Human Milk Fortifier: New Directions for Preterm Nutrition

Providing optimal nutrition for preterm infants is essential for their growth and development, as they miss critical nutrient accumulation that typically occurs in the third trimester. Breast milk alone may not meet all their nutritional needs, leading to the use of human milk fortifiers (HMF) to enhance its nutrient content.

Recent advancements have introduced new formulations and delivery methods aimed at improving outcomes for these vulnerable infants. Researchers continue refining HMF composition and manufacturing techniques to optimize safety, efficacy, and accessibility.

Composition And Key Nutrients

Human milk fortifiers augment the nutritional profile of breast milk to ensure preterm infants receive essential macronutrients and micronutrients for accelerated growth. While breast milk contains bioactive compounds and immunological factors, it often lacks sufficient protein, minerals, and vitamins required for rapid tissue development. Fortification addresses these deficits by increasing the concentration of protein, calcium, phosphorus, and key vitamins to meet preterm infants’ needs.

Protein is a primary focus, as preterm infants require higher amounts to support lean body mass development and neurocognitive maturation. The European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) recommends 3.5–4.5 g/kg/day for very low birth weight (VLBW) infants, a level unfortified human milk cannot provide. Fortifiers typically contain bovine or human-derived protein sources, with hydrolyzed proteins sometimes included to enhance digestibility. Studies show protein-enriched fortification improves weight gain and head circumference growth, critical indicators of neurodevelopment.

Mineral supplementation is equally vital, particularly calcium and phosphorus, which support bone mineralization. Preterm infants miss the peak period of fetal calcium and phosphorus deposition in the third trimester, placing them at risk for osteopenia of prematurity. Standard human milk contains insufficient levels, necessitating fortification to match intrauterine accretion rates. Fortified milk with appropriate calcium-to-phosphorus ratios has been shown to reduce metabolic bone disease incidence.

Beyond macronutrients and minerals, HMFs provide additional vitamins and trace elements often deficient in preterm infants. Vitamin D is crucial for calcium absorption and bone development, with the American Academy of Pediatrics (AAP) recommending 400–1000 IU/day—levels requiring fortification, as human milk alone provides only 20–70 IU per liter. Iron is another critical component, as preterm infants have lower stores at birth and are at risk for anemia. Fortified human milk typically includes 2–4 mg/kg/day of iron to support erythropoiesis and cognitive development. Zinc, essential for immune function and tissue repair, is included at recommended intakes of 1.4–2.0 mg/kg/day.

Manufacturing Approaches

Producing human milk fortifiers requires stringent processes to ensure safety, consistency, and nutrient bioavailability. The choice between bovine-derived or human milk-based fortifiers presents distinct challenges in formulation, sterilization, and regulatory compliance. Advances in processing techniques focus on optimizing nutrient stability while preserving bioactive components that support preterm infant development.

Bovine-derived fortifiers are widely used due to their availability and cost-effectiveness. These are produced by isolating protein fractions from cow’s milk, followed by enrichment with essential minerals and vitamins. Ultrafiltration and microfiltration concentrate specific proteins while reducing harder-to-digest components like casein. Heat treatment, including pasteurization or spray drying, ensures microbial safety without significantly compromising protein integrity. However, concerns about allergenicity and amino acid differences have led to research into enzymatic hydrolysis to improve digestibility.

Human milk-derived fortifiers use donor milk that undergoes rigorous screening and processing to remove pathogens while retaining immunological and growth-promoting factors. High-temperature short-time (HTST) pasteurization helps preserve bioactive proteins like lactoferrin and immunoglobulins, while freeze-drying maintains nutrient stability for easier storage and reconstitution. Despite these advantages, donor milk supply limitations and higher production costs restrict widespread adoption.

Ensuring homogeneity in nutrient distribution is critical. Powdered fortifiers require precise blending to prevent nutrient segregation, while liquid forms must maintain solubility and prevent mineral precipitation. Emulsification technology improves the dispersion of fat-soluble vitamins and lipids, enhancing absorption. Encapsulation techniques, such as microencapsulation of iron, prevent nutrient interactions that could affect bioavailability.

