NNIW96 - Strategies in neonatal care to promote optimized growth and development: Focus on low birth weight infants

Editor(s):
Josephine Yuson-Sunga, MD, Professor Nick Embleton, Professor Ferdinand Haschke, Lars Bode

Session I:
Optimizing feeding, nutrition and growth on the NICU and after discharge

Finding the best feeding strategy for preterm babies is complex. Clinicians need to balance goals that are sometimes in conflict, providing for nutritional needs while also managing risk of conditions such as NEC and late-onset sepsis. The more that is known about what
and how to feed preterm infants, the better informed feeding strategies will be. Janet Berrington outlines the importance of providing
preterm infants with early access to mother’s milk, as studies show that babies who are fed earlier, on day two rather than day six, also achieve full feeds earlier. Positive messaging for new mothers is vital to help them appreciate the benefits of breast milk. A baby would usually receive around 5g/kg/day protein in utero but Frank Bloomfield notes that preterm infants often receive 2g/kg/day or less. Shortfalls in protein and other essential macronutrients can impact neurodevelopment. Early parenteral nutrition of neonates may be useful, although this is accompanied by the risk of refeeding syndrome. Nick Embleton’s presentation focused on macronutrient needs of NICU babies and the importance of recognising that breast milk provides a lot more than just nutrients. More than half of the  energy expenditure of preterm babies is used by the brain. In addition to cardiorespiratory management, NICUs need to focus on babies’ nutritional needs; by the end of their second week, many infants have a protein deficit of up to 70% of their needs.


The practicalities of feeding preterm infants after discharge can be challenging, as Najda Haiden spells out. Preterm infants are at higher risk of feeding problems such as difficulties latching, sucking and swallowing. Human milk fortification after discharge in growth-
retarded infants could help ensure they get the nutrition needed to establish adequate growth and to contribute to appropriate neurodevelopmental outcomes. The time for introduction of complementary feeding in these infants should be considered in an individualize approach based on their neurological ability and nutritional status. Neena Modi’s talk looked at the increased risk of
cardiometabolic complications in young adults born preterm, and whether body composition can be used as a biomarker for this type of risk. Preterm babies at term age may look slight but magnetic resonance imaging (MRIs) show they have more internal-abdominal adipose
tissue and liver fat. Further longitudinal studies are needed to confirm the role of abdominal fat on the long- term health of preterm babies.

Starting & increasing feeds, milk tolerance and monitoring of gut health

Janet Berrington - Consultant Neonatal Paediatrician, Newcastle upon Tyne discusses research into early feeding of preterm babies and how this can help support healthy growth.

The ideal path for a newborn is to be a healthy, breastfed infant at 12 months. However, for preterm babies decisions about nutrition and feeding can be very complex. Aims for preterm babies are multiple and potentially conflicting. These include: reducing risk of life- threatening conditions such as NEC and late- onset sepsis; optimising physical growth and brain development; establishing a healthy microbiome; and ensuring good metabolic function and programming. Achieving these aims will help to reduce the risk of life-
altering conditions such as diabetes and hypertension in later life.


Early feeding of buccal colostrum to babies within six hours of birth improves immunological endpoints, which can be measured in urine lactoferrin and urinary secretory IgA levels as well as increasing the mother’s milk supply. Mothers should be given a positive message about the importance of breastfeeding and the beneficial contents of mother’s milk such as immunoglobulin (SIgA), T cells, hormones, bacteria and human milk oligosaccharides. Studies show infants who are fed early, on day two rather than day six, reach full feeds at day 18, three days earlier than later fed infants. Feeds can be increased from around day four by up to 30ml per kilo per day, although there’s no harm in going at a slower rate. Signs of milk tolerance, such as distension, green aspirates and constipation, are often subjective.
Monitoring outcomes is challenging because there is no single success measure or endpoint. Some outcomes such as good gut health are poorly understood and hard to measure. A close understanding of each practice, its outcomes and a local audit is required to assess progress.

Strategies in neonatal care to promote growth and development of the preterm infant

Frank Bloomfield - Liggins Institute, University of Auckland argues that nutrition is essential to support preterm babies’ neurodevelopment.


