Donor human milk versus infant formula for low-risk infants: a systematic review.

BACKGROUND: There is an increasing acceptance and use of donor human milk (DHM) in healthy infants. This review investigates the benefits and risks of mothers' own milk (MOM) supplementation with DHM compared to infant formula (IF) in moderate-late preterm (MLP) and early term (ET) infants. METHODS: MEDLINE, EMBASE, CINAHL, Scopus, Cochrane CENTRAL and clinical trial registries were searched for studies published up to September 2023. The primary outcome was rates of exclusive breastfeeding (EBF). Certainty of evidence was assessed using GRADE framework. RoB1 and EPHPP were used to assess risk of bias for controlled trials and observational studies, respectively. RESULTS: Eleven studies involving total of 10,147 infants and six ongoing trials were identified. Studies were of low quality, and the certainty of evidence was assessed as very low. Three studies suggested benefits of DHM compared to IF on EBF at discharge, while two suggested no difference. No clear effect was observed on EBF duration, any breastfeeding, hypoglycemia and morbidity. No health risks were reported. CONCLUSION: The effect of supplementing MOM with DHM instead of IF on EBF and other health outcomes is unclear. High-quality studies are required to determine the potential benefits or risks of DHM supplementation in this population. IMPACT: We identified 11 relevant studies reporting on supplementation of mothers' own milk (MOM) with donor human milk (DHM) compared to infant formula (IF). Studies were of low quality, had heterogeneous outcome definitions and were geographically limited; all except two were observational studies. Limited evidence showed no clear difference on rates of exclusive breastfeeding and other health outcomes. No potential risks were reported. The increasing acceptance and use of DHM in healthy infants highlights the need for future high-quality studies.

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.

High protein intake on later outcomes in preterm children: a systematic review and meta-analysis.

BACKGROUND: Appropriate protein intake is crucial for growth and development in children born preterm. We assessed the effects of high (HP) versus low protein (LP) intake on neurodevelopment, growth, and biochemical anomalies in these children. METHODS: Randomised and quasi-randomised trials providing protein to children born preterm (<37 completed weeks of gestation) were searched following PRISMA guideline in three databases and four registers (PROSPERO registration CRD42022325659). Random-effects model was used for assessing the effects of HP (≥3.5 g/kg/d) vs. LP (<3.5 g/kg/d). RESULTS: Data from forty-four studies (n = 5338) showed HP might slightly reduce the chance of survival without neurodisability at ≥12 months (four studies, 1109 children, relative risk [RR] 0.95 [95% CI 0.90, 1.01]; P = 0.13; low certainty evidence) and might increase risk of cognitive impairment at toddler age (two studies; 436 children; RR 1.36 [0.89, 2.09]; P = 0.16; low certainty evidence). At discharge or 36 weeks, HP intake might result in higher weight and greater head circumference z-scores. HP intake probably increased the risk of hypophosphatemia, hypercalcemia, refeeding syndrome and high blood urea, but reduced risk of hyperglycaemia. CONCLUSIONS: HP intake for children born preterm may be harmful for neonatal metabolism and later neurodisability and has few short-term benefits for growth. IMPACT STATEMENT: Planned high protein intake after birth for infants born preterm might be harmful for survival, neurodisability and metabolism during infancy and did not improve growth after the neonatal period. Protein intake ≥3.5 g/kg/d should not be recommended for children born preterm.

Exposure to the smell and taste of milk to accelerate feeding in preterm infants.

