Neonatal Docosahexaenoic Acid in Preterm Infants and Intelligence at 5 Years.

BACKGROUND: Docosahexaenoic acid (DHA) is a component of neural tissue. Because its accretion into the brain is greatest during the final trimester of pregnancy, infants born before 29 weeks' gestation do not receive the normal supply of DHA. The effect of this deficiency on subsequent cognitive development is not well understood. METHODS: We assessed general intelligence at 5 years in children who had been enrolled in a trial of neonatal DHA supplementation to prevent bronchopulmonary dysplasia. In the previous trial, infants born before 29 weeks' gestation had been randomly assigned in a 1:1 ratio to receive an enteral emulsion that provided 60 mg of DHA per kilogram of body weight per day or a control emulsion from the first 3 days of enteral feeds until 36 weeks of postmenstrual age or discharge home, whichever occurred first. Children from 5 of the 13 centers in the original trial were invited to undergo assessment with the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) at 5 years of corrected age. The primary outcome was the full-scale intelligence quotient (FSIQ) score. Secondary outcomes included the components of WPPSI. RESULTS: A total of 1273 infants underwent randomization in the original trial; of the 656 surviving children who had undergone randomization at the centers included in this follow-up study, 480 (73%) had an FSIQ score available - 241 in the DHA group and 239 in the control group. After imputation of missing data, the mean (±SD) FSIQ scores were 95.4±17.3 in the DHA group and 91.9±19.1 in the control group (adjusted difference, 3.45; 95% confidence interval, 0.38 to 6.53; P = 0.03). The results for secondary outcomes generally did not support that obtained for the primary outcome. Adverse events were similar in the two groups. CONCLUSIONS: In infants born before 29 weeks' gestation who had been enrolled in a trial to assess the effect of DHA supplementation on bronchopulmonary dysplasia, the use of an enteral DHA emulsion until 36 weeks of postmenstrual age was associated with modestly higher FSIQ scores at 5 years of age than control feeding. (Funded by the Australian National Health and Medical Research Council and Nu-Mega Ingredients; N3RO Australian New Zealand Clinical Trials Registry number, ACTRN12612000503820.).

DHA supplementation in infants born preterm and the effect on attention at 18 months' corrected age: follow-up of a subset of the N3RO randomised controlled trial.

Infants born preterm miss out on the peak period of in utero DHA accretion to the brain during the last trimester of pregnancy which is hypothesised to contribute to the increased prevalence of neurodevelopmental deficits in this population. This study aimed to determine whether DHA supplementation in infants born preterm improves attention at 18 months' corrected age. This is a follow-up of a subset of infants who participated in the N3RO randomised controlled trial. Infants were randomised to receive an enteral emulsion of high-dose DHA (60 mg/kg per d) or no DHA (soya oil - control) from within the first days of birth until 36 weeks' post-menstrual age. The assessment of attention involved three tasks requiring the child to maintain attention on toy/s in either the presence or absence of competition or a distractor. The primary outcome was the child's latency of distractibility when attention was focused on a toy. The primary outcome was available for seventy-three of the 120 infants that were eligible to participate. There was no evidence of a difference between groups in the latency of distractibility (adjusted mean difference: 0·08 s, 95 % CI -0·81, 0·97; P = 0·86). Enteral DHA supplementation did not result in improved attention in infants born preterm at 18 months' corrected age.

Docosahexaenoic Acid and Bronchopulmonary Dysplasia in Preterm Infants.

BACKGROUND: Studies in animals and in humans have suggested that docosahexaenoic acid (DHA), an n-3 long-chain polyunsaturated fatty acid, might reduce the risk of bronchopulmonary dysplasia, but appropriately designed trials are lacking. METHODS: We randomly assigned 1273 infants born before 29 weeks of gestation (stratified according to sex, gestational age [<27 weeks or 27 to <29 weeks], and center) within 3 days after their first enteral feeding to receive either an enteral emulsion providing DHA at a dose of 60 mg per kilogram of body weight per day or a control (soy) emulsion without DHA until 36 weeks of postmenstrual age. The primary outcome was bronchopulmonary dysplasia, defined on a physiological basis (with the use of oxygen-saturation monitoring in selected infants), at 36 weeks of postmenstrual age or discharge home, whichever occurred first. RESULTS: A total of 1205 infants survived to the primary outcome assessment. Of the 592 infants assigned to the DHA group, 291 (49.1% by multiple imputation) were classified as having physiological bronchopulmonary dysplasia, as compared with 269 (43.9%) of the 613 infants assigned to the control group (relative risk adjusted for randomization strata, 1.13; 95% confidence interval [CI], 1.02 to 1.25; P=0.02). The composite outcome of physiological bronchopulmonary dysplasia or death before 36 weeks of postmenstrual age occurred in 52.3% of the infants in the DHA group and in 46.4% of the infants in the control group (adjusted relative risk, 1.11; 95% CI, 1.00 to 1.23; P=0.045). There were no significant differences between the two groups in the rates of death or any other neonatal illnesses. Bronchopulmonary dysplasia based on a clinical definition occurred in 53.2% of the infants in the DHA group and in 49.7% of the infants in the control group (P=0.06). CONCLUSIONS: Enteral DHA supplementation at a dose of 60 mg per kilogram per day did not result in a lower risk of physiological bronchopulmonary dysplasia than a control emulsion among preterm infants born before 29 weeks of gestation and may have resulted in a greater risk. (Funded by the Australian National Health and Medical Research Council and others; Australian New Zealand Clinical Trials Registry number, ACTRN12612000503820 .).

