Nutrition and Growth in Preterm and Term Infants

Introduction

Nutrition and growth of preterm infants is attracting a lot of attention. This year, we decided to address 3 topics on which several interesting studies have been published. By Including papers on the indications and electrolyte composition of parenteral nutrition(PN), and on necrotizing enterocolitis (NEC), we thought to provide you with ample interesting topics that might change your view on how to take care of premature infants at your word. For term infants, the review addressed 4 different topics: breastfeeding, breast milk substitutes, food allergy (FA), and complementary feeding (CF)

Preterm Infants

Association between early amino acid intake and full-scale IQ at age 5 years among infants born at less than 30 weeks’ gestation

Comments: Uthaya and colleagues have compiled outcome data (up till corrected age 2 years)from over 65,000 preterm infants born <31 weeks’ gestation in England and Wales during a 12-year period ^[1]. Infants were stratified whether they had their PN initiated early after birth (i.e., within the first 2 calendar days after birth, i.e., within 48 h afterbirth) or from after the third calendar day onward (which could in fact be already 25h after birth), meaning that some overlap was inevitable. From the propensity score-matched subgroups (n = 8,147 each), it was derived that there were no differences in survival without major morbidities between both groups. However, breaking down the primary outcome, authors found that mortality was lower if started early afterbirth with PN, whereas the incidence of several major morbidities such as late-onset sepsis, bronchopulmonary dysplasia, and retinopathy of prematurity was higher in this group.

The same group of researchers also conducted a similar approach for a similarly large data set on moderately preterm born infants, i.e., those born between 30 + 0 and 32+ 6 weeks’ gestation as described in the second manuscript above ^[2]. The intervention was PN administered at any point in the first 7 days of postnatal life or not. Propensity score–matched infants (n = 8,146 in each group) were compared, and just like in the previous study, researchers found a lower mortality rate in the early PN group, but simultaneously more bronchopulmonary dysplasia, late-onset sepsis, NEC, and a slower growth during hospitalization. Remarkably, 8.1% of infants in the early PN group suffered NEC, which is a very high rate in these infants weighing on average 1.59 kg (SD 0.29).

Reasons for why PN was not initiated in the late PN group early after birth could not be derived. So residual confounding may always be responsible for the observed findings in cohort studies like these, no matter how large the size of a cohort may be or how many variables were controlled for. Indications and application for PN may vary from unit to unit ^[3], just like other therapies, treatments, and outcomes in these units. Although the cited studies controlled for regional neonatal network, individual NICU practices are difficult to control for. Thus, these studies do not provide evidence to change current practice but may provide rationale for conducting new randomized trials on the merit of PN in certain patient groups. Besides, PN may also vary in composition or quality, so that PN may not be assessed as such.

These findings could warrant what the proper indications for PN are in the neonatal population. This question is nearly automatically linked to findings from the pediatric PEPaNIC trial where it was shown that early PN after admission on a PICU resulted in adverse outcomes ^[5], also in the term neonatal population ^[6]. It is hypothesized that especially excess amino acids during an inflammatory event could also play a harmful role due to hampered autophagy processes ^[7]. This resulted in the recently published position paper by ESPHAN on how to implement PN during acute critical illness also in preterm infants ^{[8, 9]}, which was also discussed in the last year’s yearbook ^[10].

From France, by study design a reasonably similar article appeared in 2021 as well ^[4],but more or less contradicting the findings from the 2 above-discussed papers. From preterm infants born <30 weeks’ gestation in the year 2011, nutritional intakes, neonatal course, and 5 years corrected age neurodevelopmental outcomes as a primary outcome were assessed. Infants were stratified by whether they had received either less or more than 3.5 g/kg per day of intravenous amino acids or enteral protein. Each propensity score–matched cohort consisted of 717 infants who were born on average at 27.2 weeks’ gestation. Approximately 75% of total nutritional intake was via the parenteral route. Researchers found that infants who had the higher amino acid intakes (above 3.5 g/kg/day) had significantly higher full-scale IQ scores, a finding also confirmed by assessing amino acid intake as a continuous variable. Moreover, from a subset of 134 infants who had underwent MRI scanning at term equivalent age, positive correlations between amino acid intakes and white matter development were seen. Notably, mentioned correlations between amino acid intakes and later neurocognitive outcomes could not be repeated for the other macronutrients, i.e., lipids or carbohydrates. 

