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Metabolic Bone Disease of Prematurity: Risk Factors and Associated Short-Term Outcomes.
Avila-Alvarez, A, Urisarri, A, Fuentes-Carballal, J, Mandiá, N, Sucasas-Alonso, A, Couce, ML
Nutrients. 2020;(12)
Abstract
Despite the importance of early recognition of metabolic bone disease (MBD) of prematurity, there is still significant variability in screening practices across institutions. We conducted an observational study of infants born at ≤32 weeks of gestation with a birth weight of ≤1500 g (n = 218) to identify clinical factors associated with biochemical indicators of MBD. Bone mineral status was assessed by measuring alkaline phosphatase and phosphate levels between weeks 3 and 5 of life. Two comparisons were performed after classifying infants as either MBD (cases) or non-MBD (controls), and as either high or low risk for MBD, as determined based on the results of MBD screening. In total, 27 infants (12.3%) were classified as cases and 96 (44%) as high-risk. Compared with controls, MBD infants had a significantly lower gestational age and birth weight, and a longer duration of parenteral nutrition and hospital stay. Respiratory outcomes were significantly poorer in high- versus low-risk infants. Multivariate logistic regression showed that birth weight was the only independent risk factor for MBD (odds ratio [OR]/100 g, 0.811; confidence interval [CI95%], 0.656-0.992; p = 0.045) and that birth weight (OR/100 g, 0.853; CI95%, 0.731-0.991; p = 0.039) and red blood cell transfusion (OR, 2.661; CI95%, 1.308-5.467; p = 0.007) were independent risk factors for high risk of MBD. Our findings provide evidence of risk factors for MBD that could help clinicians to individualize perinatal management. The association of red blood cell transfusion with MBD is a novel finding that may be related to iron overload and that merits further study.
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Controlled Trial of Two Incremental Milk-Feeding Rates in Preterm Infants.
Dorling, J, Abbott, J, Berrington, J, Bosiak, B, Bowler, U, Boyle, E, Embleton, N, Hewer, O, Johnson, S, Juszczak, E, et al
The New England journal of medicine. 2019;(15):1434-1443
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Abstract
BACKGROUND Observational data have shown that slow advancement of enteral feeding volumes in preterm infants is associated with a reduced risk of necrotizing enterocolitis but an increased risk of late-onset sepsis. However, data from randomized trials are limited. METHODS We randomly assigned very preterm or very-low-birth-weight infants to daily milk increments of 30 ml per kilogram of body weight (faster increment) or 18 ml per kilogram (slower increment) until reaching full feeding volumes. The primary outcome was survival without moderate or severe neurodevelopmental disability at 24 months. Secondary outcomes included components of the primary outcome, confirmed or suspected late-onset sepsis, necrotizing enterocolitis, and cerebral palsy. RESULTS Among 2804 infants who underwent randomization, the primary outcome could be assessed in 1224 (87.4%) assigned to the faster increment and 1246 (88.7%) assigned to the slower increment. Survival without moderate or severe neurodevelopmental disability at 24 months occurred in 802 of 1224 infants (65.5%) assigned to the faster increment and 848 of 1246 (68.1%) assigned to the slower increment (adjusted risk ratio, 0.96; 95% confidence interval [CI], 0.92 to 1.01; P = 0.16). Late-onset sepsis occurred in 414 of 1389 infants (29.8%) in the faster-increment group and 434 of 1397 (31.1%) in the slower-increment group (adjusted risk ratio, 0.96; 95% CI, 0.86 to 1.07). Necrotizing enterocolitis occurred in 70 of 1394 infants (5.0%) in the faster-increment group and 78 of 1399 (5.6%) in the slower-increment group (adjusted risk ratio, 0.88; 95% CI, 0.68 to 1.16). CONCLUSIONS There was no significant difference in survival without moderate or severe neurodevelopmental disability at 24 months in very preterm or very-low-birth-weight infants with a strategy of advancing milk feeding volumes in daily increments of 30 ml per kilogram as compared with 18 ml per kilogram. (Funded by the Health Technology Assessment Programme of the National Institute for Health Research; SIFT Current Controlled Trials number, ISRCTN76463425.).
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Adverse Maternal and Neonatal Outcomes in Indicated Compared with Spontaneous Preterm Birth in Healthy Nulliparas: A Secondary Analysis of a Randomized Trial.