The efficacy and safety of peripheral intravenous parenteral nutrition vs 10% glucose in preterm infants born 30 to 33 weeks' gestation: a randomised controlled trial.

BACKGROUND: Preterm infants born 30 to 33 weeks' gestation often require early support with intravenous fluids because of respiratory distress, hypoglycemia or feed intolerance. When full feeds are anticipated to be reached within the first week, risks associated with intravenous delivery mode and type must be carefully considered. Recommendations are for parenteral nutrition to be infused via central venous lines (because of the high osmolarity), however, given the risks associated with central lines, clinicians may opt for 10% glucose via peripheral venous catheter when the need is short-term. We therefore compare a low osmolarity peripheral intravenous parenteral nutrition (P-PN) solution with peripheral intravenous 10% glucose on growth rate in preterm infants born 30 to 33 weeks' gestation. METHODS: In this parallel group, single centre, superiority, non-blinded, randomised controlled trial, 92 (P-PN 42, control 50) infants born 30+ 0 to 33+ 6 weeks' gestation, were randomised within 24 h of age, to receive either P-PN (8% glucose, 30 g/L amino acids, 500 IU/L heparin and SMOFlipid®) or a control of peripheral intravenous 10% glucose. Both groups received enteral feeds according to hospital protocol. The primary outcome was rate of weight gain from birth to 21 days of age. RESULTS: The rate of weight gain was significantly increased in P-PN infants compared with control (P-PN, n = 42, 18.7, SD 6.6 g/d vs control, n = 50, 14.8, SD 6.0 g/d; adjusted mean difference 3.9 g/d, 95% CI 1.3 to 6.6; P = 0.004), with the effect maintained to discharge home. Days to regain birthweight were significantly reduced and length gain significantly increased in P-PN infants. One infant in the P-PN group had a stage 3 extravasation which rapidly resolved. Blood urea nitrogen and triglyceride levels were significantly higher in the P-PN group in the first week of life, but there were no instances of abnormally high levels. There were no significant differences in any other clinical or biochemical outcomes. CONCLUSION: P-PN improves the rate of weight gain to discharge home in preterm infants born 30 to 33 weeks gestation compared with peripheral intravenous 10% glucose. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12616000925448 . Registered 12 July 2016.

Association Between Maternal Iodine Intake in Pregnancy and Childhood Neurodevelopment at Age 18 Months.

There are limited and inconsistent data suggesting that mild iodine deficiency in pregnancy might be associated with poorer developmental outcomes in children. Between 2011 and 2015, we conducted a prospective cohort study in Australia examining the relationship between maternal iodine intake in pregnancy and childhood neurodevelopment, assessed using Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), in 699 children at 18 months. Maternal iodine intake and urinary iodine concentration (UIC) were assessed at study entry (<20 weeks' gestation) and at 28 weeks' gestation. Maternal iodine intake in the lowest (<220 µg/day) or highest (≥391 µg/day) quartile was associated with lower cognitive, language, and motor scores (mean differences ranged from 2.4 (95% confidence interval (CI): 0.01, 4.8) to 7.0 (95% CI: 2.8, 11.1) points lower) and higher odds (odds ratios ranged from 2.7 (95% CI: 1.3, 5.6) to 2.8 (95% CI: 1.3, 5.7)) of cognitive developmental delay (Bayley-III score <1 SD) compared with mothers with an iodine intake in the middle quartiles. There was no association between UIC in pregnancy and Bayley-III outcomes regardless of whether UIC and the outcomes were analyzed as continuous or categorical variables. Both low and high iodine intakes in pregnancy were associated with poorer childhood neurodevelopment in this iodine-sufficient population.

Oxylipins and Free Fatty Acids in Parenteral Lipid Emulsions Currently Used in Preterm Infant Care: An In Vitro Study.

