Human Milk Fortifier Research Articles

Barcode scanning of human milk and enteral formulas improves efficiency and patient safety: A 7-year review.

Safe handling of human milk (HM) and enteral formulas for patients of all ages is critical in healthcare. Barcode scanning is commonly used to reduce errors. The purpose of this study was to evaluate the impact of barcode scanning for HM and formulas on patient safety. Scanning is used at the time of feeding preparation for HM, facility-prepared formulas, and ready-to-feed enteral formulas for patients of all ages to confirm the feeding matches the provider order, record lot numbers, and ensure expired items are not used. HM feedings are scanned at the time of administration and discharge to ensure the correct milk is being provided to the correct patient. All formulas dispensed as samples to hospital inpatients and outpatients are scanned to record patient and product information in the event of a recall. Seven-year data showed that scanning has prevented HM misadministration 1226 times. Data for 2 and a half years of fortifier and formula scanning show 480 errors have been prevented. The results show benefits for both patient safety and staff efficiency. The benefits of barcode scanning systems in healthcare are well documented. Beyond the scanning of HM, scanning of fortifiers and formulas can improve patient safety by preventing misadministration for patients of all ages. Systems that offer features such as calculating fortified HM and formula recipes, tracking product lot numbers, and verifying correct products to the provider order can further improve safety as well as efficiency.

Effect of Holder pasteurization on macronutrients and energy content of pooled donor human milk

Background: Donor human milk (DHM) is the best option for preterm nutrition when mother’s milk is unavailable. For its proven benefits on the life and health of premature babies, DHM should be part of the essential newborn care. The fortification of human milk is necessary to ensure adequate growth and consequent good neurodevelopment. Holder pasteurization is routinely practiced in human milk banks (HMBs) to ensure safety of DHM but can impact the macronutrient content. The aim of this study was to explore the effect of Holder pasteurization on fat, protein, lactose and energy content of DHM and compare our data with the literature. Methods: Protein, lactose, fats and energy of 100 DHM pools from 87 women were analyzed before and after Holder pasteurization using Miris HMA™ (Human Milk Analyzer, Miris AB, Uppsala, Sweden), with the infrared spectroscopic method. The mean macronutrient contents before and after Holder pasteurization were compared using paired t-tests, and the variations in the concentration of the components were calculated as Delta%. The data obtained were compared to other studies with the same purpose. Results: We observed a reduction in fat (3.12 ± 1.64 vs 2.55 ± 0.85, with Delta% -14.9 ± 13.0 and p-value < 0.0001), T protein (1.05 ± 0.26 vs 0.89 ± 0.20, with Delta% -8.9 ± 63.0 and p-value < 0.0001), energy content (61.38 ± 18.66 vs 55.00 ± 8.27, with Delta% -8.1 ± 9.4 and p-value 0.0001), while no significant changes were observed for lactose content (6.35 ± 0.80 vs 6.43 ± 0.58, with Delta% 6.5 ± 56.7 and p-value 0.3735). Data in the literature on the effect of Holder pasteurization on DHM macronutrients are variable, and the only constant element is the non-variation of the carbohydrate content. Conclusion: Holder pasteurization decreased protein, fat and energy content of DHM. The lactose content has not been affected after the Holder pasteurization. After having assessed a remarkable variation in the macronutrient content in comparison with other studies, the adjustable fortification, especially if based on the composition data, might be more accurate. In addition, despite the fact that Holder pasteurization is actually the method recommended by the international HMB guidelines, as it provides a compromise between microbiological safety and nutritional/biological quality of DHM, studies on alternative methods capable of treating DHM preserving the milk’s components are desirable.

Very preterm infants admitted to a tertiary neonatal unit in central Vietnam showed poor postnatal growth.

