The value of a two-armed Bayesian response adaptive randomization trial.

We investigate the value of a two-armed Bayesian response adaptive randomization (RAR) design to investigate early preterm birth rates of high versus low dose of docosahexaenoic acid during pregnancy. Unexpectedly, the COVID-19 pandemic forced recruitment to pause at 1100 participants rather than the planned 1355. The difference in power between number of participants at the pause and planned was 87% and 90% respectively. We decided to stop the study. This paper describes how the RAR was used to execute the study. The value of RAR in two-armed studies is quite high and their use in the future is promising.

DHA Supplementation Attenuates Inflammation-Associated Gene Expression in the Mammary Gland of Lactating Mothers Who Deliver Preterm.

BACKGROUND: In a randomized trial of DHA supplementation to lactating mothers who delivered preterm, there were significant increases in DHA status in the mother and her infant. OBJECTIVES: Our objective here was to characterize the mammary gland transcriptomes from the above study. We hypothesized that proinflammatory gene expression would be attenuated in the increased DHA group compared with the standard DHA group. METHODS: In the original trial, mothers delivering at <29 wk gestation at the University of Cincinnati Medical Center and intending to express their milk were randomly assigned to supplementation with 200 mg/d DHA (standard group: STD) or 1000 mg/d DHA (experimental group: EXP) within 7 d of delivery. Here, we conducted RNA-seq transcriptome analysis of n = 5 EXP and n = 4 STD extracellular mammary mRNA samples extracted from the fat layer of milk samples obtained 4 wk postenrollment. Transcripts were assessed for differential expression (false discovery rate adjusted P value <0.05) and clustering between EXP compared with STD groups. Ontological analysis of all differentially expressed genes (DEGs) was performed with Toppcluster. RESULTS: There were 409 DEGs. We observed 5 main groups of biological processes that were upregulated, including those associated with improved immune regulation and management of oxidative stress; and 3 main groups of biological processes that were downregulated, including 1 associated with immune dysregulation. For example, we observed upregulation of inflammation-inhibiting genes including NFKB inhibitor alpha (NFKBIA; fold-change (FC), adjusted P value: FC = 1.70, P = 0.007) and interleukin-18 binding protein (IL18BP: FC = 2.2, adjusted P = 0.02); and downregulation of proinflammatory genes including interleukin 7 receptor (IL7R: FC = -1.9, adjusted P = 0.02) and interleukin 1 receptor like 1 (IL1RL1: FC = -13.0, adjusted P = 0.02). CONCLUSIONS: Increased DHA supplementation during lactation can modulate the expression of inflammation-related genes within the mammary gland. This might translate to milk composition with a more optimal inflammasome profile. Future research with a larger clinical trial and greater interrogation of clinical outcomes is warranted.

A Randomized Trial of Maternal Docosahexaenoic Acid Supplementation to Reduce Inflammation in Extremely Preterm Infants.

Maternal supplementation with 1000 mg/day docosahexaenoic acid (DHA) provides third trimester DHA accretion levels in breast milk for the preterm infant. We hypothesized that DHA supplementation to mothers providing breastmilk for extremely preterm infants would result in decreased inflammatory markers, in the infant. Mother/infant dyads (n = 27) were enrolled at birth and mothers were assigned to receive 200 or 1000 mg/day of DHA. Milk and plasma samples were analyzed for fatty acids and inflammatory markers. Decreases in inflammation were observed in both maternal and infant plasma and correlated with red blood cell (RBC) DHA levels. The fact that maternal DHA supplementation decreases infant markers of inflammation implies that DHA, delivered through breastmilk, has the potential to decrease inflammation in the infant.

Assessment of DHA on reducing early preterm birth: the ADORE randomized controlled trial protocol.