Lipid emulsions used to support nutrition in preterm infants contain long-chain polyunsaturated fatty acids (LCPUFAs) as a source of essential fatty acids; these LCPUFAs and their parent polyunsaturated fatty acid (PUFA) can be oxidized by a variety of mechanisms to bioactive molecules called oxylipins, which are signaling molecules that initiate and/or resolve inflammation. The aim of this study was to explore levels of free LCPUFA and their related oxylipins in 3 commercially available lipid emulsions (Intralipid, SMOFlipid, and ClinOleic) using ultra high-performance liquid chromatography mass spectroscopy. Free LCPUFA were detected in all lipid emulsions tested. Seven, 8, and 9 different oxylipin compounds were detected in the 3 emulsions, respectively. The oxylipins detected were mainly derived from omega-6 PUFAs; these included 13-hydroxyoctadecadienoic acid from linoleic acid and 5-hydroxyeicosatetraenoic acid derived from arachidonic acid. It may be clinically important to know that oxylipins exist in lipid emulsions and to evaluate their potential effects on preterm infants.

Effects of an antenatal dietary intervention in overweight and obese women on 6 month infant outcomes: follow-up from the LIMIT randomised trial.

BACKGROUND: The immediate impact of providing an antenatal dietary intervention during pregnancy has been extensively studied, but little is known of the effects beyond the neonatal period. Our objective was to evaluate the effect of an antenatal dietary intervention in overweight or obese women on infant outcomes 6 months after birth. METHODS: We conducted a follow up study of infants born to women who participated in the LIMIT trial during pregnancy. Live-born infants at 6-months of age, and whose mother provided consent to ongoing follow-up were eligible. The primary follow-up study endpoint was the incidence of infant BMI z-score ≥90th centile for infant sex and age. Secondary study outcomes included a range of infant anthropometric measures, neurodevelopment, general health, and infant feeding. Analyses used intention to treat principles according to the treatment group allocated in pregnancy. Missing data were imputed and analyses adjusted for maternal early pregnancy BMI, parity, study centre, socioeconomic status, age, and smoking status. Outcome assessors were blinded to the allocated treatment group. RESULTS: A total of 1754 infants were assessed at age 6 months (Lifestyle Advice n = 869; Standard Care n = 885), representing 82.1% of the eligible sample (n = 2136). There were no statistically significant differences in the incidence of infant BMI z-score ≥90th centile for infants born to women in the Lifestyle Advice group, compared with the Standard Care group (Lifestyle Advice 233 (21.71%) vs. Standard Care 233 (21.90%); adjusted relative risk (aRR) 0.99; 95% confidence interval 0.82 to 1.18; p = 0.88). There were no other effects on infant growth, adiposity, or neurodevelopment. CONCLUSION: Providing pregnant women who were overweight or obese with an antenatal dietary and lifestyle intervention did not alter 6-month infant growth and adiposity. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ACTRN12607000161426).

Accounting for twin births in sample size calculations for randomised trials.

BACKGROUND: Including twins in randomised trials leads to non-independence or clustering in the data. Clustering has important implications for sample size calculations, yet few trials take this into account. Estimates of the intracluster correlation coefficient (ICC), or the correlation between outcomes of twins, are needed to assist with sample size planning. Our aims were to provide ICC estimates for infant outcomes, describe the information that must be specified in order to account for clustering due to twins in sample size calculations, and develop a simple tool for performing sample size calculations for trials including twins. METHODS: ICCs were estimated for infant outcomes collected in four randomised trials that included twins. The information required to account for clustering due to twins in sample size calculations is described. A tool that calculates the sample size based on this information was developed in Microsoft Excel and in R as a Shiny web app. RESULTS: ICC estimates ranged between -0.12, indicating a weak negative relationship, and 0.98, indicating a strong positive relationship between outcomes of twins. Example calculations illustrate how the ICC estimates and sample size calculator can be used to determine the target sample size for trials including twins. CONCLUSIONS: Clustering among outcomes measured on twins should be taken into account in sample size calculations to obtain the desired power. Our ICC estimates and sample size calculator will be useful for designing future trials that include twins. Publication of additional ICCs is needed to further assist with sample size planning for future trials.

Vaginal progesterone pessaries for pregnant women with a previous preterm birth to prevent neonatal respiratory distress syndrome (the PROGRESS Study): A multicentre, randomised, placebo-controlled trial.

