Early Amino Acids in Extremely Preterm Infants and Neurodisability at 2 Years.

BACKGROUND: Whether higher parenteral amino acid intake improves outcomes in infants with extremely low birth weight is unclear. METHODS: In this multicenter, parallel-group, double-blind, randomized, placebo-controlled trial, we assigned infants with birth weights of less than 1000 g at 8 neonatal intensive care units to receive amino acids at a dose of 1 g per day (intervention group) or placebo in addition to usual nutrition for the first 5 days after birth. The primary outcome was survival free from neurodisability as assessed with the Bayley Scales of Infant and Toddler Development and neurologic examination at 2 years, corrected for gestational age at birth. Secondary outcomes were the components of the primary outcome as well as the presence or absence of neonatal disorders, the rate of growth, and nutritional intake. RESULTS: We enrolled 434 infants (217 per group) in this trial. Survival free from neurodisability was observed in 97 of 203 children (47.8%) in the intervention group and in 102 of 205 (49.8%) in the placebo group (adjusted relative risk, 0.95; 95% confidence interval [CI], 0.79 to 1.14; P = 0.56). Death before the age of 2 years occurred in 39 of 217 children (18.0%) in the intervention group and 42 of 217 (19.4%) in the placebo group (adjusted relative risk, 0.93; 95% CI, 0.63 to 1.36); neurodisability occurred in 67 of 164 children (40.9%) in the intervention group and 61 of 163 (37.4%) in the placebo group (adjusted relative risk, 1.16; 95% CI, 0.90 to 1.50). Neurodisability was moderate to severe in 27 children (16.5%) in the intervention group and 14 (8.6%) in the placebo group (adjusted relative risk, 1.95; 95% CI, 1.09 to 3.48). More children in the intervention group than in the placebo group had patent ductus arteriosus (adjusted relative risk, 1.65; 95% CI, 1.11 to 2.46). In a post hoc analysis, refeeding syndrome occurred in 42 of 172 children in the intervention group and 26 of 166 in the placebo group (adjusted relative risk, 1.64; 95% CI, 1.09 to 2.47). Eight serious adverse events occurred. CONCLUSIONS: In infants with extremely low birth weight, extra parenteral amino acids at a dose of 1 g per day for 5 days after birth did not increase the number who survived free from neurodisability at 2 years. (Funded by the New Zealand Health Research Council and others; ProVIDe Australian New Zealand Clinical Trials Registry number, ACTRN12612001084875.).

Lower versus Higher Glycemic Criteria for Diagnosis of Gestational Diabetes.

BACKGROUND: Treatment of gestational diabetes improves maternal and infant health, although diagnostic criteria remain unclear. METHODS: We randomly assigned women at 24 to 32 weeks' gestation in a 1:1 ratio to be evaluated for gestational diabetes with the use of lower or higher glycemic criteria for diagnosis. The lower glycemic criterion was a fasting plasma glucose level of at least 92 mg per deciliter (≥5.1 mmol per liter), a 1-hour level of at least 180 mg per deciliter (≥10.0 mmol per liter), or a 2-hour level of at least 153 mg per deciliter (≥8.5 mmol per liter). The higher glycemic criterion was a fasting plasma glucose level of at least 99 mg per deciliter (≥5.5 mmol per liter) or a 2-hour level of at least 162 mg per deciliter (≥9.0 mmol per liter). The primary outcome was the birth of an infant who was large for gestational age (defined as a birth weight above the 90th percentile according to Fenton-World Health Organization standards). Secondary outcomes were maternal and infant health. RESULTS: A total of 4061 women underwent randomization. Gestational diabetes was diagnosed in 310 of 2022 women (15.3%) in the lower-glycemic-criteria group and in 124 of 2039 women (6.1%) in the higher-glycemic-criteria group. Among 2019 infants born to women in the lower-glycemic-criteria group, 178 (8.8%) were large for gestational age, and among 2031 infants born to women in the higher-glycemic-criteria group, 181 (8.9%) were large for gestational age (adjusted relative risk, 0.98; 95% confidence interval, 0.80 to 1.19; P = 0.82). Induction of labor, use of health services, use of pharmacologic agents, and neonatal hypoglycemia were more common in the lower-glycemic-criteria group than in the higher-glycemic-criteria group. The results for the other secondary outcomes were similar in the two trial groups, and there were no substantial between-group differences in adverse events. Among the women in both groups who had glucose test results that fell between the lower and higher glycemic criteria, those who were treated for gestational diabetes (195 women), as compared with those who were not (178 women), had maternal and infant health benefits, including fewer large-for-gestational-age infants. CONCLUSIONS: The use of lower glycemic criteria for the diagnosis of gestational diabetes did not result in a lower risk of a large-for-gestational-age infant than the use of higher glycemic criteria. (Funded by the Health Research Council of New Zealand and others; GEMS Australian New Zealand Clinical Trials Registry number, ACTRN12615000290594.).

Cardiovascular outcomes 50 years after antenatal exposure to betamethasone: Follow-up of a randomised double-blind, placebo-controlled trial.

BACKGROUND: Antenatal corticosteroids for women at risk of preterm birth reduce neonatal morbidity and mortality, but there is limited evidence regarding their effects on long-term health. This study assessed cardiovascular outcomes at 50 years after antenatal exposure to corticosteroids. METHODS AND FINDINGS: We assessed the adult offspring of women who participated in the first randomised, double-blind, placebo-controlled trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome (RDS) (1969 to 1974). The first 717 mothers received 2 intramuscular injections of 12 mg betamethasone or placebo 24 h apart and the subsequent 398 received 2 injections of 24 mg betamethasone or equivalent volume of placebo. Follow-up included a health questionnaire and consent to access administrative data sources. The co-primary outcomes were the prevalence of cardiovascular risk factors (any of hypertension, hyperlipidaemia, diabetes mellitus, gestational diabetes mellitus, or prediabetes) and age at first major adverse cardiovascular event (MACE) (cardiovascular death, myocardial infarction, coronary revascularisation, stroke, admission for peripheral vascular disease, and admission for heart failure). Analyses were adjusted for gestational age at entry, sex, and clustering. Of 1,218 infants born to 1,115 mothers, we followed up 424 (46% of survivors; 212 [50%] female) at mean (standard deviation) age 49.3 (1.0) years. There were no differences between those exposed to betamethasone or placebo for cardiovascular risk factors (159/229 [69.4%] versus 131/195 [67.2%]; adjusted relative risk 1.02, 95% confidence interval [CI] [0.89, 1.18;]; p = 0.735) or age at first MACE (adjusted hazard ratio 0.58, 95% CI [0.23, 1.49]; p = 0.261). There were also no differences in the components of these composite outcomes or in any of the other secondary outcomes. Key limitations were follow-up rate and lack of in-person assessments. CONCLUSIONS: There is no evidence that antenatal corticosteroids increase the prevalence of cardiovascular risk factors or incidence of cardiovascular events up to 50 years of age. Established benefits of antenatal corticosteroids are not outweighed by an increase in adult cardiovascular disease.

