Antenatal dietary supplementation with myo-inositol for preventing gestational diabetes.

BACKGROUND: Gestational diabetes with onset or first recognition during pregnancy is an increasing problem worldwide. Myo-inositol, an isomer of inositol, is a naturally occurring sugar commonly found in cereals, corn, legumes and meat. Myo-inositol is one of the intracellular mediators of the insulin signal and correlates with insulin sensitivity in type 2 diabetes. The potential beneficial effect of improving insulin sensitivity suggests that myo-inositol may be useful for women in preventing gestational diabetes. This is an update of a review first published in 2015. OBJECTIVES: To assess if antenatal dietary supplementation with myo-inositol is safe and effective, for the mother and fetus, in preventing gestational diabetes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, WHO ICTRP (17 March 2022) and the reference lists of retrieved studies. SELECTION CRITERIA: We included published and unpublished randomised controlled trials (RCTs) including cluster-RCTs and conference abstracts, assessing the effects of myo-inositol for the prevention of gestational diabetes in pregnant women. We included studies that compared any dose of myo-inositol, alone or in a combination preparation, with no treatment, placebo or another intervention. Quasi-randomised and cross-over trials were not eligible. We excluded women with pre-existing type 1 or type 2 diabetes. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, assessed risk of bias and extracted the data. We checked the data for accuracy. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included seven RCTs (one conducted in Ireland, six conducted in Italy) reporting on 1319 women who were 10 weeks to 24 weeks pregnant at the start of the studies. The studies had relatively small sample sizes and the overall risk of bias was low. For the primary maternal outcomes, meta-analysis showed that myo-inositol may reduce the incidence of gestational diabetes (risk ratio (RR) 0.53, 95% confidence interval (CI) 0.31 to 0.90; 6 studies, 1140 women) and hypertensive disorders of pregnancy (RR 0.34, 95% CI 0.19 to 0.61; 5 studies, 1052 women). However, the certainty of the evidence was low to very low. For the primary neonatal outcomes, only one study measured the risk of a large-for-gestational-age infant and found myo-inositol was associated with both appreciable benefit and harm (RR 1.40, 95% CI 0.65 to 3.02; 1 study, 234 infants; low-certainty evidence). None of the included studies reported on the other primary neonatal outcomes (perinatal mortality, mortality or morbidity composite). For the secondary maternal outcomes, we are unclear about the effect of myo-inositol on weight gain during pregnancy (mean difference (MD) -0.25 kilogram (kg), 95% CI -1.26 to 0.75 kg; 4 studies, 831 women) and perineal trauma (RR 4.0, 95% CI 0.45 to 35.25; 1 study, 234 women) because the evidence was assessed as being very low-certainty. Further, myo-inositol may result in little to no difference in caesarean section (RR 0.91, 95% CI 0.77 to 1.07; 4 studies, 829 women; low-certainty evidence). None of the included studies reported on the other secondary maternal outcomes (postnatal depression and the development of subsequent type 2 diabetes mellitus). For the secondary neonatal outcomes, meta-analysis showed no neonatal hypoglycaemia (RR 3.07, 95% CI 0.90 to 10.52; 4 studies; 671 infants; very low-certainty evidence). However, myo-inositol may be associated with a reduction in the incidence of preterm birth (RR 0.35, 95% CI 0.17 to 0.70; 4 studies; 829 infants). There were insufficient data for a number of maternal and neonatal secondary outcomes, and no data were reported for any of the long-term childhood or adulthood outcomes, or for health service utilisation outcomes. AUTHORS' CONCLUSIONS: Evidence from seven studies shows that antenatal dietary supplementation with myo-inositol during pregnancy may reduce the incidence of gestational diabetes, hypertensive disorders of pregnancy and preterm birth. Limited data suggest that supplementation with myo-inositol may not reduce the risk of a large-for-gestational-age infant.  The current evidence is based on small studies that were not powered to detect differences in outcomes such as perinatal mortality and serious infant morbidity. Six of the included studies were conducted in Italy and one in Ireland, which raises concerns about the lack of generalisability to other settings. There is evidence of inconsistency among doses of myo-inositol, the timing of administration and study population. As a result, we downgraded the certainty of the evidence for many outcomes to low or very low certainty. Further studies for this promising antenatal intervention for preventing gestational diabetes are encouraged and should include pregnant women of different ethnicities and varying risk factors. Myo-inositol at different doses, frequency and timing of administration, should be compared with placebo, diet and exercise, and pharmacological interventions. Long-term follow-up should be considered and outcomes should include potential harms, including adverse effects.

Maternal postures for fetal malposition in labour for improving the health of mothers and their infants.

BACKGROUND: Fetal malposition (occipito-posterior and persistent occipito-transverse) in labour is associated with adverse maternal and infant outcomes. Whether use of maternal postures can improve these outcomes is unclear. This Cochrane Review of maternal posture in labour is one of two new reviews replacing a 2007 review of maternal postures in pregnancy and labour. OBJECTIVES: To assess the effect of specified maternal postures for women with fetal malposition in labour on maternal and infant morbidity compared to other postures.  SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (13 July 2021), and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) or cluster-RCTs conducted among labouring women with a fetal malposition confirmed by ultrasound or clinical examination, comparing a specified maternal posture with another posture. Quasi-RCTs and cross-over trials were not eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, risk of bias, and performed data extraction. We used mean difference (MD) for continuous variables, and risk ratios (RRs) for dichotomous variables, with 95% confidence intervals (CIs). We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included eight eligible studies with 1766 women.  All studies reported some form of random sequence generation but were at high risk of performance bias due to lack of blinding. There was a high risk of selection bias in one study, detection bias in two studies, attrition bias in two studies, and reporting bias in two studies. Hands and knees The use of hands and knees posture may have little to no effect on operative birth (average RR 1.14, 95% CI 0.87 to 1.50; 3 trials, 721 women; low-certainty evidence) and caesarean section (RR 1.34, 95% CI 0.96 to 1.87; 3 trials, 721 women; low-certainty evidence) but the evidence is uncertain; and very uncertain for epidural use (average RR 0.74, 95% CI 0.41 to 1.31; 2 trials, 282 women; very low-certainty evidence), instrumental vaginal birth (average RR 1.04, 95% CI 0.57 to 1.90; 3 trials, 721 women; very low-certainty evidence), severe perineal tears (average RR 0.88, 95% CI 0.03 to 22.30; 2 trials, 586 women; very low-certainty evidence), maternal satisfaction (average RR 1.02, 95% CI 0.68 to 1.54; 3 trials, 350 women; very low-certainty evidence), and Apgar scores less than seven at five minutes (RR 0.71, 95% CI 0.21 to 2.34; 2 trials, 586 babies; very low-certainty evidence).  No data were reported for the hands and knees comparisons for postpartum haemorrhage, serious neonatal morbidity, death (stillbirth or death of liveborn infant), admission to neonatal intensive care, neonatal encephalopathy, need for respiratory support, and neonatal jaundice requiring phototherapy.  Lateral postures The use of lateral postures may have little to no effect on reducing operative birth (average RR 0.72, 95% CI 0.43 to 1.19; 4 trials, 871 women; low-certainty evidence), caesarean section (average RR 0.78, 95% CI 0.44 to 1.39; 4 trials, 871 women; low-certainty evidence), instrumental vaginal birth (average RR 0.73, 95% CI 0.39 to 1.36; 4 trials, 871 women; low-certainty evidence), and maternal satisfaction (RR 0.96, 95% CI 0.84 to 1.09; 2 trials, 451 women; low-certainty evidence), but the evidence is uncertain. The evidence is very uncertain about the effect of lateral postures on severe perineal tears (RR 0.66, 95% CI 0.17 to 2.48; 3 trials, 609 women; very low-certainty evidence), postpartum haemorrhage (RR 0.90, 95% CI 0.48 to 1.70; 1 trial, 322 women; very low-certainty evidence), serious neonatal morbidity (RR 1.41, 95% CI 0.64 to 3.12; 3 trials, 752 babies; very low-certainty evidence), Apgar scores less than seven at five minutes (RR 0.25, 95% CI 0.03 to 2.24; 1 trial, 322 babies; very low-certainty evidence), admissions to neonatal intensive care (RR 1.41, 95% CI 0.64 to 3.12; 2 trials, 542 babies; very low-certainty evidence) and neonatal death (stillbirth or death of liveborn) (1 trial, 210 women and their babies; no events).  For the lateral posture comparisons, no data were reported for epidural use, neonatal encephalopathy, need for respiratory support, and neonatal jaundice requiring phototherapy. We were not able to estimate the outcome death (stillbirth or death of liveborn infant) due to no events (1 trial, 210 participants).  AUTHORS' CONCLUSIONS: We found low- and very low-certainty evidence which indicated that the use of hands and knees posture or lateral postures in women in labour with a fetal malposition may have little or no effect on health outcomes of the mother or her infant. If a woman finds the use of hands and knees or lateral postures in labour comfortable there is no reason why they should not choose to use them. Further research is needed on the use of hands and knees and lateral postures for women with a malposition in labour. Trials should include further assessment of semi-prone postures, same-side-as-fetus lateral postures with or without hip hyperflexion, or both, and consider interventions of longer duration or that involve the early second stage of labour.