BACKGROUND: Neonatal respiratory distress syndrome, as a consequence of preterm birth, is a major cause of early mortality and morbidity. The withdrawal of progesterone, either actual or functional, is thought to be an antecedent to the onset of labour. There remains limited information on clinically relevant health outcomes as to whether vaginal progesterone may be of benefit for pregnant women with a history of a previous preterm birth, who are at high risk of a recurrence. Our primary aim was to assess whether the use of vaginal progesterone pessaries in women with a history of previous spontaneous preterm birth reduced the risk and severity of respiratory distress syndrome in their infants, with secondary aims of examining the effects on other neonatal morbidities and maternal health and assessing the adverse effects of treatment. METHODS: Women with a live singleton or twin pregnancy between 18 to <24 weeks' gestation and a history of prior preterm birth at less than 37 weeks' gestation in the preceding pregnancy, where labour occurred spontaneously or in association with cervical incompetence or following preterm prelabour rupture of the membranes, were eligible. Women were recruited from 39 Australian, New Zealand, and Canadian maternity hospitals and assigned by randomisation to vaginal progesterone pessaries (equivalent to 100 mg vaginal progesterone) (n = 398) or placebo (n = 389). Participants and investigators were masked to the treatment allocation. The primary outcome was respiratory distress syndrome and severity. Secondary outcomes were other respiratory morbidities; other adverse neonatal outcomes; adverse outcomes for the woman, especially related to preterm birth; and side effects of progesterone treatment. Data were analysed for all the 787 women (100%) randomised and their 799 infants. FINDINGS: Most women used their allocated study treatment (740 women, 94.0%), with median use similar for both study groups (51.0 days, interquartile range [IQR] 28.0-69.0, in the progesterone group versus 52.0 days, IQR 27.0-76.0, in the placebo group). The incidence of respiratory distress syndrome was similar in both study groups-10.5% (42/402) in the progesterone group and 10.6% (41/388) in the placebo group (adjusted relative risk [RR] 0.98, 95% confidence interval [CI] 0.64-1.49, p = 0.912)-as was the severity of any neonatal respiratory disease (adjusted treatment effect 1.02, 95% CI 0.69-1.53, p = 0.905). No differences were seen between study groups for other respiratory morbidities and adverse infant outcomes, including serious infant composite outcome (155/406 [38.2%] in the progesterone group and 152/393 [38.7%] in the placebo group, adjusted RR 0.98, 95% CI 0.82-1.17, p = 0.798). The proportion of infants born before 37 weeks' gestation was similar in both study groups (148/406 [36.5%] in the progesterone group and 146/393 [37.2%] in the placebo group, adjusted RR 0.97, 95% CI 0.81-1.17, p = 0.765). A similar proportion of women in both study groups had maternal morbidities, especially those related to preterm birth, or experienced side effects of treatment. In 9.9% (39/394) of the women in the progesterone group and 7.3% (28/382) of the women in the placebo group, treatment was stopped because of side effects (adjusted RR 1.35, 95% CI 0.85-2.15, p = 0.204). The main limitation of the study was that almost 9% of the women did not start the medication or forgot to use it 3 or more times a week. CONCLUSIONS: Our results do not support the use of vaginal progesterone pessaries in women with a history of a previous spontaneous preterm birth to reduce the risk of neonatal respiratory distress syndrome or other neonatal and maternal morbidities related to preterm birth. Individual participant data meta-analysis of the relevant trials may identify specific women for whom vaginal progesterone might be of benefit. TRIAL REGISTRATION: Current Clinical Trials ISRCTN20269066.

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

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

Ectrodactyly and Lethal Pulmonary Acinar Dysplasia Associated with Homozygous FGFR2 Mutations Identified by Exome Sequencing.

Ectrodactyly/split hand-foot malformation is genetically heterogeneous with more than 100 syndromic associations. Acinar dysplasia is a rare congenital lung lesion of unknown etiology, which is frequently lethal postnatally. To date, there have been no reports of combinations of these two phenotypes. Here, we present an infant from a consanguineous union with both ectrodactyly and autopsy confirmed acinar dysplasia. SNP array and whole-exome sequencing analyses of the affected infant identified a novel homozygous Fibroblast Growth Factor Receptor 2 (FGFR2) missense mutation (p.R255Q) in the IgIII domain (D3). Expression studies of Fgfr2 in development show localization to the affected limbs and organs. Molecular modeling and genetic and functional assays support that this mutation is at least a partial loss-of-function mutation, and contributes to ectrodactyly and acinar dysplasia only in homozygosity, unlike previously reported heterozygous activating FGFR2 mutations that cause Crouzon, Apert, and Pfeiffer syndromes. This is the first report of mutations in a human disease with ectrodactyly with pulmonary acinar dysplasia and, as such, homozygous loss-of-function FGFR2 mutations represent a unique syndrome.

Avoidance of bottles during the establishment of breast feeds in preterm infants.