BACKGROUND: Preterm birth contributes to 0.5 million deliveries in the United States (one of eight pregnancies) and poses a huge burden on public health with costs in the billions. Of particular concern is that the rate of earliest preterm birth (<34 weeks) (ePTB), which has decreased little since 1990 and has the greatest impact on the overall infant mortality, resulting in the greatest cost to society. Docosahexaenoic acid (DHA) supplementation provides a potential high yield, low risk strategy to reduce early preterm delivery in the US by up to 75%. We propose a Phase III Clinical Trial (randomized to low or high dose DHA, double-blinded) to examine the efficacy and safety of high dose DHA supplementation to reduce ePTB. We also plan for a secondary pregnancy efficacy analysis to determine if there is a subset of pregnancies most likely to benefit from DHA supplementation. METHODS: Between 900 and 1200 pregnant women who are ≥ 18 years old and between 12 and 20 weeks gestation will be recruited from three trial experienced academic medical institutions. Participants will be randomly assigned to two daily capsules of algal oil (totaling 800 mg DHA) or soybean and corn oil (0 mg DHA). Both groups will receive a commercially available prenatal supplement containing 200 mg DHA. Therefore, the experimental group will receive 1000 mg DHA/d and the control group 200 mg DHA/d. We will then employ a novel Bayesian response adaptive randomization design that assigns more subjects to the "winning" group and potentially allows for substantially smaller sample size while providing a stronger conclusion regarding the most effective group. The study has an overall Type I error rate of 5% and a power of 90%. Participants are followed throughout pregnancy and delivery for safety and delivery outcomes. DISCUSSION: We hypothesize that DHA will decrease the frequency of ePTB <34 weeks. Reducing ePTB is clinically important as these earliest preterm deliveries carry the highest risk of neonatal morbidity, as well as contribute significant stress for families and post a large societal burden. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov (identifier: NCT02626299 ) on December 8, 2015. Additional summary details may be found in Table 1.

Enteral zinc supplementation and growth in extremely-low-birth-weight infants with chronic lung disease.

OBJECTIVE: Zinc deficiency causes growth deficits. Extremely-low-birth-weight (ELBW) infants with chronic lung disease (CLD), also known as bronchopulmonary dysplasia, experience growth failure and are at risk for zinc deficiency. We hypothesized that enteral zinc supplementation would increase weight gain and linear growth. METHODS: A cohort of infants was examined retrospectively at a single center between January 2008 and December 2011. CLD was defined as the need for oxygen at 36 weeks postmenstrual age. Zinc supplementation was started in infants who had poor weight gain. Infants' weight gain and linear growth were compared before and after zinc supplementation using the paired t test. RESULTS: A total of 52 ELBW infants with CLD met entry criteria. Mean birth weight was 682 ± 183 g, and gestational age was 25.3 ± 2 weeks. Zinc supplementation started at postmenstrual age 33 ± 2 weeks. Most infants received fortified human milk. Weight gain increased from 10.9 before supplementation to 19.9 g · kg(-1) · day(-1) after supplementation (P < 0.0001). Linear growth increased from 0.7 to 1.1 cm/week (P = 0.001). CONCLUSIONS: Zinc supplementation improved growth in ELBW infants with CLD receiving human milk. Further investigation is warranted to reevaluate zinc requirements, markers, and balance.

[Comparison of feeding pattern of preterm infants between two hospitals in China and the United States].

OBJECTIVE: To compare the feeding pattern of preterm infants between two hospitals in China and the United States. METHODS: A retrospective cohort study was conducted. Infants <32 weeks were enrolled from Cincinnati Children's Hospital Center Cincinnati University Hospital (CCHMC group) between January 2011 and January 2012 and Peking Union Medical College Hospital (PUMCH group) between January 2011 and May 2012. Enteral and parenteral feeding data of the two groups was compared. RESULTS: Eighty-two infants in the CCHMC group and 74 infants in the PUMCH group were enrolled. The gestational age and birth weight of infants in the CCHMC group were smaller than the PUMCH group (P<0.01). The total dosage of amino acid (58±30 g/kg vs 24.0(19.6, 32.8) g/kg; P<0.01) and fat [35±16 g/kg vs 14.0(11.0, 22.5) g/kg; P<0.01], in the PUMCH group were higher than the CCHMC group. The duration of parenteral nutrition in the PUMCH group was longer than the CCHMC group[(24±10 d vs 8.0(6.0, 11.0) d; P<0.01]. The breast feeding rate in the CCHMC group was higher (94% vs 10%; P<0.01) than in the PUMCH group. The time for achieving full enteral feeding in the CCHMC group was shorter [12.0(10.0, 14.0) d vs 22.4±9.3 d, P<0.01] than in the PUMCH group. The incidences of necrotizing enterocolitis (13% vs 3%; P<0.05) and sepsis (32% vs 12%; P<0.01) in the CCHMC group were higher than in the PUMCH group. CONCLUSIONS: Preterm infants in the PUMCH group have a prolonged duration of parenteral nutrition and an increased incidence of sepsis compared to the CCHMC group. Fortified human milk feeding and more aggressive enteral feeding proposal in PUMCH is recommended.

DHA supplementation: current implications in pregnancy and childhood.

