Validation and development of models using clinical, biochemical and ultrasound markers for predicting pre-eclampsia: an individual participant data meta-analysis.

BACKGROUND: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk is needed to plan management. OBJECTIVES: To assess the performance of existing pre-eclampsia prediction models and to develop and validate models for pre-eclampsia using individual participant data meta-analysis. We also estimated the prognostic value of individual markers. DESIGN: This was an individual participant data meta-analysis of cohort studies. SETTING: Source data from secondary and tertiary care. PREDICTORS: We identified predictors from systematic reviews, and prioritised for importance in an international survey. PRIMARY OUTCOMES: Early-onset (delivery at < 34 weeks' gestation), late-onset (delivery at ≥ 34 weeks' gestation) and any-onset pre-eclampsia. ANALYSIS: We externally validated existing prediction models in UK cohorts and reported their performance in terms of discrimination and calibration. We developed and validated 12 new models based on clinical characteristics, clinical characteristics and biochemical markers, and clinical characteristics and ultrasound markers in the first and second trimesters. We summarised the data set-specific performance of each model using a random-effects meta-analysis. Discrimination was considered promising for C-statistics of ≥ 0.7, and calibration was considered good if the slope was near 1 and calibration-in-the-large was near 0. Heterogeneity was quantified using I2 and τ2. A decision curve analysis was undertaken to determine the clinical utility (net benefit) of the models. We reported the unadjusted prognostic value of individual predictors for pre-eclampsia as odds ratios with 95% confidence and prediction intervals. RESULTS: The International Prediction of Pregnancy Complications network comprised 78 studies (3,570,993 singleton pregnancies) identified from systematic reviews of tests to predict pre-eclampsia. Twenty-four of the 131 published prediction models could be validated in 11 UK cohorts. Summary C-statistics were between 0.6 and 0.7 for most models, and calibration was generally poor owing to large between-study heterogeneity, suggesting model overfitting. The clinical utility of the models varied between showing net harm to showing minimal or no net benefit. The average discrimination for IPPIC models ranged between 0.68 and 0.83. This was highest for the second-trimester clinical characteristics and biochemical markers model to predict early-onset pre-eclampsia, and lowest for the first-trimester clinical characteristics models to predict any pre-eclampsia. Calibration performance was heterogeneous across studies. Net benefit was observed for International Prediction of Pregnancy Complications first and second-trimester clinical characteristics and clinical characteristics and biochemical markers models predicting any pre-eclampsia, when validated in singleton nulliparous women managed in the UK NHS. History of hypertension, parity, smoking, mode of conception, placental growth factor and uterine artery pulsatility index had the strongest unadjusted associations with pre-eclampsia. LIMITATIONS: Variations in study population characteristics, type of predictors reported, too few events in some validation cohorts and the type of measurements contributed to heterogeneity in performance of the International Prediction of Pregnancy Complications models. Some published models were not validated because model predictors were unavailable in the individual participant data. CONCLUSION: For models that could be validated, predictive performance was generally poor across data sets. Although the International Prediction of Pregnancy Complications models show good predictive performance on average, and in the singleton nulliparous population, heterogeneity in calibration performance is likely across settings. FUTURE WORK: Recalibration of model parameters within populations may improve calibration performance. Additional strong predictors need to be identified to improve model performance and consistency. Validation, including examination of calibration heterogeneity, is required for the models we could not validate. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015029349. 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. 24, No. 72. See the NIHR Journals Library website for further project information.

WHAT IS THE PROBLEM?: Pre-eclampsia, a condition in pregnancy that results in raised blood pressure and protein in the urine, is a major cause of complications for the mother and baby. WHAT IS NEEDED?: A way of accurately identifying women at high risk of pre-eclampsia to allow clinicians to start preventative interventions such as administering aspirin or frequently monitoring women during pregnancy. WHERE ARE THE RESEARCH GAPS?: Although over 100 tools (models) have been reported worldwide to predict pre-eclampsia, to date their performance in women managed in the UK NHS is unknown. WHAT DID WE PLAN TO DO?: We planned to comprehensively identify all published models that predict the risk of pre-eclampsia occurring at any time during pregnancy and to assess if this prediction is accurate in the UK population. If the existing models did not perform satisfactorily, we aimed to develop new prediction models. WHAT DID WE FIND?: We formed the International Prediction of Pregnancy Complications network, which provided data from a large number of studies (78 studies, 25 countries, 125 researchers, 3,570,993 singleton pregnancies). We were able to assess the performance of 24 out of the 131 models published to predict pre-eclampsia in 11 UK data sets. The models did not accurately predict the risk of pre-eclampsia across all UK data sets, and their performance varied within individual data sets. We developed new prediction models that showed promising performance on average across all data sets, but their ability to correctly identify women who develop pre-eclampsia varied between populations. The models were more clinically useful when used in the care of first-time mothers pregnant with one child, compared to a strategy of treating them all as if they were at high-risk of pre-eclampsia. WHAT DOES THIS MEAN?: Before using the International Prediction of Pregnancy Complications models in various populations, they need to be adjusted for characteristics of the particular population and the setting of application.