BACKGROUND: Preterm infants start milk feeds by gavage tube. As they mature, sucking feeds are gradually introduced. Women who choose to breast feed their preterm infant are not always able to be in hospital with their baby and need an alternative approach to feeding. Most commonly, milk (expressed breast milk or formula) is given by bottle. Whether using bottles during establishment of breast feeds is detrimental to breast feeding success is a topic of ongoing debate. OBJECTIVES: To identify the effects of avoidance of bottle feeds during establishment of breast feeding on the likelihood of successful breast feeding, and to assess the safety of alternatives to bottle feeds. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2), MEDLINE via PubMed (1966 to July 2016), Embase (1980 to July 2016) and CINAHL (1982 to July 2016). We also searched databases of clinical trials and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing avoidance of bottles with use of bottles in women who have chosen to breast feed their preterm infant. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. When appropriate, we contacted study authors for additional information. Review authors used standard methods of The Cochrane Collaboration and the Cochrane Neonatal Review Group. MAIN RESULTS: We included seven trials with 1152 preterm infants. Five studies used a cup feeding strategy, one used a tube feeding strategy and one used a novel teat when supplements to breast feeds were needed. We included the novel teat study in this review, as the teat was designed to more closely mimic the sucking action of breast feeding. The trials were of small to moderate size, and two had high risk of attrition bias. Adherence with cup feeding was poor in one of the studies, indicating dissatisfaction with this method by staff and/or parents; the remaining four cup feeding studies provided no such reports of dissatisfaction or low adherence. Meta-analyses provided evidence of low to moderate quality indicating that avoiding bottles increases the extent of breast feeding on discharge home (full breast feeding typical risk ratio (RR) 1.47, 95% confidence interval (CI) 1.19 to 1.80; any breast feeding RR 1.11, 95% CI 1.06 to 1.16). Limited available evidence for three months and six months post discharge shows that avoiding bottles increases the occurrence of full breast feeding and any breast feeding at discharge and at six months post discharge, and of full (but not any) breast feeding at three months post discharge. This effect was evident at all time points for the tube alone strategy and for all except any breast feeding at three months post discharge for cup feeding. Investigators reported no clear benefit when the novel teat was used. No other benefits or harms were evident, including, in contrast to the previous (2008) review, length of hospital stay. AUTHORS' CONCLUSIONS: Evidence of low to moderate quality suggests that supplementing breast feeds by cup increases the extent and duration of breast feeding. Current insufficient evidence provides no basis for recommendations for a tube alone approach to supplementing breast feeds.

Avoidance of bottles during the establishment of breast feeds in preterm infants.

BACKGROUND: Preterm infants start milk feeds by gavage tube. As they mature, sucking feeds are gradually introduced. Women who choose to breast feed their preterm infant are not always able to be in hospital with their baby and need an alternative approach to feeding. Most commonly, milk (expressed breast milk or formula) is given by bottle. Whether using bottles during establishment of breast feeds is detrimental to breast feeding success is a topic of ongoing debate. OBJECTIVES: To identify the effects of avoidance of bottle feeds during establishment of breast feeding on the likelihood of successful breast feeding, and to assess the safety of alternatives to bottle feeds. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2), MEDLINE via PubMed (1966 to July 2016), Embase (1980 to July 2016) and CINAHL (1982 to July 2016). We also searched databases of clinical trials and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing avoidance of bottles with use of bottles in women who have chosen to breast feed their preterm infant. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. When appropriate, we contacted study authors for additional information. Review authors used standard methods of The Cochrane Collaboration and the Cochrane Neonatal Review Group. MAIN RESULTS: We included seven trials with 1152 preterm infants. Five studies used a cup feeding strategy, one used a tube feeding strategy and one used a novel teat when supplements to breast feeds were needed. We included the novel teat study in this review, as the teat was designed to more closely mimic the sucking action of breast feeding. The trials were of small to moderate size, and two had high risk of attrition bias. Adherence with cup feeding was poor in one of the studies, indicating dissatisfaction with this method by staff and/or parents; the remaining four cup feeding studies provided no such reports of dissatisfaction or low adherence. Meta-analyses provided evidence of low to moderate quality indicating that avoiding bottles increases the extent of breast feeding on discharge home (full breast feeding typical risk ratio (RR) 1.47, 95% confidence interval (CI) 1.19 to 1.80; any breast feeding RR 1.11, 95% CI 1.06 to 1.16). Limited available evidence for three months and six months post discharge shows that avoiding bottles increases the occurrence of full breast feeding and any breast feeding at discharge and at six months post discharge, and of full (but not any) breast feeding at three months post discharge. This effect was evident at all time points for the tube alone strategy and for all except any breast feeding at three months post discharge for cup feeding. Investigators reported no clear benefit when the novel teat was used. No other benefits or harms were evident, including, in contrast to the previous (2008) review, length of hospital stay. AUTHORS' CONCLUSIONS: Evidence of low to moderate quality suggests that supplementing breast feeds by cup increases the extent and duration of breast feeding. Current insufficient evidence provides no basis for recommendations for a tube alone approach to supplementing breast feeds.