Dietary supplementation with ω-3 long chain fatty acids including docosahexaenoic acid (DHA) has increased in popularity in recent years and adequate DHA supplementation during pregnancy and early childhood is of clinical importance. Some evidence has been built for the neuro-cognitive benefits of supplementation with long chain polyunsaturated fatty acids (LCPUFA) such as DHA during pregnancy; however, recent data indicate that the anti-inflammatory properties may be of at least equal significance. Adequate DHA availability in the fetus/infant optimizes brain and retinal maturation in part by influencing neurotransmitter pathways. The anti-inflammatory properties of LCPUFA are largely mediated through modulation of signaling either directly through binding to receptors or through changes in lipid raft formation and receptor presentation. Our goal is to review the current findings on DHA supplementation, specifically in pregnancy and infant neurodevelopment, as a pharmacologic agent with both preventative and therapeutic value. Given the overall benefits of DHA, maternal and infant supplementation may improve neurological outcomes especially in vulernable populations. However, optimal composition of the supplement and dosing and treatment strategies still need to be determined to lend support for routine supplementation.

DHA, nutrient intake, and maternal characteristics as predictors of pregnancy outcomes in a randomised clinical trial of DHA supplementation.

PURPOSE: To investigate the relationships among docosahexaenoic acid (DHA) intake, nutrient intake, and maternal characteristics on pregnancy outcomes in a phase III randomised clinical trial designed to determine the effect of a DHA dose of 1000 mg/day compared to 200 mg/day on early preterm birth (<34 weeks gestation). METHODS: A secondary aim of the phase III randomised trial was to explore the relationships among pregnancy outcomes (maternal red blood cell phospholipid (RBC-PL) DHA at delivery, preterm birth, gestational age at delivery, labor type, birth anthropometric measures, low birth weight, gestational diabetes, pre-eclampsia, and admission to a neonatal intensive care unit) in participants (n = 1100). We used Bayesian multiple imputation and linear and logistic regression models to conduct an analysis of five general classes of predictor variables collected during the trial: a) DHA intake, b) nutrient intake from food and supplements, c) environmental exposure to tobacco and alcohol, d) maternal demographics, and e) maternal medical history. RESULTS: DHA supplementation lowered the risk of preterm birth and NICU admission, and increased gestation and birth weight as observed in the primary analysis. Higher maternal RBC-PL-DHA at delivery was associated with DHA supplementation and formal education of a bachelor's degree or higher. DHA supplementation and maternal age were associated with a higher risk of gestational diabetes. Total vitamin A intake was associated with longer gestation, while fructose and intake of the long chain omega-6 fatty acid, arachidonic acid, were associated with shorter gestation. Risk of preterm birth was associated with a history of low birth weight, preterm birth, pre-eclampsia, and NICU admission. CONCLUSION: Bayesian models provide a comprehensive approach to relationships among DHA intake, nutrient intake, maternal characteristics, and pregnancy outcomes. We observed previously unreported relationships between gestation duration and fructose, vitamin A, and arachidonic acid that could be the basis for future research. TRIAL REGISTRATION NUMBER AND DATE: ClinicalTrials.gov (NCT02626299); December 10, 2015.

Micronutrient Gaps and Supplement Use in a Diverse Cohort of Pregnant Women.

BACKGROUND: Micronutrition in pregnancy is critical to impact not only fetal growth and development but also long-term physical and psychiatric health outcomes. OBJECTIVE: Estimate micronutrient intake from food and dietary supplements in a diverse cohort of pregnant women and compare intake to the Dietary Reference Intakes (DRIs). DESIGN: Secondary analysis of women enrolled in a multi-site clinical trial of docosahexaenoic acid (DHA) supplementation who provided their dietary intake using the diet history questionnaire-II (n = 843) or multiple 24 h recalls (n = 178) at baseline and their intake of nutritional supplements at baseline through 30 days postpartum. PARTICIPANTS/SETTING: 1021 participants from the parent trial who had reliable data for dietary intake, supplement intake, or both. MAIN OUTCOME MEASURES: Micronutrient intake from dietary and supplement sources and percentage of intakes meeting the DRIs for pregnancy. STATISTICAL ANALYSES PERFORMED: Percent of participants whose intake was below the estimated average requirement (EAR) or adequate intake (AI) and above the tolerable upper limit (UL). RESULTS: Dietary intakes of choline, folate, iron, vitamin D, zinc, vitamin E, magnesium, and potassium, were below the AI or EAR for 30-91% of the participants; thiamin and vitamin B6 were also below the AI or EAR for non-Hispanic/Latina women. Supplement intake improved the intake for most; however, 80% of the group remained below the AI for choline and 52.5% for potassium while 30% remained below the EAR for magnesium. Folate and iron intakes were above the UL for 80% and 19%, respectively. CONCLUSIONS: Dietary supplements, despite their variability, allowed the majority of this cohort of pregnant women to achieve adequate intakes for most micronutrients. Choline, magnesium, and potassium were exceptions. Of interest, folate intake was above the tolerable UL for the majority and iron for 16.8% of the participants. Clinicians have the opportunity to address the most common nutrient deficits and limits with advice on food sources that provide choline, magnesium, and potassium and to ensure folate is not overabundant. More research is needed to determine if these findings are similar in a cross-sectional population.