Sex-Specific Effects of Nutritional Supplements for Infants Born Early or Small: An Individual Participant Data Meta-Analysis (ESSENCE IPD-MA) I-Cognitive Function and Metabolic Risk.

Neonatal nutritional supplements are widely used to improve growth and development but may increase risk of later metabolic disease, and effects may differ by sex. We assessed effects of supplements on later development and metabolism. We searched databases and clinical trials registers up to April 2019. Participant-level data from randomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born preterm or small-for-gestational-age. Co-primary outcomes were cognitive impairment and metabolic risk. Supplementation did not alter cognitive impairment in toddlers (13 trials, n = 1410; adjusted relative risk (aRR) 0.88 [95% CI 0.68, 1.13]; p = 0.31) or older ages, nor alter metabolic risk beyond 3 years (5 trials, n = 438; aRR 0.94 [0.76, 1.17]; p = 0.59). However, supplementation reduced motor impairment in toddlers (13 trials, n = 1406; aRR 0.76 [0.60, 0.97]; p = 0.03), and improved motor scores overall (13 trials, n = 1406; adjusted mean difference 1.57 [0.14, 2.99]; p = 0.03) and in girls not boys (p = 0.03 for interaction). Supplementation lowered triglyceride concentrations but did not affect other metabolic outcomes (high-density and low-density lipoproteins, cholesterol, fasting glucose, blood pressure, body mass index). Macronutrient supplementation for infants born small may not alter later cognitive function or metabolic risk, but may improve early motor function, especially for girls.

Sex-Specific Effects of Nutritional Supplements for Infants Born Early or Small: An Individual Participant Data Meta-Analysis (ESSENCE IPD-MA) II: Growth.

Neonatal nutritional supplements may improve early growth for infants born small, but effects on long-term growth are unclear and may differ by sex. We assessed the effects of early macronutrient supplements on later growth. We searched databases and clinical trials registers from inception to April 2019. Participant-level data from randomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born preterm or small-for-gestational-age. Co-primary outcomes were cognitive impairment and metabolic risk. Supplementation did not alter BMI in childhood (kg/m2: adjusted mean difference (aMD) -0.11[95% CI -0.47, 0.25], p = 0.54; 3 trials, n = 333). Supplementation increased length (cm: aMD 0.37[0.01, 0.72], p = 0.04; 18 trials, n = 2008) and bone mineral content (g: aMD 10.22[0.52, 19.92], p = 0.04; 6 trials, n = 313) in infancy, but not at older ages. There were no differences between supplemented and unsupplemented groups for other outcomes. In subgroup analysis, supplementation increased the height z-score in male toddlers (aMD 0.20[0.02, 0.37], p = 0.03; 10 trials, n = 595) but not in females, and no significant sex interaction was observed (p = 0.21). Macronutrient supplementation for infants born small may not alter BMI in childhood. Supplementation increased growth in infancy, but these effects did not persist in later life. The effects did not differ between boys and girls.

Dietary recommendations for women with gestational diabetes mellitus: a systematic review of clinical practice guidelines.

CONTEXT: Dietary advice is the cornerstone of care for women with gestational diabetes mellitus (GDM) to improve maternal and infant health. OBJECTIVES: This study aimed to compare dietary recommendations made in clinical practice guidelines (CPGs) for the management of GDM, evaluate their evidence base, identify research gaps, and assess CPG quality. The PRISMA guidelines were used. DATA SOURCES: Six databases were searched for CPGs, published between 2000 and 2019, that included dietary advice for the management of GDM. DATA EXTRACTION: Two reviewers independently assessed CPG quality (using the AGREE II tool) with respect to dietary recommendations (their strength, evidence base, and research gaps). DATA ANALYSIS: Of the 31 CPGs, 68% were assessed as low quality, mainly due to lack of editorial independence. Dietary advice was recommended as the first-line treatment by all CPGs, although the dietary recommendations themselves varied and sometimes were contradictory. Most dietary recommendations were strongly made (70%), but they were often based on very low-quality (54%), or low-quality (15%) evidence. Research gaps were identified for all diet-related recommendations. CONCLUSION: High-quality research is needed to improve the evidence base and address the research gaps identified. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42019147848.

Interventions to prevent women from developing gestational diabetes mellitus: an overview of Cochrane Reviews.

BACKGROUND: The prevalence of gestational diabetes mellitus (GDM) is increasing, with approximately 15% of pregnant women affected worldwide, varying by country, ethnicity and diagnostic thresholds. There are associated short- and long-term health risks for women and their babies. OBJECTIVES: We aimed to summarise the evidence from Cochrane systematic reviews on the effects of interventions for preventing GDM. METHODS: We searched the Cochrane Database of Systematic Reviews (6 August 2019) with key words 'gestational diabetes' OR 'GDM' to identify reviews pre-specifying GDM as an outcome. We included reviews of interventions in women who were pregnant or planning a pregnancy, irrespective of their GDM risk status. Two overview authors independently assessed eligibility, extracted data and assessed quality of evidence using ROBIS and GRADE tools. We assigned interventions to categories with graphic icons to classify the effectiveness of interventions as: clear evidence of benefit or harm (GRADE moderate- or high-quality evidence with a confidence interval (CI) that did not cross the line of no effect); clear evidence of no effect or equivalence (GRADE moderate- or high-quality evidence with a narrow CI crossing the line of no effect); possible benefit or harm (low-quality evidence with a CI that did not cross the line of no effect or GRADE moderate- or high-quality evidence with a wide CI); or unknown benefit or harm (GRADE low-quality evidence with a wide CI or very low-quality evidence). MAIN RESULTS: We included 11 Cochrane Reviews (71 trials, 23,154 women) with data on GDM. Nine additional reviews pre-specified GDM as an outcome, but did not identify GDM data in included trials. Ten of the 11 reviews were judged to be at low risk of bias and one review at unclear risk of bias. Interventions assessed included diet, exercise, a combination of diet and exercise, dietary supplements, pharmaceuticals, and management of other health problems in pregnancy. The quality of evidence ranged from high to very low. Diet Unknown benefit or harm: there was unknown benefit or harm of dietary advice versus standard care, on the risk of GDM: risk ratio (RR) 0.60, 95% CI 0.35 to 1.04; 5 trials; 1279 women; very low-quality evidence. There was unknown benefit or harm of a low glycaemic index diet versus a moderate-high glycaemic index diet on the risk of GDM: RR 0.91, 95% CI 0.63 to 1.31; 4 trials; 912 women; low-quality evidence. Exercise Unknown benefit or harm: there was unknown benefit or harm for exercise interventions versus standard antenatal care on the risk of GDM: RR 1.10, 95% CI 0.66 to 1.84; 3 trials; 826 women; low-quality evidence. Diet and exercise combined Possible benefit: combined diet and exercise interventions during pregnancy versus standard care possibly reduced the risk of GDM: RR 0.85, 95% CI 0.71 to 1.01; 19 trials; 6633 women; moderate-quality evidence. Dietary supplements Clear evidence of no effect: omega-3 fatty acid supplementation versus none in pregnancy had no effect on the risk of GDM: RR 1.02, 95% CI 0.83 to 1.26; 12 trials; 5235 women; high-quality evidence. Possible benefit: myo-inositol supplementation during pregnancy versus control possibly reduced the risk of GDM: RR 0.43, 95% CI 0.29 to 0.64; 3 trials; 502 women; low-quality evidence. Possible benefit: vitamin D supplementation versus placebo or control in pregnancy possibly reduced the risk of GDM: RR 0.51, 95% CI 0.27 to 0.97; 4 trials; 446 women; low-quality evidence. Unknown benefit or harm: there was unknown benefit or harm of probiotic with dietary intervention versus placebo with dietary intervention (RR 0.37, 95% CI 0.15 to 0.89; 1 trial; 114 women; very low-quality evidence), or probiotic with dietary intervention versus control (RR 0.38, 95% CI 0.16 to 0.92; 1 trial; 111 women; very low-quality evidence) on the risk of GDM. There was unknown benefit or harm of vitamin D + calcium supplementation versus placebo (RR 0.33, 95% CI 0.01 to 7.84; 1 trial; 54 women; very low-quality evidence) or vitamin D + calcium + other minerals versus calcium + other minerals (RR 0.42, 95% CI 0.10 to 1.73; 1 trial; 1298 women; very low-quality evidence) on the risk of GDM. Pharmaceutical Possible benefit: metformin versus placebo given to obese pregnant women possibly reduced the risk of GDM: RR 0.85, 95% CI 0.61 to 1.19; 3 trials; 892 women; moderate-quality evidence. Unknown benefit or harm:eight small trials with low- to very low-quality evidence showed unknown benefit or harm for heparin, aspirin, leukocyte immunisation or IgG given to women with a previous stillbirth on the risk of GDM. Management of other health issues Clear evidence of no effect: universal versus risk based screening of pregnant women for thyroid dysfunction had no effect on the risk of GDM: RR 0.93, 95% CI 0.70 to 1.25; 1 trial; 4516 women; moderate-quality evidence. Unknown benefit or harm: there was unknown benefit or harm of using fractional exhaled nitrogen oxide versus a clinical algorithm to adjust asthma therapy on the risk of GDM: RR 0.74, 95% CI 0.31 to 1.77; 1 trial; 210 women; low-quality evidence. There was unknown benefit or harm of pharmacist led multidisciplinary approach to management of maternal asthma versus standard care on the risk of GDM: RR 5.00, 95% CI 0.25 to 99.82; 1 trial; 58 women; low-quality evidence. AUTHORS' CONCLUSIONS: No interventions to prevent GDM in 11 systematic reviews were of clear benefit or harm. A combination of exercise and diet, supplementation with myo-inositol, supplementation with vitamin D and metformin were of possible benefit in reducing the risk of GDM, but further high-quality evidence is needed. Omega-3-fatty acid supplementation and universal screening for thyroid dysfunction did not alter the risk of GDM. There was insufficient high-quality evidence to establish the effect on the risk of GDM of diet or exercise alone, probiotics, vitamin D with calcium or other vitamins and minerals, interventions in pregnancy after a previous stillbirth, and different asthma management strategies in pregnancy. There is a lack of trials investigating the effect of interventions prior to or between pregnancies on risk of GDM.

