin thresholds for the diagnosis of iron deficiency in pregnancy: a systematic review

The aim of this review was to understand the landscape of serum ferritin in diagnosing iron deficiency in the aetiology of anaemia in pregnancy. Iron deficiency in pregnancy is a major public health problem leading to the development of anaemia. Reducing the global prevalence of anaemia in women of reproductive age is a 2025 global nutrition target. Bone marrow aspiration is the gold standard test for iron deficiency but requires an invasive procedure; therefore, serum ferritin is the most clinically useful test. We undertook a systematic search of electronic databases and trial registers from inception to January 2016. Studies of iron or micronutrient supplementation in pregnancy with pre‐defined serum ferritin thresholds were included. Two independent reviewers selected studies, extracted data and assessed quality. There were 76 relevant studies mainly of observational study design (57%). The most commonly used thresholds of serum ferritin for the diagnosis of iron deficiency were <12 and <15 ng mL−1 (68%). Most primary studies provided no justification for the choice of serum ferritin threshold used, but 25 studies (33%) used thresholds defined by expert consensus in a guideline development process. There were five studies (7%) using a serum ferritin threshold defining iron deficiency derived from primary studies of bone marrow aspiration. Unified international thresholds of iron deficiency for women throughout pregnancy are required for accurate assessments of the global disease burden and for evaluating effectiveness of interventions addressing this problem.

Development of maternal and neonatal composite outcomes for trials evaluating management of late-onset pre-eclampsia.

Objective: Pre-eclampsia is associated with significant maternal and neonatal complications, and delivery is often expedited to minimise complications. For randomised trials evaluating interventions in women with late-onset (>34 weeks) mild to moderate pre-eclampsia, no single outcome has been identified to be the most clinically important. Existing composite outcomes with more than one clinically relevant endpoint to evaluate interventions in pre-eclampsia provide limited justification for selection of the components. Our objective was to develop robust, valid composite maternal and neonatal outcome measures for clinical trials evaluating interventions in women with late-onset mild and moderate pre-eclampsia. Study design: A two-generational Delphi method was used to identify these clinically important maternal and neonatal outcomes. Composite outcomes were developed based on biological plausibility, independence from each other, frequency of occurrence and level of importance. Results: The final maternal composite outcome included maternal death, eclampsia, stroke or reversible ischaemic neurological deficit, pulmonary oedema, major obstetric haemorrhage, need for positive inotropic support, haemolysis, elevated liver enzymes and low platelets syndrome and placental abruption; and the neonatal composite outcome included neonatal death, respiratory distress syndrome needing ventilator support and neurological outcomes as cystic periventricular leukomalacia and grade III/IV intraventricular haemorrhage. Conclusion: The composite outcomes developed will enable clinical trials to provide robust estimates on the effectiveness of the interventions in women with mild to moderate late onset pre-eclampsia to inform clinical practice. Caution is needed in the interpretation of composite outcomes due to variation in the importance of individual components.

Prediction of pre -eclampsia: Review of reviews

Primary studies and systematic reviews provide estimates of varying accuracy for different factors in the prediction of pre‐eclampsia. The aim of this study was to review published systematic reviews to collate evidence on the ability of available tests to predict pre‐eclampsia, to identify high‐value avenues for future research and to minimize future research waste in this field.

Development and validation of a prediction model for the risk of adverse outcomes in women with early onset pre-eclampsia (PREP): Prospective cohort study

Top Scoring Abstracts of the RCOG World Congress 2016, 20–22 June 2016, ICC Birmingham, United Kingdom

Methodological issues in the development of a prediction model for pre-eclampsia complications

PREP (Prediction of risks in early onset pre-eclampsia) is a multicentre prospective cohort study aiming to develop and validate a prediction model in women admitted with early-onset pre-eclampsia for risk of adverse maternal outcome at 48 hours and until discharge. The primary outcome was a composite of adverse maternal outcomes and the secondary outcome a composite of adverse fetal outcomes. The planned model includes multiple predictor variables in combination to predict the risk of adverse outcomes in individual patients. We highlight the methodological challenges encountered in model development. The predictor variables were pre-selected based on symptoms, signs and results of investigations routinely taken during management of pre-eclampsia. Challenges included accounting for correlation between variables, choosing the most abnormal variable within a time period or from a pre-determined time point, inconsistency in ascertainment of the data points ie blood results available later than the signs and symptoms, modelling a combination of binary, ordinal and continuous variables and the approach in prioritisation of these variables. Clinician management such as anti-hypertensives and magnesium sulphate will affect the relationship between the predictor and outcome. We will include clinical management as a covariate and assess consistency in model performance across different treatment groups to account for this. Selecting the optimum type of prediction model posed a further challenge. Logistic regression focuses on the relationship between predictor variables and adverse outcomes whereas survival analysis takes into account the time to develop the outcome. The former may be statistically more suitable but the latter clinically more useful.

Development of maternal and neonatal composite outcomes for trials evaluating timing of delivery in women with pre-eclampsia

Composite outcomes comprising more than one clinically relevant end point are used in clinical trials where there is no single important outcome or the outcome is very rare. Pre-eclampsia is associated with significant maternal and neonatal complications and delivery is often expedited to minimise complications. There is a need for a randomised trial to evaluate the timing of delivery in women with mild to moderate pre-eclampsia at late preterm gestation. No single outcome has been identified to be the most clinically important, reflecting the multisystemic nature of pre-eclampsia. We developed composite maternal and neonatal outcomes to be considered as the primary outcome measure for a clinical trial in this area. A two-generational Delphi method was used to identify these clinically important maternal and neonatal outcomes. Composite outcomes were developed based on biological plausibility, independence from each other, equal importance and frequency of occurrence. The final maternal composite outcome included maternal death, eclampsia, stroke or reversible ischaemic neurological deficit, pulmonary oedema, major obstetric haemorrhage, infusion of a third anti-hypertensive or need for positive ionotropic support, HELLP (haemolysis, elevated liver enzymes and low platelets) syndrome and placental abruption; and the neonatal composite outcome included neonatal death, respiratory distress syndrome needing ventilator support and neurological outcomes as cystic periventricular leukomalacia and grade III/IV intraventricular haemorrhage. The composite outcomes developed will enable clinical trials on the timing of delivery in women with mild to moderate pre-eclampsia to provide robust estimates for the intervention to be implemented in clinical practice.

Sample size in a prognostic study: prep (prediction of risks in early onset pre-eclampsia).

Background Significant numbers of studies struggle to recruit to target and request extension of time or additional funding. PREP is a study to develop a prediction model for adverse maternal and fetal outcomes in women with early onset pre-eclampsia. Pre-eclampsia is a condition in pregnancy associated with raised blood pressure and proteinuria and is one of the main causes of maternal and fetal mortality and morbidity. Accurate prediction of risks will aid clinicians in planning appropriate management.