Maternal docosahexaenoic acid supplementation decreases lung inflammation in hyperoxia-exposed newborn mice.

DHA is a long-chain fatty acid that has potent antiinflammatory properties. Whereas maternal DHA dietary supplementation has been shown to improve cognitive development in infants fed DHA-supplemented milk, the antiinflammatory effects of maternal DHA supplementation on the developing fetus and neonate have not been extensively explored. Pregnant C3H/HeN dams were fed purified control or DHA-supplemented diets (~0.25% of total fat) at embryonic d 16 and consumed these diets throughout the study. At birth, the nursing mouse pups were placed in room air (RA; 21% O(2)) or >95% O(2) (hyperoxia) for up to 7 d. These studies tested the hypothesis that maternal DHA supplementation would decrease inflammation and improve alveolarization in the lungs of newborn mouse pups exposed to hyperoxia. Survival, inflammatory responses, and lung growth were compared among control diet/RA, DHA/RA, control/O(2), and DHA/O(2) pups. There were fewer neutrophils and macrophages in lung tissues from pups nursed by DHA-supplemented dams than in those nursed by dams fed the control diet at 7 d of hyperoxia exposure (P < 0.015). Although differences due to hyperoxia exposure were observed, maternal diet did not affect keratinocyte-derived chemokine, macrophage inflammatory protein-2, IL-1ß, or TNFα mRNA levels in pup tissues. Hyperoxia also induced NF-κB activity, but maternal diet did not affect NF-κB or PPARγ activities. In mice, DHA supplementation decreases leukocyte infiltration in the offspring exposed to hyperoxia, suggesting a potential role for DHA supplementation as a therapy to reduce inflammation in preterm infants.

The Successful Synchronized Orchestration of an Investigator-Initiated Multicenter Trial Using a Clinical Trial Management System and Team Approach: Design and Utility Study.

BACKGROUND: As the cost of clinical trials continues to rise, novel approaches are required to ensure ethical allocation of resources. Multisite trials have been increasingly utilized in phase 1 trials for rare diseases and in phase 2 and 3 trials to meet accrual needs. The benefits of multisite trials include easier patient recruitment, expanded generalizability, and more robust statistical analyses. However, there are several problems more likely to arise in multisite trials, including accrual inequality, protocol nonadherence, data entry mistakes, and data integration difficulties. OBJECTIVE: The Biostatistics & Data Science department at the University of Kansas Medical Center developed a clinical trial management system (comprehensive research information system [CRIS]) specifically designed to streamline multisite clinical trial management. METHODS: A National Institute of Child Health and Human Development-funded phase 3 trial, the ADORE (assessment of docosahexaenoic acid [DHA] on reducing early preterm birth) trial fully utilized CRIS to provide automated accrual reports, centralize data capture, automate trial completion reports, and streamline data harmonization. RESULTS: Using the ADORE trial as an example, we describe the utility of CRIS in database design, regulatory compliance, training standardization, study management, and automated reporting. Our goal is to continue to build a CRIS through use in subsequent multisite trials. Reports generated to suit the needs of future studies will be available as templates. CONCLUSIONS: The implementation of similar tools and systems could provide significant cost-saving and operational benefit to multisite trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT02626299; https://tinyurl.com/j6erphcj.

Higher-Dose DHA Supplementation Modulates Immune Responses in Pregnancy and Is Associated with Decreased Preterm Birth.