BACKGROUND: Preterm infants (born before 37 weeks' gestation) are often unable to co-ordinate sucking, swallowing, and breathing for oral feeding because of their immaturity. In such cases, initial nutrition is provided by orogastric or nasogastric tube feeding. Feeding intolerance is common and can delay attainment of full enteral and sucking feeds, prolonging the need for nutritional support and the hospital stay. Smell and taste play an important role in the activation of physiological pre-absorptive processes that contribute to food digestion and absorption. However, during tube feeding, milk bypasses the nasal and oral cavities, limiting exposure to the smell and taste of milk. Provision of the smell and taste of milk with tube feeds offers a non-invasive and low-cost intervention that, if effective in accelerating the transition to enteral feeds and subsequently to sucking feeds, would bring considerable advantages to infants, their families, and healthcare systems. OBJECTIVES: To assess whether exposure to the smell or taste (or both) of breastmilk or formula administered with tube feeds can accelerate the transition to full sucking feeds without adverse effects in preterm infants. SEARCH METHODS: We conducted searches in CENTRAL, MEDLINE, Embase, CINAHL, and Epistemonikos to 26 April 2023. We also searched clinical trial databases and conference proceedings. SELECTION CRITERIA: We included randomised and quasi-randomised studies that evaluated exposure versus no exposure to the smell or taste of milk (or both) immediately before or at the time of tube feeds. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias, and extracted data according to Cochrane Neonatal methodology. We performed meta-analyses using risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data, with their respective 95% confidence intervals (CIs). We used GRADE to assess the certainty of evidence. MAIN RESULTS: We included eight studies (1277 preterm infants). Seven studies (1244 infants) contributed data for meta-analysis. The evidence suggests that exposure to the smell and taste of milk with tube feeds has little to no effect on time taken to reach full sucking feeds (MD -1.07 days, 95% CI -2.63 to 0.50; 3 studies, 662 infants; very low-certainty evidence). Two studies reported no adverse effects related to the intervention. The intervention may have little to no effect on duration of parenteral nutrition (MD 0.23 days, 95% CI -0.24 to 0.71; 3 studies, 977 infants; low-certainty evidence), time to reach full enteral feeds (MD -0.16 days, 95% CI -0.45 to 0.12; 1 study, 736 infants; very low-certainty evidence) or risk of necrotising enterocolitis (RR 0.93, 95% CI 0.47 to 1.84; 2 studies, 435 infants; low-certainty evidence), although the evidence for time to reach full enteral feeds is very uncertain. Exposure to the smell and taste of milk with tube feeds probably has little to no effect on risk of late infection (RR 1.14, 95% CI 0.74 to 1.75; 2 studies, 436 infants; moderate-certainty evidence). There were no data available to assess feeding intolerance. The included studies had small sample sizes and methodological limitations, including unclear or lack of randomisation (four studies), lack of blinding of participants and personnel (five studies), unclear or lack of blinding of the outcome assessor (all eight studies), and different inclusion criteria and methods of administering the interventions. AUTHORS' CONCLUSIONS: The results of our meta-analyses suggest that exposure to the smell and taste of milk with tube feeds may have little to no effect on time to reach full sucking feeds and time to reach full enteral feeds. We found no clear difference between exposure and no exposure to the smell or taste of milk on safety outcomes (adverse effects, necrotising enterocolitis, and late infection). Results from one ongoing study and two studies awaiting classification may alter the conclusions of this review. Future research should examine the effect of exposing preterm infants to the smell and taste of milk with tube feeds on health outcomes during hospitalisation, such as attainment of feeding skills, safety, feed tolerance, infection, and growth. Future studies should be powered to detect the effect of the intervention in infants of different gestational ages and on each sex separately. It is also important to determine the optimal method, frequency, and duration of exposure.

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.

Investigating behaviour from early- to mid-childhood and its association with academic outcomes in a cohort of children born at risk of neonatal hypoglycaemia.

High rates of academic underachievement at 9-10 years have been identified in children born at risk of neonatal hypoglycaemia. This study investigated the stability of behaviour from early to mid-childhood and how this relates to academic outcomes in children born with at least one risk factor of neonatal hypoglycaemia in Aotearoa, New Zealand. Behaviour data was collected using the Bayley Scales of Infant and Toddler Development, Child Behaviour Checklist 1.5-5, and the Strengths and Difficulties Questionnaire for 466 children (52 % male; 27 % Maori, 60 % New Zealand European, 2 % Pacific, 11 % Other) at multiple timepoints between ages 2 and 10 years. Academic data was collected at 9-10 years using the e-asTTle online learning and assessment tool. Findings revealed a link between early childhood behaviour and academic outcomes could be detected as early as age 2, suggesting that identifying and addressing early behavioural issues in children at risk of neonatal hypoglycaemia could aid in targeted interventions.

Early Feeding for the Prevention of Neonatal Hypoglycaemia: A Systematic Review and Meta-Analysis.