Tita, AT, Doherty, L, Roberts, JM, Myatt, L, Leveno, KJ, Varner, MW, Wapner, RJ, Thorp, JM, Mercer, BM, Peaceman, A, et al
American journal of perinatology. 2018;(7):624-631
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OBJECTIVE To compare the risks of adverse maternal and neonatal outcomes associated with spontaneous (SPTB) versus indicated preterm births (IPTB). METHODS A secondary analysis of a multicenter trial of vitamin C and E supplementation in healthy low-risk nulliparous women. Outcomes were compared between women with SPTB (due to spontaneous membrane rupture or labor) and those with IPTB (due to medical or obstetric complications). A primary maternal composite outcome included: death, pulmonary edema, blood transfusion, adult respiratory distress syndrome (RDS), cerebrovascular accident, acute tubular necrosis, disseminated intravascular coagulopathy, or liver rupture. A neonatal composite outcome included: neonatal death, RDS, grades III or IV intraventricular hemorrhage (IVH), sepsis, necrotizing enterocolitis (NEC), or retinopathy of prematurity. RESULTS Of 9,867 women, 10.4% (N = 1,038) were PTBs; 32.7% (n = 340) IPTBs and 67.3% (n = 698) SPTBs. Compared with SPTB, the composite maternal outcome was more frequent in IPTB-4.4% versus 0.9% (adjusted odds ratio [aOR], 4.0; 95% confidence interval [CI], 1.4-11.8), as were blood transfusion and prolonged hospital stay (3.2 and 3.7 times, respectively). The frequency of composite neonatal outcome was higher in IPTBs (aOR, 1.8; 95% CI, 1.1-3.0), as were RDS (1.7 times), small for gestational age (SGA) < 5th percentile (7.9 times), and neonatal intensive care unit (NICU) admission (1.8 times). CONCLUSION Adverse maternal and neonatal outcomes were significantly more likely with IPTB than with SPTB.
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Academic Performance, Motor Function, and Behavior 11 Years After Neonatal Caffeine Citrate Therapy for Apnea of Prematurity: An 11-Year Follow-up of the CAP Randomized Clinical Trial.
Schmidt, B, Roberts, RS, Anderson, PJ, Asztalos, EV, Costantini, L, Davis, PG, Dewey, D, D'Ilario, J, Doyle, LW, Grunau, RE, et al
JAMA pediatrics. 2017;(6):564-572
Abstract
IMPORTANCE Caffeine citrate therapy for apnea of prematurity reduces the rates of bronchopulmonary dysplasia, severe retinopathy, and neurodevelopmental disability at 18 months and may improve motor function at 5 years. OBJECTIVE To evaluate whether neonatal caffeine therapy is associated with improved functional outcomes 11 years later. DESIGN, SETTING, AND PARTICIPANTS A follow-up study was conducted at 14 academic hospitals in Canada, Australia, and the United Kingdom from May 7, 2011, to May 27, 2016, of English- or French-speaking children who had been enrolled in the randomized, placebo-controlled Caffeine for Apnea of Prematurity trial between October 11, 1999, and October 22, 2004. A total of 1202 children with birth weights of 500 to 1250 g were eligible for this study; 920 (76.5%) had adequate data for the main outcome. INTERVENTIONS Caffeine citrate or placebo until drug therapy for apnea of prematurity was no longer needed. MAIN OUTCOMES AND MEASURES Functional impairment was a composite of poor academic performance (defined as at least 1 standard score greater than 2 SD below the mean on the Wide Range Achievement Test-4), motor impairment (defined as a percentile rank of ≤5 on the Movement Assessment Battery for Children-Second Edition), and behavior problems (defined as a Total Problem T score ≥2 SD above the mean on the Child Behavior Checklist). RESULTS Among the 920 children (444 females and 476 males; median age, 11.4 years [interquartile range, 11.1-11.8 years]), the combined rates of functional impairment were not significantly different between the 457 children assigned to receive caffeine compared with the 463 children assigned to receive placebo (145 [31.7%] vs 174 [37.6%]; adjusted odds ratio, 0.78; 95% CI, 0.59-1.02; P = .07). With all available data, including those from up to 24 Swedish trial participants, the rates of poor academic performance on 1 or more of 4 subtests (66 of 458 [14.4%] vs 61 of 462 [13.2%]; adjusted odds ratio, 1.11; 95% CI, 0.77-1.61; P = .58) and behavior problems (52 of 476 [10.9%] vs 40 of 481 [8.3%]; adjusted odds ratio, 1.32; 95% CI, 0.85-2.07; P = .22) were broadly similar between the group that received caffeine and the group that received placebo. However, caffeine therapy was associated with a reduced risk of motor impairment compared with placebo (90 of 457 [19.7%] vs 130 of 473 [27.5%]; adjusted odds ratio, 0.66; 95% CI, 0.48-0.90; P = .009). CONCLUSIONS AND RELEVANCE Caffeine therapy for apnea of prematurity did not significantly reduce the combined rate of academic, motor, and behavioral impairments but was associated with a reduced risk of motor impairment in 11-year-old children with very low birth weight. At the doses used in this trial, neonatal caffeine therapy is effective and safe into middle school age. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00182312; isrctn.org Identifier: ISRCTN44364365.
