Preterm and Term Infants
The timespan that the present Yearbook involves, includes the start of the COVID pandemic, which had a huge impact on preterm infants and their families as well. Also from a nutritional point of view as anxiety for vertical transmission of the virus through breastfeeding emerged. This pathway forms an important route of transmission for viruses like CMV, HTLV and HIV, although, e.g., hepatitis viruses do not transmit through breastfeeding . First reports that emerged, usually first on MedRxiv, an online platform that shows submitted, non-peer reviewed manuscripts, provided some indication that indeed SARS-CoV-2 could be passed from mother to child via breastfeeding . At least, SARS-CoV-2 viral material was detected through PCR techniques. However, numerous reactions followed, indicating that environmental contamination was most likely . The ban on breastfeeding by COVID-19 lactating women was soon dismantled and nowadays in most countries (expressed) breast milk is promoted in case of maternal COVID-19. The next sections in this 2021 chapter will go along the longitudinal development of preterm infants: starting with innovative interventions directly following birth, new data on parenteral nutrition, enteral feeding advancement, and composition of formula that might affect time to reach full enteral feeding. Subsequently, we will address the use of probiotics on the NICU after the recommendation provided by the ESPGHAN and ending with long-term consequences of nutritional management.
These articles were selected out of 456 available articles related to nutrition and growth in preterm infants that were published from July 2019 and June 2020. We focused on three different topics, knowing that many other excellent papers are not discussed. With respect to term infants, selected papers relate to the composition of infant formula, vitamin D, prevention of allergy and complementary feeding.
Nutritional Interventions Directly following Birth
Oropharyngeal Colostrum Oropharyngeal colostrum positively modulates the inflammatory response in preterm neonates
Comments: Comments on this article, as well as the following 2 articles (Ferreira et al. and Tao et al.) and are incorporated in the comments on the article by Ma et al.
Oropharyngeal colostrum therapy reduces the incidence of ventilator-associated pneumonia in very low birth weight infants: A systematic review and meta-analysis
Comments: The above four papers (including two meta-analyses), emerged last year on the effects of providing colostrum to preterm infants before they started on enteral nutrition [4–7]. Driven by a paper published in 2010  that showed it seemed safe to administer colostrum already directly from birth and building on the notice that own mother’s milk reduces infections [9, 10], many papers addressed this topic. The research groups are hoping that provision of a colostrum already in the first few days would boost anti-inflammatory capacity of the preterm newborn. A small RCT involving 48 preterm infants suggested that oropharyngeal administration of colostrum decreased clinical sepsis, inhibited secretion of proinflammatory cytokines, and in creased levels of circulating immune-protective factors in extremely premature infants. However, a group of 48 children was much too small to draw any conclusions, especially when noticing an incidence of 92%(!) in the control group . Altogether, 9 RCTs are published now, with Ferreira et al.  being the last so far. In a very nicely conducted double-blind, randomized, placebo-controlled trial, they assigned 113 VLBW infants to receive 0.2 mL of maternal colostrum or sterile water (placebo) via oropharyngeal route every 2 for 48 h. They found no statistically significant differences between colostrum and placebo groups in the incidence of late-onset clinical sepsis (odds ratio 0.7602; CI: 95% 0.3–1.6) and proven sepsis (odds ratio 0.7028; CI: 5% 0.3–1.6). These, and previous results from 8 different RCTs, were combined in two separately conducted meta-analyses, both including approximately 300–350 infants per group in 8–9 studies. The study by Ferreira et al. is included in both meta-analyses and was rated as one of the highest quality studies. By including one more study with a very low enrolment, results changed from a, e.g., statistically significant reducing effect on sepsis to only a trend in reducing sepsis. Similar trends were observed in reduction of NEC or mortality. In both meta-analyses, time was significantly reduced in terms of achieving full enteral feeding. This is an important outcome as it subsequently has additional benefits and reducing days on parenteral nutrition will also be cheaper. Interestingly, bovine colostrum administration to preterm infants also hints at a better tolerance towards enteral feeding . More studies are necessary, but also planned in Brazil (n = 350) , USA (n = 260), and Mexico (n = 96), so hopefully these will help implementing this strategy when proven successful.