Overall, it is difficult to draw a conclusion which is in accordance with all 3 very well performed propensity score–matched cohort studies. Hopefully it gives ground to new large sample sized randomized controlled trials (RCTs) on the precise indications and composition of PN in preterm infants.

Higher parenteral electrolyte intakes in preterm infants during first week of life: effects on electrolyte imbalances

Comments: Over the years, several studies have described the problem of neonatal refeeding-like syndrome. In 2021, Bradford and colleagues published a nicely performed systematic review on all published studies so far, describing which infants are at particular risk, together with a range of observed clinical implications ^[13]. Hyperglycemia, prolonged mechanical ventilation, and increased incidence of sepsis and mortality from some of the frequently encountered clinical consequences of early hypophosphatemia.

Unfortunately, to date, no RCTs have been published on providing higher versus lower amounts of parenteral phosphate in order to prevent early neonatal refeeding-like syndrome. However, Ozer et al. in a nicely performed pre-post epoch cohort study compared 261 very preterm infants whether they had received 1 mmol phosphate per 100 mL in PN from birth onward or mineral-free PN during the first 48 hours afterbirth ^[14]. A marked less incidence of hypophosphatemia was seen as well as several clinical respiratory parameters such as prolonged mechanical ventilation or corticosteroid usage. Mineral-free PN should no longer be used, as also recommended byESPGHAN advising a parenteral phosphate intake of 1.0–2.0 mmol/kg/day from birth onward, and increased within several days to 1.6–3.5 mmol/kg/day ^[16].

Similarly, Späth et al. compared an epoch with their “original” parenteral regimen with a more concentrated recipe which included a higher phosphate-to-amino-acid ratio as well _^[15]. The authors elegantly showed that providing all electrolytes from birth onward to infants born on average after 27 weeks’ gestation was safe and resulted in much less serum electrolyte disturbances. Individual monitoring of phosphate serum concentrations in the first week of life, especially in those with suboptimal intrauterine growth, seems warranted, despite standard parenteral mineral provision from birth onward, as early hypophosphatemia may still be present and have direct adverse clinical consequences.

Initial laparotomy versus peritoneal drainage in extremely low birthweight infants with surgical necrotizing enterocolitis or isolated intestinal perforation: a multicenter randomized clinical trial

Comments: Berrington and Embleton elegantly show the problems with the currently used classifications in 2 different articles ^{[21, 22]}. FIP and NEC had overlapping features, such as day of onset, which made discrimination difficult. They urge caution using routinely collected data. In their study, they reviewed a large series of preterm infants born less than 32 weeks’ gestation treated over a 10-year period in a tertiary neonatal unit in Newcastle, UK. Only a few features were statistically different between infants with NEC or FIP. Clinically that difference may not be very important as initial treatment is equal, but the difference is important for research purposes. A call to action was made to international panels to develop a useful and consistent classification. Such an attempt has also previously been made by an international group of experts^[26]. They also took time of onset as one of the discriminating items, which is thus challenged by Berrington and Embleton. Others, like Lueschow et al., used standard statistics and machine learning to critically evaluate over 200 patients from a single center with NEC, FIP, and possible NEC across several different definitions of NEC ^[23]. 

In Lueschow’s paper, newer definitions ^{[26, 27]} outperformed original Bell’s criteria.Taken that into account, the article of Swanson et al. fits into this discussion as the authors state that FIP will soon be a more important surgical diagnosis than NEC ^[24].They argue that rates of NEC are decreasing over recent years whereas those of FIP(abbreviated as SIP) increase. Those data are obtained from the Pediatrix/Mednax data warehouse. As Berrington emphasizes, the definition of the different diagnosis plays a pivotal role, although also the cumulative incidence decreases. Also, Swansonet al. ^[24] acknowledge the need for better definitions than those developed by Bell. These are data from the USA, where at that time probiotics were not used. The authors contribute predominantly to the increased use of human (donor) milk to the decline. Altogether, the discussion remains and in the next few years it will become apparent which definition we will be using. For sure we will, in future years, abandon Bell’s criteria, after having served (in modified versions) for 5 decades.