We aimed to evaluate the postnatal growth of very preterm infants. This was a cross-sectional observational study of neonates born before 32weeks of gestation and admitted to the neonatal unit at Da Nang Hospital for Women and Children, Vietnam, between 1 February 2020 and 30 September 2020.Morbidities, therapies, nutrition modalities and growth status were recorded from admission to discharge. The 78 infants (51% female) were born at a median of 29weeks and mean birth weight of 1247grams. The mean weight gain velocity from regaining their birth weight until discharge was 12.7±4.9g/kg/d. At discharge, the Z-scores for weight, length, both weight and length and weight for length were lower than at birth in 94%, 67%, 64% and 95% of infants and the Delta Z-scores were less than -1 in 73%, 44%, 39% and 82%. Late-onset sepsis (LOS) and bronchopulmonary dysplasia (BPD) were significantly associated with growth failure, with adjusted odds ratios of 3.6 and 20.1, respectively. The high rate of poor growth among the very preterm infants in our study indicates the need to reduce LOS and BPD and ensure the availability of human milk fortifier, vitamin and mineral supplements.

Exploring Innovations in Human Milk Analysis in the Neonatal Intensive Care Unit: A Survey of the United States.

Introduction: Human milk (HM) is the ideal enteral feeding for nearly all infants and offers unique benefits to the very low birthweight (VLBW) infant population. It is a challenge to meet the high nutrient requirements of VLBW infants due to the known variability of HM composition. Human milk analysis (HMA) assesses the composition of HM and allows for individualized fortification. Due to recent U.S. Food and Drug Administration (FDA) approval, it has relatively recent availability for clinical use in the US.Aim: To identify current practices of HMA and individualized fortification in neonatal intensive care units (NICUs) across the United States (US) and to inform future translational research efforts implementing this nutrition management method.Methods: An institutional review board (IRB) approved survey was created and collected data on the following subjects such as NICU demographics, feeding practices, HM usage, HM fortification practices, and HMA practices. It was distributed from 10/30–12/21/2020 via online pediatric nutrition groups and listservs selected to reach the intended audience of NICU dietitians and other clinical staff. Each response was assessed prior to inclusion, and descriptive analysis was performed.Results: About 225 survey responses were recorded during the survey period with 119 entries included in the analysis. This represented 36 states and Washington D.C., primarily from level III and IV NICUs. HMA was reported in 11.8% of responding NICUs. The most commonly owned technology for HMA is the Creamatocrit Plus TM (EKF Diagnostics), followed by the HM Analyzer by Miris (Uppsala, Sweden). In NICUs practicing HMA, 84.6% are doing so clinically.Discussion: Feeding guidelines and fortification of HM remain standard of care, and interest in HMA was common in this survey. Despite the interest, very few NICUs are performing HMA and individualized fortification. Barriers identified include determining who should receive individualized fortification and how often, collecting a representative sample, and the cost and personnel required.Conclusions: Human milk analysis and individualized fortification are emerging practices within NICUs in the US. Few are using it in the clinical setting with large variation in execution among respondents and many logistical concerns regarding implementation. Future research may be beneficial to evaluate how practices change as HMA and individualized fortification gain popularity and become more commonly used in the clinical setting.

Novel multinutrient human milk-based human milk fortifier promotes growth and tolerance in premature infants.

The objective of this study was to determine whether human milk supplemented with a novel human milk-based human milk fortifier (Novel HMF), compared with a bovine milk-based HMF (Bovine HMF), supports preterm infant growth through 36 weeks' postmenstrual age (PMA). This single-center, prospective trial compared growth and nutrition outcomes of preterm infants provided a human milk-based diet (mother's own milk or donor milk) supplemented with a Novel HMF with historic controls provided Bovine HMF. Preterm infants with an estimated gestational age (EGA) between 23 and 33 weeks' PMA and birth weight between 750 and 1800 g were eligible for study inclusion. Weight, length, and head circumference (HC) were monitored weekly. The occurrence of late-onset sepsis, nil per os (NPO) days, necrotizing enterocolitis, metabolic acidosis, and serious adverse events were monitored. Birth weight, length, HC, and EGA were similar between the Novel HMF (n = 37) and Bovine HMF (n = 49) groups. The days to regain birth weight was shorter in the Novel HMF group (9.4 ± 4.0 vs 11.4 ± 4.8, P = .0343), with similar weight gain (g/day) from birth to 36 weeks' PMA. Adjusted weight growth velocity (g/kg/day) was significantly higher in the Novel HMF group at 14 and 21 days but similar at 36 weeks' PMA. The Novel HMF group experienced fewer NPO days with a similar total number of feeding days. A novel, multinutrient, human milk-based HMF is well tolerated and meets the nutrition needs of preterm infants.