External validation of prognostic models predicting pre-eclampsia: individual participant data meta-analysis.

BACKGROUND: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk during pregnancy is required to plan management. Although there are many published prediction models for pre-eclampsia, few have been validated in external data. Our objective was to externally validate published prediction models for pre-eclampsia using individual participant data (IPD) from UK studies, to evaluate whether any of the models can accurately predict the condition when used within the UK healthcare setting. METHODS: IPD from 11 UK cohort studies (217,415 pregnant women) within the International Prediction of Pregnancy Complications (IPPIC) pre-eclampsia network contributed to external validation of published prediction models, identified by systematic review. Cohorts that measured all predictor variables in at least one of the identified models and reported pre-eclampsia as an outcome were included for validation. We reported the model predictive performance as discrimination (C-statistic), calibration (calibration plots, calibration slope, calibration-in-the-large), and net benefit. Performance measures were estimated separately in each available study and then, where possible, combined across studies in a random-effects meta-analysis. RESULTS: Of 131 published models, 67 provided the full model equation and 24 could be validated in 11 UK cohorts. Most of the models showed modest discrimination with summary C-statistics between 0.6 and 0.7. The calibration of the predicted compared to observed risk was generally poor for most models with observed calibration slopes less than 1, indicating that predictions were generally too extreme, although confidence intervals were wide. There was large between-study heterogeneity in each model's calibration-in-the-large, suggesting poor calibration of the predicted overall risk across populations. In a subset of models, the net benefit of using the models to inform clinical decisions appeared small and limited to probability thresholds between 5 and 7%. CONCLUSIONS: The evaluated models had modest predictive performance, with key limitations such as poor calibration (likely due to overfitting in the original development datasets), substantial heterogeneity, and small net benefit across settings. The evidence to support the use of these prediction models for pre-eclampsia in clinical decision-making is limited. Any models that we could not validate should be examined in terms of their predictive performance, net benefit, and heterogeneity across multiple UK settings before consideration for use in practice. TRIAL REGISTRATION: PROSPERO ID: CRD42015029349 .

Do nuclear magnetic resonance (NMR)-based metabolomics improve the prediction of pregnancy-related disorders? Findings from a UK birth cohort with independent validation.

BACKGROUND: Prediction of pregnancy-related disorders is usually done based on established and easily measured risk factors. Recent advances in metabolomics may provide earlier and more accurate prediction of women at risk of pregnancy-related disorders. METHODS: We used data collected from women in the Born in Bradford (BiB; n = 8212) and UK Pregnancies Better Eating and Activity Trial (UPBEAT; n = 859) studies to create and validate prediction models for pregnancy-related disorders. These were gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HDP), small for gestational age (SGA), large for gestational age (LGA) and preterm birth (PTB). We used ten-fold cross-validation and penalised regression to create prediction models. We compared the predictive performance of (1) risk factors (maternal age, pregnancy smoking, body mass index (BMI), ethnicity and parity) to (2) nuclear magnetic resonance-derived metabolites (N = 156 quantified metabolites, collected at 24-28 weeks gestation) and (3) combined risk factors and metabolites. The multi-ethnic BiB cohort was used for training and testing the models, with independent validation conducted in UPBEAT, a multi-ethnic study of obese pregnant women. RESULTS: Maternal age, pregnancy smoking, BMI, ethnicity and parity were retained in the combined risk factor and metabolite models for all outcomes apart from PTB, which did not include maternal age. In addition, 147, 33, 96, 51 and 14 of the 156 metabolite traits were retained in the combined risk factor and metabolite model for GDM, HDP, SGA, LGA and PTB, respectively. These include cholesterol and triglycerides in very low-density lipoproteins (VLDL) in the models predicting GDM, HDP, SGA and LGA, and monounsaturated fatty acids (MUFA), ratios of MUFA to omega 3 fatty acids and total fatty acids, and a ratio of apolipoprotein B to apolipoprotein A-1 (APOA:APOB1) were retained predictors for GDM and LGA. In BiB, discrimination for GDM, HDP, LGA and SGA was improved in the combined risk factors and metabolites models. Risk factor area under the curve (AUC 95% confidence interval (CI)): GDM (0.69 (0.64, 0.73)), HDP (0.74 (0.70, 0.78)) and LGA (0.71 (0.66, 0.75)), and SGA (0.59 (0.56, 0.63)). Combined risk factor and metabolite models AUC 95% (CI): GDM (0.78 (0.74, 0.81)), HDP (0.76 (0.73, 0.79)) and LGA (0.75 (0.70, 0.79)), and SGA (0.66 (0.63, 0.70)). For GDM, HDP and LGA, but not SGA, calibration was good for a combined risk factor and metabolite model. Prediction of PTB was poor for all models. Independent validation in UPBEAT at 24-28 weeks and 15-18 weeks gestation confirmed similar patterns of results, but AUCs were attenuated. CONCLUSIONS: Our results suggest a combined risk factor and metabolite model improves prediction of GDM, HDP and LGA, and SGA, when compared to risk factors alone. They also highlight the difficulty of predicting PTB, with all models performing poorly.