In 2011, the conclusion following a Cochrane’s meta-analysis by Rao et al. was: “Evidence from two RCTs suggests no significant benefits or harms of peritoneal drainage over laparotomy. However, due to the very small sample size, clinically significant differences may have easily been missed” ^[28]. At that time only 185 preterm or low birth-weight infants were included. Thus, the study results of the recently published Necrotizing Enterocolitis Surgery Trial were very welcome and long awaited ^[25]. Witha primary hypothesis that laparotomy would result in a lower rate (−15%) of death or neurodevelopmental impairment at 18–22 months corrected age, 310 infants were included. There was no overall difference in death or neurodevelopmental impairment rates in the initial laparotomy versus drainage groups (aRR = 1.0, 95% CI: 0.87–1.14). The authors hypothesize in their discussion that it is plausible that initial laparotomy would more likely benefit infants with NEC, especially those with multiple perforations and extensive intestinal necrosis and peritonitis, whereas infants with isolated intestinal perforation with a single and often small perforation may require only a peritoneal drain. However, our previous discussion demonstrated the difficulty in discriminating between those 2 entities. The need for additional laparotomy in the initial drainage group was very high, resulting in, at the end, a similar number of operations in both groups. The study took long, almost 10 years, despite 20 centers being involved. The authors state that this questions about the level of evidence that can realistically be expected or required for treatment recommendations for rare and difficult-to-study diseases. In our view, this calls for a worldwide approach for all kinds of RCTs for rare diseases or conditions and not so much abandoning well-designed large trials for rare diseases. Platform trials may provide a solution. Platform trials area type of randomized clinical trial that allow simultaneous comparison of multiple intervention groups against a single control group that serves as a common control based on a prespecified interim analysis plan. The platform trial design enables introduction of new interventions after the trial is initiated to evaluate multiple interventions in an ongoing manner using a single overarching protocol called a master (or core) protocol. When multiple treatment candidates are available, rapid scientific therapeutic discoveries may then be made ^[29].

Efficacy and safety of enteral recombinant human insulin in preterm infants: a randomized clinical trial

Comments: For oropharyngeal colostrum administration, the jury is still out there, but does not tend to be supportive. The most recent meta-analysis (8 RCTs, 682 patients) performed by Ma et al., published in 2021, showed borderline significance in favor of using oropharyngeal colostrum administration ^[30]. However, adding the Aggarwal et al. study from India (n = 260 infants) will probably not result in a significant reduction on the incidence of NEC or other morbidities ^[31]. In conclusion, while administration of oropharyngeal colostrum to preterm infants appears safe and theoretically attractive from both an emotional and immunological point of view, especially in high-resource settings, no clear clinical benefits have consistently been proven unfortunately.

Another study of interest discussed here by Mank et al. examined the effect of recombinant human (rh) insulin on feeding tolerance ^[32]. This multicenter, double-blind, placebo-controlled randomized clinical trial was conducted at 46 neonatal intensive care units throughout Europe, Israel, and the USA and included 303 preterm infants in total. Tolerance to enteral feeding improved which was defined as a significant reduction of time to full enteral feeding (median reduction of 4 days). Besides, also of interest, there seemed to be a reduction of NEC grades 2 and 3 in the rh-insulin-supplemented groups. As this was a secondary outcome and the study was not powered to detect a significant difference, these results can only be considered as hypothesis generating. Another large RCT on rh-insulin is planned, so we will have to await those results, to see whether this may truly form another prophylactic treatment for NEC prevention in preterm infants.

Term Infants

Osteopathic manipulative treatment to improve exclusive breastfeeding at 1 month

Comment: The impact of breastfeeding remains questioned on various long-term health outcomes such as cardiometabolic health. Since it is unethical to randomly assign children into breastfeeding and non-breastfeeding treatment groups, observational studies are performed to assess the association between breastfeeding and long term health outcomes. Information on infant feeding is often collected retrospectively because it is rare to have a large cohort study to collect data at multiple timepoints during infancy to capture breastfeeding information prospectively. The TEDDYstudy is a large birth cohort study prospectively following children with increased genetic susceptibility for type 1 diabetes and celiac disease in Finland, Germany, Sweden, and the United States for the development of islet and transglutaminase autoantibodies. It collects prospective information on environmental exposures and childhood conditions, such as allergy, as well as demographic and anthropometric data, such as type and feeding and growth. Hummel et al. used information from theTEDDY cohort to investigate whether breastfeeding is associated with the development of 3 health outcomes: autoimmunity, allergy, and obesity ^[33].