The mechanism of action is thought to be within the action of human milk biofactors. Those protect against infection, providing antimicrobial, anti-inflammatory, and immunomodulatory functions. Adherence of pathogens to the gastrointestinal mucosa is hampered, growth of possible beneficial microbes is stimulated, and intestinal motility and maturation are improved. Following the earlier demonstration of increased serum IgA and IgM levels , Martín-Alvarez et al.  demonstrate that oral colostrum for 15 days resulted in a lower proinflammatory state in preterm infants by measuring serum concentrations of interleukin (IL) IL-6, IL-8, IL-10, IL-1ra, tumor necrosis factor alpha, and interferon gamma in the same population. Whether a reduced inflammatory state enhances gut motility and therefore shortens the time needed to reach full enteral feeding remains to be elucidated.
Effects of Quality and Quantity of Feeds while Advancing on Tolerance
Controlled trial of two incremental milk-feeding rates in preterm infants
Comments: The very large, randomized unblinded, pragmatic trial by Dorling et al., discussed in this chapter, compared two intentional speeds of increasing milk: faster (30 mL/kg) with slower (18 mL/kg) daily increments in milk feeding volumes . 2,804 infants were recruited from 55 hospitals and were randomized at a median age of 4 days after birth. It is important to stress that the intervention did not start directly following birth. Following inclusion, the faster-increment group reached full milk feeding volumes at a median of 7 days later, as compared with 10 days later in the slower-increment group. Actual mean volume of advancement in the aimed 30 mL/kg group from day 4 onwards was approximately 20 mL/kg/day, whereas for the 18 mL/kg group the speed of advancement reached its goal more closely: around 15 mL/kg/day. Importantly, there were no statistically significant differences in rates of sepsis or NEC. The conclusion read: the speed of advancing enteral feeding volumes – daily increments of 30 mL/kg as compared with 18 mL/ kg – did not have a significant effect on the primary outcome of survival without moderate or severe neurodevelopmental disability at a corrected age of 24 months, nor did it affect the risks of late-onset sepsis or necrotizing enterocolitis in very preterm or very-low-birth-weight infants. So, when reading this really nicely conducted pragmatic trial, it is important to realize that the actual intakes were around 20 mL/kg/day and 15 mL/kg/day and that thus these differences do not have an impact on NEC or sepsis rates. Due to a slightly less favorable outcome at 24 months, the economic evaluation revealed that average costs per infant were slightly higher for faster feeds compared with slower feeds (mean difference EUR 300, non-significant) . Fewer infants achieved the principal outcome of survival without moderate to severe neurodevelopmental disability at 24 months in the faster feeds arm (802/1,224 vs. 848/1,246).
Effectiveness and safety of fast enteral advancement in preterm infants between 1,000 and 2,000 g of birth weight
Comments: Another, but much smaller, randomized controlled trial aiming at resolving a similar question was performed in Colombia and is discussed in this chapter . Here, the authors compared an aimed speed of advancement of 20 mL/kg/day with either 30 mL/kg/day (for infants 1,000–1,499 g, n = 23) or 40 mL/kg/day (for infants 1,500–2,000 g, n = 43) starting at postnatal day 2 or 3. Those aimed intakes were reached (21 mL [controls] – 27 mL [1.0–1.5 kg] – 40 mL [1.5–2 kg]). Their conclusion was that aiming at higher intakes, especially at the higher birth weight group, resulted in benefits like a reduced number of days on parenteral nutrition and a faster attainment to reach full enteral feeding (defined as 120 mL/kg/day).