BACKGROUND: Poor feeding, among other factors, predisposes neonates to hypoglycaemia. Early feeding is widely recommended to prevent hypoglycaemia in those at risk, but the effectiveness of this is uncertain. This review aimed to summarise and analyse the evidence on the effectiveness of early feeding for prevention of neonatal hypoglycaemia. METHODS: Four databases and three clinical trial registries were searched from inception to May 24, 2023. Published and unpublished randomised controlled trials (RCTs), quasi-RCTs, cluster randomised trials, non-randomised studies of interventions, and observational studies with comparison groups were considered for inclusion with no language or publication date restrictions. We included studies of neonates who were fed early (within 60 min of birth or study defined) versus delayed. Study quality was assessed using the Cochrane Risk of Bias 1 tool or Effective Public Health Practice Project Quality Assessment tool. Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. RevMan 5.4.1 or R was used to synthesise results in random-effects meta-analyses. This review was registered prospectively with PROSPERO (CRD42022378904). RESULTS: A total of 175,392 participants were included across 19 studies, of which two were RCTs, 14 cohort studies, two cross-sectional studies, and one a case-control study. Most studies (13/19) were conducted in low- or lower-middle-income countries. Early feeding may be associated with reduced neonatal hypoglycaemia (four cohort studies, 744 infants, odds ratio [OR] 0.19 (95% CI: 0.10-0.35), p < 0.00001, I2 = 44%) and slightly reduced duration of initial hospital stay (one cohort study, 1,673 infants, mean difference: -0.20 days [95% CI: -0.31 to -0.09], p = 0.0003), but the evidence is very uncertain. One RCT found early feeding had little or no effect on the risk of neonatal mortality, but three cohort studies found early feeding may be associated with reduced risk (136,468 infants, OR 0.51 [95% CI: 0.37-0.72]; low certainty evidence; p <0.0001; I2 = 54%). CONCLUSION: We found that early feeding may reduce the incidence of neonatal hypoglycaemia, but the evidence is very uncertain. Given its many other benefits, early feeding should continue to be recommended. This review was primarily funded by the Aotearoa Foundation and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health.

Maternal ethnicity and gestational age at birth predict hypoglycaemia among neonates of mothers with gestational diabetes.

AIM: Hypoglycaemia is common in neonates born to mothers with gestational diabetes mellitus (GDM). We aimed to determine predictors of hypoglycaemia among neonates of women with GDM and association with short-term outcomes. METHODS: We conducted a secondary cohort analysis of data from a multi-centre randomised trial (the TARGET trial) conducted across ten maternity hospitals in New Zealand between May 2015 and November 2017. Data were analysed using univariate analysis and multivariable forward stepwise logistic regression. RESULTS: Among 1085 neonates, those born to Asian mothers had reduced odds of hypoglycaemia (OR [95% CI]: 0.54 [0.38, 0.75], p = 0.001), as did those born at higher gestational ages (0.76 [0.68, 0.85], p < 0.001). Neonates born to Pacific mothers had increased odds of hypoglycaemia (OR [95% CI]: 1.57 [1.04, 2.39], p = 0.034). Neonates who experienced hypoglycaemia were more likely to experience neonatal intensive care unit admission (8.3% vs. 2.1%; p ≤ 0.001), hyperbilirubinaemia (8.6% vs. 3.3%; p ≤ 0.001) and receive respiratory support (11.4% vs. 4.8%; p ≤ 0.001) and less likely to be breastfed at discharge (92.4% vs. 96.2%; p = 0.009). CONCLUSION: Among neonates of women with GDM, maternal ethnicity and gestation at birth are independent predictors of hypoglycaemia, and hypoglycaemia is associated with short-term comorbidities. Additional surveillance may be appropriate for neonates in these high-risk groups.

Nutrition guidelines for preterm infants: A systematic review.