A total of 8,676 infants were followed for the development of autoantibodies to islet autoantigens or transglutaminase allergies, and for anthropometric measurements up to a median age of 8.3 years. Information on breastfeeding was collected at 3 months of age and prospectively thereafter. The risk of obesity was assessed at 5.5years of age. Breastfeeding duration was not associated with a lower risk of either isletor transglutaminase autoimmunity. Exclusive breastfeeding >3 months was associated with a decreased risk of seasonal allergic rhinitis (adjusted HR: 0.70; 95% CI: 0.53,0.92; p < 0.01). Any breastfeeding >6 months and exclusive breastfeeding >3 months were associated with decreased risk of obesity (adjusted OR: 0.62; 95% CI: 0.47, 0.81;p < 0.001; and adjusted OR: 0.68; 95% CI: 0.47, 0.95; p < 0.05, respectively).Of note, the TEDDY study population was selected based on the presence of a human leukocyte antigen genotype conferring risk of type 1 diabetes. Therefore, the results on autoimmunity and seasonal allergic rhinitis outcomes may not be generalizable to the general population.

The relationship between breastfeeding and reduction of the risk for overweight and obesity later in life is controversial. Early evidence from observational studies suggested that breastfeeding was associated with a slightly lower mean BMI than was formula feeding ^[36], but the randomized breastfeeding promotion intervention trial from Belarus (PROBIT) did not show reduction in child obesity assessed at age 6.5years ^[37]. Two reviews of, respectively, 40 systematic reviews and 28 systematic reviews and meta-analyses published in 2016 both demonstrated an association between breastfeeding and a modest reduction (the odds decreased by 13% based on high-quality studies) in the risk of later overweight and obesity in children ^{[38, 39]}. 

Given the observational nature of available studies, confounding could not be ruled out. Education, socioeconomic status, and race are associated with both initiation and duration of breastfeeding in high-income countries. Socioeconomic factors are also associated with BMI and/or overweight and obesity in early childhood.

In the development of the 2020–2025 Dietary Guidelines for Americans, another systematic review was conducted on the relation between breast milk consumption and subsequent overweight and obesity. This review included 42 articles from 31 individual studies, primarily observational, with a focus on healthy full-term infants ^[40].To address the issue of confounding, Dewey et al. have synthesized the results from the above-mentioned systematic review with emphasis on the 6 cohorts with sibling pair analysis and the PROBIT study. The advantage of sibling-pair studies is that they should reduce confounding due to genetics, parenting practices, and environmental characteristics.

Moderate evidence suggested that “ever,” compared with “never,” consuming breast milk is associated with a lower risk of overweight and obesity at ages 2 years and older, particularly if the duration of breast milk consumption is >6 months. However,residual confounding could not be ruled out. Evidence was insufficient to determine the relation between the duration of any human milk consumption and overweight and/or obesity at age 2 years and older. This was based on the inconsistency in the findings.

Further research is needed to better understand the relationship between infant feeding practices and the risk of overweight or obesity in later life, as well as the biological and behavioral mechanisms if the relation is causal.

The use of OMT in pediatrics is very limited due to the lack of evidence with respect to safety and efficacy. A systematic, scoping review of pediatric osteopathic medicine published in 2021 yielded 315 unique articles. It was concluded that there is little strong, scientific, evidence-based literature demonstrating the therapeutic benefit ofOMT for pediatric care ^[41]. Among breastfeeding-support programs, OMT is a frequently used approach, although with no evidence of efficacy. Jouhier et al. hypothesized that OMT, when added to medical support, would improve rates of exclusive breastfeeding at 1 month of age ^[35]. Breastfed term infants recruited at the University Hospital of Nantes, France were eligible if one of the following criteria was met:suboptimal breastfeeding behavior, maternal cracked nipples, or maternal pain. Theinfants were randomly assigned to the intervention or the control group. The intervention consisted of 2 sessions of early OMT, while in the control group, the manipulations were performed on a doll behind a screen. A total of 128 mother-infant dyadswere randomized, with 64 assigned to each group. There was no statistical difference in the rate of breastfeeding at the age of 1 month between the 2 groups, and no adverse effects were reported in either group. Jouhier et al. concluded that OMT did nothave a significant effect on the rate of exclusive breastfeeding at 1 month and thatthere is insufficient evidence to recommend OMT for breastfeeding support.