Effects of Total Enteral Nutrition on Early Growth, Immunity, and Neuronal Development of Preterm Infants.

The feeding of colostrum and mother’s transitional milk improves immune protection and neurodevelopmental outcomes. It also helps with gut maturation and decreases the risks of infection. The supply of nutrients from human milk (HM) is not adequate for preterm infants, even though preterm mother’s milk contains higher concentrations of protein, sodium, zinc, and calcium than mature HM. The human milk fortifiers, particularly those with protein, calcium, and phosphate, should be used to supplement HM to meet the necessities of preterm infants. The management of fluid and electrolytes is a challenging aspect of neonatal care of preterm infants. Trace minerals such as iron, zinc, copper, iodine, manganese, molybdenum, selenium, chromium, and fluoride are considered essential for preterm infants. Vitamins such as A, D, E, and K play an important role in the prevention of morbidities, such as bronchopulmonary dysplasia, retinopathy of prematurity, and intraventricular hemorrhage. Therefore, supplementation of HM with required nutrients is recommended for all preterm infants.

Recommendations to promote breast milk feeding and enhance nutritional care for preterm infants in the Asia-Pacific region: highlights from a roundtable discussion of key opinion leaders

Introduction: Preterm infants are vulnerable to nutritional deficiencies, thus optimal nutrition is crucial in promoting growth among these infants. However, socio-cultural complexities and limited resources in the Asia-Pacific demands a judicious approach in implementing nutritional care that is pragmatic to align with current evidence-based recommendations. Methods: A roundtable meeting was held in Jakarta in 2017 for key opinion leaders in neonatology from the AsiaPacific to discuss issues when delivering nutritional care in this region and the unique circumstances encountered. Results: Priority areas discussed include: (i) breast milk feeding, (ii) donor milk bank/sharing, (iii) human milk fortification, and (iv) nutrient-enriched breast milk substitutes. Socio-cultural practices impeding breastfeeding, insufficient maternity leave, the religious issue of milk kinship, and limited availability of specialty nutritional care products were among the most challenging factors. Conclusion: The group proposed recommendations to enhance breastfeeding uptake, accessibility to a complete portfolio of specialty nutritional care products, and encouraging more active collaborations to engage policy makers in addressing these contemporary issues.

A Systematic Review and Meta-Analysis of Human Milk Feeding and Short-Term Growth in Preterm and Very Low Birth Weight Infants.

Human milk (HM) is the gold standard for feeding infants but has been associated with slower growth in preterm infants compared with preterm formula. This systematic review and meta-analysis summarises the post-1990 literature to examine the effect of HM feeding on growth during the neonatal admission of preterm infants with birth weight ≤1500 g and/or born ≤28 weeks’ gestation. Medline, PubMed, CINAHL, and Scopus were searched, and comparisons were grouped as exclusive human milk (EHM) vs. exclusive preterm formula (EPTF), any HM vs. EPTF, and higher vs. lower doses of HM. We selected studies that used fortified HM and compared that with a PTF; studies comparing unfortified HM and term formula were excluded. Experimental and observational studies were pooled separately. The GRADE system was used to evaluate risk of bias and certainty of evidence. Forty-four studies were included with 37 (n = 9963 infants) included in the meta-analyses. In general, due to poor quality studies, evidence of the effect of any HM feeds or higher versus lower doses of HM was inconclusive. There was a possible effect that lower doses of HM compared with higher doses of HM improved weight gain during the hospital admission, and separately, a possible effect of increased head circumference growth in infants fed EPTF vs. any HM. The clinical significance of this is unclear. There was insufficient evidence to determine the effects of an exclusive HM diet on any outcomes.