Shorter time to full preterm feeding using intact protein formula: A randomized controlled trial
Comments: In this industry sponsored, pilot study, the authors describe a blinded RCT aimed to evaluate the effect of hydrolyzing the protein in a preterm formula on time to reach full enteral feeding, defined as >140 mL/kg/day . Although the title suggests otherwise, in the intention to treat analyses with both 30 infants (gestational age around 30–31 weeks) per group, no differences between the infants who were assigned to the intact protein formula group versus the hydrolyzed protein formula were noted. As is common in NICUs nowadays, most infants received mother’s own milk, only 23 out of 60 infants received >75% of their intake as study formula. The conclusion from the last year’s Cochrane systematic review remains identical: more trials are needed to suggest that either intact or hydrolyzed protein formulas exert a beneficial effect on outcomes in the NICU .
Quality and Quantity of Lipids during the First Few Weeks of Life
A mixed lipid emulsion containing fish oil and its effect on electrophysiological brain maturation in infants of extremely low birth weight: A secondary analysis of a randomized clinical trial
Comments: Comments on this article, as well as the following article (Ottolini et al.) are incorporated in the comments on the article by Thanhaeuser et al.
Containing fish oil in infants of extremely low birth weight: Neurodevelopmental outcome at 12 and 24 months corrected age, a secondary outcome analysis
After many decades of a single-lipid emulsion, based upon soybean oil only, many other lipid emulsions became available in many countries. Single component or mixtures of medium-chain triglycerides, olive oil, fish oil and soybean in different combinations were used, each with its own characteristics. Next to a pure soybean-based mixture, a solution with all four components became popular as there were theoretical advantages to use such a mixture. Here, we present three different studies on the short- and longer-term effects of the usage of such a multicomponent mixture [20–22]. Two of those studies were preceded by an article published in 2018  that described an RCT in which the incidence of parenteral nutrition-associated cholestasis was not significantly reduced using a mixed lipid emulsion compared to a pure soybean-based emulsion in 230 ELBW infants. Quite interestingly, the researchers applied bi-weekly amplitude-integrated electroencephalography from birth to discharge. In that way, electrophysiological brain maturation (background activity, sleep-wake cycling, and brain maturational scores) was assessed in about half of the included infants. Electrophysiological brain maturation was accelerated in preterm infants using a mixed parenteral lipid emulsion that contained fish oil . The accelerated maturation of amplitude-integrated electroencephalogram assessed between birth and hospital discharge could point out to cerebral DHA incorporation using the
mixed lipid emulsion in preterm infants. This created considerable expectations for longer-term neurodevelopmental follow-up. Certainly, this year another study from a different group described in a cohort of 67 VLBW infants a positive association of cumulative lipid intake in the first 2 weeks of life with significantly greater cerebellar volume at term-equivalent age, even though the administered lipid emulsion contained soybean oil only . No relationship was seen between carbohydrate or protein intake in the first month of life and cerebral volume.
Disappointingly, at 2 years corrected age, with still 80% of the infants included, those infants who received parenteral nutrition using a mixed lipid emulsion containing fish oil did not have a better neurodevelopment when compared to those receiving a soybean-based emulsion. These results fit in the studies described in the 2016 Cochrane meta-analysis on the effects of enterally administered DHA . Whereas one could speculate that parenterally provided additional DHA in the first weeks following birth may exert a larger effect, apparently this is not the case. However, this is not the first study with no clear effect of a fish oil containing emulsion on developmental outcome at 2 years corrected age [25, 26] although the number of infants studied at later age is still very low. So, the jury is still out there, but with many ongoing trials, the answer will be there in the next few years.