Pregnancy and parturition involve extensive changes in the maternal immune system. In our randomized, multi-site, double-blind superiority trial using a Bayesian adaptive design, we demonstrated that 1000 mg/day of docosahexaenoic acid (DHA) was superior to 200 mg/day in preventing both early preterm birth (less than 34 weeks' gestation) and preterm birth (less than 37 weeks' gestation). The goal of this secondary study is to compare the effects of 1000 mg/day versus 200 mg/day on maternal inflammation, a possible mechanism by which DHA may prevent preterm birth. Maternal blood samples were collected at enrollment (12-20 weeks' gestation) and at delivery. Red blood cell DHA levels were measured by gas chromatography, and plasma concentrations of sRAGE, IL-6, IL-1ß, TNFα, and INFγ were measured by ELISA. Data were analyzed for associations with the DHA dose, gestational age at birth, and preterm birth (<37 weeks). Higher baseline and lower delivery levels of maternal sRAGE were associated with a greater probability of longer gestation and delivery at term gestation. Higher-dose DHA supplementation increased the probability of a smaller decrease in delivery sRAGE levels. Higher IL-6 concentrations at delivery were associated with the probability of delivering after 37 weeks, and higher-dose DHA supplementation increased the probability of greater increases in IL-6 concentrations between enrollment and delivery. These data provide a proposed mechanistic explanation of how a higher dose of DHA during pregnancy provides immunomodulatory regulation in the initiation of parturition by influencing sRAGE and IL-6 levels, which may explain its ability to reduce the risk of preterm birth.

Higher dose docosahexaenoic acid supplementation during pregnancy and early preterm birth: A randomised, double-blind, adaptive-design superiority trial.

BACKGROUND: Several meta analyses have concluded n-3 fatty acids, including docosahexaenoic acid (DHA), reduce early preterm birth (EPB, < 34 weeks), however, the amount of DHA required is unclear. We hypothesized that 1000 mg DHA per day would be superior to 200 mg, the amount in most prenatal supplements. METHODS: This randomised, multicentre, double-blind, adaptive-design, superiority trial was conducted in three USA medical centres. Women with singleton pregnancies and 12 to 20 weeks gestation were eligible. randomization was generated in SAS® by site in blocks of 4. The planned adaptive design periodically generated allocation ratios favoring the better performing dose. Managing study personnel were blind to treatment until 30 days after the last birth. The primary outcome was EPB by dose and by enrolment DHA status (low/high). Bayesian posterior probabilities (pp) were determined for planned efficacy and safety outcomes using intention-to-treat. The study is registered with ClinicalTrials.gov (NCT02626299) and closed to enrolment. FINDINGS: Eleven hundred participants (1000 mg, n = 576; 200 mg, n = 524) were enrolled between June 8, 2016 and March 13, 2020 with the last birth September 5, 2020. 1032 (n = 540 and n = 492) were included in the primary analyses. The higher dose had a lower EPB rate [1.7% (9/540) vs 2.4% (12/492), pp=0.81] especially if participants had low DHA status at enrolment [2.0% (5/249) vs 4.1%, (9/219), pp=0.93]. Participants with high enrolment DHA status did not realize a dose effect [1000 mg: 1.4% (4/289); 200 mg: 1.1% (3/271), pp = 0.57]. The higher dose was associated with fewer serious adverse events (maternal: chorioamnionitis, premature rupture of membranes and pyelonephritis; neonatal: feeding, genitourinary and neurologic problems, all pp>0.90). INTERPRETATION: Clinicians could consider prescribing 1000 mg DHA daily during pregnancy to reduce EPB in women with low DHA status if they are able to screen for DHA. FUNDING: The National Institutes of Health Child Health and Human Development (NICHD) funded the study. Life's DHA™-S oil, DSM Nutritional Products LLC, Switzerland provided all capsules.

Docosahexaenoic Acid and Amino Acid Contents in Pasteurized Donor Milk are Low for Preterm Infants.

OBJECTIVE: To evaluate whether pasteurized donor human milk meets the nutritional needs of preterm infants in terms of free fatty acid and amino acid contents. STUDY DESIGN: Milk samples were prospectively collected from 39 donors to the Mothers' Milk Bank of Ohio. The fatty acid and amino acid compositions in donor milk samples were measured before and after pasteurization, and values were compared with previously published findings and preterm infant nutrition guidelines. The nutritional adequacy of donor milk for preterm infants was based on estimated daily intake of 150 mL/kg. Statistical significance was adjusted to account for multiple comparisons. RESULTS: Pasteurization did not appreciably affect donor milk composition. Docosahexaenoic acid level (0.1 mol wt %), and concentrations of glycine, aspartate, valine, phenylalanine, proline, lysine, arginine, serine, and histidine in donor milk were all significantly lower than previously reported concentrations in milk. CONCLUSIONS: Donor milk is not substantially affected by pasteurization, but has low concentrations of docosahexaenoic acid and amino acids. Targeted nutritional supplementation of human donor milk for feeding preterm infants might be warranted.