The effect of antenatal dietary and lifestyle advice for women who are overweight or obese on emotional well-being: the LIMIT randomized trial.

INTRODUCTION: Our aim was to evaluate the effect of dietary and lifestyle advice given to women who were overweight or obese during pregnancy on maternal quality of life, anxiety and risk of depression, and satisfaction with care. MATERIAL AND METHODS: We conducted a randomized trial, involving pregnant women with body mass index ≥25 kg/m(2) , recruited from maternity units in South Australia. Women were randomized to Lifestyle Advice or Standard Care, and completed questionnaires assessing risk of depression (Edinburgh Postnatal Depression Scale), anxiety (Spielberger State-Trait Anxiety Inventory), and quality of life (SF-36) at trial entry, 28 and 36 weeks' gestation, and 4 months postpartum. Secondary trial outcomes assessed for this analysis were risk of depression, anxiety, maternal quality of life, and satisfaction with care. RESULTS: One or more questionnaires were completed by 976 of 1108 (90.8%) women receiving Lifestyle Advice and 957 of 1104 (89.7%) women receiving Standard Care. The risk of depression [adjusted risk ratio 1.01; 95% confidence interval (CI) 0.82-1.24; p = 0.95], anxiety (adjusted risk ratio 1.09; 95% CI 0.93-1.27; p = 0.31), and health-related quality of life were similar between the two groups. Women receiving Lifestyle Advice reported improved healthy food choice [Lifestyle Advice 404 (68.9%) vs. Standard Care 323 (51.8%); p < 0.0001], and exercise knowledge [Lifestyle Advice 444 (75.8%) vs. Standard Care 367 (58.8%); p < 0.0001], and reassurance about their health [Lifestyle Advice 499 (85.3%) vs. Standard Care 485 (77.9%); p = 0.0112], and health of their baby [Lifestyle Advice 527 (90.2%) vs. Standard Care 545 (87.6%); p = 0.0143]. CONCLUSION: Lifestyle advice in pregnancy improved knowledge and provided reassurance without negatively impacting well-being.

The N3RO trial: a randomised controlled trial of docosahexaenoic acid to reduce bronchopulmonary dysplasia in preterm infants < 29 weeks' gestation.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a major cause of mortality and long-term respiratory and neurological morbidity in very preterm infants. While survival rates of very preterm infants have increased over the past two decades there has been no decrease in the rate of BPD in surviving infants. Evidence from animal and human studies has suggested potential benefits of docosahexaenoic acid (DHA), an n-3 long chain polyunsaturated fatty acid, in the prevention of chronic lung disease. This randomised controlled trial aims to determine the effectiveness of supplementary DHA in reducing the rate of BPD in infants less than 29 weeks' gestation. METHODS/DESIGN: This is a multicentre, parallel group, randomised, blinded and controlled trial. Infants born less than 29 weeks' gestation, within 3 days of first enteral feed and with parent informed consent are eligible to participate. Infants will be randomised to receive an enteral emulsion containing DHA or a control emulsion without DHA. The DHA emulsion will provide 60 mg/kg/day of DHA. The study emulsions will continue to 36 weeks' postmenstrual age (PMA). The primary outcome is BPD as assessed by the requirement for supplemental oxygen and/or assisted ventilation at 36 weeks' PMA. Secondary outcomes include the composite of death or BPD; duration of respiratory support and hospitalisation, major neonatal morbidities. The target sample size is 1244 infants (622 per group), which will provide 90 % power to detect a clinically meaningful absolute reduction of 10 % in the incidence of BPD between the DHA and control emulsion (two tailed α =0.05). DISCUSSION: DHA supplementation has the potential to reduce respiratory morbidity in very preterm infants. This multicentre trial will provide evidence on whether an enteral DHA supplement reduces BPD in very preterm infants. TRIAL REGISTRATION: Australia and New Zealand Clinical Trial Registry: ACTRN12612000503820 . Registered 09 May 2012.

Early discharge with home support of gavage feeding for stable preterm infants who have not established full oral feeds.