Distribution and Function of Prostaglandin E2 Receptors in Mouse Uterus: Translational Value for Human Reproduction.

Prostaglandin (PG) E analogs are used clinically to ripen the cervix and induce labor. However, selective receptor agonists may have potential to improve induction response rates or manage unwanted uterine hypercontractility in conditions such as dysmenorrhea and preterm labor. To characterize their therapeutic value, PGE2 analogs were used to investigate the functional E-type prostanoid (EP) receptor population in isolated human uterus. Responsiveness in mouse tissues was also examined to validate its use as a preclinical model. Uterine samples were obtained from mice at dioestrus (n = 12), term gestation (n = 14), and labor (n = 12) and from the lower uterus of women undergoing hysterectomy (n = 12) or Caesarean section (n = 18). Vehicle and agonist effects were assessed using superfusion and immersion techniques. PGE2 evoked predominant excitatory responses in mouse and relaxation in human tissues. Selective EP4 agonists inhibited tissue activity in both nonpregnant species, while the EP2 mimetic CP533536 also attenuated uterine contractions throughout gestation. The uterotonic effects of the EP3/1 agonist sulprostone were more pronounced than the EP1 agonist ONO-D1-004, corresponding to abundant EP3 receptor expression in all samples. The contractile phenotype in mouse compared with human uteri may relate to regional differences as well as high expression of EP3 receptor transcripts. Similarities in nonpregnant and gestational tissues across species suggest that EP3 may represent a valuable translational drug target for preventing uterine hypercontractility by employing a selective antagonist. SIGNIFICANCE STATEMENT: This research validates the use of nonpregnant mice for preclinical drug discovery of uterine EP receptor targets. To determine the utility of novel drugs and delivery systems at term pregnancy and labor, pharmacological agents interacting with EP3 receptors have clear translational value.

Publisher Correction: Population reference and healthy standard blood pressure range charts in pregnancy: findings from the Born in Bradford cohort study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

An evaluation of the influence of the publication of the UK National Institute for health and Care Excellence's guidance on hypertension in pregnancy: a retrospective analysis of clinical practice.

BACKGROUND: The UK National Institute for health and Care Excellence (NICE) publish guidance aimed at standardising practice. Evidence regarding how well recommendations are implemented and what clinicians think about guidance is limited. We aimed to establish the extent to which the NICE Hypertension in pregnancy (HIP) guidance has influenced care and assess clinician's attitudes to this guidance. METHODS: Five maternity units in the Midlands and North of England took part in the retrospective evaluation of 2490 birth records from randomly selected dates in 2008-2010 and 2013-2015. The proportion of women where care was adhered to before (2008-2010) and after (2013-2015) guidance publication was examined and differences estimated. Eleven midwives and obstetricians employed by Bradford Hospitals were interviewed. RESULTS: The proportion of high risk women prescribed Aspirin rose (before 14%, after 54%, p = < 0.01 (confidence interval of change (CI) 37, 43%) as well as for moderate risk women (before 3%, after 54%, p = < 0.01, CI 48, 54%) following guidance publication. Three quarters had blood pressure and a third proteinuria measured at every antenatal visit before and after guidance. Early birth < 37 weeks and ≥ 37 weeks gestation was more frequently offered after guidance publication than before (< 37 weeks: before 9%, after 18%, p = 0.01, CI 2, 16% and ≥ 37 weeks before 30%, after 52%, p = < 0.01, CI 9, 35%). Few were informed of future risk of developing a hypertensive disorder or had a documented postnatal review; however there was an increase in women advised to see their GP for this review (58% before and 90% after guidance p = < 0.01, CI 24, 39%). All clinicians said the NICE HIP guidance was informative and provided robust evidence, however they said length of the document made use in practice challenging. They did not always access NICE guidance, preferring to use local guidance at least initially; both obstetricians and midwives said they accessed NICE guidance for in-depth information. CONCLUSIONS: NICE HIP guidance is valued, used by clinicians and has influenced important aspects of care that may help improve outcomes for women who develop hypertension or pre-eclampsia, however some recommendations have had limited impact and therefore interventions are required to improve adherence.

Maternal Physical Activity and Neonatal Cord Blood Lipid Levels: Findings From a Prospective Pregnancy Cohort.