Nutrition Support Team Guide to Maternal Diet for the Human-Milk-Fed Infant.

BACKGROUND: Human milk feeding is encouraged for all infants; however, the mammary gland depends on maternal dietary intake of vitamins A, B1, B2, B6, B12, D, docosahexaenoic acid (DHA), choline, and iodine. Nutrition support team knowledge of maternal feeding guidelines for these nutrient sources can therefore impact infant intake. We hypothesized that these key nutrients for lactation in the mother's diet would be less than the dietary guidelines in the United States. METHODS: This was a secondary analysis of nutrition data collected during a randomized, controlled trial. Dietary records were analyzed from 16 mothers (13 with singleton and 3 with multiple births) completing the study. Mean dietary intakes of selected nutrients were calculated and compared with the current dietary reference intakes. RESULTS: Mean maternal dietary intake for singletons was significantly (P < .05) lower than the dietary reference intakes for (vitamin A (58%), vitamin D (44%), and choline (58%);) DHA comprised only 5% of the current expert recommendation. Based on singleton recommendations, mothers to twins consumed an adequate intake except for DHA. CONCLUSIONS: Women providing breast milk for singleton preterm infants did not consume dietary reference intakes for key nutrients. Twin mothers' diets were adequate except for DHA, but these guidelines are based on singleton pregnancies and remain poorly understood for twin needs. The nutrition support team can have a unique role in maternal dietary education to impact human milk nutrient delivery to the infant.

Enhancing parenteral nutrition therapy for the neonate.

The neonate receiving parenteral nutrition (PN) therapy requires a physiologically appropriate solution in quantity and quality given according to a timely, cost-effective strategy. Maintaining tissue integrity, metabolism, and growth in a neonate is challenging. To support infant growth and influence subsequent development requires critical timing for nutrition assessment and intervention. Providing amino acids to neonates has been shown to improve nitrogen balance, glucose metabolism, and amino acid profiles. In contrast, supplying the lipid emulsions (currently available in the United States) to provide essential fatty acids is not the optimal composition to help attenuate inflammation. Recent investigations with an omega-3 fish oil IV emulsion are promising, but there is need for further research and development. Complications from PN, however, remain problematic and include infection, hepatic dysfunction, and cholestasis. These complications in the neonate can affect morbidity and mortality, thus emphasizing the preference to provide early enteral feedings, as well as medication therapy to improve liver health and outcome. Potential strategies aimed at enhancing PN therapy in the neonate are highlighted in this review, and a summary of guidelines for practical management is included.

Comparison of enteral feeding of preterm infants between two hospitals in China and United States.

AIM: To compare the details of preterm infants enteral feeding between the two hospitals in China and in the United States, and to analyze the reason of the differences. METHODS: A retrospective cohort study was conducted. Infants < 32 weeks were enrolled from Cincinnati University Hospital (CUH) during January 2011 to January 2012 and Peking Union Medical College Hospital (PUMCH) during January 2011 to May 2012. Basic data and enteral feeding data of the two groups were compared. RESULTS: Eighty-two infants in CUH group and 74 infants in PUMCH group were enrolled, infants in CUH group were much smaller than PUMCH group (gestational age (29.1 ± 2.0) versus (30.6 ± 1.3) weeks, p = 0.000, birth weight (1204 ± 328) versus (1406 ± 320) g, p = 0.000). Significantly more infants in CUH group received human milk as the first enteral feeding (78/82 versus 7/74, p = 0.000). Human milk feeding rate in first 28 days in CUH group was much higher (77/82 versus 7/74, p = 0.000). The initial milk volume, and the milk volume on the 7th, 14th, 21st and 27th day of CUH group were significant larger [(15.9 versus 9.3 ml/kg·d, p = 0.000), (79.8 versus 35.2 ml/kg·d, p = 0.000), (133.2 versus 76.4 ml/kg·d, p = 0.000), (140.6 versus 108.6 ml/kg·d, p = 0.000), (142.2 versus 121.5 ml/kg·d, p = 0.002)]. CUH group achieved full enteral feeding sooner (12.0 versus 22.4 d, p = 0.000). CONCLUSION: Preterm infants achieved full enteral feeding sooner at CUH compared to PUMCH. Human milk feeding may improve enteral feeding tolerance. We need more aggressive enteral feeding proposal in PUMCH.