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus.

BACKGROUND: Magnesium sulphate is a common therapy in perinatal care. Its benefits when given to women at risk of preterm birth for fetal neuroprotection (prevention of cerebral palsy for children) were shown in a 2009 Cochrane review. Internationally, use of magnesium sulphate for preterm cerebral palsy prevention is now recommended practice. As new randomised controlled trials (RCTs) and longer-term follow-up of prior RCTs have since been conducted, this review updates the previously published version. OBJECTIVES: To assess the effectiveness and safety of magnesium sulphate as a fetal neuroprotective agent when given to women considered to be at risk of preterm birth. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) on 17 March 2023, as well as reference lists of retrieved studies. SELECTION CRITERIA: We included RCTs and cluster-RCTs of women at risk of preterm birth that assessed prenatal magnesium sulphate for fetal neuroprotection compared with placebo or no treatment. All methods of administration (intravenous, intramuscular, and oral) were eligible. We did not include studies where magnesium sulphate was used with the primary aim of preterm labour tocolysis, or the prevention and/or treatment of eclampsia. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed RCTs for inclusion, extracted data, and assessed risk of bias and trustworthiness. Dichotomous data were presented as summary risk ratios (RR) with 95% confidence intervals (CI), and continuous data were presented as mean differences with 95% CI. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included six RCTs (5917 women and their 6759 fetuses alive at randomisation). All RCTs were conducted in high-income countries. The RCTs compared magnesium sulphate with placebo in women at risk of preterm birth at less than 34 weeks' gestation; however, treatment regimens and inclusion/exclusion criteria varied. Though the RCTs were at an overall low risk of bias, the certainty of evidence ranged from high to very low, due to concerns regarding study limitations, imprecision, and inconsistency. Primary outcomes for infants/children: Up to two years' corrected age, magnesium sulphate compared with placebo reduced cerebral palsy (RR 0.71, 95% CI 0.57 to 0.89; 6 RCTs, 6107 children; number needed to treat for additional beneficial outcome (NNTB) 60, 95% CI 41 to 158) and death or cerebral palsy (RR 0.87, 95% CI 0.77 to 0.98; 6 RCTs, 6481 children; NNTB 56, 95% CI 32 to 363) (both high-certainty evidence). Magnesium sulphate probably resulted in little to no difference in death (fetal, neonatal, or later) (RR 0.96, 95% CI 0.82 to 1.13; 6 RCTs, 6759 children); major neurodevelopmental disability (RR 1.09, 95% CI 0.83 to 1.44; 1 RCT, 987 children); or death or major neurodevelopmental disability (RR 0.95, 95% CI 0.85 to 1.07; 3 RCTs, 4279 children) (all moderate-certainty evidence). At early school age, magnesium sulphate may have resulted in little to no difference in death (fetal, neonatal, or later) (RR 0.82, 95% CI 0.66 to 1.02; 2 RCTs, 1758 children); cerebral palsy (RR 0.99, 95% CI 0.69 to 1.41; 2 RCTs, 1038 children); death or cerebral palsy (RR 0.90, 95% CI 0.67 to 1.20; 1 RCT, 503 children); and death or major neurodevelopmental disability (RR 0.81, 95% CI 0.59 to 1.12; 1 RCT, 503 children) (all low-certainty evidence). Magnesium sulphate may also have resulted in little to no difference in major neurodevelopmental disability, but the evidence is very uncertain (average RR 0.92, 95% CI 0.53 to 1.62; 2 RCTs, 940 children; very low-certainty evidence). Secondary outcomes for infants/children: Magnesium sulphate probably reduced severe intraventricular haemorrhage (grade 3 or 4) (RR 0.76, 95% CI 0.60 to 0.98; 5 RCTs, 5885 infants; NNTB 92, 95% CI 55 to 1102; moderate-certainty evidence) and may have resulted in little to no difference in chronic lung disease/bronchopulmonary dysplasia (average RR 0.92, 95% CI 0.77 to 1.10; 5 RCTs, 6689 infants; low-certainty evidence). Primary outcomes for women: Magnesium sulphate may have resulted in little or no difference in severe maternal outcomes potentially related to treatment (death, cardiac arrest, respiratory arrest) (RR 0.32, 95% CI 0.01 to 7.92; 4 RCTs, 5300 women; low-certainty evidence). However, magnesium sulphate probably increased maternal adverse effects severe enough to stop treatment (average RR 3.21, 95% CI 1.88 to 5.48; 3 RCTs, 4736 women; moderate-certainty evidence). Secondary outcomes for women: Magnesium sulphate probably resulted in little to no difference in caesarean section (RR 0.96, 95% CI 0.91 to 1.02; 5 RCTs, 5861 women) and postpartum haemorrhage (RR 0.94, 95% CI 0.80 to 1.09; 2 RCTs, 2495 women) (both moderate-certainty evidence). Breastfeeding at hospital discharge and women's views of treatment were not reported. AUTHORS' CONCLUSIONS: The currently available evidence indicates that magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus, compared with placebo, reduces cerebral palsy, and death or cerebral palsy, in children up to two years' corrected age, and probably reduces severe intraventricular haemorrhage for infants. Magnesium sulphate may result in little to no difference in outcomes in children at school age. While magnesium sulphate may result in little to no difference in severe maternal outcomes (death, cardiac arrest, respiratory arrest), it probably increases maternal adverse effects severe enough to stop treatment. Further research is needed on the longer-term benefits and harms for children, into adolescence and adulthood. Additional studies to determine variation in effects by characteristics of women treated and magnesium sulphate regimens used, along with the generalisability of findings to low- and middle-income countries, should be considered.

Prevalence and determinants of perinatal mental disorders in women with gestational diabetes in New Zealand: Findings from a national longitudinal study.

