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Abstract
Objective To compare growth, tolerance and safety parameters in very preterm infants receiving human milk (HM) fortified with a multicomponent cow’s milk-based HM fortifier (HMF; control) versus a novel HMF-containing lipids (including docosahexaenoic acid and arachidonic acid), higher protein and lower carbohydrate levels (test). Our hypothesis was that weight growth velocity in the test group would be non-inferior to that in the control group.
Design Double-blind, randomised controlled trial.
Setting Nine European neonatal intensive care units.
Patients HM-fed infants born at <32-week gestational age.
Interventions Fortification of HM with Test or Control HMF for a minimum of 21 days.
Primary outcome Weight growth velocity between baseline and intervention day 21.
Results From March 2018 to July 2020, 102 and 103 infants were enrolled in the test and control groups, respectively. Weight growth velocity during the first 21 days in the test group (mean 18.4 g/kg/day) was non-inferior to that of controls (mean 18.5 g/kg/day), with a difference in estimated means of –0.175 g/kg/day (90% CI –1.34 to +0.99 g/kg/day; per-protocol population). No significant differences between groups were observed for gain in length, head circumference or anthropometric Z-scores. Rates of digestive intolerance, stool frequency and consistency were comparable. No significant differences were reported in common neonatal morbidities including necrotising enterocolitis (test: 2.9%, control: 6.9%, mean difference –4.0% (95% CI –11.1% to 2.2%); all subjects treated population).
Conclusions Use of the novel HMF containing lipids, higher protein and lower carbohydrate levels supports adequate postnatal growth and appears safe and well tolerated in very preterm infants.
Trial registration number NCT03315221
- Neonatology
- Growth
- Intensive Care Units, Neonatal
Data availability statement
Data are available upon reasonable request. Reasonable requests for access to the data that support the findings of this study will be considered by contacting the Sponsor. Qualified researchers are required to submit a research proposal which is subject to a critical appraisal of compliance with the Danone Nutricia Research (DNR) Clinical Study Data Sharing policy and approved by a dedicated DNR review committee. Proposals should be directed to datasharing.clinicalresearchnutricia@danone.com. To gain access, data requestors will need to sign a data access agreement. Data are available for the period defined in the data access agreement.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Fortification of human milk with a multinutrient human milk fortifier (HMF) is recommended to promote optimal growth in preterm infants with a weight <1800 g.
The optimal composition of multinutrient HMFs is still a topic of debate.
WHAT THIS STUDY ADDS
Very low birth weight (VLBW) infants receiving a novel HMF with lipids, a lower carbohydrate and higher protein content had a non-inferior weight growth velocity compared with VLBW infants receiving a conventional HMF.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Use of the novel lower osmolality HMF was safe and well tolerated in this population of VLBW infants and supported adequate postnatal growth.
Introduction
Human milk (HM) is the preferred nutrition for preterm infants.1 2 However, levels of macronutrients and micronutrients in HM are considered inadequate to support their optimal growth, body composition and neurodevelopment, especially in very preterm infants.1–5 Therefore, multinutrient fortification of HM is recommended to enhance nutrient content and promote growth in preterm infants with a birthweight <1800 g.2 6 7 Human milk fortifiers (HMFs) are especially important to reduce cumulative nutrient deficits and postnatal growth restriction because poor growth is associated with impaired neurodevelopmental outcomes.8 9
Although HM fortification is standard practice in very low birth weight (VLBW; <1500 g) infants, the optimal composition of multinutrient HMFs is a topic of debate. Optimal protein content of HMFs is unclear, as that of mothers’ own milk varies between and within individuals, is influenced by many factors including time after delivery,10 11 and is often lower than needed to support postnatal growth.10 12
As preterm infants are at risk of long-chain polyunsaturated fatty acid (LCPUFA) deficiency, dietary supplementation with docosahexaenoic acid (DHA) and arachidonic acid (ARA) is recommended.2 11–14 Addition of lipids to HMFs, at the expense of carbohydrates, allows for a reduction in osmolality and an enhanced LCPUFA supply.
A novel multicomponent lower osmolality HMF was developed to improve fatty acid supply when compared with conventional HMF. It contains DHA and ARA in equal amounts, easily absorbed fats (ie, medium chain triglycerides and anhydrous milk fat), higher protein and lower carbohydrate levels. This study’s objectives were to: (1) demonstrate non-inferiority of weight growth velocity during the first 21 days of intervention for the novel HMF compared with control HMF and (2) confirm that the novel HMF is safe and well-tolerated in VLBW infants.
Methods
Participants
Infants born <32 weeks gestational age (GA) with birthweight <1500 g who were fed HM, enterally and needing HMF for minimum 21 days, were eligible. Nine neonatal intensive care units (NICUs) in the United Kingdom, France, Netherlands and Germany participated.
Exclusion criteria were chromosomal anomaly, metabolic disorder, genetic syndrome, congenital central nervous system malformation, gastrointestinal malformation/compromise, no realistic prospect of survival or participation in another investigational study. All parents/guardians provided written informed consent before enrolment.