For normal brain development, an infant needs macronutrients such as protein, energy and fat, as well as micronutrients and vitamins such as zinc, thiamine, iron and copper. Babies have a protein intake of around 5g/kg/day in utero but for preterm babies this drops to no more than 2g/kg/day at birth, even with careful attention to nutrition. Growth is often associated with positive neurodevelopmental outcomes, but there is insufficient high quality evidence showing that growth is a reliable proxy for neurodevelopmental outcomes in NICU.
Further evidence is also needed on optimal nutritional strategies to support neurodevelopment. “Many preterm babies can be considered
to have suffered malnutrition.” Some studies suggest that late, rather than early, parenteral nutrition of neonates may be of benefit. The
lack of research has led to the ProVIDe trial in extremely preterm babies, exploring whether an additional 1g of intravenous protein per day for the first five days improves survival free from neurodisability at two years old. The results should be published later in 2021.
It is vital to be aware of the increased risk of refeeding syndrome in preterm infants, where the sudden provision of nutrition leads to a decline in phosphate and an increase in calcium. Its effects include sepsis, haemorrhage, lung disease and increased mortality. Refeeding syndromes is more common in small for gestational age (SGA) babies.

Nutritional interventions to improve brain outcomes in preterm infants

Nick Embleton - Newcastle University describes the complexity of providing nutrition for preterm babies.


Nutrition is more than simply nutrients. In recent years, we’ve started to recognise the importance of other elements: functional components including HMOs, growth factors, enzymes and microbes; microbes and probiotics; and technical and socio-behavioural
elements such as skin-to-skin and taste. Human brains are up to 20 times bigger than other mammals and 90% of final brain volume is acquired between 34 weeks gestation and two years of age. Neuronal processes are under the control of IGF-1, which is in turn impacted by nutrients, especially macronutrients. “Babies in the neonatal unit require an energy intake of 120-130 kcal/kg/day - 20-30% more intense than the most intensive sporting activities.”


More than half of all energy expenditure in preterm babies is happening in the brain. Most NICU care and monitoring is focused on cardiorespiratory management, but it’s very easy to fail to give babies adequate levels of macronutrients. We now recommend close to 4g/kg/day of protein, but by the end of the second week, preterm babies have accrued a huge deficit of protein of up to 70% of their needs. The two key aims should be to maximise intake of mother’s own milk and to meet macronutrient intake recommendations. We need to be cautious about adding more docosahexaenoic acid (DHA) to the baby’s diet after studies showed a possible increase in
bronchopulmonary dysplasia (BPD). A forthcoming large UK trial will look at choline and DHA supplementation. Careful attention to nutritional management in preterm infants is required to ensure adequate nutrients for brain growth and development.

Post-discharge nutrition: Breastfeeding, complementary foods, eating behavior and feeding problems

Najda Haiden - Medical University of Vienna tells how preterm infants have additional need for nutrition, but may have challenges with feeding.

Preterm infants have a high need for nutrients due to a limited reserve and organ immaturity, which contributes to the challenge of achieving adequate dietary intakes. They are at high risk of feeding problems, with difficulties in latching, sucking and swallowing coordination, and have persistent issues such as chronic lung disease and short bowel syndrome. “We need to individualise the nutritional approach.” Preterm infants need a higher intake of energy, protein, long-chain polyunsaturated fatty acids (LCPUFAs), iron, zinc, calcium and selenium but there are no specific recommendations on feeding post discharge. Several studies have shown the advantages of human milk fortification after discharge, such as better lung function at age six, better visual function and better anthropometric parameters. There is no evidence-based guideline for the best time to introduce complementary feeding to preterm infants and it should be based on individual development. Studies show that preterm infants and those formula-fed are introduced to solids earlier, but there is no difference in weight outcome in introducing solids at four months or at six months. A significant number of preterm infants have problems
eating, linked to intrinsic immaturity, neurological deficits, co-morbidities and psychological roots caused by unpleasant procedures such as intubation. Emotional factors could play a significant role. It is important to address these challenges to reduce the risk of postnatal growth deviation.