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The Speed of Increasing milk Feeds: a randomised controlled trial.
Abbott, J, Berrington, J, Bowler, U, Boyle, E, Dorling, J, Embleton, N, Juszczak, E, Leaf, A, Linsell, L, Johnson, S, et al
BMC pediatrics. 2017;(1):39
Abstract
BACKGROUND In the UK, 1-2% of infants are born very preterm (<32 weeks of gestation) or have very low birth weight (<1500 g). Very preterm infants are initially unable to be fed nutritional volumes of milk and therefore require intravenous nutrition. Milk feeding strategies influence several long and short term health outcomes including growth, survival, infection (associated with intravenous nutrition) and necrotising enterocolitis (NEC); with both infection and NEC being key predictive factors of long term disability. Currently there is no consistent strategy for feeding preterm infants across the UK. The SIFT trial will test two speeds of increasing milk feeds with the primary aim of determining effects on survival without moderate or severe neurodevelopmental disability at 24 months of age, corrected for prematurity. The trial will also examine many secondary outcomes including infection, NEC, time taken to reach full feeds and growth. METHODS/DESIGN Two thousand eight hundred very preterm or very low birth weight infants will be recruited from approximately 30 hospitals across the UK to a randomised controlled trial. Infants with severe congenital anomaly or no realistic chance of survival will be excluded. Infants will be randomly allocated to either a faster (30 ml/kg/day) or slower (18 ml/kg/day) rate of increase in milk feeds. Data will be collected during the neonatal hospital stay on weight, infection rates, episodes of NEC, length of stay and time to reach full milk feeds. Long term health outcomes comprising vision, hearing, motor and cognitive impairment will be assessed at 24 months of age (corrected for prematurity) using a parent report questionnaire. DISCUSSION Extensive searches have found no active or proposed studies investigating the rate of increasing milk feeds. The results of this trial will have importance for optimising incremental milk feeding for very preterm and/or very low birth weight infants. No additional resources will be required to implement an optimal feeding strategy, and therefore if successful, the trial results could rapidly be adopted across the NHS at low cost. TRIAL REGISTRATION ISRCTN Registry; ISRCTN76463425 on 5 March, 2013.
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Bifidobacterium breve BBG-001 in very preterm infants: a randomised controlled phase 3 trial.
Costeloe, K, Hardy, P, Juszczak, E, Wilks, M, Millar, MR, ,
Lancet (London, England). 2016;(10019):649-660
Abstract
BACKGROUND Probiotics may reduce necrotising enterocolitis and late-onset sepsis after preterm birth. However, there has been concern about the rigour and generalisability of some trials and there is no agreement about whether or not they should be used routinely. We aimed to test the effectiveness of the probiotic Bifidobacterium breve BBG-001 to reduce necrotising enterocolitis, late-onset sepsis, and death in preterm infants. METHODS In this multicentre, randomised controlled phase 3 study (the PiPS trial), we recruited infants born between 23 and 30 weeks' gestational age within 48 h of birth from 24 hospitals in southeast England. Infants were randomly assigned (1:1) to probiotic or placebo via a minimisation algorithm randomisation programme. The probiotic intervention was B breve BBG-001 suspended in dilute elemental infant formula given enterally in a daily dose of 8·2 to 9·2 log10 CFU; the placebo was dilute infant formula alone. Clinicians and families were masked to allocation. The primary outcomes were necrotising enterocolitis (Bell stage 2 or 3), blood culture positive sepsis more than 72 h after birth; and death before discharge from hospital. All primary analyses were by intention to treat. This trial is registered with ISRCTN, number 05511098 and EudraCT, number 2006-003445-17. FINDINGS Between July 1, 2010, and July 31, 2013, 1315 infants were recruited; of whom 654 were allocated to probiotic and 661 to placebo. Five infants had consent withdrawn after randomisation, thus 650 were analysed in the probiotic group and 660 in the placebo group. Rates of the primary outcomes did not differ significantly between the probiotic and placebo groups. 61 infants (9%) in the probiotic group had necrotising enterocolitis compared with 66 (10%) in the placebo group (adjusted risk ratio 0·93 (95% CI 0·68-1·27); 73 (11%) infants in the probiotics group had sepsis compared with 77 (12%) in the placebo group (0·97 (0·73-1·29); and 54 (8%) deaths occurred before discharge home in the probiotic group compared with 56 (9%) in the placebo group (0·93 [0·67-1·30]). No probiotic-associated adverse events were reported. INTERPRETATION There is no evidence of benefit for this intervention in this population; this result does not support the routine use of B breve BBG-001 for prevention of necrotising enterocolitis and late-onset sepis in very preterm infants. FUNDING UK National Institute for Health Research Health Technology Assessment programme.