Study design and intervention
A double-blind parallel-group, non-inferiority RCT was conducted (online supplemental figure 1). Infants were randomly allocated (block size of four), on a 1:1 basis, stratified by site to receive the test or control HMF daily. For multiples, other eligible siblings were allocated the same HMF as the first sibling randomised. Site staff responsible for feeding administration and study assessments were blinded to the actual HMF allocation (online supplemental methods). The intervention lasted ≥21 days, from the first use of HMF until the infant no longer required HMF, or was discharged home or to a non-participating NICU, whichever came first. Infants were followed up until 24 months corrected age (CA). The study was conducted in compliance with the principles of the Declaration of Helsinki, according to ICH-GCP, and approved by Ethics Review Boards of participating centres/countries.
Supplemental material
Feeding regimen
During the study period, infants were fed mother’s own milk or pasteurised donor milk when the former was insufficient or not available. Preterm infant formula was provided if fortified HM was insufficient. Fortification of HM was started when a sufficient enteral feeding volume was reached according to each unit’s protocol. Both study products were powdered multinutrient HMFs (200 g tins). The novel HMF (test) provided 17 kcal, 0.7 g lipids, 1.3 g protein and 1.5 g carbohydrates per 4.0 g (dose per 100 mL HM; table 1). The added lipids included (phospholipid- and triglyceride-bound) DHA and ARA, medium-chain triglycerides and anhydrous milk fat as source of beta-palmitate. The control HMF, a product in widespread clinical use at the time of study conduct, provided 15 kcal, 0.0 g lipids, 1.1 g protein and 2.7 g carbohydrates per 4.4 g (dose per 100 mL HM). Both HMFs contained extensively hydrolysed protein (casein:whey ratio 50:50) and maltodextrin, as this glucose polymer is preferred to glucose due to its lower osmolality.2 The test HMF had a higher protein content than the control HMF, as recent studies have shown that a HMF protein level of 1.0–1.1 g/100 mL may result in lower than recommended protein intakes.2 Products were manufactured by Danone Nutricia according to Good Manufacturing Practices (FSSC 22000 standard). Osmolalities of HM fortified with HMF were: test 410 mOsm/kg; control 450 mOsm/kg.
Nutrient composition of intervention human milk fortifiers (HMFs)
Primary and secondary outcomes
The primary outcome was weight growth velocity (g/kg/day) between the start of intervention (baseline) and intervention day 21. Secondary outcomes were gains in length, head circumference (HC) and anthropometric z-scores, digestive tolerance parameters and adverse events (AEs). Weight-for-age, length-for-age, HC-for-age z-scores and percentiles were calculated using Fenton growth charts for preterm infants15 (online supplemental methods).
Data collection
Data were collected from randomisation until 24 months CA, captured into an electronic database (online supplemental methods).
Safety monitoring
Information on AEs, including onset, duration, relationship with study product, severity, seriousness, actions taken, outcomes, concomitant medication use and medical interventions, were recorded (online supplemental methods).
Statistical analysis
A sample size of 91 per group was calculated with a one-sided test (α=0.05, power=0.80, dropout rate=20%, potential loss of df due to number of sites (>5)). With the predefined non-inferiority margin of −1.6 g/kg/day,16 difference between groups of 0.2 g/kg/day17 and standard deviation (SD) of 4.3 g/kg/day.18 Analyses for weight growth velocity were performed using a parametric growth curve mixed-effects model with a quadratic effect of time adjusted for potentially prognostic fixed effect covariates and a family-specific random effect to account for the correlation of the growth outcomes in twins/multiples (online supplemental methods).19 20 The all subjects treated (AST) population, which included infants with at least one feeding with study HMF, was used for the analyses of safety and digestive tolerance parameters. The per protocol (PP) population was the primary dataset for the efficacy analyses. In non-inferiority trials, there is a general concern that by including participants who did not receive the planned interventions, the two comparison groups become more similar, resulting in incorrect conclusions of non-inferiority.21–23 Supplementary analyses were performed in the all subjects randomised (ASR) population to evaluate the robustness of the results obtained in the PP population.
Results
Infant characteristics
Between March 2018 and July 2020, 205 infants (102 test, 103 control) were enrolled, of whom 183 were randomised and 22 siblings of multiples were allocated (figure 1). One infant did not consume any study HMF and was excluded from the AST population. The PP population included 155 infants. Dropout rates and reasons for early termination were similar in both groups.
Subject flow. HMF, human milk fortifier. ‡Allocated subjects were siblings assigned to the same group. #One subject randomised to the Control group received Test HMF. 3Noncompliance with study: subjects with major protocol deviations: A. Major violation of the inclusion or exclusion criteria: n=0. B. Non-compliance with study product intake, as indicated by exposure to study product for <21 days: n=50. C. Not having any post-baseline measurements of weight – no additional exclusions. 4PP subjects were all subjects without major protocol deviations.