Quality of growth, body composition and longer term metabolic outcomes

Neena Modi - Imperial College London discusses whether the body composition of preterm babies can be used as a biomarker for metabolic risk in later life.

Research suggests young adults born preterm are at higher risk of cardiometabolic complications than full-term adults. Body composition can be used as a biomarker for metabolic risk for children and adults, but it is unclear if the same is true for infants. Preterm men had an average of half a kilo more abdominal adipose tissue, three times more hepatic lipid content and significantly increased blood pressure.
Further research suggests adults born preterm are more likely to have ischaemic heart disease, diabetes, metabolic syndrome and a reduced lifespan. “ Adults who were born preterm have an average increase of around 0.5kg in internal-abdominal adipose tissue compared to those born at term.” The factors influencing infant adiposity include sex, ethnicity, birth gestational age, breast or formula
feeding, protein intake, maternal adiposity and gestational diabetes. Further research is required to determine how these factors interconnect. For example, breastfeeding does not appear to make a difference to body composition in babies born to mothers with
gestational diabetes. Preterm babies may look very thin when they reach the age of full term, but MRI showed they had more internal-abdominal adipose tissue and liver fat. Formula- fed infants have lower fat mass than their breastfed counterparts up to the age of 12 months when the trend is reversed, and formula-fed infants have a higher fat-free mass throughout infancy. Formula with a lower protein
content has been found to reduce obesity at school age. Although it is known that body composition in children and adults is a biomarker of metabolic risk, there is insufficient evidence to confirm whether the same can be said of body composition in infancy. Further longitudinal studies are required to look at the relationship between infant body composition and health.

Session II: Personalized Nutrition of Preterm Infants 

Preterm babies are sometimes spoken about as if they all have exactly the same needs, but a baby born weighing 500g will need a different approach to one who weighs 2000g at birth. VLBW infants require fortified breast milk, but the exact specification for optimal fortification remains open for debate. The speakers gave some valuable contributions to this area. Christopher Fusch discussed the use of
donor human milk. As the pandemic developed, donor milk banks needed to consider safety concerns and manage a reduced supply as donors were reluctant to visit hospitals.


Chris van den Akker explained that being born prematurely still leads to a major gap in growth which has only improved slightly over recent years. The fortification of human milk with protein, on top of standard fortification, could help address the gap. An individualized approach to fortification can also respond to the specific composition of a mother’s milk or donor milk. The subject of amino acid (AA) fortification of human milk was the basis of Ferdinand Haschke’s talk. He examined the different AAs that can be used to provide for preterm infants’ protein intake needs. Recent studies suggest that the levels currently provided through fortified human milk might not be enough. Nadja Haiden explained that many mothers discontinued fortification of their infant’s milk soon after discharge from the NICU because it interfered with breastfeeding. Professor Haiden has developed a finger feeder device that can be used in tandem with breastfeeding.
This could help to improve adherence to a milk fortification regime. Andrew McPhee described the role of LCPUFAs in key
areas such as tissue development, organogenesis, the central nervous system, immune modulation and resolving inflammation. Docosahexaenoic acid (DHA) and arachidonic acid (ARA) can be added to infant formula to help address deficiencies in these
vital nutrients. Both nutrition and stress play a fundamental role in shaping the development of the fetus, as Hans van Goudoever stated in his presentation. Managing perinatal adversity and understanding the mechanisms of this stress could help to reduce harmful effects.
Magnus Domellöf’s talk centred on micronutrients and the significant impact they can have on health, growth and development. He encouraged physicians to consider micronutrient supplementation alongside other elements of nutrition such as protein, fat and carbohydrates.

Donor milk banking: Safety, efficacy, new methodologies

Christopher Fusch - Paracelsus Medical University, Nuernberg discussed donor milk banking, including safety aspects and the impact of the COVID pandemic on supply.

