Individualized versus standard diet fortification for growth and development in preterm infants receiving human milk.

BACKGROUND: Human milk as compared to formula reduces morbidity in preterm infants but requires fortification to meet their nutritional needs and to reduce the risk of extrauterine growth failure. Standard fortification methods are not individualized to the infant and assume that breast milk is uniform in nutritional content. Strategies for individualizing fortification are available; however it is not known whether these are safe, or if they improve outcomes in preterm infants. OBJECTIVES: To determine whether individualizing fortification of breast milk feeds in response to infant blood urea nitrogen (adjustable fortification) or to breast milk macronutrient content as measured with a milk analyzer (targeted fortification) reduces mortality and morbidity and promotes growth and development compared to standard, non-individualized fortification for preterm infants receiving human milk at < 37 weeks' gestation or at birth weight < 2500 grams. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 9), in the Cochrane Library; Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), on September 20, 2019. We also searched clinical trials databases and the reference lists of retrieved articles for pertinent randomized controlled trials (RCTs) and quasi-randomized trials. SELECTION CRITERIA: We considered randomized, quasi-randomized, and cluster-randomized controlled trials of preterm infants fed exclusively breast milk that compared a standard non-individualized fortification strategy to individualized fortification using a targeted or adjustable strategy. We considered studies that examined any use of fortification in eligible infants for a minimum duration of two weeks, initiated at any time during enteral feeding, and providing any regimen of human milk feeding. DATA COLLECTION AND ANALYSIS: Data were collected using the standard methods of Cochrane Neonatal. Two review authors evaluated the quality of the studies and extracted data. We reported analyses of continuous data using mean differences (MDs), and dichotomous data using risk ratios (RRs). We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: Data were extracted from seven RCTs, resulting in eight publications (521 total participants were enrolled among these studies), with duration of study interventions ranging from two to seven weeks. As compared to standard non-individualized fortification, individualized (targeted or adjustable) fortification of enteral feeds probably increased weight gain during the intervention (typical mean difference [MD] 1.88 g/kg/d, 95% confidence interval [CI] 1.26 to 2.50; 6 studies, 345 participants), may have increased length gain during the intervention (typical MD 0.43 mm/d, 95% CI 0.32 to 0.53; 5 studies, 242 participants), and may have increased head circumference gain during the intervention (typical MD 0.14 mm/d, 95% CI 0.06 to 0.23; 5 studies, 242 participants). Compared to standard non-individualized fortification, targeted fortification probably increased weight gain during the intervention (typical MD 1.87 g/kg/d, 95% CI 1.15 to 2.58; 4 studies, 269 participants) and may have increased length gain during the intervention (typical MD 0.45 mm/d, 95% CI 0.32 to 0.57; 3 studies, 166 participants). Adjustable fortification probably increased weight gain during the intervention (typical MD 2.86 g/kg/d, 95% CI 1.69 to 4.03; 3 studies, 96 participants), probably increased gain in length during the intervention (typical MD 0.54 mm/d, 95% CI 0.38 to 0.7; 3 studies, 96 participants), and increased gain in head circumference during the intervention (typical MD 0.36 mm/d, 95% CI 0.21 to 0.5; 3 studies, 96 participants). We are uncertain whether there are differences between individualized versus standard fortification strategies in the incidence of in-hospital mortality, bronchopulmonary dysplasia, necrotizing enterocolitis, culture-proven late-onset bacterial sepsis, retinopathy of prematurity, osteopenia, length of hospital stay, or post-hospital discharge growth. No study reported severe neurodevelopmental disability as an outcome. One study that was published after our literature search was completed is awaiting classification. AUTHORS' CONCLUSIONS: We found moderate- to low-certainty evidence suggesting that individualized (either targeted or adjustable) fortification of enteral feeds in very low birth weight infants increases growth velocity of weight, length, and head circumference during the intervention compared with standard non-individualized fortification. Evidence showing important in-hospital and post-discharge clinical outcomes was sparse and of very low certainty, precluding inferences regarding safety or clinical benefits beyond short-term growth.

The serotonin reuptake inhibitor fluoxetine induces human fetal membrane sterile inflammation through p38 MAPK activation.