BACKGROUND: Early discharge of stable preterm infants still requiring gavage feeds offers the benefits of uniting families sooner and reducing healthcare and family costs compared with discharge home when on full sucking feeds. Potential disadvantages of early discharge include increased care burden for the family and risk of complications related to gavage feeding. OBJECTIVES: To determine the effects of a policy of early discharge of stable preterm infants with home support of gavage feeding compared with a policy of discharge of such infants when they have reached full sucking feeds.We planned subgroup analyses to determine whether safety and efficacy outcomes are altered by the type of support received (outpatient visits vs home support) or by the maturity of the infants discharged (gestational age ≤ 28 weeks at birth or birth weight ≤ 1000 grams). SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group, together with searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 3), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to March 2015), EMBASE (1980 to March 2015) and MEDLINE (1950 to March 2015). We found no new trials. SELECTION CRITERIA: We included all randomised and quasi-randomised trials among infants born at < 37 weeks and requiring no intravenous nutrition at the point of discharge. Trials were required to compare early discharge home with gavage feeds and healthcare support versus later discharge home when full sucking feeds were attained. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. We conducted study authors for additional information. We performed data analysis in accordance with the standards of the Cochrane Neonatal Review Group. MAIN RESULTS: We included in the review data from one quasi-randomised trial with 88 infants from 75 families. Infants in the early discharge programme with home gavage feeding had a mean hospital stay that was 9.3 days shorter (mean difference (MD) -9.3, 95% confidence interval (CI) -18.49 to -0.11) than that of infants in the control group. Infants in the early discharge programme also had lower risk of clinical infection during the home gavage period compared with those in the control group spending corresponding time in hospital (risk ratio 0.35, 95% CI 0.17 to 0.69). No significant differences were noted between groups in duration and extent of breast feeding, weight gain, re-admission within the first 12 months post discharge from the home gavage programme or from hospital, scores reflecting parental satisfaction or overall health service use. AUTHORS' CONCLUSIONS: Experimental evidence on the benefits and risks for preterm infants of early discharge from hospital with home gavage feeding compared with later discharge upon attainment of full sucking feeds is limited to the results of one small quasi-randomised controlled trial. High-quality trials with concealed allocation, complete follow-up of all randomly assigned infants and adequate sample size are needed before practice recommendations can be made.

The effects of antenatal dietary and lifestyle advice for women who are overweight or obese on maternal diet and physical activity: the LIMIT randomised trial.

BACKGROUND: Overweight and obesity is a significant health concern during pregnancy. Our aim was to investigate the effect of providing antenatal dietary and lifestyle advice to women who are overweight or obese on components of maternal diet and physical activity. METHODS: We conducted a randomised controlled trial, in which pregnant women with a body mass index≥25 kg/m2, and singleton gestation between 10(+0) to 20(+0) weeks were recruited and randomised to Lifestyle Advice (involving a comprehensive dietary and lifestyle intervention over their pregnancy) or Standard Care. Within the intervention group, we conducted a nested randomised trial in which a subgroup of women were further randomised to receive access to supervised group walking sessions in addition to the standard information presented during the intervention contacts (the Walking group) or standard information only. The outcome measures were maternal dietary intake, (including food groups, macronutrient and micronutrient intake, diet quality (using the Healthy Eating Index; HEI), dietary glycaemic load, and glycaemic index) and maternal physical activity. Women completed the Harvard Semi-Structured Food Frequency Questionnaire, and the Short Questionnaire to Assess Health-enhancing Physical Activity (SQUASH), at trial entry, 28 and 36 weeks' gestational age, and 4 months postpartum. Analyses were performed on an intention-to-treat basis, using linear mixed effects models with adjustment for the stratification variables. RESULTS: Women randomised to Lifestyle Advice demonstrated a statistically significant increase in the number of servings of fruit and vegetables consumed per day, as well as increased consumption of fibre, and reduced percentage energy intake from saturated fats (P<0.05 for all). Maternal HEI was significantly improved at both 28 (73.35±6.62 versus 71.86±7.01; adjusted difference in means 1.58; 95% CI 0.89 to 2.27; P<0.0001) and 36 (72.95±6.82 versus 71.17±7.69; adjusted difference in means 1.77; 95% CI 1.01 to 2.53; P<0.0001) weeks. There were no differences in dietary glycaemic index or glycaemic load. Women randomised to Lifestyle Advice also demonstrated greater total physical activity (adjusted difference in means 359.76 metabolic equivalent task units (MET) minutes/week; 95% CI 74.87 to 644.65; P=0.01) compared with women receiving Standard Care. The supervised walking group was poorly utilised. CONCLUSIONS: For women who are overweight or obese, antenatal lifestyle advice improves maternal diet and physical activity during pregnancy. Please see related articles: http://www.biomedcentral.com/1741-7015/12/163 and http://www.biomedcentral.com/1741-7015/12/201. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ( ACTRN12607000161426).

The effects of antenatal dietary and lifestyle advice for women who are overweight or obese on neonatal health outcomes: the LIMIT randomised trial.