BACKGROUND: Physical activity performed while pregnant is beneficially associated with maternal cardiovascular health. It is unknown if benefits extend to neonatal cardiovascular health. This study investigated associations of maternal physical activity with neonatal cord blood lipid and lipoprotein concentrations. METHODS: Cord blood lipids were measured at birth in a pseudorandomly selected subgroup of Born in Bradford birth cohort participants (N = 1634). Pregnant women were grouped into 4 activity categories (inactive/somewhat active/moderately active/active) based on their self-reported physical activity at 26- to 28-weeks gestation. Regression was used to calculate adjusted mean differences in neonatal cord blood lipid concentrations among the 4 groups of physical activity. RESULTS: Maternal physical activity was associated with higher neonatal cord blood high-density lipoprotein cholesterol. Cord blood high-density lipoprotein cholesterol was higher in neonates of women who were somewhat and moderately active compared with neonates of women who were inactive. There were no associations of pregnancy physical activity with triglycerides, low-density lipoprotein, very low-density lipoprotein cholesterol, or adiponectin levels. CONCLUSIONS: Maternal physical activity is favorably associated with neonatal cord blood high-density lipoprotein cholesterol levels. This novel beneficial finding highlights the potential for physical activity in pregnancy to aid the early prevention of cardiovascular disease.

Associations of Pregnancy Physical Activity with Maternal Cardiometabolic Health, Neonatal Delivery Outcomes and Body Composition in a Biethnic Cohort of 7305 Mother-Child Pairs: The Born in Bradford Study.

OBJECTIVE: Physical activity is advocated for a range of benefits to the uncomplicated pregnancy. We investigated associations of mid-pregnancy physical activity with maternal and neonatal health in white British and Pakistani-origin women from a deprived urban setting. METHODS: The study was performed in 6921 pregnant women (53% Pakistani-origin) who contributed data for 7305 singleton births. At 26-28 weeks gestation, women were grouped into four activity levels (inactive/somewhat active/moderately active/active) based on their self-reported physical activity. Linear regression with robust standard errors was used to calculate adjusted mean differences in health markers between the four groups of physical activity (reference group: inactive). RESULTS: Three-quarters (74%) of Pakistani-origin women and 39% of white British women were inactive. Trend-tests revealed that more active white British women tended to be less adipose, had lower fasting and postload glucose levels, lower triglyceride concentrations, and their babies were less adipose (smaller triceps and subscapular skinfolds) than less active white British women. Somewhat active Pakistani-origin women exhibited lower triglyceride concentrations and systolic blood pressure, higher high-density lipoprotein cholesterol levels, and their babies were less adipose (smaller mid-upper arm and abdominal circumferences; lower cord-blood leptin concentration) compared to inactive Pakistani-origin women. No associations were observed for gestational age or birth weight. CONCLUSIONS: Physical activity performed mid-pregnancy was beneficially associated with maternal cardiometabolic health and neonatal adiposity, without influencing gestational age or birth weight. Associations were dose-dependent in white British women, and even a small amount of mid-pregnancy physical activity appeared to benefit some health markers in Pakistani-origin women.

Population reference and healthy standard blood pressure range charts in pregnancy: findings from the Born in Bradford cohort study.

Women who develop gestational hypertension are at increased risk of adverse perinatal and longer-term outcomes. Reference charts may aid early detection of raised blood pressure (BP) and in doing so reduce adverse outcome risk. We used repeated BP measurements to produce 'reference' (whole population) and 'standard' (healthy pregnancies only) gestational-age-specific BP charts for all pregnant women (irrespective of ethnicity) and for White British (WB) and Pakistani (P) women. We included 9218 women recruited to the Born in Bradford study with 74,770 BPs. 19% of the whole population, 11% and 25% of WB and P women respectively were defined as healthy pregnancies. For reference and standard charts, for all women and each ethnic group, SBP/DBP at 12 and 20 weeks gestation was similar before rising at 37 weeks. DBP/SBP of reference charts for all women and for each ethnic group were higher than those of the corresponding standard charts. Compared to WB, P women had lower SBP/DBP at 12, 20 and 37 weeks gestation. To conclude; maternal population BP reference charts are higher compared to standard charts (healthy pregnancies) and are influenced by ethnicity.

Blood pressure change across pregnancy in white British and Pakistani women: analysis of data from the Born in Bradford cohort.

The incidence of gestational hypertension (GH) and pre-eclampsia (PE) is increasing. Use of blood pressure (BP) change patterns may improve early detection of BP abnormalities. We used Linear spline random-effects models to estimate BP patterns across pregnancy for white British and Pakistani women. Pakistani women compared to white British women had lower BP during the first two trimesters of pregnancy, irrespective of the development of GH or PE or presence of a risk factor. Pakistani compared to white British women with GH and PE showed steeper BP increases towards the end of pregnancy. Pakistani women were half as likely to develop GH, but as likely to develop PE than white British women. To conclude; BP trajectories differ by ethnicity. Because GH developed evenly from 20 weeks gestation, and PE occurred more commonly after 36 weeks in both ethnic groups, the lower BP up to the third trimester in Pakistani women resulted in a lower GH rate, whereas PE rates, influenced by the steep third trimester BP increase were similar. Criteria for diagnosing GH and PE may benefit from considering ethnic differences in BP change across pregnancy.

Associations of maternal vitamin D, PTH and calcium with hypertensive disorders of pregnancy and associated adverse perinatal outcomes: Findings from the Born in Bradford cohort study.