A modified low-protein infant formula supports adequate growth in healthy, term infants: A randomized, double-blind, equivalence trial
Comments: A high protein intake in early life is associated with an increased risk of overweight and obesity later in life, but the causality of this association (the “early protein hypothesis”) remains to be demonstrated . The protein requirements in infancy have been recently updated, enabling a reduction in total protein content and thus in protein intake. Taking into consideration the protein intake considered adequate for the majority of infants during the first 6 months of life by the European Food Safety Authority (EFSA) in 2013  and the EFSA Opinion on the essential composition of infant and follow-on formulae , the European Commission set in 2015 a minimum and maximum protein content in infant formula (IF) of 1.8 and 2.5 g/100 kcal, respectively , as compared to 1.8 and 3.0 g/100 kcal laid down in the 2006 Directive . Securing a sufficient supply of essential amino acids is necessary for healthy growth, particularly in early life when growth velocity is high. Consequently, both the protein quantity and quality in IF should be considered.
In a double-blind, randomized controlled trial involving 178 infants from enrollment (age ≤45 days) to 6 months of age, Kouwenhoven et al. compared a modified lowprotein (mLP) IF (1.7 g protein/100 kcal) with a control (Ctrl) IF (2.1 g protein/100 kcal). Weight gain from baseline up to the age of 17 weeks was equivalent between the mLP and CTRL formula groups. No differences in other growth parameters, body composition, or in adverse events were observed . Infants not or not fully breastfed should receive IF delivering protein in amounts similar to human milk contents, with high protein quality .
The therapeutic efficacy of Bifidobacterium animalis subsp. lactis BB-12® in infant colic: A randomised, double blind, placebo-controlled trial
Comments: The pathophysiology of infant colic is thought to be multifactorial, involving feeding disorders, dysmotility, hormone alterations, or behavioral factors . Differences in gut microbiota have been shown between infants with or without colic. Probiotics are live microorganisms that alter the microflora of the host and provide beneficial health effects. There is a growing body of evidence to suggest that intestinal flora in colicky infants differ from that in healthy infants, and that probiotics can redress this balance and provide a healthier intestinal microbiota landscape . The Bifidobacterium animalis subsp. lactis, BB-12® strain is the most documented Bifidobacterium. The BB-12® strain received in 2002 a Generally Recognized as Safe (GRAS) status by the Food and Drug Administration (FDA) in the US for both infants and the general population. In Europe, B. animalis has been granted Qualified Presumption of Safety (QPS) status since 2007 by EFSA.
Nocerino et al.  performed an RCT in otherwise exclusively breastfed infants with infantile colic who were randomly allocated to receive BB-12 (1 × 109 colony-forming units/day) or placebo for 28 days. The rate of infants with reduction of ≥50% of meandaily crying duration after 28 days of intervention was higher in infants treated with BB-12, starting from the end of 2nd week. The mean number of crying episodes decreased in both groups, with a significantly higher effect in BB-12. The take-home message from this study of good methodological quality is that a positive effect of a supplementation with BB-12 on infant colic is demonstrated in exclusively breastfed infants. There is no evidence to support a supplementation of IF with BB-12 in nonbreastfed infants.
Improved neurodevelopmental outcomes associated with bovine milk fat globule membrane and lactoferrin in infant formula: A randomized, controlled trial
Comments: Human milk contains a wide variety of bioactive compounds with antimicrobial and immunomodulating activities that contribute to the protection of infants against infections and the modulation of inflammatory reactions. A prominent protein in this respect is lactoferrin (around 2 g/L in mature breast milk). Lactoferrin has broad-spectrum, anti-microbial activity against bacteria, fungi, viruses, and protozoa. A decreased risk of diarrhea and young children and lower rates of lower respiratory infections in children receiving dietary bovine lactoferrin (BL) have been reported . Lipids are secreted in breast milk in the form of unique colloidal structures called milk fat globules (MFG), which are enveloped by a biological membrane named the milk fat globule membrane (MFGM). The MFGM surrounds the MFG core, enabling the dispersion of lipids into the breast milk aqueous environment [38, 39]. Polar lipids contained in the MFGM are glycerophospholipids, sphingomyelin, and in a much less amount, neutral glycosphingolipids comprising uncharged sugars/cerebrosides and acidic glycosphingolipids comprising sialic acid, namely, the gangliosides. With regard to neurodevelopment, the ganglioside content of the MFGM might be highly relevant, considering the high ganglioside content in nervous tissue, the high requirement in the perinatal period due to the rapid brain growth, and the demonstrated uptake of dietary gangliosides. MFGM also contains proteins (25–70% on a per weight basis) with bioactivities as Mucin 1, lactadherin, and fatty acid-binding protein among others, that have been suggested to contribute to the protection against bacteria and viruses in the neonatal gastrointestinal tract and to affect the immune system. Positive effects of the occurrence of MFGM in infant food on cognitive development have also been reported.