Infant formulas with postbiotics: an updated systematic review

Comments: Helfer et al. conducted a systematic review to evaluate the conduct and reporting of formula milk trials. They had a special interest in understanding the risk of bias in published formula trials and if trial procedures could cause harm by undermining breastfeeding of participants ^[42]. 

A total of 307 trials published between 2006 and 2020 were identified, of which only 73 (24%) trials in 13,197 children were prospectively registered. Another 111 unpublished but registered trials in 17,411 children were identified. Detailed analysis was undertaken for 125 trials (23,757 children) published since 2015. Only 17 (14%) of these trials were conducted independently of breast milk substitute companies, 26(21%) were prospectively registered with a clear aim and primary outcome, and authors or sponsors shared prospective protocols for 11 (9%) trials. Risk of bias was low in only 5 (4%) and high in 100 (80%) recently published trials, mainly because of inappropriate exclusions from analysis and selective reporting. Primary outcomes were reported by authors as favorable in 86 (69%) trials, and 115 (92%) abstract conclusions were favorable. One of 38 (3%) trials in partially breastfed infants reported adequate support for breastfeeding, and 14 of 87 (16%) trials in non-breastfed infants confirmed the decision not to breastfeed was firmly established before enrollment in the trial. In most recent trials, investigators were employed by, or had financial links to,the industry, who were often involved in the statistical analysis and writing. There is a lack of transparency of clinical trials, and evidence of selective reporting between and within trials.

Lactoferrin is a multifunctional protein of the transferrin family. Lactoferrin can be purified from milk or produced recombinantly. Human colostrum has the highest concentration, followed by mature breast milk, then cow’s milk. Lactoferrin from breast milk has a bacteriostatic activity against Escherichia coli, and was also found to be able to kill pathogens, such as Vibrio cholera and Streptococcus mutans. Lactoferrinalso can affect and modulate immune function in the infant, thereby affecting health outcomes. Human and bovine lactoferrin are analogous with respect to structure and function; about 78% of the human lactoferrin sequence is similar to the bovine lactoferrin. Various studies have demonstrated its protective role against respiratory tract infections (RTIs). Ali et al. performed a meta-analysis [43] to elucidate the association of lactotransferrin supplementation to infant formula in reducing the risk of RTIs by systematically reviewing the data from RCTs.

The primary outcome was a reduction in respiratory illness and decrease in  frequency, symptoms, and duration. A total of 9 RCTs were eligible for this review, of which were included in the meta-analysis. Two studies demonstrated a high risk of bias. The meta-analysis revealed a significantly reduced odds of developing RTIs with the use of lactotransferrin relative to the control (pooled odds ratio 0.57; 95% confidence interval 0.44 – 0.74, n = 1,194). Of note, the findings of this meta-analysis are limited by undersized cohorts and substantial risk of biases in few studies. Very well-designed RCTs are needed to warrant the routine use of lactotransferrin in infant formula.

The term postbiotic appropriately refers to substances derived after the microorganisms are no longer alive. The microbes comprising a postbiotic may be inanimate, intact cells or may be structural fragments of microbes, such as cell walls. Many preparations of postbiotics also retain microbe-produced substances, such as metabolites, proteins, or peptides, which may contribute to the overall health effect conferred by a postbiotic. Postbiotics are also known as fermented formulas, that is, those fermented with lactic acid–producing bacteria during the production process and not containing significant amounts of viable bacteria in the final product. Infant formulas supplemented with postbiotics are available in a growing number of countries worldwide. They are more expensive than regular infant formulas and often bear claims, including health claims the substantiation of which may not be supported by strong scientific data.