Comparative effectiveness of liquid human milk fortifiers: A systematic review and meta-analysis.

To determine the effectiveness of liquid human milk fortifiers (HMFs) derived from exclusive HM or hydrolyzed protein on growth, necrotizing enterocolitis (NEC), or late-onset sepsis in North American very low-birth-weight (VLBW) infants compared with powder HMFs (control). Prospective trials published between 2009 and 2020 were systematically reviewed, and meta-analysis was conducted by using a random-effects model. Five studies were identified for up to 591 participants across 39 centers. Study treatments included whey or casein hydrolysate HMF and exclusive HM HMF. Infants fed whey or casein hydrolysate HMF had growth differences compared with the control. No differences were found across treatments in regard to NEC or sepsis. Very low-quality evidence suggests greater linear growth in VLBW infants fed whey hydrolysate liquid HMF, as well as greater weight gain in those fed casein hydrolysate HMF, compared with the control. Additional prospective, multicenter randomized controlled trials are needed to confirm these estimates because of sparsity of evidence. There is insufficient evidence to support HMF decisions regarding NEC or late-onset sepsis prophylaxis.

Powdered to Liquid Human Milk Fortifiers in the Preterm Infant.

In preterm infants, the goal of aggressive extrauterine nutritional management is to mimic in utero growth and nutrient accretion. Over the latter half of the 20th century, nutritional optimization through the practice of fortifying human milk rose to practice with increased survival rates in preterm infants of younger gestational age. The quest for optimal preterm fortification and nutrition remains a contentious area of debate. This review aims to summarize the historical perspectives of human milk fortification as well as the current literature advocating for the use of liquid human milk fortifiers in enterally fed premature infants.

Is Lactoferrin Supplementation Beneficial for All Preterm Infants?

Human milk (HM) has antibacterial properties due to the presence of immune-modulators, including lactoferrin (LF). This study will determine effect(s) of HM maturation, fortification, and storage conditions on LF levels and its antibacterial properties. HM samples (n = 30) were obtained from preterm and term mothers. The LF levels were analyzed by ELISA, and the antibacterial activity was measured after inoculation with Escherichia coli. The highest level of LF in preterm HM was observed in the first week of lactation. However, storage of preterm HM at 4°C decreased LF levels significantly. Both LF levels and antibacterial activity in preterm HM was lower compared with term HM, but significantly higher than donor HM even after HM-based fortification. LF supplementation of donor HM improved its antibacterial activity. Preterm infants fed donor HM, formula, or stored HM at 4°C may benefits from LF supplementation to improve HM antibacterial properties. · Milk LF levels vary with storage and maturity.. · Donor milk is deficient in LF even after adding HM-based fortification.. · Donor HM and formula fed infants may benefit from LF..

Risk Factors and Clinical Characteristics of Metabolic Bone Disease of Prematurity.