Li et al.  performed an RCT in healthy term infants with the objective to assess neurodevelopment, growth, and health outcomes in infants receiving bovine MFGM and BL up to 1 year of age. The mean cognitive, language, and motor scores were significantly higher at 1 year of age for the MFGM + LF group. The overall incidence of respiratory-associated adverse events and diarrhea was significantly lower for the MFGM + LF group. The addition of MFGM and BL in IF is safe and contributes to beneficial cognitive, gastrointestinal, and respiratory health outcomes.
Adherence to vitamin D intake guidelines in the United States
Comments: Comments on this article, as well as the following article (Dawodu et al.) are incorporated in the comments on the article by Thorisdottir et al.
Infant feeding, vitamin D and IgE sensitization to food allergens at 6 years in a longitudinal Icelandic cohort
Comments: Vitamin D has a major role in phosphocalcic homeostasis and bone health as well as a series of actions in cell differentiation, proliferation and apoptosis, and immunomodulation . Many studies, mostly observational, have suggested a protective role of vitamin D against allergic, infectious, autoimmune, and cardiovascular disease as well as cancer. As an example, an association between vitamin D deficiency and severity/mortality of COVID-19 has been shown recently . However, the level of evidence remains insufficient to confirm the causality of these actions, independent of phosphocalcic metabolism. In recent years, reports suggesting a resurgence of vitamin D deficiency in the Western world, combined with the above-mentioned health benefits of vitamin D, have resulted in increased interest from healthcare professionals and the lay people.
All guidelines published since 2010 worldwide, including those from the ESPGHAN (European Society for Gastroenterology, Hepatology and Nutrition) Committee on Nutrition published in 2013, state that infant vitamin D intake should be 400 IU per day during the first year of life . Simon and Ahrens examined the rate of adherence with the 2008 American Academy of Pediatrics (AAP) guidelines (reaffirmed in 2014) on vitamin D supplementation in infants <1 year of age . Specifically, exclusive or partially breastfeeding infants and non-breastfeeding infants consuming <1 L of formula should be supplemented with 400 IU daily. Overall, 27.1% of infants 0 to 11
months from the NHANES (National Health and Nutrition Examination Survey) 2009–2016 met the 2008 AAP guidelines. Non-breastfeeding infants were more likely to meet guidelines than breastfeeding infants (31.1 vs. 20.5%, respectively; p < 0.01). From 2009–2010 to 2015–2016, there was no change in the percentage of infants who met the guidelines for vitamin D intake. There is an urgent need to consider how to best meet vitamin D intake guidelines in infants.