Types Of Fortifiers

Human milk fortifiers are classified based on source, composition, and method of administration. The two primary types are bovine-derived and human milk-based fortifiers, each with distinct advantages and challenges.

Bovine-derived fortifiers are the most widely used due to their standardized nutrient content and accessibility. These formulations use concentrated protein, minerals, and vitamins extracted from cow’s milk, with modifications to better align with human milk composition. However, concerns exist regarding feeding intolerance in some preterm infants, as bovine proteins differ structurally from those in human milk. Hydrolyzed protein versions have been developed to enhance digestibility and reduce gastrointestinal complications. Some NICUs use phased fortification, gradually increasing protein and mineral content to improve tolerance while minimizing metabolic stress.

Human milk-based fortifiers, derived from donor breast milk, more closely mimic the bioactive and structural components of maternal milk. Studies suggest they may lower the risk of necrotizing enterocolitis (NEC) compared to bovine-based options. However, their limited availability and higher production costs make them less accessible. Some institutions use a combination approach, reserving human milk-based fortifiers for the most vulnerable infants while using bovine-derived options for those with higher tolerance.

Liquid and powdered formulations provide further differentiation. Liquid fortifiers offer uniform nutrient distribution and ease of mixing, reducing the risk of nutrient loss due to incomplete dissolution. These are often preferred in clinical settings where precision is crucial. Powdered versions provide greater flexibility for individualized dosing and longer shelf stability, making them practical in settings with storage and supply chain constraints. The choice between liquid and powder depends on institutional protocols, infant-specific needs, and the ability to monitor fortification adjustments in real time.

Use In Preterm And Low Birth Weight Infants

Preterm and low birth weight infants face considerable nutritional challenges due to incomplete fetal development and limited nutrient stores at birth. Human milk fortifiers enhance breast milk’s nutritional density to support postnatal growth. Without fortification, these infants often struggle to achieve adequate weight gain, linear growth, and head circumference expansion—key markers of long-term neurodevelopment. Clinical guidelines from ESPGHAN and AAP recommend fortification for infants born before 32 weeks gestation or weighing less than 1500 grams, as unfortified human milk alone is insufficient for their metabolic demands.

The timing and method of fortifier introduction impact feeding tolerance and growth. Many NICUs implement a gradual fortification strategy, starting with a lower concentration and increasing incrementally as the infant demonstrates tolerance. This approach helps reduce gastrointestinal complications such as abdominal distension and delayed gastric emptying. Standard practice involves initiating fortification once enteral feeds reach 80–100 mL/kg/day, ensuring the infant can handle the increased nutrient load. Some institutions also practice targeted fortification, adjusting nutrients based on serum biochemical markers to optimize growth.

Delivery Formats

The method of delivering human milk fortifiers affects nutrient absorption, feeding tolerance, and ease of administration. Healthcare providers consider gestational age, digestive capacity, and clinical stability when selecting the most appropriate format. Advances in formulation technology have led to several options, each with unique benefits and limitations.

Liquid fortifiers are commonly used in hospital settings due to their ease of mixing and consistent nutrient distribution. These pre-mixed solutions reduce dosing errors and ensure even dispersion throughout the feeding. They also minimize handling time, which is beneficial in NICU environments where precision and efficiency are priorities. However, liquid formulations often have shorter shelf lives and require refrigeration, complicating storage and logistics. Some manufacturers have developed concentrated liquid fortifiers that require smaller volumes, reducing overall feeding volume while maintaining nutrient density—especially beneficial for extremely low birth weight (ELBW) infants with limited gastric capacity.

Powdered fortifiers offer greater dosing flexibility and are preferred when individualized nutrient adjustments are necessary. They allow for customized fortification strategies, such as targeted protein or mineral supplementation based on an infant’s specific growth trajectory and biochemical markers. Powdered formats also have longer shelf lives and are more cost-effective, making them practical for both hospital and home use. However, achieving uniform dispersion in breast milk can be challenging, particularly with minerals like calcium and phosphorus, which may precipitate. Proper mixing techniques and specialized stirring devices help mitigate this issue. Additionally, strict handling protocols are required to minimize contamination risks, as preterm infants are highly vulnerable to infections. Some NICUs implement sterile preparation areas and single-use packaging to reduce microbial exposure.