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CeasIng Cpap At standarD criteriA (CICADA): predicting a successful outcome.
Yin, Y, Broom, M, Wright, A, Hovey, D, Abdel-Latif, ME, Shadbolt, B, Todd, DA
European journal of pediatrics. 2016;(1):81-7
Abstract
UNLABELLED This is a retrospective analysis of a multicentre randomised controlled trial (RCT) where we concluded that CeasIng Cpap At standerD criteriA (CICADA) in premature babies (PBs) <30 weeks gestational age (GA) was the significantly better method of ceasing CPAP. To identify factors that may influence the number of attempts to cease CPAP, we reviewed the records of 50 PBs from the RCT who used the CICADA method. PBs were grouped according to number of attempts to cease CPAP (fast group ≤2 attempts and slow group >2 attempts to cease CPAP). There were 26 (fast group) and 24 (slow group) PBs included in the analysis. Results showed significant differences in mean GA (27.8 ± 0.3 vs 26.9 ± 0.3 [weeks ± SE], p = 0.03) and birth weight ([Bwt]; 1080 ± 48.8 vs 899 ± 45.8 [grams ± SE], p = 0.01) between groups. Significantly fewer PBs in the fast group had a patent ductus arteriosus (PDA) compared to the slow group (5/26 (19.2%) vs 13/24 (54.2 %), p = 0.02). Bwt was a significant negative predictor of CPAP duration (r = -0.497, p = 0.03) and CPAP ceasing attempts (r = -0.290, p = 0.04). CONCLUSION PBs with a higher GA and Bwt without a PDA ceased CPAP earlier using the CICADA method. Bwt was better than GA for predicting CPAP duration and attempts to cease CPAP. WHAT IS KNOWN Our previous studies showed that CeasIng Cpap At standarD criteriA (CICADA) significantly reduces CPAP time, oxygen requirements and caffeine use. Some PBs however using the CICADA method required >2 attempts to cease CPAP ('slow CICADA' group). WHAT IS NEW PBs in the 'fast CICADA' group (<3 attempts to cease CPAP) (a) have longer gestational age and higher birth weight, (b) shorter mechanical ventilation and (c) lower incidence of patent ductus arteriosus. Attempts to cease CPAP decreased by 0.5 times per 1 week increase in GA and 0.3 times per 100-g increase in birth weight for PBs <30 weeks gestation.
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Cardiovascular risk factors in children after repeat doses of antenatal glucocorticoids: an RCT.
McKinlay, CJ, Cutfield, WS, Battin, MR, Dalziel, SR, Crowther, CA, Harding, JE, ,
Pediatrics. 2015;(2):e405-15
Abstract
BACKGROUND Treatment of women at risk for preterm birth with repeat doses of glucocorticoids reduces neonatal morbidity but could have adverse long-term effects on cardiometabolic health in offspring. We assessed whether exposure to repeat antenatal betamethasone increased risk factors for later cardiometabolic disease in children whose mothers participated in the Australasian Collaborative Trial of Repeat Doses of Corticosteroids. METHODS Women were randomized to betamethasone or placebo treatment, ≥ 7 days after an initial course of glucocorticoids, repeated each week that they remained at risk for preterm birth at <32 weeks' gestation. In this follow-up study, children were assessed at 6 to 8 years' corrected age for body composition, insulin sensitivity, ambulatory blood pressure, and renal function. RESULTS Of 320 eligible childhood survivors, 258 were studied (81%; 123 repeat betamethasone group; 135 placebo [single course] group). Children exposed to repeat antenatal betamethasone and those exposed to placebo had similar total fat mass (geometric mean ratio 0.98, 95% confidence interval [CI] 0.78 to 1.23), minimal model insulin sensitivity (geometric mean ratio 0.89, 95% CI 0.74 to 1.08), 24-hour ambulatory blood pressure (mean difference systolic 0 mm Hg, 95% CI -2 to 2; diastolic 0 mm Hg, 95% CI -1 to 1), and estimated glomerular filtration rate (mean difference 1.2 mL/min/1.73 m(2), 95% CI -3.2 to 5.6). CONCLUSIONS Exposure to repeat doses of antenatal betamethasone compared with a single course of glucocorticoids does not increase risk factors for cardiometabolic disease at early school age.