The study aimed to analyze the risk factors and clinical features of metabolic bone disease of prematurity (MBDP) in premature infants compared with infants of similar gestational age and birth weight without MBDP. This retrospective case-control study was performed by comparing 81 cases of MBDP with 63 controls to identify potential risk factors. Premature infants with a gestational age ≤33 weeks and birth weight <1,500 g were included. Medical records were examined in terms of maternal conditions, potential risk factors, and clinical characteristics. Bone fractures and invasive ventilator dependence were the most common clinical features of MBDP. Duration of invasive ventilation and total mechanical ventilation days, necrotizing enterocolitis, corticosteroid use, anticonvulsive drug use, duration of dexamethasone and caffeine use, total parenteral nutrition, and length of hospitalization were significantly higher in neonates with MBDP (p < 0.05). Breastfed neonates and those receiving human milk fortifier had a lower incidence of MBDP than those premature formula or mixed feeding (p < 0.05). Anticonvulsive drug use (odds ratio: 2.935; 95% confidence interval: 1.265-6.810) was identified as a risk factor for MBDP at multiple regression analysis. Our results show that anticonvulsive drug use is a significant risk factor for the development of MBDP. If long-term use is not required, anticonvulsive drugs should be stopped as soon as possible. Further studies involving patients with MBDP are required to determine the risk factors and clinical features. · MBDP is a multifactorial disorder.. · Anticonvulsive drug use is an important risk factor for the development of MBDP.. · Bone fractures and invasive ventilator dependence are the most common clinical features of MBDP..

Fortification of Breast Milk With Preterm Formula Powder vs Human Milk Fortifier in Preterm Neonates

Fortification of expressed breast milk (EBM) using commercially available human milk fortifiers (HMF) increases short-term weight and length in preterm very low-birth-weight (VLBW) neonates. However, the high cost and increased risk of feed intolerance limit their widespread use. Preterm formula powder fortification (PTF) might be a better alternative in resource-limited settings. To demonstrate that fortification of EBM by preterm formula powder is noninferior to fortification by HMF, in terms of short-term weight gain, in VLBW neonates. Open-label, noninferiority, randomized trial conducted from December 2017 to June 2019 at a level 3 neonatal unit in India. The trial enrolled preterm (born at or before 34 weeks of gestation) VLBW neonates receiving at least 100 mL/kg/d of feeds and consuming 75% of milk or more as EBM. Neonates were randomly assigned to receive fortification by either PTF or HMF. Calcium, phosphorus, iron, vitamin D, and multivitamins were supplemented in PTF and only vitamin D in the HMF group to meet the recommended dietary allowances. The primary outcome was the weight gain until discharge from the hospital or 40 weeks' postmenstrual age, whichever was earlier; the prespecified noninferiority margin was 2 g/kg/d. Secondary outcomes included morbidities such as necrotizing enterocolitis, feed intolerance, and extrauterine growth restriction (<10th percentile on the Fenton chart at 40 weeks' postmenstrual age). Of the 123 neonates enrolled, 60 and 63 were randomized to the PTF and HMF groups, respectively. The mean gestation (30.5 vs 29.9 weeks) and birth weight (1161 vs 1119 g) were comparable between the groups. There was no difference in the mean (SD) weight gain between the PTF and HMF groups (15.7 [3.9] vs 16.3 [4.0] g/kg/d; mean difference, -0.5 g/kg/d; 95% CI, -1.9 to 0.7). The lower bound of 95% CI did not cross the noninferiority margin. The incidence of feed intolerance was lower in the PTF group (1.4 vs 6.8 per 1000 patient-days; incidence rate ratio 0.19; 95% CI, 0.04 to 0.95), and fewer neonates required withholding of fortification for 24 hours or more (5% vs 22%; risk ratio, 0.22; 95% CI, 0.07 to 0.75). The incidence of necrotizing enterocolitis stage II or more (0 vs 5%) and extrauterine growth restriction (73% vs 81%) was comparable between the groups. Fortification with preterm formula powder is not inferior to fortification with human milk fortifiers in preterm neonates. Given the possible reduction in feed intolerance and lower costs, preterm formula might be a better option for fortification, especially in resource-restricted settings. Clinical Trial Registry, India Identifier: CTRI/2017/11/010593.

Human Milk Fortification for Preterm Infants

Oft-villainized infant formula has been invited back into the neonatal intensive care unit (NICU) by Chinnappan et al,1 who demonstrate the role of preterm formula (PTF) to supplement, rather than supplant, human milk (HM).