INTRODUCTION: Concurrent diagnosis of gestational diabetes mellitus and mental disorders is associated with adverse outcomes for mother and child, but there is limited information about prevalence or which women are at risk. MATERIAL AND METHODS: This study was a prospective cohort study of women with gestational diabetes from 10 hospitals in New Zealand who reported anxiety (6-item Spielberger State-Trait Anxiety Inventory), depression (Edinburgh Postnatal Depression Scale) and health-related quality of life (36-Item Short-Form General Health Survey) at time of gestational diabetes diagnosis (baseline), 36 weeks' gestation, and 6 months postpartum. Potential predictors were assessed using multivariable logistic regression. RESULTS: Among 414 respondents, 17% reported anxiety, 16% vulnerability to depression and 27% poor mental health-related quality of life at time of gestational diabetes diagnosis. At 36 weeks' gestation, prevalence decreased for vulnerability to depression (8%) and poor mental health-related quality of life (20%). Younger maternal age, Pacific ethnicity, previous history of gestational diabetes, and older gestational age at time of gestational diabetes diagnosis were associated with poorer mental health outcomes. At 6 months postpartum the prevalence of mental disorders did not differ from in late pregnancy and they were associated with later gestational age at time of gestational diabetes diagnosis and elevated 2-hour postprandial glucose concentrations. CONCLUSIONS: Perinatal mental disorders are common at time of diagnosis among women with gestational diabetes in New Zealand and had decreased by late pregnancy and at 6 months after birth. These disorders are more common among women with specific risk factors who may therefore benefit from additional support.

Intrapartum maternal glycaemic control for the prevention of neonatal hypoglycaemia: a systematic review and meta-analysis.

BACKGROUND: Neonatal hypoglycaemia is the most common metabolic disorder in infants, and may be influenced by maternal glycaemic control. This systematic review evaluated the effect of intrapartum maternal glycaemic control on neonatal hypoglycaemia. METHODS: We included randomised controlled trials (RCTs), quasi-RCTs, non-randomised studies of interventions, and cohort or case-control studies that examined interventions affecting intrapartum maternal glycaemic control compared to no or less stringent control. We searched four databases and three trial registries to November 2023. Quality assessments used Cochrane Risk of Bias 1 or the Effective Public Health Practice Project Quality Assessment Tool. Certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE). Meta-analysis was performed using random-effects models analysed separately for women with or without diabetes. The review was registered prospectively on PROSPERO (CRD42022364876). RESULTS: We included 46 studies of women with diabetes and five studies of women without diabetes: one RCT, 32 cohort and 18 case-control studies (11,273 participants). For women with diabetes, the RCT showed little to no difference in the incidence of neonatal hypoglycaemia between tight versus less tight intrapartum glycaemic control groups (76 infants, RR 1.00 (0.45, 2.24), p = 1.00, low certainty evidence). However, 11 cohort studies showed tight intrapartum glycaemic control may reduce neonatal hypoglycaemia (6,152 infants, OR 0.44 (0.31, 0.63), p < 0.00001, I2 = 58%, very low certainty evidence). For women without diabetes, there was insufficient evidence to determine the effect of tight intrapartum glycaemic control on neonatal hypoglycaemia. CONCLUSIONS: Very uncertain evidence suggests that tight intrapartum glycaemic control may reduce neonatal hypoglycaemia in infants of women with diabetes. High-quality RCTs are required.

Umbilical cord milking and delayed cord clamping for the prevention of neonatal hypoglycaemia: a systematic review and meta-analysis.

BACKGROUND: Placental management strategies such as umbilical cord milking and delayed cord clamping may provide a range of benefits for the newborn. The aim of this review was to assess the effectiveness of umbilical cord milking and delayed cord clamping for the prevention of neonatal hypoglycaemia. METHODS: Three databases and five clinical trial registries were systematically reviewed to identify randomised controlled trials comparing umbilical cord milking or delayed cord clamping with control in term and preterm infants. The primary outcome was neonatal hypoglycaemia (study defined). Two independent reviewers conducted screening, data extraction and quality assessment. Quality of the included studies was assessed using the Cochrane Risk of Bias tool (RoB-2). Certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Meta-analysis using a random effect model was done using Review Manager 5.4. The review was registered prospectively on PROSPERO (CRD42022356553). RESULTS: Data from 71 studies and 14 268 infants were included in this review; 22 (2 537 infants) compared umbilical cord milking with control, and 50 studies (11 731 infants) compared delayed with early cord clamping. For umbilical cord milking there were no data on neonatal hypoglycaemia, and no differences between groups for any of the secondary outcomes. We found no evidence that delayed cord clamping reduced the incidence of hypoglycaemia (6 studies, 444 infants, RR = 0.87, CI: 0.58 to 1.30, p = 0.49, I2 = 0%). Delayed cord clamping was associated with a 27% reduction in neonatal mortality (15 studies, 3 041 infants, RR = 0.73, CI: 0.55 to 0.98, p = 0.03, I2 = 0%). We found no evidence for the effect of delayed cord clamping for any of the other outcomes. The certainty of evidence was low for all outcomes. CONCLUSION: We found no data for the effectiveness of umbilical cord milking on neonatal hypoglycaemia, and no evidence that delayed cord clamping reduced the incidence of hypoglycaemia, but the certainty of the evidence was low.

Betamethasone for Preterm Birth: Auckland Steroid Trial Full Results and New Insights 50 Years on.

OBJECTIVES: The objective of this study was to use modern analysis and reporting methods to present the full results of the first randomized trial of antenatal corticosteroids, performed 50 years ago. STUDY DESIGN: In this single-center trial, women at risk of preterm birth at 24 to less than 37 weeks of gestation were randomized to receive 2 doses of betamethasone or placebo, 24 hours apart. Women and their caregivers were blinded to treatment allocation. The primary outcome was respiratory distress syndrome. Secondary outcomes included measures of neonatal mortality and morbidity, mode of birth, and maternal infection. RESULTS: Between 1969 and 1974, 1115 women (1142 pregnancies) were randomized, 560 pregnancies (601 infants) to betamethasone and 582 (617 infants) to placebo. The risk of respiratory distress syndrome was significantly reduced in the betamethasone group compared with placebo (8.8% vs 14.4%, adjusted relative risk 0.62, 95% CI 0.45-0.86, P = .004). Subgroup analyses indicated greater efficacy in male than female infants but no effect of tocolytic therapy or doubling of betamethasone dose. Fetal or neonatal death, neonatal or maternal infection, neonatal hypoglycaemia, cesarean delivery, and lactation status at discharge were not different between the groups. CONCLUSIONS: Antenatal betamethasone administered to women at risk of preterm birth between 24 and less than 37 weeks of gestation reduces the incidence of respiratory distress syndrome, with greater effect in male than in female infants. Doubling the dose of betamethasone does not provide additional benefit.