Impact of macronutrient supplements on later growth of children born preterm or small for gestational age: A systematic review and meta-analysis of randomised and quasirandomised controlled trials.

BACKGROUND: Nutritional supplements may improve short-term growth of infants born small (preterm or small for gestational age), but there are few data on long-term effects and concerns that body composition may be adversely affected. Effects also may differ between girls and boys. Our systematic review and meta-analysis assessed the effects of macronutrient supplements for infants born small on later growth. METHODS AND FINDINGS: We searched OvidMedline, Embase, Cochrane CENTRAL, and Cochrane Database of Systematic Reviews from inception to January 30, 2020, and controlled-trials.com, clinicaltrials.gov, and anzctr.org.au on January 30, 2020. Randomised or quasirandomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born small and growth was assessed after discharge. Primary outcome was body mass index (BMI) in childhood. Data were pooled using random-effect models. Outcomes were evaluated in toddlers (< 3 years), childhood (3 to 8 years), adolescence (9 to 18 years), and adulthood (>18 years). Forty randomised and 2 quasirandomised trials of variable methodological quality with 4,352 infants were included. Supplementation did not alter BMI in childhood (7 trials, 1,136 children; mean difference [MD] -0.10 kg/m2, [95% confidence interval (CI) -0.37 to 0.16], p = 0.45). In toddlers, supplementation increased weight (31 trials, 2,924 toddlers; MD 0.16 kg, [0.01 to 0.30], p = 0.03) and length/height (30 trials, 2,889 toddlers; MD 0.44 cm, [0.10 to 0.77], p = 0.01), but not head circumference (29 trials, 2,797 toddlers; MD 0.15 cm, [-0.03 to 0.33], p = 0.10). In childhood, there were no significant differences between groups in height (7 trials, 1,136 children; MD 0.22 cm, [-0.48 to 0.92], p = 0.54) or lean mass (3 trials, 354 children; MD -0.07 kg, [-0.98 to 0.85], p = 0.88), although supplemented children appeared to have higher fat mass (2 trials, 201 children; MD 0.79 kg, [0.19 to 1.38], p = 0.01). In adolescence, there were no significant differences between groups in BMI (2 trials, 216 adolescents; MD -0.48 kg/m2, [-2.05 to 1.08], p = 0.60), height (2 trials, 216 adolescents; MD -0.55 cm, [-2.95 to 1.86], p = 0.65), or fat mass (2 trials, 216 adolescents; MD -1.3 5 kg, [-5.76 to 3.06], p = 0.55). In adulthood, there also were no significant differences between groups in weight z-score (2 trials, 199 adults; MD -0.11, [-0.72 to 0.50], p = 0.73) and height z-score (2 trials, 199 adults; MD -0.07, [-0.36 to 0.22], p = 0.62). In subgroup analysis, supplementation was associated with increased length/height in toddler boys (2 trials, 173 boys; MD 1.66 cm, [0.75 to 2.58], p = 0.0003), but not girls (2 trials, 159 girls; MD 0.15 cm, [-0.71 to 1.01], p = 0.74). Limitations include considerable unexplained heterogeneity, low to very low quality of evidence, and possible bias due to low or unbalanced followup. CONCLUSIONS: In this systematic review and meta-analysis, we found no evidence that early macronutrient supplementation for infants born small altered BMI in childhood. Although supplements appeared to increase weight and length in toddlers, effects were inconsistent and unlikely to be clinically significant. Limited data suggested that supplementation increased fat mass in childhood, but these effects did not persist in later life. PROSPERO registration: CRD42019126918.

Relationships between Neonatal Nutrition and Growth to 36 Weeks' Corrected Age in ELBW Babies-Secondary Cohort Analysis from the Provide Trial.

A key modifiable factor for improving neurodevelopment in extremely low birthweight (ELBW) babies may be improving growth, especially head growth, by optimising nutrition in the early neonatal period. We aimed to investigate relationships between nutrient intakes in the 4 weeks after birth, and growth from birth to 36 weeks' corrected age (CA) in ELBW babies. We undertook a prospective cohort study of 434 participants enrolled in a randomised controlled trial (ProVIDe) in eight New Zealand and Australian neonatal intensive care units. Macronutrient intakes from birth to 4 weeks and weight, length and head circumference measurements from birth to 36 weeks' CA were collected. From birth to 36 weeks' CA, the median (IQR) z-score changes were: weight -0.48 (-1.09, 0.05); length -1.16 (-1.86, -0.43), and head circumference -0.82 (-1.51, -0.19). Changes in z-score to 4 weeks and 36 weeks' CA were correlated with protein intake. Each 1 g·Kg-1·d-1 total protein intake in week 2 was associated with 0.26 z-score increase in head circumference at 36 weeks' CA. Both nutritional intake and change in z-scores to 36 weeks' CA differed widely amongst sites. Correlations between nutrition and growth, and differences in these amongst sites, indicate there may be potential to improve growth with enhanced nutrition practices.

Impact of macronutrient supplements for children born preterm or small for gestational age on developmental and metabolic outcomes: A systematic review and meta-analysis.

BACKGROUND: Nutritional supplements may improve development of infants born small (preterm or small for gestational age [SGA]) but may increase the risk of later metabolic disease. We conducted a systematic review and meta-analysis to assess the effects of macronutrient supplements for infants born small on later development and metabolism. METHODS AND FINDINGS: We searched OvidMedline, Embase, Cochrane CENTRAL, and Cochrane Database of Systematic Reviews from inception to April 1, 2019, and controlled-trials.com, clinicaltrials.gov, and anzctr.org.au. Randomised or quasirandomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born small and assessed post-discharge outcomes. Co-primary outcomes were cognitive impairment and metabolic risk, evaluated in toddlers (<3 years), childhood (3 to 8 years), and adolescence (9 to 18 years). Two reviewers independently extracted data. Quality was assessed using the Cochrane Risk of Bias tool, and data were pooled using random-effect models. Twenty-one randomised and one quasirandomised trial of variable methodological quality involving 3,680 infants were included. In toddlers born small, supplementation did not alter cognitive impairment (relative risk [RR] 1.00; 95% confidence interval [CI] 0.67 to 1.49; P = 0.99), and there were no differences in cognitive scores (mean difference [MD] 0.57; 95% CI -0.71 to 1.84; P = 0.38) or motor scores (MD 1.16; 95% CI -0.32 to 2.65; P = 0.12) between supplemented and unsupplemented groups. However, fewer supplemented children had motor impairment (RR 0.76; 95% CI 0.62 to 0.94; P = 0.01). In subgroup analyses, supplementation improved cognitive scores in boys (MD 5.60; 95% CI 1.07 to 10.14; P = 0.02), but not girls born small (MD -2.04; 95% CI -7.04 to 2.95; P = 0.42), and did not alter cognitive or motor scores in the subgroup of children born SGA. In childhood, there was no difference in cognitive impairment (RR 0.81; 95% CI 0.26 to 2.57; P = 0.72) or cognitive scores (MD 1.02; 95% CI -1.91 to 3.95; P = 0.50) between supplemented and unsupplemented groups. There were also no differences in blood pressure, triglyceride, and low-density lipoprotein (LDL) concentrations (all P > 0.05). However, supplemented children had lower fasting glucose (mmol/L: MD -0.20; 95% CI -0.34 to -0.06; P = 0.005) and higher high-density lipoprotein (HDL) concentrations (mmol/L: MD 0.11; 95% CI 0.02 to 0.19; P = 0.02). In subgroup analyses, there was no evidence of differences in blood pressure between supplemented and unsupplemented groups in boys or girls born small, or in SGA children. In adolescence, there was no difference between supplemented and unsupplemented groups in blood pressure, triglycerides, LDL and HDL concentrations, fasting blood glucose, insulin resistance, and fasting insulin concentrations (all P > 0.05). Limitations include considerable unexplained heterogeneity, low to very low quality of the evidence, and limited data beyond early childhood. CONCLUSIONS: In this systematic review and meta-analysis of randomised trials, we found no evidence that early macronutrient supplementation for infants born small altered later cognitive function, although there was some evidence that supplementation may decrease motor impairment in toddlers. Contrary to the findings from observational studies, evidence from randomised trials suggests that early macronutrient supplementation for infants born small improves some metabolic outcomes in childhood. PROSPERO REGISTRATION: CRD42019127858.