Current issues surrounding donor human milk (DHM) banking include the Covid burden and safe supply, new aspects on pasteurisation procedures, donor screening and the nutrient variability of DHM. There is no evidence that Covid can be transmitted via breastmilk1,2 and WHO recommends no change of practice. However there has been a deferral of donors for 28 days in case of Covid history. Supply of DHM has decreased due to donors avoiding hospitals and with the closure of transport infrastructures. “ Donor milk supply has decreased during the SARS-CoV-2 pandemic but demand remains unchanged.” Our observation is that the percentage of breastfeeding mothers increased during lockdown as there was less distraction and disruption, which helped with bonding and getting the milk flow going.
It is now known that Holder pasteurisation of DHM is effective in inactivating SARS-CoV-2. Work is ongoing into alternative ways to pasteurise human milk, including at high temperature, high pressure and with ultraviolet-C irradiation. High pressure pasteurisation and
lyophilisation (freeze-drying) are promising methods in killing germs while preserving bioactivity. Negative aspects of DHM are that the macronutrient content is variable and not balanced and the protein content is too low, especially for preterms. Donor pooling and additional supplementation of protein may help with avoiding macronutrient depletion. Milk banks should measure and disclose the nutrient content of their batches in order to allow better fortification procedures.

Meeting protein and energy requirements of preterm infants receiving human milk
 

Chris van den Akker - Amsterdam UMC says we still lack evidence to indicate the optimal milk fortification strategy for preterm infants.

For healthy growth, infants need quality nutrition including good quality protein, energy to support protein synthesis, essential fatty acids and micronutrients, especially phosphate and calcium. There is still a major gap between growth in utero and in NICU after birth for preterm babies, and over the years this has only improved slightly. Poor growth is associated with poor neurodevelopmental outcomes. It has been known since the 1980s that preterm infants fed with human milk and a newly designed preterm formula grew better and had improved neurological outcomes up to the age of 16. “ There are different types of fortifiers and also many different strategies to use
fortifiers in practice.” Mother’s own milk is the best source of nutrition for preterm infants, provided it is suitably fortified. Since it is very clear that unfortified human milk results in poor postnatal growth, it is advised by different that for all preterm infants a multi-nutrient fortifier is added to human milk. Within two to four weeks after birth the protein content of human milk reduces to 1.0 - 1.2 g/ dL; standard multi-nutrient fortification may not provide protein intake at the recommended level of 3.5 - 4.5 g/ kg/day. Individualised protein fortification can be done in 2 different ways, by adjusting according to measured serum urea concentrations (adjustable fortification) or by meeting target content goals after analysing the milk (targeted fortification). Optimal fortification strategies are relatively poorly studied. Areas that need further research include: when to begin fortification; whether standard, adjustable or targeted fortification is optimal; using fortifiers with
bovine or human origin; and powdered or liquid fortifiers.

Human milk fortifiers for preterm infants: Are we offering the best amino acid mix?

Ferdinand Haschke - Paracelsus Medical University, Salzburg explained how important it is to ensure preterm babies have the right intake of amino acids (AA).

Because of their rapid increase of lean body mass, preterm infants have much higher protein requirements than term infants. The use of human milk fortifiers (HMF) is necessary to achieve the recommended protein, energy, and micronutrient intakes for preterm infants. Recommendations on the protein requirements of preterm infants is available but more research is required to understand the best protein quality AA profile of HMF, as there are no guidelines available. “ ELBW infants have much higher AA requirements than LBW infants for growth, development and long-term health.” In HMF the AA mix is close to that of human milk, but it is unclear if this is the appropriate level for extremely low birth weight (ELBW) babies. Two recent studies which measured protein concentration in human milk provided
to VLBW and LBW infants indicated that delivering 1.4 - 1.8g of HMF protein with 100ml of milk might not be sufficient. The recommended level of protein for ELBW and VLBW is 4g per kg, per day. In particular, ELBW infants, weighing 400-900g, can have a lower AA intake which results in a cumulative deficit of 3.6 g/kg over three weeks. However, VLBW infants receive the recommended intake. There are four AA with lower percentages in human milk than is required during foetal gain – lysine, methionine, phenylalanine and histidine. The lower percentage is greater with two conditionally essential AA, glycine and arginine. Therefore, AA composition of HMF for ELBW should be reconsidered: spiking HMF protein with specific AA or providing targeted AA based HMF could be some options. Clinical studies are necessary with improved AA mix in HMF.