Vitamin D and parathyroid hormone (PTH) regulate mineral metabolism and are required to maintain calcium levels. Vitamin D deficiency is common, particularly during pregnancy, and has been associated with hypertensive disorders of pregnancy. We sought to determine whether maternal 25(OH)D, PTH and calcium concentrations at 26 weeks gestation are associated with adverse outcomes of pregnancy and establish whether these differ by ethnicity. This study included 476 White British and 534 Pakistani origin mother-offspring pairs from the Born in Bradford cohort study. We used multinomial or logistic regression to explore the association between vitamin D, PTH and calcium with gestational hypertension (GH), pre-eclampsia (PE), caesarean section (CS), preterm birth (PTB) and small for gestational age (SGA). Pakistani women had lower 25(OH)D (median 13.0 vs 36.0 nmol/L), higher PTH (median 7.7 vs 3.3 pmol/L) and similar calcium concentrations compared to White British women. In Pakistani women, higher concentrations of 25(OH)D were associated with a 60% increased odds of GH, and a 37% reduced odds of SGA; PTH was associated with a 45% reduction in the odds of GH. In White British women, each 1 SD increase in calcium concentration was associated with a 34% increase in developing GH but a 33% reduction in the odds of PTB. Associations with PE and CS were consistent with the null. In conclusion, there are ethnic differences in the associations of 25(OH)D, PTH and calcium with important perinatal outcomes. Future research would benefit from examining the associations of 25(OH)D, PTH and calcium together with a range of perinatal outcomes in order to assess the risk-benefit action of each.

Author Correction: Associations of social and economic and pregnancy exposures with blood pressure in UK White British and Pakistani children age 4/5.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Omega-3 polyunsaturated fatty acids favourably modulate cardiometabolic biomarkers in type 2 diabetes: a meta-analysis and meta-regression of randomized controlled trials.

BACKGROUND: Randomized controlled trials (RCTs) suggest that supplementation with omega-3 polyunsaturated fatty acids (n-3PUFAs) may favourably modify cardiometabolic biomarkers in type 2 diabetes (T2DM). Previous meta-analyses are limited by insufficient sample sizes and omission of meta-regression techniques, and a large number of RCTs have subsequently been published since the last comprehensive meta-analysis. Updated information regarding the impact of dosage, duration or an interaction between these two factors is therefore warranted. The objective was to comprehensively assess the effect of n-3PUFAs supplementation on cardiometabolic biomarkers including lipid profiles, inflammatory parameters, blood pressure, and indices of glycaemic control, in people with T2DM, and identify whether treatment dosage, duration or an interaction thereof modify these effects. METHODS: Databases including PubMed and MEDLINE were searched until 13th July 2017 for RCTs investigating the effect of n-3PUFAs supplementation on lipid profiles, inflammatory parameters, blood pressure, and indices of glycaemic control. Data were pooled using random-effects meta-analysis and presented as standardised mean difference (Hedges g) with 95% confidence intervals (95% CI). Meta-regression analysis was performed to investigate the effects of duration of supplementation and total dosage of n-3PUFAs as moderator variables where appropriate. RESULTS: A total of 45 RCTs were identified, involving 2674 people with T2DM. n-3PUFAs supplementation was associated with significant reductions in LDL [ES: - 0.10, (95% CI - 0.17, - 0.03); p = 0.007], VLDL (ES: - 0.26 (- 0.51, - 0.01); p = 0.044], triglycerides (ES: - 0.39 (- 0.55, - 0.24; p ≤ 0.001] and HbA1c (ES: - 0.27 (- 0.48, - 0.06); p = 0.010]. Moreover, n-3PUFAs supplementation was associated with reduction in plasma levels of TNF-α [ES: - 0.59 (- 1.17, - 0.01); p = 0.045] and IL-6 (ES: - 1.67 (- 3.14, - 0.20); p = 0.026]. All other lipid markers, indices of glycaemic control, inflammatory parameters, and blood pressure remained unchanged (p > 0.05). CONCLUSIONS: n-3PUFAs supplementation produces favourable hypolipidemic effects, a reduction in pro-inflammatory cytokine levels and improvement in glycaemia. Neither duration nor dosage appear to explain the observed heterogeneity in response to n-3PUFAs. Trial registration This trial was registered at http://www.crd.york.ac.uk as CRD42016050802.

Associations of social and economic and pregnancy exposures with blood pressure in UK White British and Pakistani children age 4/5.

South Asians have higher rates of coronary heart disease (CHD) than White European individuals. Blood pressure (BP) is one of the most important risk factors for CHD and ethnic differences in BP have been identified in childhood. Early life exposures could explain some of these differences. We examined associations of family social and economic and maternal pregnancy exposures and BP at age 4/5 in 1644 White British and 1824 Pakistani mother-offspring pairs from the Born in Bradford study. We found that systolic BP was similar but diastolic BP was higher, in Pakistani compared to White British children (adjusted mean differences were -0.170 mmHg 95% CI -0.884, 0.543 for systolic BP; 1.328 mmHg 95% CI 0.592, 2.064 for diastolic BP). Social and economic exposures were not associated with BP in either ethnic group. Maternal BMI was positively associated with BP in both groups but this association was mediated by child BMI. Only gestational hypertension was associated with child systolic and diastolic BP and this was only identified in Pakistani mother-offspring pairs. These findings suggest that Pakistani populations may have a different BP trajectory compared to White British groups and that this is already evident at age 4/5 years.