Glycemic control in gestational diabetes and impact on biomarkers in women and infants.

BACKGROUND: Gestational diabetes mellitus (GDM) is linked to the dysregulation of inflammatory markers in women with GDM compared to women without. It is unclear whether the intensity of glycemic control influences these biomarkers. We aimed to assess whether different glycemic targets for women with GDM and compliance influence maternal and infant biomarkers. METHODS: Maternity hospitals caring for women with GDM were randomized in the TARGET Trial to tight or less tight glycemic targets. Maternal blood was collected at study entry, 36 weeks' gestation, and 6 months postpartum, and cord plasma after birth. We assessed compliance to targets and concentrations of maternal serum and infant biomarkers. RESULTS: Eighty-two women and infants were included in the study. Concentrations of maternal and infant biomarkers did not differ between women assigned to tighter and less tight glycemic targets; however, concentrations were altered in maternal serum leptin and CRP and infant cord C-peptide, leptin, and IGF in women who complied with tighter targets. CONCLUSIONS: Use of tighter glycemic targets in women with GDM does not change the concentrations of maternal and infant biomarkers compared to less tight targets. However, when compliance is achieved to tighter targets, maternal and infant biomarkers are altered. IMPACT: The use of tighter glycemic targets in gestational diabetes does not result in changes to maternal or cord plasma biomarkers. However, for women who complied with tighter targets, maternal serum leptin and CRP and infant cord C-peptide, leptin and IGF were altered compared with women who complied with the use of the less tight targets. This article adds to the current evidence base regarding the impact of gestational diabetes on maternal and infant biomarkers. This article highlights the need for further research to assess enablers to meet the tighter target recommendations and to assess the impact on relevant biomarkers.

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.

Different intensities of glycaemic control for women with gestational diabetes mellitus.

BACKGROUND: Gestational diabetes mellitus (GDM) has major short- and long-term implications for both the mother and her baby. GDM is defined as a carbohydrate intolerance resulting in hyperglycaemia or any degree of glucose intolerance with onset or first recognition during pregnancy from 24 weeks' gestation onwards and which resolves following the birth of the baby. Rates for GDM can be as high as 25% depending on the population and diagnostic criteria used, and overall rates are increasing globally. There is wide variation internationally in glycaemic treatment target recommendations for women with GDM that are based on consensus rather than high-quality trials. OBJECTIVES: To assess the effect of different intensities of glycaemic control in pregnant women with GDM on maternal and infant health outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (26 September 2022), and reference lists of the retrieved studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs), cluster-RCTs, and quasi-RCTs. Trials were eligible for inclusion if women were diagnosed with GDM during pregnancy and the trial compared tighter and less-tight glycaemic targets during management. We defined tighter glycaemic targets as lower numerical glycaemic concentrations, and less-tight glycaemic targets as higher numerical glycaemic concentrations. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods for carrying out data collection, assessing risk of bias, and analysing results. Two review authors independently assessed trial eligibility for inclusion, evaluated risk of bias, and extracted data for the four included studies. We assessed the certainty of evidence for selected outcomes using the GRADE approach. Primary maternal outcomes included hypertensive disorders of pregnancy and subsequent development of type 2 diabetes. Primary infant outcomes included perinatal mortality, large-for-gestational-age, composite of mortality or serious morbidity, and neurosensory disability. MAIN RESULTS: This was an update of a previous review completed in 2016. We included four RCTs (reporting on 1731 women) that compared a tighter glycaemic control with less-tight glycaemic control in women diagnosed with GDM. Three studies were parallel RCTs, and one study was a stepped-wedged cluster-RCT. The trials took place in Canada, New Zealand, Russia, and the USA. We judged the overall risk of bias to be unclear. Two trials were only published in abstract form. Tight glycaemic targets used in the trials ranged between ≤ 5.0 and 5.1 mmol/L for fasting plasma glucose and ≤ 6.7 and 7.4 mmol/L postprandial. Less-tight targets for glycaemic control used in the included trials ranged between < 5.3 and 5.8 mmol/L for fasting plasma glucose and < 7.8 and 8.0 mmol/L postprandial. For the maternal outcomes, compared with less-tight glycaemic control, the evidence suggests a possible increase in hypertensive disorders of pregnancy with tighter glycaemic control (risk ratio (RR) 1.16, 95% confidence interval (CI) 0.80 to 1.69, 2 trials, 1491 women; low certainty evidence); however, the 95% CI is compatible with a wide range of effects that encompass both benefit and harm. Tighter glycaemic control likely results in little to no difference in caesarean section rates (RR 0.98, 95% CI 0.82 to 1.17, 3 studies, 1662 women; moderate certainty evidence) or induction of labour rates (RR 0.96, 95% CI 0.78 to 1.18, 1 study, 1096 women; moderate certainty evidence) compared with less-tight control. No data were reported for the outcomes of subsequent development of type 2 diabetes, perineal trauma, return to pre-pregnancy weight, and postnatal depression. For the infant outcomes, it was difficult to determine if there was a difference in perinatal mortality (RR not estimable, 2 studies, 1499 infants; low certainty evidence), and there was likely no difference in being large-for-gestational-age (RR 0.96, 95% CI 0.72 to 1.29, 3 studies, 1556 infants; moderate certainty evidence). The evidence suggests a possible reduction in the composite of mortality or serious morbidity with tighter glycaemic control (RR 0.84, 95% CI 0.55 to 1.29, 3 trials, 1559 infants; low certainty evidence); however, the 95% CI is compatible with a wide range of effects that encompass both benefit and harm. There is probably little difference between groups in infant hypoglycaemia (RR 0.92, 95% CI 0.72 to 1.18, 3 studies, 1556 infants; moderate certainty evidence). Tighter glycaemic control may not reduce adiposity in infants of women with GDM compared with less-tight control (mean difference -0.62%, 95% CI -3.23 to 1.99, 1 study, 60 infants; low certainty evidence), but the wide CI suggests significant uncertainty. We found no data for the long-term outcomes of diabetes or neurosensory disability. Women assigned to tighter glycaemic control experienced an increase in the use of pharmacological therapy compared with women assigned to less-tight glycaemic control (RR 1.37, 95% CI 1.17 to 1.59, 4 trials, 1718 women). Tighter glycaemic control reducedadherence with treatment compared with less-tight glycaemic control (RR 0.41, 95% CI 0.32 to 0.51, 1 trial, 395 women). Overall the certainty of evidence assessed using GRADE ranged from low to moderate, downgraded primarily due to risk of bias and imprecision. AUTHORS' CONCLUSIONS: This review is based on four trials (1731 women) with an overall unclear risk of bias. The trials provided data on most primary outcomes and suggest that tighter glycaemic control may increase the risk of hypertensive disorders of pregnancy. The risk of birth of a large-for-gestational-age infant and perinatal mortality may be similar between groups, and tighter glycaemic targets may result in a possible reduction in composite of death or severe infant morbidity. However, the CIs for these outcomes are wide, suggesting both benefit and harm. There remains limited evidence regarding the benefit of different glycaemic targets for women with GDM to minimise adverse effects on maternal and infant health. Glycaemic target recommendations from international professional organisations vary widely and are currently reliant on consensus given the lack of high-certainty evidence. Further high-quality trials are needed, and these should assess both short- and long-term health outcomes for women and their babies; include women's experiences; and assess health services costs in order to confirm the current findings. Two trials are ongoing.

