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 SELECTION CRITERIA: We included published and unpublished randomised controlled trials (RCTs) including cluster-RCTs and conference abstracts, assessing the effects of myo-inositol for the prevention of gestational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.

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.

Sex-specific effects of nutritional supplements in infants born early or small: protocol for an individual participant data meta-analysis (ESSENCE IPD-MA).

INTRODUCTION: Preterm and small for gestational age (SGA) infants are at increased risk of poor growth, disability and delayed development. While growing up they are also at increased risk of obesity, diabetes and later heart disease. The risk of such adverse outcomes may be altered by how preterm and SGA infants are fed after birth. Faltering postnatal growth is common due to failure to achieve recommended high energy and protein intakes, and thus preterm and SGA infants are often provided with supplemental nutrition soon after birth. Enhanced nutrition has been associated with improved early growth and better cognitive development. However, limited evidence suggests that faster growth may increase the risk for later adiposity, metabolic and cardiovascular disease, and that such risks may differ between girls and boys. METHODS AND ANALYSIS: We will search Ovid MEDLINE, Embase, Cochrane CENTRAL, Cochrane Database of Systematic Reviews, controlled-trials.com, ClinicalTrials.gov and anzctr.org.au for randomised trials that studied the effects of macronutrient supplements for preterm and SGA infants on (i) developmental and metabolic and (ii) growth outcomes after hospital discharge. The outcomes will be (i) cognitive impairment and metabolic risk (co-primary) and (ii) body mass index. Individual participant data (IPD) from all available trials will be included using an intention-to-treat approach. A one-stage procedure for IPD meta-analysis (MA) will be used, accounting for clustering of participants within studies. Exploratory subgroup analyses will further investigate sources of heterogeneity, including sex and size of infants, different timing, duration and type of supplements. ETHICS AND DISSEMINATION: This IPD-MA is approved by the University of Auckland Human Participants Ethics Committee (reference number: 019874). Individual studies have approval from relevant local ethics committees. Results will be disseminated in a peer-reviewed journal and presented at international conferences. PROSPERO REGISTRATION NUMBER: CRD42017072683.

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.