BACKGROUND: There is no consensus on optimal nutrition for preterm infants, leading to substantial practice variation. We aimed to assess the quality of nutrition guidelines for preterm infants, the consistency of recommendations, and the gaps in recommendations. METHODS: We searched databases and websites for nutrition guidelines for preterm infants before first hospital discharge, which were endorsed, prepared, or authorized by a regional, national, or international body, written in English, and published between 2012 and 2023. Two reviewers independently screened articles and extracted the recommendations. Four reviewers appraised the included guidelines using Appraisal of Guidelines, Research, and Evaluation II. RESULTS: A total of 7051 were identified, with 27 guidelines included, 26% of which were high in quality. Most guidelines lacked stakeholder involvement and rigor of development. We found considerable variation in recommendations, many of which lacked details on certainty of evidence and strength of recommendation. Recommendations for type of feed and breastmilk fortification were consistent among high-quality guidelines, but recommendations varied for intakes of almost all nutrients and monitoring of nutrition adequacy. Different guidelines gave different certainty of evidence for the same recommendations. Most gaps in recommendations were due to very low certainty of evidence. CONCLUSION: Future development of nutrition guidelines for preterm infants should follow the standard guideline development method and ensure the rigorous process, including stakeholders' involvement, to improve the reporting of strength of recommendation, certainty of evidence, and gaps in recommendation. Evidence is needed to support recommendations about macro and micronutrient intakes, breastmilk fortification, and markers on adequacy of intake of different nutrients.

Oral dextrose gel to prevent hypoglycaemia in at-risk neonates.

BACKGROUND: Neonatal hypoglycaemia is a common condition that can be associated with brain injury. Current practice usually includes early identification of at-risk infants (e.g. infants of diabetic mothers; preterm, small- or large-for-gestational-age infants), and prophylactic measures are advised. However, these measures often involve use of formula milk or admission to the neonatal unit. Dextrose gel is non-invasive, inexpensive and effective for treatment of neonatal hypoglycaemia. Prophylactic dextrose gel can reduce the incidence of neonatal hypoglycaemia, thus potentially reducing separation of mother and baby and supporting breastfeeding, as well as preventing brain injury. This is an update of a previous Cochrane Review published in 2021. OBJECTIVES: To assess the effectiveness and safety of oral dextrose gel in preventing hypoglycaemia before first hospital discharge and reducing long-term neurodevelopmental impairment in newborn infants at risk of hypoglycaemia. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase and Epistemonikos in April 2023. We also searched clinical trials databases and the reference lists of retrieved articles. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing oral dextrose gel versus placebo, no intervention, or other therapies for the prevention of neonatal hypoglycaemia. We included newborn infants at risk of hypoglycaemia, including infants of mothers with diabetes (all types), high or low birthweight, and born preterm (< 37 weeks), age from birth to 24 hours, who had not yet been diagnosed with hypoglycaemia. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the risk of bias. We contacted investigators to obtain additional information. We used fixed-effect meta-analyses. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included two studies conducted in high-income countries comparing oral dextrose gel versus placebo in 2548 infants at risk of neonatal hypoglycaemia. Both of these studies were included in the previous version of this review, but new follow-up data were available for both. We judged these two studies to be at low risk of bias in 13/14 domains, and that the evidence for most outcomes was of moderate certainty. Meta-analysis of the two studies showed that oral dextrose gel reduces the risk of hypoglycaemia (risk ratio (RR) 0.87, 95% confidence interval (CI) 0.79 to 0.95; risk difference (RD) -0.06, 95% CI -0.10 to -0.02; 2548 infants; high-certainty evidence). Evidence from two studies showed that there may be little to no difference in the risk of major neurological disability at two years of age after oral dextrose gel (RR 1.00, 95% CI 0.59 to 1.68; 1554 children; low-certainty evidence). Meta-analysis of the two studies showed that oral dextrose gel probably reduces the risk of receipt of treatment for hypoglycaemia during initial hospital stay (RR 0.89, 95% CI 0.79 to 1.00; 2548 infants; moderate-certainty evidence) but probably makes little or no difference to the risk of receipt of intravenous treatment for hypoglycaemia (RR 1.01, 0.68 to 1.49; 2548 infants; moderate-certainty evidence). Oral dextrose gel may have little or no effect on the risk of separation from the mother for treatment of hypoglycaemia (RR 1.12, 95% CI 0.81 to 1.55; two studies, 2548 infants; low-certainty evidence). There is probably little or no difference in the risk of adverse effects in infants who receive oral dextrose gel compared to placebo gel (RR 1.22, 95% CI 0.64 to 2.33; two studies, 2510 infants; moderate-certainty evidence), but there are no studies comparing oral dextrose with other comparators such as no intervention or other therapies. No data were available on exclusive breastfeeding after discharge. AUTHORS' CONCLUSIONS: Prophylactic oral dextrose gel reduces the risk of neonatal hypoglycaemia in at-risk infants and probably reduces the risk of treatment for hypoglycaemia without adverse effects. It may make little to no difference to the risk of major neurological disability at two years, but the confidence intervals include the possibility of substantial benefit or harm. Evidence at six to seven years is limited to a single small study. In view of its limited short-term benefits, prophylactic oral dextrose gel should not be incorporated into routine practice until additional information is available about the balance of risks and harms for later neurological disability. Additional large follow-up studies at two years of age or older are required. Future research should also be undertaken in other high-income countries, low- and middle-income countries, preterm infants, using other dextrose gel preparations, and using comparators other than placebo gel. There are three studies awaiting classification and one ongoing study which may alter the conclusions of the review when published.