Szajewska et al. report an update of their 2015 systematic review on infant formula with postbiotics ^[44]. They assessed safety and clinical effects of the consumption of infant formula with probiotics (with or without the addition of other ingredients)compared with standard infant formula. Eleven RCTs were included in the systematic review. Five trials had an overall high risk of bias, and 6 trials had some concerns of bias. Most data were available on infant formula fermented with Bifidobacterium breve C50 and Streptococcus thermophilus (BB/ST). These infant formulas were safe and well tolerated. Postbiotic infant formulas with additional modifications (i.e., infant formulas fermented with BB/ST and prebiotics, partly fermented infant formulas with BB/ST and prebiotics with or without modified milk fat, partly fermented anti regurgitation infant formulas with BB/ST and prebiotics) were safe and well tolerated but did not offer clear benefits replicated in other studies. Several trials have evaluated the gut microbiota and documented that the administration of a postbiotic infant formula results in gut microbiota closer to that in breastfed infants. However, direct causal links between the gut microbiota and health outcomes have not been well established. Overall, the findings from published trials evaluated in this review provide reassurance that infant formulas supplemented with postbiotics are safe and well tolerated by infants who cannot be breastfed. However, their use was not associated with any health benefits.

Early food intervention and skin emollients to prevent food allergy in young children (PreventADALL): a factorial, multicentre, cluster-randomised trial

Comments: The aim of the review article from many well-known international experts in the field was to provide an overview of the incidence of FA, causes, prevention strategies, diagnostic methods, and recommendations for treatment in FA ^[45]. Studies in the USA found that 7.6% of children and 10.8% of adults had probable FA; in children with FA,40% were affected by more than 1 FA. Birth cohorts from Europe showed a mean incidence at age 2 years of 1.23% for egg allergy, and 0.54% for cow’s milk allergy. InAsia, South and Central America, and Africa, reliable epidemiological data are limited. The 2 most important risk factors for FA development early in life are delayed introduction of allergenic solid foods and skin barrier dysfunction. The dual allergen exposure hypothesis suggests that food allergen exposure through damaged skin before exposure through the alimentary tract might lead to the development of FA.

Findings from recent studies of early-life dietary interventions for FA prevention have led to revised guidelines, moving from an avoidance approach of allergenic foods to actively recommending introduction of allergenic foods in the first 4–6 months of life. There is no consistent evidence that breastfeeding is effective for the prevention of allergic disease. However, for optimal health of the infant, the WHO and the European Academy of Allergology and Clinical Immunology recommend exclusive breastfeeding for a duration of 6 months and 4 months, respectively. There is no evidence that hydrolyzed formula prevents atopic disease in infants, even in those at high risk for allergic disease. The European Academy of Allergology and Clinical Immunology Guidelines also recommend against the use of regular cow’s milk formula in the first week of life. Oral immunotherapy (OIT) is increasingly advocated by pediatric allergologists, and an OIT drug for peanut allergy, in children aged 4–17 years, has been approved by FDA and European Medicines Agency in 2020.

Evidence to support early introduction of food allergens before the age of 4 months in all infants from the general population irrespective of individual allergy risk is still a matter of debate since data are scarce. In addition, starting early introduction <6 months contradicts with the WHO recommendations, i.e., exclusive breastfeeding for the first 6 months of life and introduction of complementary foods thereafter.

Atopic dermatitis, a common chronic inflammatory skin disease associated with reduced skin barrier function, is a strong risk factor for subsequent FA. Combining dietary modifications and improved skin barrier function in early infancy to prevent FAhas therefore been suggested. The PreventADALL (Preventing Atopic Dermatitis andALLergies in children) study is the first large, population-based RCT combining the early introduction of food allergens and regular emollients aiming to prevent atopicdermatitis or FA in children. In this study, Skjerven et al. aimed at determining whether early food or skin interventions prevented FA at age 36 months [46]. This cluster randomized trial was performed at Oslo University Hospital and Østfold HospitalTrust, Oslo, and Karolinska University Hospital, Stockholm. Infants of women recruited antenatally at the routine 18-week ultrasound examination were cluster-randomized at birth to the following groups: (1) no intervention group; (2) the skin intervention group (skin emollients; bath additives and facial cream; from age 2 weeks to <9 months, both at least 4 times per week); (3) the food intervention group (early CF of peanut, cow’s milk, wheat, and egg from age 3 months); or (4) the combined intervention group (skin and food interventions). The primary outcome was allergy to any interventional food at 36 months of age. A total of 2,697 women with 2,701 pregnancieswere recruited, from whom 2,397 newborn infants were enrolled. FA was diagnosedin 44 children; 14 (2.3%) of 596 infants in the non-intervention group, 17 (3.0%) of 574infants in the skin intervention group, 6 (0.9%) of 641 infants in the food interventiongroup, and 7 (1.2%) of 583 infants in the combined intervention group. Peanut allergywas diagnosed in 32 children, egg allergy in 12 children, and milk allergy in 4 children.Prevalence of FA was reduced in the food intervention group compared with the nointervention group (risk difference −1.6% [95% CI −2.7 to −0.5]; odds ratio [OR] 0.4[95% CI 0.2 to 0.8]), but not compared with the skin intervention group (0.4% [95% CI−0.6 to 1.5%]; OR 1.3 [0.7 to 2.3]). The overall protective effect of the intervention wasdriven by the peanut allergy results: 23 (2.0%) of 1,170 infants in the no food intervention groups had peanut allergy compared with 9 (0.7%) of 1,224 infants in the foodintervention groups, i.e., a 63% reduction. The proportion of infants with egg allergyat 3 years was low in both groups (7 [0.6%] of 1,170 infants in the no food interventiongroups; 5 [0.4%] of 1,224 infants in the food intervention groups). No serious adverseevents were observed. Since families were not asked to record the actual amount ofallergenic foods consumed, there is residual uncertainty regarding the dose of foodrequired to induce tolerance. The results of this well-designed study demonstrates that early introduction of common allergenic foods from 3 months of age is a safe and effective strategy to prevent FA in all infants, including those not at risk of FA in whom most cases of FA occur.