Micronutrient Needs of Children New ways to provide a human milk fortifier during breastfeeding

In her second talk, Nadja Haiden - Medical University of Vienna explained how mothers of preterm infants are often frustrated that the need to fortify human milk means they have to pump and bottle feed. An innovative finger feeder could offer a solution.

Fortification of human milk is strongly recommended for preterm infants, but this is often discontinued after discharge from hospital. This means breastfed preterm infants are exposed to an increased risk of nutritional deficit, with a possible impact on neurodevelopmental
outcomes. The current procedure is that the mother pumps, the milk is fortified and then fed via a bottle. This means that although an infant may only consume milk from its mother, at least some of this milk has to be given by bottle or other suitable containers. This can be
frustrating for mothers. Nadja Haiden from the Medical University of Vienna has helped to develop a finger feeder device connected to a syringe to give fortified milk during breastfeeding. Mothers use 7g of fortifier soluble in 5ml of water, in combination with breast milk. The device is inserted into the corner of the baby’s mouth during breastfeeding. “ Using the new devices meant that moms didn’t have to pump anymore and it was possible to exclusively breastfeed.” The JOGNN study, Administration of Fortifier by Finger Feeder During Breastfeeding in Preterm Infants, co- authored by Professor Haiden into use of the finger feeder reported no difference in weight gain and a third of mothers had problems with drooling or insufficient latching, but they liked being able to breastfeed. Further research could produce a ready-to-use application, with a dose of fortifier already mixed in a vial and a squeezing device replacing the syringe.

LCPUFAs in preterm nutrition

Andrew J McPhee - South Australian Health and Medical Research Institute shared the current understanding of the role played by long-chain polyunsaturated fatty acids (LCPUFA) in key areas of development for the preterm infant.

LCPUFAs have important roles to play in many functions including tissue development, organogenesis, the central nervous system (particularly vision), immune modulation and resolving inflammation. Correcting deficiencies in LCPUFAs, especially DHA and ARA, in preterm infants has the potential to improve neurodevelopment and vision and perhaps even reduce some inflammatory morbidities.
Trials have seen that adding DHA and ARA to breast milk from week one for preterm babies led to higher problem-solving scores and better recognition memory at six months, and better attention at 20 months. The promising result of a recent Swedish study was a 50%
reduction in severe retinopathy of prematurity (ROP) after an enteral LCPUFA supplement with both DHA and ARA. “ Preterm babies have low levels of DHA at birth because requirements rise through the third trimester of gestation.” The DINO trial in Australia fed preterm babies high doses of DHA and resulted in improved visual acuity at four months and a lower rate of BPD, with a significant reduction in babies born weighing less than 1,250g. However, in further studies in Australia and Canada, high DHA intake was associated with a surprising increase in BPD while the impact of high dose DHA + ARA was unclear and requires further study. High dose DHA has no effect on ROP, combination high dose DHA + ARA has some promising results but needs further study. High dose DHA had no effect on other outcomes such as sepsis and NEC, but high dose DHA + ARA requires further study. In terms of developmental outcomes, both high dose DHA and high dose DHA + ARA indicate short term benefits, but more research is needed on longer term outcomes. Carefully designed animal and human studies are needed to identify the primary nutritional factors that should be targeted in the context of perinatal stress to optimize intervention strategies that could ameliorate adverse effects on child neurodevelopment.

Micronutrient intakes and health outcomes in preterm infants

Magnus Domellöf - Umeå University explained how deficiencies of key micronutrients such as iron, phosphate and calcium impact preterm infants.