Macronutrient Supplements in Preterm and Small-for-Gestational-Age Animals: A Systematic Review and Meta-analysis.

Early macronutrient supplementation in preterm and/or small-for-gestational-age (SGA) infants may improve growth but have detrimental effects on later cardio-metabolic health which may be sex-specific. We systematically reviewed the long-term effects of early macronutrient supplementation in preterm and SGA animals and whether these differ by sex. Using Cochrane Neonatal and SYRCLE methodologies we included random or quasi-random studies that allocated non-human mammals to macronutrient supplements or no supplements between birth and weaning and assessed post-weaning outcomes. We used random-effects models to calculate standardized mean differences (SMD) with 95% confidence intervals (CIs). Six studies provided low to very-low-quality evidence that macronutrient supplementation increased weight in juvenile rats (SMD; 95% CI: 2.13; 1.00, 3.25; 1 study, n = 24), increased leptin concentrations in older adults (1.31; 0.12, 2.51; 1 study, n = 14 male rats), but decreased leptin concentrations in young adults (-1.13; -2.21, -0.05; 1 study, n = 16 female rats) and improved spatial learning and memory (qualitative data; 1 study). There was no evidence of sex-specific effects and no overall effect on length, serum lipids, body composition, HOMA-IR, or blood pressure. Macronutrient supplements may affect later growth, metabolism, and neurodevelopment of preterm and SGA animals, but evidence is limited and low quality.

Effect of antenatal dietary interventions in maternal obesity on pregnancy weight-gain and birthweight: Healthy Mums and Babies (HUMBA) randomized trial.

BACKGROUND: Pregnancy interventions that improve maternal and infant outcomes are urgently needed in populations with high rates of obesity. We undertook the Healthy Mums and Babies (HUMBA) randomized controlled trial to assess the effect of dietary interventions and or probiotics in a multiethnic population of pregnant women with obesity, living in an area of high deprivation. OBJECTIVES: To determine whether a culturally tailored dietary intervention and or daily probiotic capsules in pregnant women with obesity reduces the co-primary outcomes of (1) excessive gestational weight gain (mean >0.27 kg/week) and (2) birthweight. STUDY DESIGN: We conducted a 2 × 2 factorial, randomized controlled trial in women without diabetes at pregnancy booking, body mass index ≥30 kg/m2, and a singleton pregnancy. At 12+0 to 17+6 weeks' gestation, eligible women were randomized to a dietary intervention (4 tailored educational sessions at ≤28 weeks' gestation by a community health worker trained in key aspects of pregnancy nutrition plus text messaging until birth) or to routine dietary advice; and to daily capsules containing either (Lactobacillus rhamnosus GG and Bifidobacterium lactis BB12, minimum 6.5 × 109 colony forming units), or placebo, until birth. Analysis was by intention to treat with adjustment for maternal baseline body mass index. Infant outcomes were additionally adjusted for ethnicity, sex, and gestational age at birth. RESULTS: In total, 230 women were recruited between April 2015 and June 2017 (dietary intervention N = 116 vs routine dietary advice N = 114; probiotics N = 115 vs placebo N = 115). Baseline characteristics and demographic variables were similar across all groups. There was no significant difference between intervention groups, for the co-primary outcomes of (1) proportion of women with excessive gestational weight gain (dietary intervention vs routine advice: 79/107 [73.8%] vs 90/110 [81.8%], adjusted relative risk [relative risk, 0.92; 95% confidence interval, 0.80-1.05]; probiotics versus placebo: 89/108 [82.4%] and 80/109 [73.4%], relative risk, 1.14, 95% confidence interval, 0.99-1.31) or (2) birthweight (dietary intervention vs routine advice: 3575 vs 3612 g, adjusted mean difference, -24 g, 95% confidence interval, -146 to 97; probiotics vs placebo: 3685 vs 3504 g, adjusted mean difference, 107 g, 95% confidence interval, -14 to 228). Total maternal weight gain, a secondary outcome, was lower with dietary intervention compared with routine dietary advice (9.7 vs 11.4 kg, adjusted mean difference, -1.76, 95% confidence interval, -3.55 to 0.03). There were no significant differences between intervention groups in other secondary maternal or neonatal outcomes. CONCLUSION: Although dietary education and or probiotics did not alter rates of excessive gestational weight gain or birthweight in this multiethnic, high-deprivation population of pregnant women with obesity, dietary education was associated with a modest reduction in total weight gain with potential future benefit for the health of mothers and their offspring if sustained.

Oral dextrose gel to treat neonatal hypoglycaemia: Clinician survey.

AIMS: To determine the use of oral dextrose gel to treat neonatal hypoglycaemia in New Zealand (NZ), to identify barriers and enablers to the implementation of the guideline and to determine if there is variation in management between clinical disciplines caring for at-risk babies. METHODS: An online survey was distributed to clinicians (including doctors, midwives and nurses) caring for babies with neonatal hypoglycaemia via stakeholders and maternity hospitals. RESULTS: A total of 251 clinicians from all 20 District Health Boards (DHBs) completed the survey. Of the responding clinicians, 148 (59%) from 15 (75%) DHBs reported oral dextrose gel use in their hospital, and of these, 129 (87%) reported a local guideline. In 12 of 15 (80%) DHBs, oral dextrose gel could be prescribed by midwives. For a clinical scenario of a baby with neonatal hypoglycaemia, doctors were more likely to prescribe oral dextrose gel than midwives (odds ratio (95% confidence interval), 2.9 (2.2-3.8), P < 0.0001). Of 32 possible combinations of treatment options for this scenario, 31 were selected by one or more clinicians. A guideline was perceived to be the most useful enabler, and availability of oral dextrose gel was seen as the most important barrier. CONCLUSIONS: Oral dextrose gel is widely used to treat neonatal hypoglycaemia in NZ. Increasing availability of dextrose gel and the clinical practice guideline are likely to further increase the use of oral dextrose gel.

Neonatal interventions for preventing cerebral palsy: an overview of Cochrane Systematic Reviews.