Starting complementary feeding with vegetables only increases vegetable acceptance at 9 months: a randomized controlled trial

Comments: Ultraprocessed foods (UPF) are industrial formulations of substances derived from foods with little or no whole food and often containing added colorings, flavorings, emulsifiers, thickeners, and other cosmetic additives to make them palatable. UPFnegatively impacts the quality of the diet with a high content in energy, saturated and trans fats, sodium, and a low content in fiber and micronutrients. In the adult and elderly population, there is increasing evidence on the association of UPF consumption with the development of noncommunicable diseases such as obesity, type 2 diabetes, cardiovascular disease, cancer, depression, gastrointestinal disorders, mortality from all causes, and risk of cardiometabolic diseases. There is also consensus that a healthy diet in early life, including exclusive breastfeeding up to 6 months and complemented breastfeeding up to 2 years or more, is key to establishing healthy eating habits. On the other hand, adolescent motherhood can negatively affect breastfeeding initiation and duration, as well as prompt the consumption of unhealthy foods in early life. Lazzeri et al. aimed at evaluating the impact of an educational intervention to promote breastfeeding and healthy CF in young infants of adolescent mothers, on the consumption of UPF at the age of 4–7 years [47]. A total of 323 teenage mothers and their infants from South Brazil were enrolled, 163 were allocated to the intervention group and 160 to the control group. Intervention consisted of sessions on breastfeeding and healthy CF promotion and was carried out in the maternity ward and at home after delivery. Food consumption was assessed at child's age of 4–7 years. The intervention reduced the risk of high consumption of UPF by 35% (relative risk: 0.65,95% CI 0.43, 0.98).

Vegetables are an important part of the diet as they provide nutrients needed for growth, development, and overall health. In the United States, children’s consumption of fruit but not vegetables has increased [49], and the Feeding Infants and Toddlers Study showed that consumption of dark green vegetables is particularly low among infants[50]. Reasons for poor vegetable intake range from infant preferences for sweet/energy dense foods to simple lack of access, maternal dislike, or cultural practices.

Rapson et al. aimed to test whether exposure to vegetables only during the first 4 weeks of CF increases later vegetable acceptance compared with a control group receiving fruit and vegetables [48]. In this RCT, 117 infants from Auckland, New Zealand,received either vegetables only or a combination of fruit and vegetables for a duration of 4 weeks, starting from the first day of CF at around 4–6 months of age. The veg-only infants consumed more target vegetables (broccoli and spinach) than controls (mean difference [95% CI]: 11.83 [0.82, 22.84] g, p = 0.036 and 10.19 [0.50, 19.87]g, p = 0.039, respectively). Also, veg-only infants consumed more vegetables as a whole than controls (86.3 [52.5, 146.3] compared with 67.5 [37.5, 101.3] g, respectively, p = 0.042). Introducing vegetables as the first food was not associated with 9-month iron status. Rapson et al. concluded that providing vegetables as first foods increased vegetable intake at 9 months of age and may be an effective strategy for improving child vegetable consumption and developing preferences for vegetables in infancy.

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