Skin-to-skin contact for the prevention of neonatal hypoglycaemia: a systematic review and meta-analysis.

BACKGROUND: Skin-to-skin contact between mother and infant after birth is recommended to promote breastfeeding and maternal-infant bonding. However, its impact on the incidence of neonatal hypoglycaemia is unknown. We conducted a systematic review and meta-analysis to assess this. METHODS: Published randomised control trials (RCTs), quasi-RCTs, non-randomised studies of interventions, cohort, or case-control studies with an intervention of skin-to-skin care compared to other treatment were included without language or date restrictions. The primary outcome was neonatal hypoglycaemia (study-defined). We searched 4 databases and 4 trial registries from inception to May 12th, 2023. Quality of studies was assessed using Cochrane Risk of Bias 1 or Effective Public Health Practice Project Quality Assessment tools. Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results were synthesised using RevMan 5.4.1 or STATA and analysed using random-effects meta-analyses where possible, otherwise with direction of findings tables. This review was registered prospectively on PROSPERO (CRD42022328322). RESULTS: This review included 84,900 participants in 108 studies, comprising 65 RCTs, 16 quasi-RCTs, seven non-randomised studies of intervention, eight prospective cohort studies, nine retrospective cohort studies and three case-control studies. Evidence suggests skin-to-skin contact may result in a large reduction in the incidence of neonatal hypoglycaemia (7 RCTs/quasi-RCTs, 922 infants, RR 0.29 (0.13, 0.66), p < 0.0001, I2 = 47%). Skin-to-skin contact may reduce the incidence of admission to special care or neonatal intensive care nurseries for hypoglycaemia (1 observational study, 816 infants, OR 0.50 (0.25-1.00), p = 0.050), but the evidence is very uncertain. Skin-to-skin contact may reduce duration of initial hospital stay after birth (31 RCTs, 3437 infants, MD -2.37 (-3.66, -1.08) days, p = 0.0003, I2 = 90%, p for Egger's test = 0.02), and increase exclusive breastmilk feeding from birth to discharge (1 observational study, 1250 infants, RR 4.30 (3.19, 5.81), p < 0.0001), but the evidence is very uncertain. CONCLUSION: Skin-to-skin contact may lead to a large reduction in the incidence of neonatal hypoglycaemia. This, along with other established benefits, supports the practice of skin-to-skin contact for all infants and especially those at risk of hypoglycaemia.

Do glycaemic treatment targets affect the perinatal mental health status of women with gestational diabetes? - Data from the TARGET Trial.

BACKGROUND: Gestational diabetes mellitus is associated with perinatal mental disorders. Effective management may reduce this risk, but there is little evidence on effects of different glycaemic treatment targets. We assessed whether tight glycaemic treatment targets compared with less-tight targets reduce the risk of poor mental health outcomes in women with gestational diabetes. METHODS: This was a secondary analysis of data from women who consented to complete perinatal mental health questionnaires as participants in the TARGET Trial, a stepped-wedge cluster randomized trial in 10 hospitals in New Zealand. All hospitals initially used less tight glycaemic targets for management of gestational diabetes and were sequentially randomized, in clusters of two at 4-monthly intervals, to using tighter glycaemic targets. Data were collected from 414 participants on anxiety (6-item Spielberger State Anxiety scale), depression (Edinburgh Postnatal Depression Scale), and health-related quality of life (36-Item Short-Form General Health Survey) at the time of diagnosis (baseline), 36 weeks of gestation, and 6 months postpartum. The primary outcome was composite poor mental health (any of anxiety, vulnerability to depression, or poor mental health-related quality of life). Generalized linear mixed models were used to determine the main treatment effect with 95% confidence intervals using an intention-to-treat approach. RESULTS: We found no differences between randomised glycaemic target groups in the primary outcome at 36 weeks' (relative risk (RR): 1.07; 95% confidence interval 0.58, 1.95) and 6 months postpartum (RR: 1.03; 0.58, 1.81). There were similarly no differences in the components of the primary outcome at 36 weeks' [anxiety (RR: 0.85; 0.44, 1.62), vulnerability to depression (RR: 1.10; 0.43, 2.83), or poor mental health-related quality of life (RR: 1.05; 0.50, 2.20)] or at 6 months postpartum [anxiety (RR:1.21; 0.59, 2.48), vulnerability to depression (RR:1.41; 0.53, 3.79), poor mental health-related quality of life (RR: 1.11; 0.59, 2.08)]. CONCLUSION: We found no evidence that adoption of tighter glycaemic treatment targets in women with gestational diabetes alters their mental health status at 36 weeks' gestation and at 6 months postpartum. TRIAL REGISTRATION: The Australian New Zealand Clinical Trials Registry (ANZCTR). ACTRN12615000282583 (ANZCTR-Registration). Date of registration: 25 March 2015.

Prenatal Intravenous Magnesium at 30-34 Weeks' Gestation and Neurodevelopmental Outcomes in Offspring: The MAGENTA Randomized Clinical Trial.