BACKGROUND: Cerebral palsy is an umbrella term that encompasses disorders of movement and posture attributed to non-progressive disturbances occurring in the developing foetal or infant brain. As there are diverse risk factors and aetiologies, no one strategy will prevent cerebral palsy. Therefore, there is a need to systematically consider all potentially relevant interventions for prevention. OBJECTIVES: PrimaryTo summarise the evidence from Cochrane Systematic Reviews regarding effects of neonatal interventions for preventing cerebral palsy (reducing cerebral palsy risk).SecondaryTo summarise the evidence from Cochrane Systematic Reviews regarding effects of neonatal interventions that may increase cerebral palsy risk. METHODS: We searched the Cochrane Database of Systematic Reviews (27 November 2016) for reviews of neonatal interventions reporting on cerebral palsy. Two review authors assessed reviews for inclusion, extracted data, and assessed review quality (using AMSTAR and ROBIS) and quality of the evidence (using the GRADE approach). Reviews were organised by topic; findings were summarised in text and were tabulated. Interventions were categorised as effective (high-quality evidence of effectiveness); possibly effective (moderate-quality evidence of effectiveness); ineffective (high-quality evidence of harm); probably ineffective (moderate-quality evidence of harm or lack of effectiveness); and no conclusions possible (low- to very low-quality evidence). MAIN RESULTS: Forty-three Cochrane Reviews were included. A further 102 reviews pre-specified the outcome cerebral palsy, but none of the included randomised controlled trials (RCTs) reported this outcome. Included reviews were generally of high quality and had low risk of bias, as determined by AMSTAR and ROBIS. These reviews involved 454 RCTs; data for cerebral palsy were available from 96 (21%) RCTs involving 15,885 children. Review authors considered interventions for neonates with perinatal asphyxia or with evidence of neonatal encephalopathy (3); interventions for neonates born preterm and/or at low or very low birthweight (33); and interventions for other specific groups of 'at risk' neonates (7). Quality of evidence (GRADE) ranged from very low to high.Interventions for neonates with perinatal asphyxia or with evidence of neonatal encephalopathyEffective interventions: high-quality evidence of effectivenessResearchers found a reduction in cerebral palsy following therapeutic hypothermia versus standard care for newborns with hypoxic ischaemic encephalopathy (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.54 to 0.82; seven trials; 881 children).No conclusions possible: very low-quality evidenceOne review observed no clear differences in cerebral palsy following therapeutic hypothermia versus standard care.Interventions for neonates born preterm and/or at low or very low birthweightPossibly effective interventions: moderate-quality evidence of effectivenessResearchers found a reduction in cerebral palsy with prophylactic methylxanthines (caffeine) versus placebo for endotracheal extubation in preterm infants (RR 0.54, 95% CI 0.32 to 0.92; one trial; 644 children).Probably ineffective interventions: moderate-quality evidence of harmResearchers reported an increase in cerebral palsy (RR 1.45, 95% CI 1.06 to 1.98; 12 trials; 1452 children) and cerebral palsy in assessed survivors (RR 1.50, 95% CI 1.13 to 2.00; 12 trials; 959 children) following early (at less than eight days of age) postnatal corticosteroids versus placebo or no treatment for preventing chronic lung disease in preterm infants.Probably ineffective interventions: moderate-quality evidence of lack of effectivenessTrial results showed no clear differences in cerebral palsy following ethamsylate versus placebo for prevention of morbidity and mortality in preterm or very low birthweight infants (RR 1.13, 95% CI 0.64 to 2.00; three trials, 532 children); volume expansion versus no treatment (RR 0.76, 95% CI 0.48 to 1.20; one trial; 604 children); gelatin versus fresh frozen plasma (RR 0.94, 95% CI 0.52 to 1.69; one trial, 399 children) for prevention of morbidity and mortality in very preterm infants; prophylactic indomethacin versus placebo for preventing mortality and morbidity in preterm infants (RR 1.04, 95% CI 0.77 to 1.40; four trials; 1372 children); synthetic surfactant versus placebo for respiratory distress syndrome in preterm infants (RR 0.76, 95% CI 0.55 to 1.05; five trials; 1557 children); or prophylactic phototherapy versus standard care (starting phototherapy when serum bilirubin reached a pre-specified level) for preventing jaundice in preterm or low birthweight infants (RR 0.96, 95% CI 0.50 to 1.85; two trials; 756 children).No conclusions possible: low- to very low-quality evidenceNo clear differences in cerebral palsy were observed with interventions assessed in 21 reviews.Interventions for other specific groups of 'at risk' neonatesNo conclusions possible: low- to very low-quality evidenceReview authors observed no clear differences in cerebral palsy with interventions assessed in five reviews. AUTHORS' CONCLUSIONS: This overview summarises evidence from Cochrane Systematic Reviews regarding effects of neonatal interventions on cerebral palsy, and can be used by researchers, funding bodies, policy makers, clinicians, and consumers to aid decision-making and evidence translation. To formally assess other benefits and/or harms of included interventions, including impact on risk factors for cerebral palsy, review of the included Reviews is recommended.Therapeutic hypothermia versus standard care for newborns with hypoxic ischaemic encephalopathy can prevent cerebral palsy, and prophylactic methylxanthines (caffeine) versus placebo for endotracheal extubation in preterm infants may reduce cerebral palsy risk. Early (at less than eight days of age) postnatal corticosteroids versus placebo or no treatment for preventing chronic lung disease in preterm infants may increase cerebral palsy risk.Cerebral palsy is rarely identified at birth, has diverse risk factors and aetiologies, and is diagnosed in approximately one in 500 children. To date, only a small proportion of Cochrane Systematic Reviews assessing neonatal interventions have been able to report on this outcome. There is an urgent need for long-term follow-up of RCTs of such interventions addressing risk factors for cerebral palsy (through strategies such as data linkage with registries) and for consideration of the use of relatively new interim assessments (including the General Movements Assessment). Such RCTs must be rigorous in their design and must aim for consistency in cerebral palsy outcome measurement and reporting to facilitate pooling of data and thus to maximise research efforts focused on prevention.

Midwife or doctor local opinion leader to implement a national guideline in babies on postnatal wards (DesIGN): protocol of a cluster-randomised, blinded, controlled trial.

INTRODUCTION: Neonatal hypoglycaemia is a common condition that can cause developmental delay. Treatment of neonatal hypoglycaemia with oral dextrose gel has been shown to reverse hypoglycaemia and reduce admissions to neonatal intensive care for hypoglycaemia. An evidence-based clinical practice guideline was written to guide the use of dextrose gel to treat neonatal hypoglycaemia in New Zealand. However, it is unclear what clinical discipline might most effectively lead the implementation of the guideline recommendations. OBJECTIVE: To determine if midwife or doctor local opinion leaders are more effective in implementing a clinical practice guideline for use of oral dextrose gel to treat hypoglycaemia in babies on postnatal wards. METHODS AND ANALYSIS: A cluster-randomised, blinded, controlled trial. New Zealand maternity hospitals that care for babies born at risk of neonatal hypoglycaemia will be randomised to having either a local midwife or doctor lead the guideline implementation at that hospital. The primary outcome will be the change in the proportion of hypoglycaemic babies treated with dextrose gel from before implementation of the guideline to 3 months after implementation. ETHICS AND DISSEMINATION: Approved by Health and Disability Ethics Committee: 15/NTA/31. Findings will be disseminated to peer-reviewed journals, guideline developers and the public. TRIAL REGISTRATION NUMBER: ISRCTN61154098.

Screening for gestational diabetes mellitus based on different risk profiles and settings for improving maternal and infant health.

BACKGROUND: Gestational diabetes mellitus (GDM) is a form of diabetes that occurs in pregnancy. Although GDM usually resolves following birth, it is associated with significant morbidities for mothers and their infants in the short and long term. There is strong evidence to support treatment for GDM. However, there is uncertainty as to whether or not screening all pregnant women for GDM will improve maternal and infant health and if so, the most appropriate setting for screening. This review updates a Cochrane Review, first published in 2010, and subsequently updated in 2014. OBJECTIVES: To assess the effects of screening for gestational diabetes mellitus based on different risk profiles and settings on maternal and infant outcomes. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (31 January 2017), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (14 June 2017), and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised and quasi-randomised trials evaluating the effects of different protocols, guidelines or programmes for screening for GDM based on different risk profiles and settings, compared with the absence of screening, or compared with other protocols, guidelines or programmes for screening. We planned to include trials published as abstracts only and cluster-randomised trials, but we did not identify any. Cross-over trials are not eligible for inclusion in this review. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility, extracted data and assessed the risk of bias of the included trials. We resolved disagreements through discussion or through consulting a third reviewer. MAIN RESULTS: We included two trials that randomised 4523 women and their infants. Both trials were conducted in Ireland. One trial (which quasi-randomised 3742 women, and analysed 3152 women) compared universal screening versus risk factor-based screening, and one trial (which randomised 781 women, and analysed 690 women) compared primary care screening versus secondary care screening. We were not able to perform meta-analyses due to the different interventions and comparisons assessed.Overall, there was moderate to high risk of bias due to one trial being quasi-randomised, inadequate blinding, and incomplete outcome data in both trials. We used GRADEpro GDT software to assess the quality of the evidence for selected outcomes for the mother and her child. Evidence was downgraded for study design limitations and imprecision of effect estimates. Universal screening versus risk-factor screening (one trial) MotherMore women were diagnosed with GDM in the universal screening group than in the risk-factor screening group (risk ratio (RR) 1.85, 95% confidence interval (CI) 1.12 to 3.04; participants = 3152; low-quality evidence). There were no data reported under this comparison for other maternal outcomes including hypertensive disorders of pregnancy, caesarean birth, perineal trauma, gestational weight gain, postnatal depression, and type 2 diabetes. ChildNeonatal outcomes: large-for-gestational age, perinatal mortality, mortality or morbidity composite, hypoglycaemia; and childhood/adulthood outcomes: adiposity, type 2 diabetes, and neurosensory disability, were not reported under this comparison. Primary care screening versus secondary care screening (one trial) MotherThere was no clear difference between the primary care and secondary care screening groups for GDM (RR 0.91, 95% CI 0.50 to 1.66; participants = 690; low-quality evidence), hypertension (RR 1.41, 95% CI 0.77 to 2.59; participants = 690; low-quality evidence), pre-eclampsia (RR 0.80, 95% CI 0.36 to 1.78; participants = 690;low-quality evidence), or caesarean section birth (RR 1.00, 95% CI 0.80 to 1.27; participants = 690; low-quality evidence). There were no data reported for perineal trauma, gestational weight gain, postnatal depression, or type 2 diabetes. ChildThere was no clear difference between the primary care and secondary care screening groups for large-for-gestational age (RR 1.37, 95% CI 0.96 to 1.96; participants = 690; low-quality evidence), neonatal complications: composite outcome, including: hypoglycaemia, respiratory distress, need for phototherapy, birth trauma, shoulder dystocia, five minute Apgar less than seven at one or five minutes, prematurity (RR 0.99, 95% CI 0.57 to 1.71; participants = 690; low-quality evidence), or neonatal hypoglycaemia (RR 1.10, 95% CI 0.28 to 4.38; participants = 690; very low-quality evidence). There was one perinatal death in the primary care screening group and two in the secondary care screening group (RR 1.10, 95% CI 0.10 to 12.12; participants = 690; very low-quality evidence). There were no data for neurosensory disability, or childhood/adulthood adiposity or type 2 diabetes. AUTHORS' CONCLUSIONS: There are insufficient randomised controlled trial data evaluating the effects of screening for GDM based on different risk profiles and settings on maternal and infant outcomes. Low-quality evidence suggests universal screening compared with risk factor-based screening leads to more women being diagnosed with GDM. Low to very low-quality evidence suggests no clear differences between primary care and secondary care screening, for outcomes: GDM, hypertension, pre-eclampsia, caesarean birth, large-for-gestational age, neonatal complications composite, and hypoglycaemia.Further, high-quality randomised controlled trials are needed to assess the value of screening for GDM, which may compare different protocols, guidelines or programmes for screening (based on different risk profiles and settings), with the absence of screening, or with other protocols, guidelines or programmes. There is a need for future trials to be sufficiently powered to detect important differences in short- and long-term maternal and infant outcomes, such as those important outcomes pre-specified in this review. As only a proportion of women will be diagnosed with GDM in these trials, large sample sizes may be required.