Human milk contains very little vitamin D and is not sufficient by itself to meet the recommended daily intake of 400 IU of vitamin D for infants. As an alternative strategy to daily vitamin D supplementation, Dawodu et al.  compared in a 6-month postpartum RCT the effect of high-dose maternal vitamin D supplementation alone
(6,000 IU/day) with maternal (600 IU/day) plus infant (400 IU/day) vitamin D supplementation in breastfeeding infants. A total of 96% of mothers on 6,000 IU, achieved an adequate serum 25(OH)D level (≥50 nmol/L) compared with only 52% in mothers on 600 IU (p < 0.0001). Infants of mothers on 600 IU and also supplemented with 400 IU vitamin D had slightly higher serum 25(OH)D than infants of mothers on 6,000 IU alone (109 vs. 92 nmol/L, p = 0.03); however, similar percentage of infants in both
groups achieved adequate serum 25(OH)D ≥50 nmol/L (91 vs. 89%, NS). Safety measurements, including serum calcium and urine calcium/creatinine ratios in the mother and serum calcium levels in the infants were similar in both groups. This study confirms the results of a recent RCT comparing serum 25(OH)D of infants who had direct vitamin D supplementation with 400 IU/day plus maternal supplementation of 400 IU/day and infants of mothers on 6,400 IU/day supplementation alone . Interestingly, a recent study found maternal preference for taking medication themselves as opposed to giving the vitamin D supplement to their infants . It should kept in mind that the tolerable upper limit of intake (UL) for vitamin D has been set by EFSA in 2012 at 100 μg (4,000 UI)/day for lactating women . This UL is lower than the daily dose of 6,000 IU given in the study from Dawodu et al., even if the duration of the supplementation is limited to 6 months. More studies are needed: (1) to confirm
the safety of this high-dose vitamin D supplementation in breastfeeding mothers; (2) to assess the efficiency on the vitamin D status of both mothers and infants with lower
doses of vitamin D supplementation.
Due to the northern latitude, vitamin D is of special importance in the Nordic countries. In the Nordic Nutrition Recommendations (NNR) as well as national guidelines
in all Nordic countries, parents are advised to give vitamin D supplements (400 IU/ day) to their infants . While vitamin D deficiency in infancy or childhood has been
associated with higher immunoglobulin E (IgE) levels and sensitization to food allergens , other studies suggest that infant vitamin D supplementation increases the risk of later atopy and allergy . In a population-based study of Icelandic children, solid food introduction prior to 4 months was more common, and total vitamin D intake at 12 months was lower among 6-year-old IgE-sensitized versus non-sensitized children . Vitamin D supplement use at 6 years was less common among IgE-sensitized children. The results add to the present literature about early life exposures and IgE outcomes in childhood, although this observational study cannot determine causality.
Prevention of Allergy
Primary prevention of cow’s milk sensitization and food allergy by avoiding supplementation with cow’s formula at birth: A randomized clinical trial
Comments: Comments on this article are incorporated in the comments on the article by Perkin et al.
Efficacy of the Enquiring About Tolerance (EAT) study among infants at high risk of developing food allergy
Comments: Although the impact of breastfeeding on the development of allergy has been extensively investigated, the issue still remains a matter of debate. Whatever this protective effect, women with a family history of allergy should be encouraged to breastfeed their infants like everyone else, and, in this targeted population, exclusive breastfeeding is recommended until the age of 6 months. There is evidence that dietary exposure in infancy can influence the risk of allergy later in life, with a specific concern that exposure to intact cows’ milk protein in the form of IF during the first days of life in breastfed infants could trigger the onset of allergic disease. It is the well-known concept of the “dangerous bottle.” The use of cow’s milk formula to supplement breastfeeding is very popular in Japan, based on maternal preferences but not clinical evidence. Urashima et al.  conducted an RCT to assess whether the risk of cow’s milk formula (CMF) sensitization and food allergy is decreased by avoiding or supplementing with CMF at birth. Immediately after birth, newborns were randomized to breastfeeding (BF) with or without amino acid-based elemental formula (EF) for at least the first 3 days of life (BF/EF group) or BF supplemented with CMF (5 mL/day) from the first day of life to 5 months of age (BF/CMF group). Sensitization to cow’s milk at 2 years of age was significantly less frequent in the BF/EF group (16.8%) than in the BF/ CMF group (32.2%): relative risk (RR), 0.52; 95% CI: 0.34–0.81. Furthermore, the prevalence of food allergy at 2 years of age was significantly lower in the BF/EF than in the BF/CMF group for immediate (4 [2.6%] vs. 20 [13.2%]; RR, 0.20; 95% CI: 0.07–0.57) and anaphylactic (1 [0.7%] vs. 13 [8.6%]; RR, 0.08; 95% CI: 0.01–0.58) types.