Importance: Intravenous magnesium sulfate administered to pregnant individuals before birth at less than 30 weeks' gestation reduces the risk of death and cerebral palsy in their children. The effects at later gestational ages are unclear. Objective: To determine whether administration of magnesium sulfate at 30 to 34 weeks' gestation reduces death or cerebral palsy at 2 years. Design, Setting, and Participants: This randomized clinical trial enrolled pregnant individuals expected to deliver at 30 to 34 weeks' gestation and was conducted at 24 Australian and New Zealand hospitals between January 2012 and April 2018. Intervention: Intravenous magnesium sulfate (4 g) was compared with placebo. Main Outcomes and Measures: The primary outcome was death (stillbirth, death of a live-born infant before hospital discharge, or death after hospital discharge before 2 years' corrected age) or cerebral palsy (loss of motor function and abnormalities of muscle tone and power assessed by a pediatrician) at 2 years' corrected age. There were 36 secondary outcomes that assessed the health of the pregnant individual, infant, and child. Results: Of the 1433 pregnant individuals enrolled (mean age, 30.6 [SD, 6.6] years; 46 [3.2%] self-identified as Aboriginal or Torres Strait Islander, 237 [16.5%] as Asian, 82 [5.7%] as Maori, 61 [4.3%] as Pacific, and 966 [67.4%] as White) and their 1679 infants, 1365 (81%) offspring (691 in the magnesium group and 674 in the placebo group) were included in the primary outcome analysis. Death or cerebral palsy at 2 years' corrected age was not significantly different between the magnesium and placebo groups (3.3% [23 of 691 children] vs 2.7% [18 of 674 children], respectively; risk difference, 0.61% [95% CI, -1.27% to 2.50%]; adjusted relative risk [RR], 1.19 [95% CI, 0.65 to 2.18]). Components of the primary outcome did not differ between groups. Neonates in the magnesium group were less likely to have respiratory distress syndrome vs the placebo group (34% [294 of 858] vs 41% [334 of 821], respectively; adjusted RR, 0.85 [95% CI, 0.76 to 0.95]) and chronic lung disease (5.6% [48 of 858] vs 8.2% [67 of 821]; adjusted RR, 0.69 [95% CI, 0.48 to 0.99]) during the birth hospitalization. No serious adverse events occurred; however, adverse events were more likely in pregnant individuals who received magnesium vs placebo (77% [531 of 690] vs 20% [136 of 667], respectively; adjusted RR, 3.76 [95% CI, 3.22 to 4.39]). Fewer pregnant individuals in the magnesium group had a cesarean delivery vs the placebo group (56% [406 of 729] vs 61% [427 of 704], respectively; adjusted RR, 0.91 [95% CI, 0.84 to 0.99]), although more in the magnesium group had a major postpartum hemorrhage (3.4% [25 of 729] vs 1.7% [12 of 704] in the placebo group; adjusted RR, 1.98 [95% CI, 1.01 to 3.91]). Conclusions and Relevance: Administration of intravenous magnesium sulfate prior to preterm birth at 30 to 34 weeks' gestation did not improve child survival free of cerebral palsy at 2 years, although the study had limited power to detect small between-group differences. Trial Registration: anzctr.org.au Identifier: ACTRN12611000491965.

Tighter or less tight glycaemic targets for women with gestational diabetes mellitus for reducing maternal and perinatal morbidity: A stepped-wedge, cluster-randomised trial.

BACKGROUND: Treatment for gestational diabetes mellitus (GDM) aims to reduce maternal hyperglycaemia. The TARGET Trial assessed whether tighter compared with less tight glycaemic control reduced maternal and perinatal morbidity. METHODS AND FINDINGS: In this stepped-wedge, cluster-randomised trial, identification number ACTRN12615000282583, 10 hospitals in New Zealand were randomised to 1 of 5 implementation dates. The trial was registered before the first participant was enrolled. All hospitals initially used less tight targets (fasting plasma glucose (FPG) <5.5 mmol/L (<99 mg/dL), 1-hour <8.0 mmol/L (<144 mg/dL), 2 hour postprandial <7.0 mmol/L (<126 mg/dL)) and every 4 months, 2 hospitals moved to use tighter targets (FPG ≤5.0 mmol/L (≤90 mg/dL), 1-hour ≤7.4 mmol/L (≤133 mg/dL), 2 hour postprandial ≤6.7 mmol/L) (≤121 mg/dL). Women with GDM, blinded to the targets in use, were eligible. The primary outcome was large for gestational age. Secondary outcomes assessed maternal and infant health. Analyses were by intention to treat. Between May 2015 and November 2017, data were collected from 1,100 women with GDM (1,108 infants); 598 women (602 infants) used the tighter targets and 502 women (506 infants) used the less tight targets. The rate of large for gestational age was similar between the treatment target groups (88/599, 14.7% versus 76/502, 15.1%; adjusted relative risk [adjRR] 0.96, 95% confidence interval [CI] 0.66 to 1.40, P = 0.839). The composite serious health outcome for the infant of perinatal death, birth trauma, or shoulder dystocia was apparently reduced in the tighter group when adjusted for gestational age at diagnosis of GDM, BMI, ethnicity, and history of GDM compared with the less tight group (8/599, 1.3% versus 13/505, 2.6%, adjRR 0.23, 95% CI 0.06 to 0.88, P = 0.032). No differences were seen for the other infant secondary outcomes apart from a shorter stay in intensive care (P = 0.041). Secondary outcomes for the woman showed an apparent increase for the composite serious health outcome that included major haemorrhage, coagulopathy, embolism, and obstetric complications in the tighter group (35/595, 5.9% versus 15/501, 3.0%, adjRR 2.29, 95% CI 1.14 to 4.59, P = 0.020). There were no differences between the target groups in the risk for pre-eclampsia, induction of labour, or cesarean birth, but more women using tighter targets required pharmacological treatment (404/595, 67.9% versus 293/501, 58.5%, adjRR 1.20, 95% CI 1.00 to 1.44, P = 0.047). The main study limitation is that the treatment targets used may vary to those in use in some countries. CONCLUSIONS: Tighter glycaemic targets in women with GDM compared to less tight targets did not reduce the risk of a large for gestational age infant, but did reduce serious infant morbidity, although serious maternal morbidity was increased. These findings can be used to aid decisions on the glycaemic targets women with GDM should use. TRIAL REGISTRATION: The Australian New Zealand Clinical Trials Registry (ANZCTR). ACTRN12615000282583.

Repeat doses of prenatal corticosteroids for women at risk of preterm birth for improving neonatal health outcomes.