Oral anti-diabetic pharmacological therapies for the treatment of women with gestational diabetes.

BACKGROUND: Gestational diabetes mellitus (GDM) is a major public health issue with rates increasing globally. Gestational diabetes, glucose intolerance first recognised during pregnancy, usually resolves after birth and is associated with short- and long-term complications for the mother and her infant. Treatment options can include oral anti-diabetic pharmacological therapies. OBJECTIVES: To evaluate the effects of oral anti-diabetic pharmacological therapies for treating women with GDM. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (14 May 2016), ClinicalTrials.gov, WHO ICTRP (14 May 2016) and reference lists of retrieved studies. SELECTION CRITERIA: We included published and unpublished randomised controlled trials assessing the effects of oral anti-diabetic pharmacological therapies for treating pregnant women with GDM. We included studies comparing oral anti-diabetic pharmacological therapies with 1) placebo/standard care, 2) another oral anti-diabetic pharmacological therapy, 3) combined oral anti-diabetic pharmacological therapies. Trials using insulin as the comparator were excluded as they are the subject of a separate Cochrane systematic review.Women with pre-existing type 1 or type 2 diabetes were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and trial quality. Two review authors independently extracted data and data were checked for accuracy. MAIN RESULTS: We included 11 studies (19 publications) (1487 women and their babies). Eight studies had data that could be included in meta-analyses. Studies were conducted in Brazil, India, Israel, UK, South Africa and USA. The studies varied in diagnostic criteria and treatment targets for glycaemic control for GDM. The overall risk of bias was 'unclear' due to inadequate reporting of methodology. Using GRADE the quality of the evidence ranged from moderate to very low quality. Evidence was downgraded for risk of bias (reporting bias, lack of blinding), inconsistency, indirectness, imprecision and for oral anti-diabetic therapy versus placebo for generalisability. Oral anti-diabetic pharmacological therapies versus placebo/standard careThere was no evidence of a difference between glibenclamide and placebo groups for hypertensive disorders of pregnancy (risk ratio (RR) 1.24, 95% confidence interval (CI) 0.81 to 1.90; one study, 375 women, very low-quality evidence), birth by caesarean section (RR 1.03, 95% CI 0.79 to 1.34; one study, 375 women, very low-quality evidence), perineal trauma (RR 0.98, 95% CI 0.06 to 15.62; one study, 375 women, very low-quality evidence) or induction of labour (RR 1.18, 95% CI 0.79 to 1.76; one study, 375 women; very low-quality evidence). No data were reported for development of type 2 diabetes or other pre-specified GRADE maternal outcomes (return to pre-pregnancy weight, postnatal depression). For the infant, there was no evidence of a difference in the risk of being born large-for-gestational age (LGA) between infants whose mothers had been treated with glibenclamide and those in the placebo group (RR 0.89, 95% CI 0.51 to 1.58; one study, 375, low-quality evidence). No data were reported for other infant primary or GRADE outcomes (perinatal mortality, death or serious morbidity composite, neurosensory disability in later childhood, neonatal hypoglycaemia, adiposity, diabetes). Metformin versus glibenclamideThere was no evidence of a difference between metformin- and glibenclamide-treated groups for the risk of hypertensive disorders of pregnancy (RR 0.70, 95% CI 0.38 to 1.30; three studies, 508 women, moderate-quality evidence), birth by caesarean section (average RR 1.20, 95% CI 1.20; 95% CI 0.83 to 1.72, four studies, 554 women, I2 = 61%, Tau2 = 0.07 low-quality evidence), induction of labour (0.81, 95% CI 0.61 to 1.07; one study, 159 women; low-quality evidence) or perineal trauma (RR 1.67, 95% CI 0.22 to 12.52; two studies, 158 women; low-quality evidence). No data were reported for development of type 2 diabetes or other pre-specified GRADE maternal outcomes (return to pre-pregnancy weight, postnatal depression). For the infant there was no evidence of a difference between the metformin- and glibenclamide-exposed groups for the risk of being born LGA (average RR 0.67, 95% CI 0.24 to 1.83; two studies, 246 infants, I2 = 54%, Tau2 = 0.30 low-quality evidence). Metformin was associated with a decrease in a death or serious morbidity composite (RR 0.54, 95% CI 0.31 to 0.94; one study, 159 infants, low-quality evidence). There was no clear difference between groups for neonatal hypoglycaemia (RR 0.86, 95% CI 0.42 to 1.77; four studies, 554 infants, low-quality evidence) or perinatal mortality (RR 0.92, 95% CI 0.06 to 14.55, two studies, 359 infants). No data were reported for neurosensory disability in later childhood or for adiposity or diabetes. Glibenclamide versus acarboseThere was no evidence of a difference between glibenclamide and acarbose from one study (43 women) for any of their maternal or infant primary outcomes (caesarean section, RR 0.95, 95% CI 0.53 to 1.70; low-quality evidence; perinatal mortality - no events; low-quality evidence; LGA , RR 2.38, 95% CI 0.54 to 10.46; low-quality evidence). There was no evidence of a difference between glibenclamide and acarbose for neonatal hypoglycaemia (RR 6.33, 95% CI 0.87 to 46.32; low-quality evidence). There were no data reported for other pre-specified GRADE or primary maternal outcomes (hypertensive disorders of pregnancy, development of type 2 diabetes, perineal trauma, return to pre-pregnancy weight, postnatal depression, induction of labour) or neonatal outcomes (death or serious morbidity composite, adiposity or diabetes). AUTHORS' CONCLUSIONS: There were insufficient data comparing oral anti-diabetic pharmacological therapies with placebo/standard care (lifestyle advice) to inform clinical practice. There was insufficient high-quality evidence to be able to draw any meaningful conclusions as to the benefits of one oral anti-diabetic pharmacological therapy over another due to limited reporting of data for the primary and secondary outcomes in this review. Short- and long-term clinical outcomes for this review were inadequately reported or not reported. Current choice of oral anti-diabetic pharmacological therapy appears to be based on clinical preference, availability and national clinical practice guidelines.The benefits and potential harms of one oral anti-diabetic pharmacological therapy compared with another, or compared with placebo/standard care remains unclear and requires further research. Future trials should attempt to report on the core outcomes suggested in this review, in particular long-term outcomes for the woman and the infant that have been poorly reported to date, women's experiences and cost benefit.

A randomised controlled demonstration trial of multifaceted nutritional intervention and or probiotics: the healthy mums and babies (HUMBA) trial.