BACKGROUND: Overweight and obesity during pregnancy represents a considerable health burden. While research has focused on interventions to limit gestational weight gain, there is little information describing their impact on neonatal health. Our aim was to investigate the effect on a range of pre-specified secondary neonatal outcomes of providing antenatal dietary and lifestyle advice to women who are overweight or obese. METHODS: We report a range of pre-specified secondary neonatal outcomes from a large randomised trial in which antenatal dietary and lifestyle advice was provided to women who were overweight or obese. Pregnant women were eligible for participation with a body mass index of 25 kg/m(2) or over, and singleton gestation between 10(+0) and 20(+0) weeks. Outcome measures included gestational age at birth; Apgar score below 7 at 5 minutes of age; need for resuscitation at birth; birth weight above 4.5 kg or below 2.5 kg; birth weight, length and head circumference (and Z-scores); admission to the nursery; respiratory distress syndrome; and postnatal length of stay. Data relating to the primary outcome (large for gestational age infants defined as birth weight above the 90th centile) and birth weight above 4 kg have been reported previously. Analyses used intention-to-treat principles. RESULTS: In total, 2,142 infants were included in the analyses. Infants born to women following lifestyle advice were significantly less likely to have birth weight above 4.5 kg (2.15% versus 3.69%; adjusted risk ratio (aRR)=0.59; 95% confidence interval (CI) 0.36 to 0.98; P=0.04), or respiratory distress syndrome (1.22% versus 2.57%; aRR=0.47; 95% CI 0.24 to 0.90; P=0.02), particularly moderate or severe disease, and had a shorter length of postnatal hospital stay (3.94±7.26 days versus 4.41±9.87 days; adjusted ratio of means 0.89; 95% CI 0.82 to 0.97; P=0.006) compared with infants born to women who received Standard Care. CONCLUSIONS: For women who are overweight or obese, antenatal dietary and lifestyle advice has health benefits for infants, without an increase in the risk of harm. Continued follow-up into childhood will be important to assess the longer-term effects of a reduction in high infant birth weight on risk of child obesity. Please see related articles: http://www.biomedcentral.com/1741-7015/12/161 and http://www.biomedcentral.com/1741-7015/12/201 . CLINICAL TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ( ACTRN12607000161426 ).

Screening and subsequent management for gestational diabetes for improving maternal and infant health.

BACKGROUND: Gestational diabetes mellitus (GDM) is a form of diabetes that occurs in pregnancy. Although GDM usually resolves following birth, it is associated with significant morbidities for mother and baby both perinatally and in the long term. There is strong evidence to support treatment for GDM. However, there is little consensus on whether or not screening for GDM will improve maternal and infant health and if so, the most appropriate protocol to follow. OBJECTIVES: To assess the effects of different methods of screening for GDM and maternal and infant outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (1 December 2013). SELECTION CRITERIA: Randomised and quasi-randomised trials evaluating the effects of different methods of screening for GDM. DATA COLLECTION AND ANALYSIS: Two review authors independently conducted data extraction and quality assessment. We resolved disagreements through discussion or through a third author. MAIN RESULTS: We included four trials involving 3972 women in the review. One quasi-randomised trial compared risk factor screening with universal or routine screening by 50 g oral glucose challenge testing. Women in the universal screening group were more likely to be diagnosed with GDM (one trial, 3152 women, risk ratio (RR) 0.44, 95% confidence interval (CI) 0.26 to 0.75). This trial did not report on the other primary outcomes of the review (positive screen for GDM, mode of birth, large-for-gestational age, or macrosomia). Considering secondary outcomes, infants of mothers in the risk factor screening group were born marginally earlier than infants of mothers in the routine screening group (one trial, 3152 women, mean difference (MD) -0.15 weeks, 95% CI -0.27 to -0.03).The remaining three trials evaluated different methods of administering a 50 g glucose load. Two small trials compared glucose monomer with glucose polymer testing, with one of these trials including a candy bar group. One trial compared a glucose solution with food. No differences in diagnosis of GDM were found between each comparison. However, in one trial significantly more women in the glucose monomer group screened positive for GDM than women in the candy bar group (80 women, RR 3.49, 95% CI 1.05 to 11.57). The three trials did not report on the primary review outcomes of mode of birth, large-for-gestational age or macrosomia. Overall, women drinking the glucose monomer experienced fewer side effects from testing than women drinking the glucose polymer (two trials, 151 women, RR 2.80, 95% CI 1.10 to 7.13). However, we observed substantial heterogeneity between the trials for this result (I² = 61%). AUTHORS' CONCLUSIONS: There was insufficient evidence to determine if screening for gestational diabetes, or what types of screening, can improve maternal and infant health outcomes.