BACKGROUND: Infants born preterm (before 37 weeks' gestation) are at risk of respiratory distress syndrome (RDS) and need for respiratory support due to lung immaturity. One course of prenatal corticosteroids, administered to women at risk of preterm birth, reduces the risk of respiratory morbidity and improves survival of their infants, but these benefits do not extend beyond seven days. Repeat doses of prenatal corticosteroids have been used for women at ongoing risk of preterm birth more than seven days after their first course of corticosteroids, with improvements in respiratory outcomes, but uncertainty remains about any long-term benefits and harms. This is an update of a review last published in 2015. OBJECTIVES: To assess the effectiveness and safety, using the best available evidence, of a repeat dose(s) of prenatal corticosteroids, given to women who remain at risk of preterm birth seven or more days after an initial course of prenatal corticosteroids with the primary aim of reducing fetal and neonatal mortality and morbidity. SEARCH METHODS: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials, including cluster-randomised trials, of women who had already received one course of corticosteroids seven or more days previously and were still at risk of preterm birth, randomised to further dose(s) or no repeat doses, with or without placebo. Quasi-randomised trials were excluded. Abstracts were accepted if they met specific criteria. All trials had to meet criteria for trustworthiness, including a search of the Retraction Watch database for retractions or expressions of concern about the trials or their publications. DATA COLLECTION AND ANALYSIS: We used standard Cochrane Pregnancy and Childbirth methods. Two review authors independently selected trials, extracted data, and assessed trial quality and scientific integrity. We chose primary outcomes based on clinical importance as measures of effectiveness and safety, including serious outcomes, for the women and their fetuses/infants, infants in early childhood (age two to less than five years), the infant in mid- to late childhood (age five to less than 18 years) and the infant as an adult. We assessed risk of bias at the outcome level using the RoB 2 tool and assessed certainty of evidence using GRADE. MAIN RESULTS: We included 11 trials (4895 women and 5975 babies). High-certainty evidence from these trials indicated that treatment of women who remain at risk of preterm birth seven or more days after an initial course of prenatal corticosteroids with repeat dose(s) of corticosteroids, compared with no repeat corticosteroid treatment, reduced the risk of their infants experiencing the primary infant outcome of RDS (risk ratio (RR) 0.82, 95% confidence interval (CI) 0.74 to 0.90; 3540 babies; number needed to treat for an additional beneficial outcome (NNTB) 16, 95% CI 11 to 29) and had little or no effect on chronic lung disease (RR 1.00, 95% CI 0.83 to 1.22; 5661 babies). Moderate-certainty evidence indicated that the composite of serious infant outcomes was probably reduced with repeat dose(s) of corticosteroids (RR 0.88, 95% CI 0.80 to 0.97; 9 trials, 5736 babies; NNTB 39, 95% CI 24 to 158), as was severe lung disease (RR 0.83, 95% CI 0.72 to 0.97; NNTB 45, 95% CI 27 to 256; 4955 babies). Moderate-certainty evidence could not exclude benefit or harm for fetal or neonatal or infant death less than one year of age (RR 0.95, 95% CI 0.73 to 1.24; 5849 babies), severe intraventricular haemorrhage (RR 1.13, 95% CI 0.69 to 1.86; 5066 babies) and necrotising enterocolitis (RR 0.84, 95% CI 0.59 to 1.22; 5736 babies).  In women, moderate-certainty evidence found little or no effect on the likelihood of a caesarean birth (RR 1.03, 95% CI 0.98 to 1.09; 4266 mothers). Benefit or harm could not be excluded for maternal death (RR 0.32, 95% 0.01 to 7.81; 437 women) and maternal sepsis (RR 1.13, 95% CI 0.93 to 1.39; 4666 mothers). The evidence was unclear for risk of adverse effects and discontinuation of therapy due to maternal adverse effects. No trials reported breastfeeding status at hospital discharge or risk of admission to the intensive care unit.  At early childhood follow-up, moderate- to high-certainty evidence identified little or no effect of exposure to repeat prenatal corticosteroids compared with no repeat corticosteroids for primary outcomes relating to neurodevelopment (neurodevelopmental impairment: RR 0.97, 95% CI 0.85 to 1.10; 3616 children), survival without neurodevelopmental impairment (RR 1.01, 95% CI 0.98 to 1.04; 3845 children) and survival without major neurodevelopmental impairment (RR 1.02, 95% CI 0.98 to 1.05; 1816 children). An increase or decrease in the risk of death since randomisation could not be excluded (RR 1.06, 95% CI 0.81 to 1.40; 5 trials, 4565 babies randomised). At mid-childhood follow-up, moderate-certainty evidence identified little or no effect of exposure to repeat prenatal corticosteroids compared with no repeat corticosteroids on survival free of neurocognitive impairment (RR 1.01, 95% CI 0.95 to 1.08; 963 children) or survival free of major neurocognitive impairment (RR 1.00, 95% CI 0.97 to 1.04; 2682 children). Benefit or harm could not be excluded for death since randomisation (RR 0.93, 95% CI 0.69 to 1.26; 2874 babies randomised) and any neurocognitive impairment (RR 0.96, 95% CI 0.72 to 1.29; 897 children). No trials reported data for follow-up into adolescence or adulthood.  Risk of bias across outcomes was generally low although there were some concerns of bias. For childhood follow-up, most outcomes had some concerns of risk of bias due to missing data from loss to follow-up. AUTHORS' CONCLUSIONS: The short-term benefits for babies included less respiratory distress and fewer serious health problems in the first few weeks after birth with repeat dose(s) of prenatal corticosteroids for women still at risk of preterm birth seven days or more after an initial course. The current available evidence reassuringly shows no significant harm for the women or child in early and mid-childhood, although no benefit. Further research is needed on the long-term benefits and risks for the baby into adulthood.

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.

Prophylactic Oral Dextrose Gel and Neurosensory Impairment at 2-Year Follow-up of Participants in the hPOD Randomized Trial.