Effect of the Addition of Human Milk Fortifier to Breast Milk on the Early Recovery of Infants After Congenital Cardiac Surgery

Objective: This article studied the effect of breast milk supplemented with human milk fortifier (HMF) on the early recovery of infants after congenital cardiac surgery.Methods: Infants undergoing congenital cardiac surgery were randomly divided into an intervention group (n = 27) and a control group (n = 27). Infants in the intervention group received HMF, and those in the control group were exclusively breastfed. The nutritional indicators at discharge, the postoperative recovery status, and nutritional-related complications were recorded.Results: Compared with the control group at the time of discharge, the weight and albumin and prealbumin levels of the intervention group were significantly increased (P < 0.05). The length of hospital stay of the intervention group was significantly reduced compared with that of the control group (P < 0.05). Although the length of ICU stay for the intervention group was shorter than that of the control group, the difference was not significant (P > 0.05). No significant difference in the incidence of postoperative nutrition-related complications was noted between the two groups (P > 0.05).Conclusion: Compared with breastfeeding alone, with HMF can improve postoperative weight gains, reduce the length of stay, and promote infants' early recovery after congenital cardiac surgery.

Targeting human milk fortification to improve very preterm infant growth and brain development: study protocol for Nourish, a single-center randomized, controlled clinical trial

BackgroundHuman milk is recommended for very preterm infants, but its variable macronutrient content may contribute to undernutrition during a critical period in development. We hypothesize that individually targeted human milk fortification is more effective in meeting macronutrient requirements than the current standard of care.MethodsWe designed a single-center randomized, controlled trial enrolling 130 infants born < 31 completed weeks’ gestation. Participants will receive fortified maternal and/or pasteurized donor milk but no formula. For participants in the intervention group, milk will be individually fortified with protein and fat modulars to achieve target levels based on daily point-of-care milk analysis with mid-infrared spectroscopy, in addition to standard fortification. The study diet will continue through 36 weeks’ postmenstrual age (PMA). Clinical staff and parents will be masked to study group. Primary outcomes include: 1) body length and lean body mass by air displacement plethysmography at 36 weeks’ PMA; 2) quantitative magnetic resonance imaging-based measures of brain size and microstructure at term equivalent age; and 3) Bayley-IV scales at 2 years’ corrected age.DiscussionWe expect this trial to provide important data regarding the effectiveness of individually targeted human milk fortification in the neonatal intensive care unit (NICU).Trial registrationNCT03977259, registered 6 June, 2019.

What are the effects of different protein concentrations of human milk fortifier for promoting growth and neurological development in preterm infants?

What are the effects of different protein concentrations of human milk fortifier for promoting growth and neurological development in preterm infants?

Estimating Neonatal Necrotizing Enterocolitis Based on Feeding Practices.

(1) Background: The relationship between enteral nutrition and neonatal necrotizing enterocolitis (NEC) among premature neonates is still unclear. The present work was designed to assess the relationship between NEC and feeding strategies compared to control infants. (2) Methods: A retrospective case-control study of premature infants (<35 weeks’ gestation) with or without NEC that examined feeding practices and clinical characteristics at birth and 3, 7, and 14-day hospitalization, with a longitudinal and cross-sectional analysis. (3) Results: A total of 100 newborns with NEC diagnosis and 92 neonates without the disease with similar demographic and clinical characteristics were included. The median day of NEC diagnosis was 15 days (Interquartile Range (IQR) 5–25 days). A significantly higher number of neonates that were fasting on days 7 and 14 developed NEC (p < 0.05). In the longitudinal analysis, generalized linear and mixed models were fit to evaluate NEC association with feeding strategies and showed that exclusive mother’s own milk (MM) and fortified human milk (FHM) across time were significantly less likely associated with NEC (p < 0.001) and that enteral fasting was positively related with NEC. In the cross-sectional analysis, a binary logistic regression model was fit and predicted 80.7% of NEC cases. MM was also found to correlate with a reduced risk for NEC (OR 0.148, 95% CI 0.044–0.05, p = 0.02), and in particular, on day 14, several factors were related to a decreased odd for NEC, including birth weight, antenatal steroids, and the use of FHM (p < 0.001). (4) Conclusions: MM and FHM were associated with less NEC compared to fasting on days 7 and 14. Feeding practices in Neonatal Intensive Care Units (NICUs) should promote exclusive MM across the two-week critical period as a potential guideline to improve NEC outcome.