The results of this RCT of good methodological quality suggest that both sensitization to cow’s milk and food allergy, including cow’s milk allergy and anaphylaxis, are primary preventable by avoiding CMF supplementation for at least the first days of life. It should be kept in mind that this study does not allow to conclude that a hydrolyzed IF is efficient in reducing the risk for food allergy in infants. Their use in infants at risk for allergy is very controversial. In their 2018 Cochrane review, Osborn et al.  found no evidence to support short-term or prolonged feeding with a hydrolyzed IF compared with exclusive breastfeeding for prevention of allergic disease and no evidence to support prolonged feeding with a hydrolyzed formula compared with a CMF for prevention of allergic disease in non-exclusively breastfed infants. Boyle et al.  also concluded that there was no evidence to support that a hydrolyzed formula could reduce the risk of eczema and prevent allergy to cows’ milk.
The Enquiring About Tolerance (EAT) Study, an RCT of the early introduction of allergenic solids into the infant diet from 3 months of age, was conceived to reduce the
burden of food allergies through early oral tolerance induction to specific food antigens. The intervention effect did not reach statistical significance in the intention-totreat (ITT) analysis of the primary outcome, i.e. food allergy to one or more of six foods between 1 year and 3 years of age . Perkin et al.  performed a secondary ITT analysis in subgroups at high risk of allergy identified in the EAT Study: nonwhite infants; infants with visible eczema at enrollment with severity determined by SCORAD; and infants with food sensitization at enrollment (specific IgE ≥0.1 kU/L). Early introduction was effective in preventing the development of food allergy in infants sensitized to egg or to any food at enrollment and those with eczema of increasing severity at enrollment. These results could help to update the current recommendations on the age of introduction of allergenic foods in infants at high risk of allergy.
Appropriate age range for introduction of complementary feeding into an infant’s diet
Comments: Complementary feeding (CF), which embraces all solid and liquid foods other than breast milk or IF, is the process starting when breast milk or IF alone is no longer sufficient to meet the nutritional requirements of infants so that other foods and liquids are needed. Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) revised its Scientific Opinion of 2009 on the appropriate age for introduction of complementary feeding of infants . This request arose in the context of the information regarding the use of processed cereal-based foods and baby foods. Indeed, the Directive 2006/125/EC requires the mandatory indication of a statement on the appropriate age from which processed cereal-based foods and baby foods may be used, that shall be not less than 4 months for any products .
The main conclusions of this EFSA Scientific Opinion can be summarized as follows
1. The available data do not allow the determination of a single age for the introduction of complementary foods (CFs) for infants living in Europe. The appropriate age range depends on the individual’s characteristics and development, even more so if the infant was born preterm.
2. As long as the foods are given in an age-appropriate texture, are nutritionally appropriate, and prepared according to good hygiene practices, there is no evidence that the introduction of CFs is associated with either adverse or beneficial health effects (except for infants at risk of iron depletion) at any age investigated in the included studies (<1 month to <6 months for earlier introduction).
3. For nutritional reasons, the majority of infants need CFs from around 6 months of age. For preterm infants, this refers to post-term age. Infants at risk of iron depletion
(exclusively breastfed infants born to mothers with low iron status, or with early umbilical cord clamping [<1 min after birth], or born preterm, or born smallfor- gestational age or with high growth velocity) may benefit from introduction of CFs that are a source of iron before 6 months of age.