Importance: Prophylactic oral dextrose gel reduces neonatal hypoglycemia, but later benefits or harms remain unclear. Objective: To assess the effects on later development of prophylactic dextrose gel for infants born at risk of neonatal hypoglycemia. Design, Setting, and Participants: Prospective follow-up of a multicenter randomized clinical trial conducted in 18 Australian and New Zealand hospitals from January 2015 to May 2019. Participants were late preterm or term at-risk infants; those randomized in 9 New Zealand centers (n = 1359) were included and followed up between January 2017 and July 2021. Interventions: Infants were randomized to prophylactic 40% dextrose (n = 681) or placebo (n = 678) gel, 0.5 mL/kg, massaged into the buccal mucosa 1 hour after birth. Main Outcomes and Measures: The primary outcome of this follow-up study was neurosensory impairment at 2 years' corrected age. There were 44 secondary outcomes, including cognitive, language, and motor composite Bayley-III scores (mean [SD], 100 [15]; higher scores indicate better performance). Results: Of eligible infants, 1197 (91%) were assessed (581 females [49%]). Neurosensory impairment was not significantly different between the dextrose and placebo gel groups (20.8% vs 18.7%; unadjusted risk difference [RD], 2.09% [95% CI, -2.43% to 6.60%]; adjusted risk ratio [aRR], 1.13 [95% CI, 0.90 to 1.41]). The risk of cognitive and language delay was not significantly different between the dextrose and placebo groups (cognitive: 7.6% vs 5.3%; RD, 2.32% [95% CI, -0.46% to 5.11%]; aRR, 1.40 [95% CI, 0.91 to 2.17]; language: 17.0% vs 14.7%; RD, 2.35% [95% CI, -1.80% to 6.50%]; aRR, 1.19 [95% CI, 0.92 to 1.54]). However, the dextrose gel group had a significantly higher risk of motor delay (2.5% vs 0.7%; RD, 1.81% [95% CI, 0.40% to 3.23%]; aRR, 3.79 [95% CI, 1.27 to 11.32]) and significantly lower composite scores for cognitive (adjusted mean difference [aMD], -1.30 [95% CI, -2.55 to -0.05]), language (aMD, -2.16 [95% CI, -3.86 to -0.46]), and motor (aMD, -1.40 [95% CI, -2.60 to -0.20]) performance. There were no significant differences between groups in the other 27 secondary outcomes. Conclusions and Relevance: Among late preterm and term infants born at risk of neonatal hypoglycemia, prophylactic oral 40% dextrose gel at 1 hour of age, compared with placebo, resulted in no significant difference in the risk of neurosensory impairment at 2 years' corrected age. However, the study may have been underpowered to detect a small but potentially clinically important increase in risk, and further research including longer-term follow-up is required. Trial Registration: anzctr.org.au Identifier: ACTRN12614001263684.

Evaluation of oral dextrose gel for prevention of neonatal hypoglycemia (hPOD): A multicenter, double-blind randomized controlled trial.

BACKGROUND: Neonatal hypoglycemia is common and can cause brain injury. Buccal dextrose gel is effective for treatment of neonatal hypoglycemia, and when used for prevention may reduce the incidence of hypoglycemia in babies at risk, but its clinical utility remains uncertain. METHODS AND FINDINGS: We conducted a multicenter, double-blinded, placebo-controlled randomized trial in 18 New Zealand and Australian maternity hospitals from January 2015 to May 2019. Babies at risk of neonatal hypoglycemia (maternal diabetes, late preterm, or high or low birthweight) without indications for neonatal intensive care unit (NICU) admission were randomized to 0.5 ml/kg buccal 40% dextrose or placebo gel at 1 hour of age. Primary outcome was NICU admission, with power to detect a 4% absolute reduction. Secondary outcomes included hypoglycemia, NICU admission for hypoglycemia, hyperglycemia, breastfeeding at discharge, formula feeding at 6 weeks, and maternal satisfaction. Families and clinical and study staff were unaware of treatment allocation. A total of 2,149 babies were randomized (48.7% girls). NICU admission occurred for 111/1,070 (10.4%) randomized to dextrose gel and 100/1,063 (9.4%) randomized to placebo (adjusted relative risk [aRR] 1.10; 95% CI 0.86, 1.42; p = 0.44). Babies randomized to dextrose gel were less likely to become hypoglycemic (blood glucose < 2.6 mmol/l) (399/1,070, 37%, versus 448/1,063, 42%; aRR 0.88; 95% CI 0.80, 0.98; p = 0.02) although NICU admission for hypoglycemia was similar between groups (65/1,070, 6.1%, versus 48/1,063, 4.5%; aRR 1.35; 95% CI 0.94, 1.94; p = 0.10). There were no differences between groups in breastfeeding at discharge from hospital (aRR 1.00; 95% CI 0.99, 1.02; p = 0.67), receipt of formula before discharge (aRR 0.99; 95% CI 0.92, 1.08; p = 0.90), and formula feeding at 6 weeks (aRR 1.01; 95% CI 0.93, 1.10; p = 0.81), and there was no hyperglycemia. Most mothers (95%) would recommend the study to friends. No adverse effects, including 2 deaths in each group, were attributable to dextrose gel. Limitations of this study included that most participants (81%) were infants of mothers with diabetes, which may limit generalizability, and a less reliable analyzer was used in 16.5% of glucose measurements. CONCLUSIONS: In this placebo-controlled randomized trial, prophylactic dextrose gel 200 mg/kg did not reduce NICU admission in babies at risk of hypoglycemia but did reduce hypoglycemia. Long-term follow-up is needed to determine the clinical utility of this strategy. TRIAL REGISTRATION: ACTRN 12614001263684.

Effect of Prophylactic Dextrose Gel on Continuous Measures of Neonatal Glycemia: Secondary Analysis of the Pre-hPOD Trial.

OBJECTIVE: To determine the effects of different doses of prophylactic dextrose gel on glycemic stability assessed using continuous glucose monitoring in the first 48 hours when given to babies at risk of neonatal hypoglycemia. STUDY DESIGN: Continuous glucose monitoring was undertaken for the first 48 hours in 133 infants at risk of hypoglycemia who participated in the pre-hPOD randomized dosage trial of dextrose gel prophylaxis. RESULTS: Low glucose concentrations were detected in 41% of infants by blood glucose monitoring and 68% by continuous interstitial glucose monitoring. The mean ± SD duration of low interstitial glucose concentrations was 295 ± 351 minutes in the first 48 hours. Infants who received any dose of dextrose gel seemed to be less likely than those who received placebo gel to experience low glucose concentrations (<47 mg/dL [2.6 mmol/L]; P = .08), particularly if they received a single dose of 200 mg/kg (relative risk, 0.70; 95% CI, 0.50-0.10; P = .049). They also spent a greater proportion of time in the central glucose concentration range of 54-72 mg/dL (3-4 mmol/L) (any dose, mean ± SD, 58.2 ± 20.3%; placebo, 50.0 ± 21.9%; mean difference, 8.20%; 95% CI, 0.43-15.9%; P = .038). Dextrose gel did not increase recurrent or severe episodes of low glucose concentrations and did not increase the peak glucose concentration. These effects were similar for all trial dosages. CONCLUSIONS: Low glucose concentrations were common in infants at risk of hypoglycemia despite blood glucose monitoring and treatment. Prophylactic dextrose gel reduced the risk of hypoglycemia without adverse effects on glucose stability.