Feeding Strategies in Preterm Very Low Birth-Weight Infants: State-of-the-Science Review.

Providing enteral feeds to preterm very low birth-weight (VLBW) infants is critical to optimize nutrition, enhance growth, and reduce complications. Protocols guiding feeding practices can improve outcomes, but significant variation exists between institutions, which may limit their utility. To be most effective, protocols should be based on the best available evidence. To examine the state of the science on several key components of feeding protocols for VLBW infants. The authors searched PubMed, CINAHL, and EMBASE databases for terms related to feeding VLBW infants less than 32 weeks' gestational age, including initiation of feedings, rate of feeding advancement, timing of human milk (HM) fortification, and feeding during blood transfusions, when diagnosed with a patent ductus arteriosus (PDA) and during medical treatment of PDA closure. Initiation of feeds within the first 3 days of life and advancement by 30 mL/kg/d may decrease time to attain full feeds without increasing complications. Insufficient evidence guides optimal timing of HM fortification, as well as feeding infants undergoing blood transfusions, infants diagnosed with a PDA, and infants receiving medical treatment of PDA closure. Integration of existing research regarding feeding initiation and advancement into feeding protocols may improve outcomes. Infants at highest risk of feeding-related complications may benefit from a personalized feeding approach. Additional research is needed to provide evidence concerning the optimal timing of HM fortification and feeding strategies for infants undergoing blood transfusions and those diagnosed with a PDA or receiving medical treatment of PDA closure to incorporate into evidence-based feeding protocols.

Fortification of Human Milk With Infant Formula for Very Low Birth Weight Preterm Infants: A Systematic Review

Off-label fortification of expressed human milk (HM) with infant milk formula (IMF) is common in developing countries, though its benefits and safety are unclear. To study the effects of IMF fortification of HM on growth of very low birth weight (VLBW) preterm infants. Systematic review and meta-analysis of randomized and quasi-randomized controlled trials (RCTs). MEDLINE, EMBASE, CINAHL, CENTRAL and other databases were searched for articles published in English language from inception to December 2019, evaluating the effects of HM fortified with IMF as intervention, compared to unfortified HM or HM fortified with human milk fortifier (HMF). Five RCTs including 423 VLBW preterm infants. Feeding with HM fortified with IMF compared to unfortified or HMF-fortified HM. Primary outcome measure was assessment of growth as weight, length and head circumference (HC) gain velocity. Secondary outcome measures were incidences of feed intolerance (FI), necrotizing enterocolitis (NEC), time to reach full feeds, concentration of nutritional biomarkers, duration of hospital-stay and cost of intervention. Of the five studies included in the review, pooled effects regarding weight gain velocity (SMD 0.27 g/day; 95% CI 0.08 to 0.62), length gain (MD 0.07cm/week; 95% CI 0.02 to 0.16) and HC gain (MD 0.05 cm/wk; 95% CI 0.01 to 0.11), were not statistically significant. Sensitivity analysis by pooling studies using unfortified milk as comparator yielded a statistically significant result for all growth parameters. Risk of FI or NEC was comparable. Length of hospitalstay was reduced in the intervention group. A very-low quality evidence suggested that IMF fortification of HM is superior to unfortified milk and may be a safe alternative for HMF for short term growth of VLBW preterm infants.