Micronutrients include all nutrients apart from protein, fat and carbohydrates. Micronutrients can have a drastic impact on health and an important effect on growth, retinopathy of prematurity (ROP) and brain development, in both the short term and the long term. One study showed that adding iron drops from six weeks to six months of age significantly reduced behavioural problems at three years and the effect remained at age seven. However, it is important to be aware of the toxic effect of iron overload. Sodium supplements are often needed in preterms from day 4, when hyponatremia replaces hypernatremia due to sodium losses in urine. “ Doctors should consider micronutrients when prescribing nutrition.” Hypophosphatemia is common in VLBW infants during the first week and is not a deficiency but a shift between fluid compartments. However late hypophosphatemia, common in VLBW after 4 weeks is associated with osteopenia and a deficiency of phosphorus and calcium. Treatment involves phosphate, calcium and vitamin D supplements.


Preterm infants might need a balance of extra AA and DHA because deficiencies in LCPUFAs are quite common due to the level in breastmilk being strongly influenced by the mother’s diet. There is no clear evidence that more than 400 IU/d of vitamin D supplement improves bone health, with possible adverse effects of nephrocalcinosis. The new vitamin D recommendation from ESPGHAN is for 400-700 IU per kilo per day, up to a maximum of 1000 IU/day. This replaces the previous recommendation of 800 - 1000 IU/day. Micronutrient intakes have crucial short and long term impacts on health outcomes in preterm infants. Research is ongoing in this area, and recommendations are available to indicate suitable enteral and parenteral intakes. Physicians should always consider micronutrients
when prescribing nutrition for preterm infants.

Session III: The role of HMOs and the microbiome in the health of very low birth weight infants

According to the Lancet’s Breastfeeding Series 2016, “The deaths of 823,000 children and 20,000 mothers each year could be averted through universal breastfeeding, along with economic savings of US $300 billion.” With these figures in mind, it is important to discover
more about the different constituent parts of breastmilk in order to inform the care of the very smallest babies. We know that the microbiome play a vital role. HMOs have a wide range of functions including acting as prebiotics, anti adhesives/antimicrobials, and epithelial cell modulators. In his talk, Christopher Stewart discusses the main effects of an altered microbiome in preterm infants, such as
NEC and shared some results of his research into the microbiome of preterm infants up to 12 months of age. It was found that surprisingly, gestational age and birth weight were not significant factors in microbiome profiles but antibiotics, probiotics, breast milk and breast
milk fortifiers were important. Hania Szajewska revises the clinical evidence of infant formulas supplemented with HMOs for term infants. It
has been shown that supplementation with some HMOs is safe and well tolerated, and may have a favourable effect on some health outcomes and reduction of medication usage such as antibiotics. Gut microbiota can be categorised into six clusters, according to Jean-Michel Hascoët. His presentation found that the prominent bacterium in an infant’s gut could influence risk of sepsis and morbidity. He also
presents the first clinical trial with supplementation of 2 HMOs (2’FL and LNnT) in preterm infants, showing it is safe, promotes adequate growth and reduces time to reach full enteral feeding. Ryan Carvalho set out some of the key components of human milk, explaining that as well as nutritional content, some non-nutritive components help to fight against infection and inflammation. Understanding more
about human milk bioactive compounds could facilitate improved support for both infants and mothers in future.

HMOs: What they are and what they do

Lars Bode - University of California, San Diego explained the fascinating role of human milk oligosaccharides, the third most abundant solid component in human milk.

HMOs are an important part of a mother’s milk and the third most abundant solid component, with 5 - 15g per litre compared to 0.05g in bovine milk (the basis of infant formula). They are a group of complex sugars – the name comes from the Greek for “a few sugars”. There are between 150 and 200 different structures for HMOs and each mother’s is slightly different, like a thumbprint. HMOs are not digested by infants, instead they have a range of functions including acting as prebiotics, anti adhesives/antimicrobials, and epithelial cell modulators.
They affect outcomes such as infectious disease and diarrhea, growth, neurodevelopment and cognition, immune system development and response and NEC and sepsis. One key area of research asks what it is in human milk which makes it so powerful to save preterm infants with NEC. NEC is a disease developed by 5% of VLBW babies. Preterm infants who receive human milk are up to 10 times less likely to develop it. “ We are only at the tip of the iceberg - there is so much to discover about what HMOs can do.” Animal studies have shown survival rates rise significantly with pups fed infant formula with oligosaccharides, and the specific one which stood out as being particularly effective was identified as disialyllacto-N-tetraose (DSLNT). In cohort studies on humans, the more DSLNT in their milk, the less likely infants are to develop NEC.