Serotonin Reuptake Inhibitors (SRIs) are often used as first line therapy for depression and other psychiatric disorders. SRI use during pregnancy is associated with preterm premature rupture of membranes (PPROM) and subsequent preterm birth. The objective of this study was to investigate the mechanism(s) responsible for SRI-associated PPROM. Putative mechanisms underlying PPROM include fetal membrane (FM) inflammation, increased apoptosis, and/or accelerated senescence, the later which may be reversed by statins. Human FM explants from normal term deliveries without labor, infection, or antidepressant use were treated with or without the SRI, fluoxetine (FLX), either alone or in the presence of a p38 MAPK inhibitor or the statins, simvastatin or rosuvastatin. FMs were also collected from women either unexposed or exposed to FLX during pregnancy. FLX significantly increased FM p38 MAPK activity and secretion of inflammatory IL-6. Inhibition of p38 MAPK reduced FM IL-6 secretion in response to FLX. Statins did not reduce the SRI-induced FM IL-6 production. FMs from women exposed to FLX during pregnancy expressed elevated levels of p38 MAPK activity compared to matched unexposed women. FMs exposed to FLX did not exhibit signs of increased apoptosis and/or accelerated senescence. These results indicate that the SRI, FLX, may induce sterile FM inflammation during pregnancy through activation of the p38 MAPK pathway, and in the absence of apoptosis and senescence. These findings may better inform clinicians and patients as they weigh the risks and benefits of SRI antidepressant treatment during pregnancy.

Softer More Frequent Stools in Infants With Difficult Stooling Fed Hydrolyzed Protein Formula With Added Prebiotics: Randomized Controlled Trial.

Objective: To evaluate stool consistency in infants with reported hard or infrequent stools fed hydrolyzed protein formula with added prebiotics designed to promote stool softening. Methods: In this multi-center, double-blind, controlled study, eligible infants (28-300 days of age at enrollment) were randomized to: partially hydrolyzed cow's milk protein formula (PHF, 75% carbohydrate as lactose; 12 mg Mg/100 kcal; n = 49) or routine intact protein cow's milk-based infant formula (Control, 92% carbohydrate as lactose; 8 mg Mg/100 kcal; n = 51) over a 14-day period. Both formulas had a prebiotic blend (polydextrose and galactooligosaccharides, 4 g/L; 1:1 ratio). Parent-reported stool consistency (hard = 1 through watery = 5) and other daily outcomes were collected by diary. Endpoint stool consistency (mean score over last 3 days of study feeding) was the primary outcome. Adverse events were recorded. Results: Baseline stool consistency (Control: 1.4 ± 0.1, PHF: 1.4 ± 0.1) and frequency were similar between groups; the majority had hard (n = 61, 64%) or formed (n = 30, 32%) stools. Stool consistency became softer over Day 1-3 (Control: 2.5 ± 0.1, PHF: 2.6 ± 0.1) and remained similar from Day 4 to 6 through study end (post hoc analysis). For PHF vs Control, endpoint stool consistency was significantly softer (3.4 ± 0.1 vs 3.0 ± 0.1; P = 0.019) and frequency significantly higher (1.5 ± 0.1 vs 1.0 ± 0.1; P = 0.002). Crying, fussing, and appearance of pain during stooling decreased from baseline to study end in both groups. Formula intake, infant fussiness and incidence of adverse events were similar between groups. Conclusion: An infant formula designed to promote stool softening was well-tolerated and associated with softer, more frequent stools in infants with reported hard or infrequent stools.

Factors in Early Feeding Practices That May Influence Growth and the Challenges that Arise in Growth Outcomes Research.

Growth in preterm infants is associated with improved outcomes during both the initial hospitalization and long-term. A single center investigation evaluated preterm infant in-hospital growth trajectory and how it related to early nutritional practices as a way to identify areas for quality improvement. Infants born <34 weeks' gestational age and with discharge at or prior to 40 weeks' gestational age were included and were divided into quartiles based on their change in weight z-score through hospitalization. Early nutritional factors were compared between the lowest and highest growth quartiles. Although the highest growth quartile experienced less days of parenteral nutrition and higher enteral caloric density in the first week, as the data was analyzed, potential statistical pitfalls became apparent. Therefore, the aim of this study was to investigate selection bias and cohort effect related to both the inclusion criteria for this cohort as well as the inherent challenges in comparison of preterm infant growth trajectories by standard fetal growth charts.