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Does magnesium exposure affect neonatal resuscitation?
Drassinower, D, Friedman, AM, Levin, H, Običan, SG, Gyamfi-Bannerman, C
American journal of obstetrics and gynecology. 2015;(3):424.e1-5
Abstract
OBJECTIVE Research on immediate neonatal resuscitation suggests that maternal magnesium exposure may be associated with increased risk of low Apgar scores, hypotonia, and neonatal intensive care unit admission. However, not all studies support these associations. Our objective was to determine whether exposure to magnesium at the time of delivery affects initial neonatal resuscitation. STUDY DESIGN This is a secondary analysis of the Randomized Controlled Trial of Magnesium Sulfate for the Prevention of Cerebral Palsy that evaluated whether the study drug (magnesium or placebo) that was administered at the time of delivery was associated with increased risk for a composite adverse neonatal resuscitation outcome (5-minute Apgar score <7, oxygen administration in the delivery room, intubation, chest compressions, hypotension, and hypotonicity). A subgroup analysis was performed among patients who delivered at ≥30 weeks of gestation. Log-linear regression was used to control for possible confounders. RESULTS Data for 1047 patients were analyzed, of whom 461 neonates (44%) were exposed to magnesium. There was no increased risk for the primary composite outcome associated with magnesium exposure. Individual adverse neonatal outcomes and other secondary short-term neonatal outcomes that were evaluated also did not demonstrate an association with magnesium exposure. CONCLUSION Exposure to magnesium sulfate did not affect neonatal resuscitation or other short-term outcomes. These findings may be useful in planning neonatal care and patient counseling.
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Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial.
Benjamin, DK, Hudak, ML, Duara, S, Randolph, DA, Bidegain, M, Mundakel, GT, Natarajan, G, Burchfield, DJ, White, RD, Shattuck, KE, et al
JAMA. 2014;(17):1742-9
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IMPORTANCE Invasive candidiasis in premature infants causes death and neurodevelopmental impairment. Fluconazole prophylaxis reduces candidiasis, but its effect on mortality and the safety of fluconazole are unknown. OBJECTIVE To evaluate the efficacy and safety of fluconazole in preventing death or invasive candidiasis in extremely low-birth-weight infants. DESIGN, SETTING, AND PATIENTS This study was a randomized, blinded, placebo-controlled trial of fluconazole in premature infants. Infants weighing less than 750 g at birth (N = 361) from 32 neonatal intensive care units (NICUs) in the United States were randomly assigned to receive either fluconazole or placebo twice weekly for 42 days. Surviving infants were evaluated at 18 to 22 months corrected age for neurodevelopmental outcomes. The study was conducted between November 2008 and February 2013. INTERVENTIONS Fluconazole (6 mg/kg of body weight) or placebo. MAIN OUTCOMES AND MEASURES The primary end point was a composite of death or definite or probable invasive candidiasis prior to study day 49 (1 week after completion of study drug). Secondary and safety outcomes included invasive candidiasis, liver function, bacterial infection, length of stay, intracranial hemorrhage, periventricular leukomalacia, chronic lung disease, patent ductus arteriosus requiring surgery, retinopathy of prematurity requiring surgery, necrotizing enterocolitis, spontaneous intestinal perforation, and neurodevelopmental outcomes-defined as a Bayley-III cognition composite score of less than 70, blindness, deafness, or cerebral palsy at 18 to 22 months corrected age. RESULTS Among infants receiving fluconazole, the composite primary end point of death or invasive candidiasis was 16% (95% CI, 11%-22%) vs 21% in the placebo group (95% CI, 15%-28%; odds ratio, 0.73 [95% CI, 0.43-1.23]; P = .24; treatment difference, -5% [95% CI, -13% to 3%]). Invasive candidiasis occurred less frequently in the fluconazole group (3% [95% CI, 1%-6%]) vs the placebo group (9% [95% CI, 5%-14%]; P = .02; treatment difference, -6% [95% CI, -11% to -1%]). The cumulative incidences of other secondary outcomes were not statistically different between groups. Neurodevelopmental impairment did not differ between the groups (fluconazole, 31% [95% CI, 21%-41%] vs placebo, 27% [95% CI, 18%-37%]; P = .60; treatment difference, 4% [95% CI, -10% to 17%]). CONCLUSIONS AND RELEVANCE Among infants with a birth weight of less than 750 g, 42 days of fluconazole prophylaxis compared with placebo did not result in a lower incidence of the composite of death or invasive candidiasis. These findings do not support the universal use of prophylactic fluconazole in extremely low-birth-weight infants. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00734539.