HMOs are just one of a number of bioactives found in human milk. HMOs contribute to shaping the infant gut microbiome and may impact infant growth and development. To fully understand the effects and functions of HMOs, we need further preclinical, cohort and clinical studies.

Importance of the gut microbiome in preterm infants

Christopher Stewart - Newcastle University detailed how stool samples from preterm babies reveal more about the neonatal gut microbiome.

Newcastle Neonatal and NEC Research has been investigating the importance of bacteria in the gut – the microbiome – in preterm infants. NEC is the leading cause of death in preterm infants. It is an inflammatory response that leads to necrosis of the bowel, particularly the terminal ileum. In the worst cases, infants require surgery to have affected regions of the bowel resected. NEC is associated with infants who have an unstable microbiome. Breast milk is the main factor associated with microbiome development up to 12 months of age. One of the primary roles of HMOs is to serve as a prebiotic, particularly for Bifidobacterium. Breastfeeding increases Bifidobacterium in early life. Using 1,477 stool samples from healthy preterm infants to look at the clinical variables associated with the gut
microbiome, it’s surprising that gestational age and birth weight were not significant factors in microbiome profiles. Far more significant were antibiotics, human milk and human milk fortifiers, while probiotics were most associated with an altered microbiome development.
Probiotics support the transition to microbiome clusters dominated by Bifidobacterium, as opposed to less mature clusters dominated by Staphylococcus. It’s striking how Lactobacillus acidophilus in particular rarely occurs naturally in preterm infants. The microbiome in NEC is highly unstable. Infants with higher levels of Disialyllacto-N-Tetraose (DSLNT) progressed into more mature clusters dominated by
Bifidobacterium. “ We’re increasingly appreciating the role of microbes and bacteria in human health.” The evidence suggests that the infant gut bacteria Bifidobacterium is associated with protection from NEC for preterm infants and that breastfeeding increases the
level of Bifidobacterium in early life. Enteroid-anaerobe co-culture allows mechanistic investigation into host- microbe interaction in early life.

Selected human milk oligosaccharides added to infant formulas for term infants

Hania Szajewska - Medical University of Warsaw discussed research into the addition of HMOs to infant formula.

Breast is best is the long-established advice from health organisations, but not all infants can or will be breastfed. It’s therefore important to look at infant formula and understand the ways in which they may be improved. The current interest in HMOs is due to advances
in analysis and progress in biotechnology, plus the independent confirmation of the safety of adding 2’-fucosyllactose (2’-FL) and Lacto-N-neotetraose (LNnT) to infant formula. The structure of HMOs used in infant formula are identical to those found in human milk. HMOs have no nutritional value but support the infant’s immune system. Human cohort studies have looked at specific HMOs in breast milk and their effect on infections, sepsis, allergies, growth, body composition, neurodevelopment and NEC. “ Human Milk Oligosaccharides: Known for years. Discovered again.” High levels of 2’-FL in breast milk lowers the risk of diarrhoea caused by Campylobacter jejuni. This HMO
also fights viruses including influenza, rotavirus, human immunodeficiency virus and norovirus. HMOs act as decoy receptors on the surface of the virus to prevent it attaching to gut epithelial cells. Evidence indicates that adding 2’-FL and LNnt to infant formula supports normal growth and is safe and well tolerated. This supplementation also leads to reduced lower respiratory infections and bronchitis and a 31% reduction in antibiotic use. A recent study demonstrated that infant formula with a blend of five HMOs supports age-appropriate growth, is safe and well-tolerated. The structures are 2’-FL, LNT (Lacto-N-tetraose), DFL (di-fucosyllactose), 3’-SL (3’-sialyllactose) and 6’-SL (6’-sialyllactose). Conducting studies looking at infant feeding is challenging because it would be unethical to randomly assign infants to breast-fed or formula fed groups. Instead, studies are designed with a randomized comparison structure; this is also challenging as study protocols may require infants to be exclusively formula fed to be eligible for randomization. Experts are working on a standard providing criteria for clinical trials of breast milk substitutes. In summary, HMOs found in breast milk may contribute to health outcomes later on, and HMOs with identical structures to those found in breast milk can be added to infant formula safely and with good tolerance. Conducting studies in this area is challenging but high standards must be followed in order to produce reliable evidence.