Association of maternal exposures with adiposity at age 4/5 years in white British and Pakistani children: findings from the Born in Bradford study.

AIMS/HYPOTHESIS: There is evidence that, from birth, South Asians are fatter, for a given body mass, than Europeans. The role of developmental overnutrition related to maternal adiposity and circulating glucose in these ethnic differences is unclear. Our aim was to compare associations of maternal gestational adiposity and glucose with adiposity at age 4/5 years in white British and Pakistani children. METHODS: Born in Bradford is a prospective study of children born between 2007 and 2010 in Bradford, UK. Mothers completed an OGTT at 27-28 weeks of gestation. We examined associations between maternal gestational BMI, fasting glucose, post-load glucose and diabetes (GDM) and offspring height, weight, BMI and subscapular skinfold (SSF) and triceps skinfold (TSF) thickness at age 4/5 years, using data from 6060 mother-offspring pairs (2717 [44.8%] white British and 3343 [55.2%] Pakistani). RESULTS: Pakistani mothers had lower BMI and higher fasting and post-load glucose and were twice as likely to have GDM (defined using modified WHO criteria) than white British women (15.8% vs 6.9%). Pakistani children were taller and had lower BMI than white British children; they had similar SSF and lower TSF. Maternal BMI was positively associated with the adiposity of offspring in both ethnic groups, with some evidence of stronger associations in Pakistani mother-offspring pairs. For example, the difference in adjusted mean BMI per 1 kg/m2 greater maternal BMI was 0.07 kg/m2 (95% CI 0.05, 0.08) and 0.10 kg/m2 (95% CI 0.09. 0.11) in white British and Pakistani children, respectively, with equivalent results for SSF being 0.07 mm (95% CI 0.05, 0.08) and 0.09 mm (95% CI 0.08. 0.11) (p for ethnic difference < 0.03 for both). There was no strong evidence of association of fasting and post-load glucose, or GDM, with outcomes in either group. CONCLUSIONS/INTERPRETATION: At age 4/5 years, Pakistani children are taller and lighter than white British children. While maternal BMI is positively associated with offspring adiposity, gestational glycaemia is not clearly related to offspring adiposity in either ethnic group.

Different strategies for diagnosing gestational diabetes to improve maternal and infant health.