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.

Expressed breast milk and maternal expression of breast milk for the prevention and treatment of neonatal hypoglycemia: a systematic review and meta-analysis.

BACKGROUND: Worldwide, many guidelines recommend the use of expressed breast milk (EBM) and maternal expression of breast milk for the prevention and treatment of neonatal hypoglycemia. However, the impact of both practices on neonatal hypoglycemia is unclear. This study aims to determine the effectiveness of EBM and maternal expression of breast milk in preventing and treating neonatal hypoglycemia. METHODS: We registered our review in PROSPERO (CRD42022328072). We systematically reviewed five databases and four clinical trial registries to identify randomized controlled trials (RCT), non-randomized studies of intervention (NRSI), and cohort studies that compared infants who received EBM to infants who did not, and similar study designs that compared infants whose mothers expressed breast milk to infants whose mothers did not. Two independent reviewers carried out screening, data extraction, and quality assessment. The quality of included RCT, NRSI, and cohort studies were respectively assessed with the Cochrane Risk of Bias 2, Risk Of Bias In Non-randomised Studies-of Interventions, and the Newcastle-Ottawa Scale tools. Results from studies on EBM were synthesized separately from those on maternal expression of breast milk. Meta-analysis was undertaken using Revman 5.4. and fixed-effect models. RESULTS: None of the ten included studies was specifically designed to determine the effect of EBM or maternal expression of breast milk on neonatal hypoglycemia. The effect of EBM on neonatal hypoglycemia was not estimable. There was no difference in the risk of hypoglycaemia among neonates whose mothers expressed breast milk compared to those whose mothers did not [RR (95%CI); one RCT: 0.92 (0.77, 1.10), high-certainty evidence; one cohort: 1.10 (0.74, 1.39), poor quality study]. CONCLUSIONS: There is insufficient evidence to determine the effectiveness of EBM for preventing or treating neonatal hypoglycemia. Limited data suggests maternal breast milk expression may not alter the risk of neonatal hypoglycemia. High-quality randomized controlled trials are needed to determine the effectiveness of EBM and maternal expression of breast milk for the prevention and treatment of neonatal hypoglycemia.

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.

Nitrate contamination in drinking water and adverse reproductive and birth outcomes: a systematic review and meta-analysis.

Exposure to low levels of nitrate in drinking water may have adverse reproductive effects. We reviewed evidence about the association between nitrate in drinking water and adverse reproductive outcomes published to November 2022. Randomized trials, cohort or case-control studies published in English that reported the relationship between nitrate intake from drinking water and the risk of perinatal outcomes were included. Random-effect models were used to pool data. Three cohort studies showed nitrate in drinking water is associated with an increased risk of preterm birth (odds ratio for 1 mg/L NO3-N increased (OR1) = 1.01, 95% CI 1.00, 1.01, I2 = 23.9%, 5,014,487 participants; comparing the highest versus the lowest nitrate exposure groups pooled OR (ORp) = 1.05, 95% CI 1.01, 1.10, I2 = 0%, 4,152,348 participants). Case-control studies showed nitrate in drinking water may be associated with the increased risk of neural tube defects OR1 = 1.06, 95% CI 1.02, 1.10; 2 studies, 2196 participants; I2 = 0%; and ORp = 1.51, 95% CI 1.12, 2.05; 3 studies, 1501 participants; I2 = 0%). The evidence for an association between nitrate in drinking water and risk of small for gestational age infants, any birth defects, or any congenital heart defects was inconsistent. Increased nitrate in drinking water may be associated with an increased risk of preterm birth and some specific congenital anomalies. These findings warrant regular review as new evidence becomes available.

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.