4. The earliest developmental skills relevant for the consumption of spoon-fed pureed CFs can be observed between 3 and 4 months of age. Skills necessary for
consuming self-fed finger foods can be observed in some infants at 4 months, but more commonly between 5 and 7 months of age. For preterm infants, this refers to post-term age.
5. The fact that an infant may be ready from a neurodevelopmental point of view to progress from a liquid to a more diversified diet before 6 months of age does not imply that there is a need to introduce CFs.
6. There is no reason to postpone the introduction of potentially allergenic foods (egg, cereals, fish, and peanut) to a later age than that of other CFs as far as the risk of developing atopic diseases is concerned. Regarding the risk of coeliac disease, gluten can be introduced with other CFs.
This EFSA Opinion is another piece of information on the optimal timing of introduction of CF in infants among several other publications. The main conclusions of ESPGHAN in 2017  were that “CFs should not be introduced before 4 months but should not be delayed beyond 6 months. Allergenic foods may be introduced when CFs are started any time after 4 months. Infants at high risk of peanut allergy should have peanut introduced between 4 and 11 months, following evaluation by an appropriate trained specialist and gluten may be introduced between 4 and 12 months.” The US Department of Agriculture (USDA) and the Department of Health and Human Services launched in 2012 the Pregnancy and Birth to 24- months project (https://www.fns.usda.gov/resource/pregnancy-and-birth-24-months), which involved conducting a series of systematic reviews about the timing of introduction of complementary feeding in healthy term infants. Limited evidence was found that introducing
CFs before 4 months compared with later could increase the odds of overweight and obesity . There was moderate evidence for no association between the age of
CF introduction and the risk of developing food allergy, atopic dermatitis, or childhood asthma . Limited to strong evidence (depending on the specific food studied)
suggested that the risk of food allergy and atopic dermatitis did not increase by introducing allergenic foods after 4 months of age but within the first year of life. For
bone health and developmental milestones, insufficient evidence was available to draw conclusions on the relationships [62, 64]. For micronutrient status, there was
moderate evidence that introducing CFs at 4 months of age compared with 6 months does not affect iron status, derived from evidence generated in high-income countries
. There is an increasing consensus that no single age where all infants should be started with foods other than milk can be defined. Parents and caregivers should take into account, among others, the neurodevelopment and readiness of the infant.
Nutrition during pregnancy, lactation, and early childhood and its implications for maternal and long-term child health: The EarlyNutrition Project recommendations
Comments: Since the seminal work of Barker in the UK, a lot of attention has been given over the past 30 years to the influence of nutrition in utero and during critical periods of growth on health in adulthood, an area termed “fetal origins hypothesis” or “fetal programming”; it was later modified to the “developmental origins of health and disease” (DOHaD) to better reflect both the gestational and postnatal periods. Barker et al. [66, 67] conducted studies using the Hertfordshire birth cohort, which included more than 15,000 infants for whom birth weight and early feeding practices were documented in the early 1900s. From this cohort, it was reported that children born small have a higher risk for developing type 2 diabetes, hypertension, and cardiovascular disease (coronary heart disease, stroke). Similar results have been replicated using birth cohorts from many other countries worldwide. There is a scientific consensus nowadays that poor nutrition and/or growth during the first 1,000 days of life (from conception up to 2 years of age) are risk factors for a number of chronic diseases later in life.
Researchers across the European Union, the US, and Australia collaborate in the European Commission-funded “EarlyNutrition Research Project” (http://www.project- earlynutrition.eu). This research collaboration explores how nutrition and metabolism during sensitive time periods of early developmental plasticity can impact on cytogenesis, organogenesis, metabolic and endocrine responses as well as epigenetic modification of gene expression, thereby modulating later health . These researchers, including many key opinion leaders in pediatric nutrition, consolidated the scientific evidence base and existing recommendations . They present in this paper updated recommendations for optimized nutrition before and during pregnancy, during lactation, infancy, and toddlerhood, with special reference to later health outcomes.