BACKGROUND: Maternal obesity is associated with adverse pregnancy outcomes and has lifelong negative implications for offspring health. The Institute of Medicine recommends limited gestational weight gain (GWG) in obese women for optimal maternal and infant outcomes. However, there is a gap regarding an effective and sustainable intervention strategy to achieve this goal. The aim of the healthy mums and babies (HUMBA) demonstration trial is to assess whether a multifaceted nutritional intervention and/or an oral probiotic treatment in obese pregnant women can reduce excessive GWG and optimise pregnancy outcomes. METHODS AND DESIGN: The study is a two by two factorial randomised controlled demonstration trial conducted in Counties Manukau health region, New Zealand, a multi-ethnic region with a high prevalence of obesity. A total of 220 non-diabetic obese women with a singleton pregnancy will be recruited between 120 and 176 weeks. At recruitment, women are randomised to receive either a culturally tailored multifaceted dietary intervention or routine dietary advice, and either an oral probiotic or placebo capsule. Randomisation is undertaken via a web-based protocol, randomize.net, with a 1:1 ratio using stratification by body mass index (BMI) category (BMI of 30-34.9 or BMI ≥35 kg/m2). The dietary intervention includes 4 customised nutrition education visits by a trained community health worker combined with motivational text messaging. Probiotic capsules consist of Lactobacillus rhamnosus GG and Bifidobacterium lactis BB12 at a dose of 7 × 109 colony-forming units one per day until birth. Probiotic and placebo capsules are identically pre-packed and labelled by a third party, and are prescribed in a double blinded fashion. Research assessments are conducted at enrolment, 28 weeks, 36 weeks, at birth and at 5 months post-delivery. The primary outcomes for the study are proportion of women with excessive GWG and infant birthweight. DISCUSSION: The HUMBA demonstration trial will assess the efficacy of a culturally tailored multifaceted dietary intervention and probiotic treatment in limiting excessive GWG and optimising birthweight in a multiethnic sample of obese pregnant women. If successful, either one or both of the interventions may be incorporated into future studies powered to investigate important pregnancy outcomes. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry registration number: ACTRN12615000400561 , Universal Trial Number: U1111-1155-0409. Date registered: 29th April 2015.

Dietary supplementation with myo-inositol in women during pregnancy for treating gestational diabetes.

BACKGROUND: Gestational diabetes mellitus (GDM) is any degree of glucose intolerance that first presents and is recognised during pregnancy and usually resolves after the birth of the baby. GDM is associated with increased short- and long-term morbidity for the mother and her baby. Treatment usually includes lifestyle modification and/or pharmacological therapy (oral antidiabetic agents or insulin) with the aim to maintain treatment targets for blood glucose concentrations. Finding novel treatment agents which are effective, acceptable and safe for the mother and her baby are important. One such emerging potential intervention is myo-inositol which is an isomer of inositol and occurs endogenously and is found in natural dietary sources such as fruits, vegetables, nuts and cereals. OBJECTIVES: To assess if dietary supplementation with myo-inositol during pregnancy is safe and effective, for the mother and fetus, in treating gestational diabetes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 April 2016), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (7 April 2016), and reference lists of retrieved studies. SELECTION CRITERIA: All published and unpublished randomised controlled trials or cluster-randomised controlled trials reporting on the use of myo-inositol compared with placebo, no treatment or another intervention for the treatment of women with gestational diabetes. Quasi-randomised and cross-over studies are not eligible for inclusion. Women with pre-existing diabetes were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. For key outcomes (where data were available), we assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: We included two studies (142 women and infants), both were conducted in women in Italy and compared myo-inositol with a placebo control.None of the maternal primary outcomes pre-specified for this review were reported in the included studies: hypertensive disorders of pregnancy; caesarean section; development of subsequent type 2 diabetes mellitus. No data were reported for the majority of this review's maternal secondary outcomes. We could only perform meta-analysis for two secondary outcomes: fasting oral glucose tolerance test and additional pharmacological treatment. All other results are based on data from single studies. Overall, the risk of bias of the included studies was judged to be unclear due to lack of key methodological information.There was no evidence of a difference between treatment groups in need for additional pharmacotherapy or weight gain during pregnancy, although myo-inositol was associated with a lower body mass index (BMI) change (mean difference (MD) -1.50 kg/m2; 95% confidence interval (CI) -2.35 to -0.65; one trial, n = 73). Myo-inositol was associated with a reduction in the fasting blood glucose concentration at the end of treatment (MD -0.47 mmol/L; 95% CI -0.59 to -0.35; two trials, n = 142 women) compared with the control group. One small trial reported that myo-inositol was associated with a reduction in one-hour post-prandial blood glucose concentration at the end of treatment (MD -0.90 mmol/L; 95% CI -1.73 to -0.07; one trial, n = 73 women) compared with the control group. There was no difference between groups for the two-hour post-prandial blood glucose concentrations between groups (MD -0.70 mmol/L; 95% CI -1.46 to 0.06; one trial, n = 73 women). The one-hour and two-hour blood glucose concentrations show evidence of imprecision associated with wide CIs and small sample size.For the infant, there was no evidence of a difference in the risk for being born large-for-gestational age between the myo-inositol and the control group (risk ratio (RR) 0.36; 95% CI 0.02 to 8.58; one trial, n = 73 infants; low-quality evidence). The evidence was downgraded due to imprecision. This review's other primary outcomes were not reported in the included trials: perinatal mortality (stillbirth and neonatal mortality); mortality of morbidity composite (as defined by the trials); neurosensory disability. Infants in the myo-inositol group were less likely to have neonatal hypoglycaemia compared with the placebo group (RR 0.05; 95% CI 0.00 to 0.85; one study, n = 73 infants; low-quality evidence). There is evidence of imprecision for this outcome with low event rates and small sample size. There was no evidence of a difference between treatment and placebo groups for preterm birth or birthweight. Myo-inositol was associated with a later gestational age at birth compared with the placebo group (MD 2.10 weeks; 95% CI 1.27 to 2.93; one trial, n = 73 infants). No data were reported for any of the other neonatal outcomes for this review.No long-term outcomes were reported for the mother, infant as a child, infant as an adult, or health service outcomes. AUTHORS' CONCLUSIONS: There are insufficient data to evaluate the effect of myo-inositol for the treatment of gestational diabetes, with no data to examine the majority of outcomes in this review. There do not appear to be any benefits for the infant associated with exposure to myo-inositol such as reduced risk of being born large-for-gestational age. Although the risk of neonatal hypoglycaemia is reduced for the myo-inositol group, there is evidence of imprecision. Evidence from two studies suggested that myo-inositol was associated with a reduced change in maternal BMI and fasting blood sugar concentration compared with placebo. There is a lack of reporting of the clinically meaningful outcomes pre-specified for this review.Uncertainty of the effectiveness of myo-inositol as a treatment for GDM for key maternal and infant outcomes remains and further high- quality trials with appropriate sample sizes are required to further investigate the role of myo-inositol as a treatment or co-treatment for women with gestational diabetes. Future trials should report on the core outcomes for GDM identified in the methods section of this review. Participants of varying ethnicities and with varying risk factors for GDM should be included in future trials. In addition, further trials of myo-inositol for the treatment of GDM should explore the optimal dose, frequency and timing of supplementation, report on adverse effects and assess the long- term effects of this intervention. Economic analysis or health service use and costs should also be included.

Antenatal dietary supplementation with myo-inositol in women during pregnancy for preventing gestational diabetes.