Neurocognitive Outcomes at Age 2 Years After Neonatal Hypoglycemia in a Cohort of Participants From the hPOD Randomized Trial.

Importance: Neonatal hypoglycemia is common, but its association with later neurodevelopment is uncertain. Objective: To examine associations between neonatal hypoglycemia and neurocognitive outcomes at corrected age 2 years. Design, Setting, and Participants: Exploratory cohort analysis of the Hypoglycaemia Prevention With Oral Dextrose (hPOD) randomized clinical trial was conducted. The trial recruited participants from January 9, 2015, to May 5, 2019, with follow-up between January 26, 2017, and July 31, 2021. Infants were recruited from 9 maternity hospitals in New Zealand and assessed at home or in a research clinic. Children born late preterm and at term at risk of neonatal hypoglycemia but without evidence of acute or imminent illness in the first hour after birth were screened and treated to maintain blood glucose concentrations greater than or equal to 47 mg/dL. Exposures: Hypoglycemia was defined as any blood glucose concentration less than 47 mg/dL, recurrent as 3 or more episodes, and severe as less than 36 mg/dL. Main Outcomes and Measures: Neurologic examination and tests of development (Bayley III) and executive function. The primary outcome was neurosensory impairment (any of the following: blindness, deafness, cerebral palsy, developmental delay, or executive function total score worse than 1.5 SD below the mean). Results: A total of 1197 of 1321 (91%) eligible children were assessed at a mean of corrected age 24 months; 616 (52%) were male. Compared with the normoglycemia group, children who experienced hypoglycemia were more likely to have neurosensory impairment (111 [23%] vs 125 [18%]; adjusted risk ratio [aRR], 1.28; 95% CI, 1.01-1.60), particularly if they experienced severe episodes (30 [28%] vs 125 [18%]; aRR, 1.68; 95% CI, 1.20-2.36), but not recurrent episodes (12 [19%] vs 125 [18%]; aRR, 1.06; 95% CI, 0.63-1.80). The risk of cognitive, language, or motor delay was similar between groups, but children who experienced hypoglycemia had lower Bayley-III composite cognitive (adjusted mean difference [aMD], -1.48; 95% CI, -2.79 to -0.18) and motor scores (aMD, -2.05; 95% CI, -3.30 to -0.79). Conclusions and Relevance: In children born at risk of hypoglycemia but otherwise well, those who experienced neonatal hypoglycemia were more likely to have neurosensory impairment at corrected age 2 years, with higher risks after severe episodes. Further research is required to determine causality.

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.

Diagnostic Management of Oncogenic HPV Cervical Infections: The Field Experience in Wuxi, China.

Introduction: A liquid-based cytology test was introduced for cervical cancer screening in the 2000s worldwide. However, the concordance of diagnostic findings between the liquid-based cytology test and cervical biopsy has not been fully investigated, especially the overall failure rate on the diagnosis of cervical cancer and high-grade squamous intraepithelial lesion (HSIL) by cytology testing. The aim of this retrospective study was to investigate the concordance between ThinPrep cytology and histology test in the diagnosis of cervical cancer and HSIL in HPV-positive women. Methods: ThinPrep cytology test was performed in 2,472 HPV-positive women. Out of 2,472 HPV-positive women, the cervical biopsy was concurrently performed in 1,533 women. Data on the HPV type and the diagnostic findings of the ThinPrep cytology test and cervical biopsy were collected from our hospital electronic database. The concordance of diagnostic findings between cytology and histology was compared. Results: The rate of agreement in the diagnosis of the low-grade squamous intraepithelial lesion (LSIL) or HSIL between cervical biopsy and ThinPrep cytology test was 58 or 49%. The overall false negative rate in the diagnosis of cervical cancer and HSIL by ThinPrep cytology test was 6%. However, when considering the total number of HPV-positive women diagnosed with cervical cancer (n = 36) and HSIL (n = 117) by cervical biopsy, we found that a significant number of HPV-positive women with cervical cancer (n = 12, 33%), or women with HSIL (n = 77, 66%) were failed to be diagnosed by the ThinPrep cytology test. These HPV-positive women were either diagnosed with cervical infection or ASCUS, or LSIL. Discussion: Our data demonstrated that in order to ensure an accurate diagnosis, an immediate cervical biopsy in women with cervical infection or ASCUS or LSIL should be strongly recommended in clinical practice.

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.