Microbiota and HMOs in preterm infants

Jean-Michel Hascoët - University of Lorraine explained that gut microbiota can present different patterns
related to NICU practices and may be associated with outcomes for infants.

Bifidobacterium is the most represented bacterium in the gastrointestinal tract of term-born, breastfed infants. Research has discovered a significant relationship between Clostridium Neonatale and the occurrence of NEC in premature babies. The NEC infants did not have
Bifidobacterium in their gastrointestinal tract. Studies have grouped gut microbiota into six clusters, defined by one prominent bacterium. Cluster three, dominated by Escherichia, had higher rates of breastfeeding and skin-to-skin in the first week than the other clusters. It also had significantly lower rates of sepsis and 6% morbidity compared to up to 37% in clusters four to six. “ HMOs supplementation, when given soon after birth, is safe and well tolerated.” The milk of mothers who deliver preterm has been found to have significantly lower levels of 2’-Fucosyllactose (2’-FL) than mothers who deliver at term. Also, 2’-FL and Lacto-N-neotetraose (LNnT) added to infant formula shifts the gut microbiota closer to that of breastfed infants. An ongoing French study is designed to demonstrate the effect of a liquid supplement containing two HMOs, 2’-FL and LNnT, in preterm infants. The study looked at infants born at 27-33 weeks gestation in a prospective, double- blind, controlled trial in seven French centres. The study results showed that an HMOs supplement reduces the
mean time to reach full enteral feeding and that use of an HMOs supplement may support improved early postnatal growth. Weight gain was similar in both groups but head circumference and length were slightly greater at discharge for the HMO group. HMOs play an important role in supporting the gut microbiota of premature infants. HMOs supplementation was shown in a first clinical trial to be safe and well tolerated by premature infants. It supports age- appropriate growth in weight and is consistent with length and head circumference improved early postnatal growth.

Human milk bioactives: Future perspectives

Ryan Carvalho - Nestlé Nutrition explains what we have learned about the non-nutritive components of human milk.

Breast milk provides the best nutrition for infants and a part of optimal levels of nutrients, including macro and micronutrients for growth and development. It also contains bioactive components that serve a variety of biological functions whose impact on health outcomes
we need to better understand. These bioactives are thought to protect against infection and inflammation and contribute to immune maturation, organ development and healthy microbial colonisation. The three main sources of bioactive components in human milk are production and secretion in the mammary epithelium; production by cells carried within the milk; or they are drawn from the maternal serum. “ The next generation of research should focus on the complex interactions and inter-relations between bioactive components in human milk.” The many bioactive components of human milk include oligosaccharides, gangliosides, mucins, chemokines, cytokine inhibitors, growth factors and hormones. The three major human microbial bioactives which have been studied are lactoferrin, lactadherin and osteopontin. Metabolic hormones such as adiponectin are being increasingly studied. HMOs and other bioactive compounds found in human milk provide a range of benefits including stimulating beneficial colonization and reducing colonization with pathogens; reduced
inflammation; blocking infection from viruses and bacteria and stimulation of cell proliferation. SigA is an antibody that plays a critical role in immune function, blocking pathogens by adhering to the gut lining. Lactoferrin and osteopontin further activate the cellular immune system. Antioxidant levels are significantly higher in preterm mothers’ milk compared to term infants, and have a role to play in eliminating
superoxide anions and hydrogen peroxide, and in the regeneration of other antioxidants. The bioactive components in human milk have great promise in furthering the understanding of health benefits of breast milk. Future research should focus on the interaction and inter-relations between these bioactive components. If we know more about the factors that influence expression of bioactive components, we may be able to improve maternal health solutions that enable continued breastfeeding. Understanding the bioactivity of human milk in preterms and special needs infants will also allow for therapeutic potential in the future