BACKGROUND: Gestational diabetes, glucose intolerance with onset or first recognition during pregnancy, is a rising problem worldwide. Both non-pharmacological and pharmacological approaches to the prevention of gestational diabetes have been, and continue to be explored. Myo-inositol, an isomer of inositol, is a naturally occurring sugar commonly found in cereals, corn, legumes and meat. It is one of the intracellular mediators of the insulin signal and correlated with insulin sensitivity in type 2 diabetes. The potential beneficial effect on improving insulin sensitivity suggests that myo-inositol may be useful for women in preventing gestational diabetes. OBJECTIVES: To assess if antenatal dietary supplementation with myo-inositol is safe and effective, for the mother and fetus, in preventing gestational diabetes. SEARCH METHODS: We searched the Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov, WHO ICTRP (2 November 2015) and reference lists of retrieved studies. SELECTION CRITERIA: We sought published and unpublished randomised controlled trials, including conference abstracts, assessing the effects of myo-inositol for the prevention of gestational diabetes mellitus (GDM). Quasi-randomised and cross-over trials were not eligible for inclusion, but cluster designs were eligible. Participants in the trials were pregnant women. Women with pre-existing type 1 or type 2 diabetes were excluded. Trials that compared the administration of any dose of myo-inositol, alone or in a combination preparation were eligible for inclusion. Trials that used no treatment, placebo or another intervention as the comparator were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, risk of bias and extracted the data. Data were checked for accuracy. MAIN RESULTS: We included four randomised controlled trials (all conducted in Italy) reporting on 567 women who were less than 11 weeks' to 24 weeks' pregnant at the start of the trials. The trials had small sample sizes and one trial only reported an interim analysis. Two trials were open-label. The overall risk of bias was unclear.For the mother, supplementation with myo-inositol was associated with a reduction in the incidence of gestational diabetes compared with control (risk ratio (RR) 0.43, 95% confidence interval (CI) 0.29 to 0.64; three trials; n = 502 women). Using GRADE methods this evidence was assessed as low with downgrading due to unclear risk of bias for allocation concealment in two of the included trials and lack of generalisability of findings. For women who received myo-inositol supplementation, the incidence of GDM ranged from 8% to 18%; for women in the control group, the incidence of GDM was 28%, using International Association of Diabetes and Pregnancy Study Groups Consensus Panel 2010 criteria to diagnose GDM.Two trials reported on hypertensive disorders of pregnancy, a primary maternal outcome of this review. There was no clear difference in risk of hypertensive disorders of pregnancy between the myo-inositol and control groups (average RR 0.43, 95% CI 0.02 to 8.41; two trials; n = 398 women; Tau(2) = 3.23; I(2) = 69%). Using GRADE methods, this evidence was assessed as very low, with downgrading due to wide confidence intervals with very low event rates, a small sample size, and lack of blinding and unclear allocation concealment methods, and a lack of generalisability. For women who received myo-inositol the risk of hypertensive disorders of pregnancy ranged from 0% to 33%; for women in the control group the risk was 4%.For the infant, none of the included trials reported on the primary neonatal outcomes of this systematic review (large-for-gestational age, perinatal mortality, mortality or morbidity composite).In terms of this review's secondary outcomes, there was no clear difference in the risk of caesarean section between the myo-inositol and control groups (RR 0.95, 95% CI 0.76 to 1.19; two trials; n = 398 women). Using GRADE methods, this evidence was assessed as low, with downgrading due to unclear risk of bias in one trial and lack of generalisability. For women who received myo-inositol supplementation, the risk of having a caesarean section ranged from 34% to 54%; for women in the control group the was 45%. There were no maternal adverse effects of therapy in the two trials that reported on this outcome (the other two trials did not report this outcome).Two trials found no clear difference in the risk of macrosomia between infants whose mothers received myo-inositol supplementation compared with controls (average RR 0.35, 95% CI 0.02 to 6.37; two trials; n = 398 infants;Tau(2) = 3.33; I(2) = 73%). Similarly, there was no clear difference between groups in terms of neonatal hypoglycaemia (RR 0.36, 95% CI 0.01 to 8.66) or shoulder dystocia (average RR 2.33, 95% CI 0.12 to 44.30, Tau(2) = 3.24; I(2) = 72%).There was a lack of data available for a large number of maternal and neonatal secondary outcomes, and no data for any of the long-term childhood or adulthood outcomes, or for health service cost outcomes. AUTHORS' CONCLUSIONS: Evidence from four trials of antenatal dietary supplementation with myo-inositol during pregnancy shows a potential benefit for reducing the incidence of gestational diabetes. No data were reported for any of this review's primary neonatal outcomes. There were very little outcome data for the majority of this review's secondary outcomes. There is no clear evidence of a difference for macrosomia when compared with control.The current evidence is based on small trials that are not powered to detect differences in outcomes including perinatal mortality and serious infant morbidity. All of the included studies were conducted in Italy which raises concerns about the lack of generalisability of the evidence to other settings. There is evidence of inconsistency and indirectness and as a result, many of the judgements on the quality of the evidence were downgraded to low or very low quality (GRADEpro Guideline Development Tool).Further trials for this promising antenatal intervention for preventing gestational diabetes are encouraged and should include pregnant women of different ethnicities and varying risk factors and use of myo-inositol (different doses, frequency and timing of administration) in comparison with placebo, diet and exercise or pharmacological interventions. Outcomes should include potential harms including adverse effects.

Different treatment regimens of magnesium sulphate for tocolysis in women in preterm labour.

BACKGROUND: Magnesium sulphate has been used to inhibit preterm labour to prevent preterm birth. There is no consensus as to the safety profile of different treatment regimens with respect to dose, duration, route and timing of administration. OBJECTIVES: To assess the efficacy and safety of alternative magnesium sulphate regimens when used as single agent tocolytic therapy during pregnancy. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2015) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised trials comparing different magnesium sulphate treatment regimens when used as single agent tocolytic therapy during pregnancy in women in preterm labour. Quasi-randomised trials were eligible for inclusion but none were identified. Cross-over and cluster trials were not eligible for inclusion. Health outcomes were considered at the level of the mother, the infant/child and the health service. INTERVENTION: intravenous or oral magnesium sulphate given alone for tocolysis.Comparison: alternative dosing regimens of magnesium sulphate given alone for tocolysis. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and quality and extracted data. MAIN RESULTS: Three trials including 360 women and their infants were identified as eligible for inclusion in this review. Two trials were rated as low risk of bias for random sequence generation and concealment of allocation. A third trial was assessed as unclear risk of bias for these domains but did not report data for any of the outcomes examined in this review. No trials were rated to be of high quality overall.Intravenous magnesium sulphate was administered according to low-dose regimens (4 g loading dose followed by 2 g/hour continuous infusion and/or increased by 1 g/hour hourly until successful tocolysis or failure of treatment), or high-dose regimens (4 g loading dose followed by 5 g/hour continuous infusion and increased by 1 g/hour hourly until successful tocolysis or failure of treatment, or 6 g loading dose followed by 2 g/hour continuous infusion and increased by 1 g/hour hourly until successful tocolysis or failure of treatment).There were no differences seen between high-dose magnesium sulphate regimens compared with low-dose magnesium sulphate regimens for the primary outcome of fetal, neonatal and infant death (risk ratio (RR) 0.43, 95% confidence interval (CI) 0.12 to 1.56; one trial, 100 infants). Using the GRADE approach, the evidence for fetal, neonatal and infant death was considered to be VERY LOW quality. No data were reported for any of the other primary maternal and infant health outcomes (birth less than 48 hours after trial entry; composite serious infant outcome; composite serious maternal outcome).There were no clear differences seen between high-dose magnesium sulphate regimens compared with low-dose magnesium sulphate regimens for the secondary infant health outcomes of fetal death; neonatal death; and rate of hypocalcaemia, osteopenia or fracture; and secondary maternal health outcomes of rate of caesarean birth; pulmonary oedema; and maternal self-reported adverse effects. Pulmonary oedema was reported in two women given high-dose magnesium sulphate, but not in any of the women given low-dose magnesium sulphate.In a single trial of high and low doses of magnesium sulphate for tocolysis including 100 infants, the risk of respiratory distress syndrome was lower with use of a high-dose regimen compared with a low-dose regimen (RR 0.31, 95% CI 0.11 to 0.88; one trial, 100 infants). Using the GRADE approach, the evidence for respiratory distress syndrome was judged to be LOW quality. No difference was seen in the rate of admission to the neonatal intensive care unit. However, for those babies admitted, a high-dose regimen was associated with a reduction in the length of stay in the neonatal intensive care unit compared with a low-dose regimen (mean difference -3.10 days, 95% confidence interval -5.48 to -0.72).We found no data for the majority of our secondary outcomes. AUTHORS' CONCLUSIONS: There are limited data available (three studies, with data from only two studies) comparing different dosing regimens of magnesium sulphate given as single agent tocolytic therapy for the prevention of preterm birth. There is no evidence examining duration of therapy, timing of therapy and the role for repeat dosing.Downgrading decisions for our primary outcome of fetal, neonatal and infant death were based on wide confidence intervals (crossing the line of no effect), lack of blinding and a limited number of studies. No data were available for any of our other important outcomes: birth less than 48 hours after trial entry; composite serious infant outcome; composite serious maternal outcome. The data are limited by volume and the outcomes reported. Only eight of our 45 pre-specified primary and secondary maternal and infant health outcomes were reported on in the included studies. No long-term outcomes were reported. Downgrading decisions for the evidence on the risk of respiratory distress were based on wide confidence intervals (crossing the line of no effect) and lack of blinding.There is some evidence from a single study suggesting a reduction in the length of stay in the neonatal intensive care unit and a reduced risk of respiratory distress syndrome where a high-dose regimen of magnesium sulphate has been used compared with a low-dose regimen. However, given that evidence has been drawn from a single study (with a small sample size), these data should be interpreted with caution.Magnesium sulphate has been shown to be of benefit in a wide range of obstetric settings, although it has not been recommended for tocolysis. In clinical settings where health benefits are established, further trials are needed to address the lack of evidence regarding the optimal dose (loading dose and maintenance dose), duration of therapy, timing of therapy and role for repeat dosing in terms of efficacy and safety for mothers and their children. Ongoing examination of different regimens with respect to important health outcomes is required.