BACKGROUND: Gestational diabetes mellitus (GDM) is carbohydrate intolerance resulting in hyperglycaemia with onset or first recognition during pregnancy. If untreated, perinatal morbidity and mortality may be increased. Accurate diagnosis allows appropriate treatment. Use of different tests and different criteria will influence which women are diagnosed with GDM. This is an update of a review published in 2011 and 2015. OBJECTIVES: To evaluate and compare different testing strategies for diagnosis of gestational diabetes mellitus to improve maternal and infant health while assessing their impact on healthcare service costs. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP) (9 January 2017) and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised trials if they evaluated tests carried out to diagnose GDM. We excluded studies that used a quasi-random model, cluster-randomised or cross-over trials. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. The quality of the evidence was assessed using the GRADE approach. MAIN RESULTS: We included a total of seven small trials, with 1420 women. One trial including 726 women was identified by this update and examined the two step versus one step approach. These trials were assessed as having varying risk of bias, with few outcomes reported. We prespecified six outcomes to be assessed for quality using the GRADE approach for one comparison: 75 g oral glucose tolerance test (OGTT) versus 100 g OGTT; data for only one outcome (diagnosis of gestational diabetes) were available for assessment. One trial compared three different methods of delivering glucose: a candy bar (39 women), a 50 g glucose polymer drink (40 women) and a 50 g glucose monomer drink (43 women). We have included the results reported by this trial as separate comparisons. No trial reported on measures of costs of health services.We examined six main comparisons. 75 g OGTT versus 100 g OGTT (1 trial, 248 women): women who received 75 g OGTT had a higher relative risk of being diagnosed with GDM (risk ratio (RR) 2.55, 95% confidence interval (CI) 0.96 to 6.75; very-low quality evidence). No data were reported for the following additional outcomes prespecified for GRADE assessment: caesarean section, macrosomia > 4.5 kg or however defined in the trial, long-term type 2 diabetes maternal, long-term type 2 diabetes infant and economic costs. Candy bar versus 50 g glucose monomer drink (1 trial, 60 women): more women receiving the candy bar, rather than glucose monomer, preferred the taste of the candy bar (RR 0.60, 95% CI 0.42 to 0.86) and 1-hour glucose was less with the candy bar. There were no differences in the other outcomes reported (maternal side effects). No infant outcomes were reported or any review primary outcomes. 50 g glucose polymer drink versus 50 g glucose monomer drink (3 trials, 239 women): mean difference (MD) in gestation at birth was -0.80 weeks (1 trial, 100 women; 95% CI -1.69 to 0.09). Total side effects were less common with the glucose polymer drink (1 trial, 63 women; RR 0.21, 95% CI 0.07 to 0.59), and no clear difference in taste acceptability was reported (1 trial, 63 women; RR 0.99, 95% CI 0.76 to 1.29). Fewer women reported nausea following the 50 g glucose polymer drink compared with the 50 g glucose monomer drink (1 trial, 66 women; RR 0.29, 95% CI 0.11 to 0.78). No other measures of maternal morbidity or outcomes for the infant were reported. 50 g glucose food versus 50 g glucose drink (1 trial, 30 women): women receiving glucose in their food, rather than as a drink, reported fewer side effects (RR 0.08, 95% CI 0.01 to 0.56). No clear difference was noted in the number of women requiring further testing (RR 0.14, 95% CI 0.01 to 2.55). No other measures of maternal morbidity or outcome were reported for the infant or review primary outcomes. 75 g OGTT World Health Organization (WHO) criteria versus 75 g OGTT American Diabetes Association (ADA) criteria (1 trial, 116 women): no clear differences in included outcomes were observed between women who received the 75 g OGTT and were diagnosed using criteria based on WHO (1999) recommendations and women who received the 75 g OGTT and were diagnosed using criteria recommended by the ADA (1979). Outcomes measured included diagnosis of gestational diabetes (RR 1.47, 95% CI 0.66 to 3.25), caesarean section (RR 1.07, 95% CI 0.85 to 1.35), macrosomia defined as > 90th percentile by ultrasound or birthweight equal to or exceeding 4000 g (RR 0.73, 95% CI 0.19 to 2.79), stillbirth (RR 0.49, 95% CI 0.02 to 11.68) and instrumental birth (RR 0.21, 95% CI 0.01 to 3.94). No other secondary outcomes were reported. Two-step approach (50 g oral glucose challenge test followed by selective 100 g OGTT Carpenter and Coustan criteria) versus one-step approach (universal 75 g OGTT ADA criteria) (1 trial, 726 women): women allocated the two-step approach had a lower risk of being diagnosed with GDM at 11 to 14 weeks' gestation compared to women allocated the one-step approach (RR 0.51, 95% CI 0.28 to 0.95). No other primary or secondary outcomes were reported. AUTHORS' CONCLUSIONS: There is insufficient evidence to suggest which strategy is best for diagnosing GDM. Large randomised trials are required to establish the best strategy for correctly identifying women with GDM.

Treatments for gestational diabetes: a systematic review and meta-analysis.

OBJECTIVE: To investigate the effectiveness of different treatments for gestational diabetes mellitus (GDM). DESIGN: Systematic review, meta-analysis and network meta-analysis. METHODS: Data sources were searched up to July 2016 and included MEDLINE and Embase. Randomised trials comparing treatments for GDM (packages of care (dietary and lifestyle interventions with pharmacological treatments as required), insulin, metformin, glibenclamide (glyburide)) were selected by two authors and double checked for accuracy. Outcomes included large for gestational age, shoulder dystocia, neonatal hypoglycaemia, caesarean section and pre-eclampsia. We pooled data using random-effects meta-analyses and used Bayesian network meta-analysis to compare pharmacological treatments (ie, including treatments not directly compared within a trial). RESULTS: Forty-two trials were included, the reporting of which was generally poor with unclear or high risk of bias. Packages of care varied in their composition and reduced the risk of most adverse perinatal outcomes compared with routine care (eg, large for gestational age: relative risk0.58 (95% CI 0.49 to 0.68; I2=0%; trials 8; participants 3462). Network meta-analyses suggest that metformin had the highest probability of being the most effective treatment in reducing the risk of most outcomes compared with insulin or glibenclamide. CONCLUSIONS: Evidence shows that packages of care are effective in reducing the risk of most adverse perinatal outcomes. However, trials often include few women, are poorly reported with unclear or high risk of bias and report few outcomes. The contribution of each treatment within the packages of care remains unclear. Large well-designed and well-conducted trials are urgently needed. TRIAL REGISTRATION NUMBER: PROSPERO CRD42013004608.

Lifestyle interventions for the treatment of women with gestational diabetes.

BACKGROUND: Gestational diabetes (GDM) is glucose intolerance, first recognised in pregnancy and usually resolving after birth. GDM is associated with both short- and long-term adverse effects for the mother and her infant. Lifestyle interventions are the primary therapeutic strategy for many women with GDM. OBJECTIVES: To evaluate the effects of combined lifestyle interventions with or without pharmacotherapy in treating women with gestational diabetes. SEARCH METHODS: We searched the Pregnancy and Childbirth Group's Trials Register (14 May 2016), ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP) (14th May 2016) and reference lists of retrieved studies. SELECTION CRITERIA: We included only randomised controlled trials comparing a lifestyle intervention with usual care or another intervention for the treatment of pregnant women with GDM. Quasi-randomised trials were excluded. Cross-over trials were not eligible for inclusion. Women with pre-existing type 1 or type 2 diabetes were excluded. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by the Cochrane Collaboration. All selection of studies, data extraction was conducted independently by two review authors. MAIN RESULTS: Fifteen trials (in 45 reports) are included in this review (4501 women, 3768 infants). None of the trials were funded by a conditional grant from a pharmaceutical company. The lifestyle interventions included a wide variety of components such as education, diet, exercise and self-monitoring of blood glucose. The control group included usual antenatal care or diet alone. Using GRADE methodology, the quality of the evidence ranged from high to very low quality. The main reasons for downgrading evidence were inconsistency and risk of bias. We summarised the following data from the important outcomes of this review. Lifestyle intervention versus control groupFor the mother:There was no clear evidence of a difference between lifestyle intervention and control groups for the risk of hypertensive disorders of pregnancy (pre-eclampsia) (average risk ratio (RR) 0.70; 95% confidence interval (CI) 0.40 to 1.22; four trials, 2796 women; I2 = 79%, Tau2 = 0.23; low-quality evidence); caesarean section (average RR 0.90; 95% CI 0.78 to 1.05; 10 trials, 3545 women; I2 = 48%, Tau2 = 0.02; low-quality evidence); development of type 2 diabetes (up to a maximum of 10 years follow-up) (RR 0.98, 95% CI 0.54 to 1.76; two trials, 486 women; I2 = 16%; low-quality evidence); perineal trauma/tearing (RR 1.04, 95% CI 0.93 to 1.18; one trial, n = 1000 women; moderate-quality evidence) or induction of labour (average RR 1.20, 95% CI 0.99 to 1.46; four trials, n = 2699 women; I2 = 37%; high-quality evidence).More women in the lifestyle intervention group had met postpartum weight goals one year after birth than in the control group (RR 1.75, 95% CI 1.05 to 2.90; 156 women; one trial, low-quality evidence). Lifestyle interventions were associated with a decrease in the risk of postnatal depression compared with the control group (RR 0.49, 95% CI 0.31 to 0.78; one trial, n = 573 women; low-quality evidence).For the infant/child/adult:Lifestyle interventions were associated with a reduction in the risk of being born large-for-gestational age (LGA) (RR 0.60, 95% CI 0.50 to 0.71; six trials, 2994 infants; I2 = 4%; moderate-quality evidence). Birthweight and the incidence of macrosomia were lower in the lifestyle intervention group.Exposure to the lifestyle intervention was associated with decreased neonatal fat mass compared with the control group (mean difference (MD) -37.30 g, 95% CI -63.97 to -10.63; one trial, 958 infants; low-quality evidence). In childhood, there was no clear evidence of a difference between groups for body mass index (BMI) ≥ 85th percentile (RR 0.91, 95% CI 0.75 to 1.11; three trials, 767 children; I2 = 4%; moderate-quality evidence).There was no clear evidence of a difference between lifestyle intervention and control groups for the risk of perinatal death (RR 0.09, 95% CI 0.01 to 1.70; two trials, 1988 infants; low-quality evidence). Of 1988 infants, only five events were reported in total in the control group and there were no events in the lifestyle group. There was no clear evidence of a difference between lifestyle intervention and control groups for a composite of serious infant outcome/s (average RR 0.57, 95% CI 0.21 to 1.55; two trials, 1930 infants; I2 = 82%, Tau2 = 0.44; very low-quality evidence) or neonatal hypoglycaemia (average RR 0.99, 95% CI 0.65 to 1.52; six trials, 3000 infants; I2 = 48%, Tau2 = 0.12; moderate-quality evidence). Diabetes and adiposity in adulthood and neurosensory disability in later childhoodwere not prespecified or reported as outcomes for any of the trials included in this review. AUTHORS' CONCLUSIONS: Lifestyle interventions are the primary therapeutic strategy for women with GDM. Women receiving lifestyle interventions were less likely to have postnatal depression and were more likely to achieve postpartum weight goals. Exposure to lifestyle interventions was associated with a decreased risk of the baby being born LGA and decreased neonatal adiposity. Long-term maternal and childhood/adulthood outcomes were poorly reported.The value of lifestyle interventions in low-and middle-income countries or for different ethnicities remains unclear. The longer-term benefits or harms of lifestyle interventions remains unclear due to limited reporting.The contribution of individual components of lifestyle interventions could not be assessed. Ten per cent of participants also received some form of pharmacological therapy. Lifestyle interventions are useful as the primary therapeutic strategy and most commonly include healthy eating, physical activity and self-monitoring of blood glucose concentrations.Future research could focus on which specific interventions are most useful (as the sole intervention without pharmacological treatment), which health professionals should give them and the optimal format for providing the information. Evaluation of long-term outcomes for the mother and her child should be a priority when planning future trials. There has been no in-depth exploration of the costs 'saved' from reduction in risk of LGA/macrosomia and potential longer-term risks for the infants.