Baseline characteristics were similar between groups in both PP (table 2) and ASR populations (online supplemental table 1). Infants were born at a mean GA of 27.8 (SD: 2.1) weeks with a mean birth weight of 986 g (SD: 264 g). Thirteen per cent of infants were small for GA (birthweight <10th percentile).
Demographics and infant characteristics of the per protocol population
Growth
The primary outcome measure, that is, weight growth velocity during the first 21 days of intervention, of the test group (mean 18.4 g/kg/day), was non-inferior to that of controls (mean 18.5 g/kg/day). The difference in estimated means between groups was –0.175 g/kg/day (90% CI, –1.34 to +0.99) for the PP population, with the lower CI above the pre-defined non-inferiority margin (table 3). No significant differences between groups were observed in length gain, HC gain or changes in anthropometric z-scores (table 3). Results were similar for ASR analyses (data not shown).
Weight growth velocity, length gain, head circumference gain, anthropometric z-scores and changes in anthropometric z-scores during the first 21 days of the intervention (per protocol population)
At the start of the intervention, 33 (38.8%) test and 21 (30.4%) control infants had a weight <10th percentile (PP population). At day 21 and day 28 after the start of intervention, 35 (41.2%) and 31 (41.3%) of the test and 28 (40.6%) and 17 (29.8%) of the control infants had a weight <10th percentile respectively.
Model estimates for weight, length, HC and anthropometric z-scores during the first 21 days of intervention are presented in online supplemental figures 2 and 3. The weight-for-age z-scores were stable in both groups.
HMF intake and digestive tolerance
Infants reached enteral feeding volumes of ≥150 mL/kg/day at an average age of 13.7 (test) and 13.4 days (control; AST population). Mean (SD) enteral feeding intake during the first 21 days of intervention was 144 (19.4) mL/kg/day in test and 143 (18.8) mL/kg/day in control groups. In both groups, the dominant feeding was own mother’s milk (81%–87%), with donor milk and preterm formula comprising 10%–15% and 1%–6% of the feeding volumes, respectively. During the first 21 days of intervention, 99 (96.1%) infants in the test group received own mother’s milk, 28 (27.2%) received donor milk and 20 (19.4%) infants received preterm infant formula next to the supplemented HM. In the control group, this was 95 (94.1%), 32 (31.7%) and 29 (28.7%), respectively (AST; online supplemental table 2). Overall, infants started with HMF at a mean (SD) postnatal age of 10.6 (5.6) days. With a mean (SD) number of 40 (20.8) days on study HMF in test and 32 (19.8) days in Control groups.
Average stool frequency was 2.9 stools/day in the first three intervention weeks, without significant differences between groups. In both groups, most infants (>75%) had soft stools.
Percentages of infants with occurrences of vomiting, regurgitation or clinically significant gastric residuals during the first 21 days of intervention were similar between groups (online supplemental table 3). There was a small difference in the number of vomiting occurrences per day (medians: 0.3 vs 0.1, p<0.001) in infants with vomiting (test: n=35; control: n=33). A higher percentage of infants with any vomiting in test versus control groups was seen in the first week only, with the difference statistically significant in one site (online supplemental table 4).
AEs and clinical parameters
Out of 204 infants in the AST population, at least one AE was reported for 77.7% of test subjects and 75.2% of controls. Similar incidence of AEs was observed between groups.
At least one serious AE (SAE) was reported in 41.7% of test subjects and 36.6% of controls. No significant differences between groups were observed for any SAE category, except for a lower incidence of ‘gastrointestinal disorders’ in the test group (7.8% in test and 16.8% in control; Δ –9.1% (95% CI –18.56% to –0.04%); online supplemental table 5).
No significant differences were observed between groups in rates of common neonatal morbidities: necrotising enterocolitis, retinopathy of prematurity, bronchopulmonary dysplasia, periventricular leukomalacia and intraventricular haemorrhage (table 4).
Neonatal morbidities; percentages of occurrence* and point estimate of difference between study groups, with 95% CIs for the all subjects treated population
The number of infants with an AE leading to product withdrawal was similar between groups: test, n=7 (6.8%); control, n=9 (8.9%), as was the number of infants who terminated the study early: test, n=3 (2.9%); control, n=4 (3.9%), reasons for termination were also similar.
Blood levels of urea, blood urea nitrogen, pH, bicarbonate, sodium, potassium and albumin were available for a subgroup when collected as part of standard care. In this subgroup (n=46), mean (SD) urea levels for test versus control were comparable; 5.9 (3.7) versus 5.4 (2.7) mmol/L in the third week of intervention, respectively.
There was no difference between groups in postnatal age at discharge from NICU, postnatal age at discharge home or mortality during hospital stay (online supplemental table 6).
Discussion
In this double-blind randomised, controlled trial, we demonstrated non-inferiority in weight growth velocity during the first 21 days of intervention in VLBW infants receiving a novel lower osmolality HMF containing lipids (including DHA and ARA), higher protein and lower carbohydrate levels compared with those receiving a control HMF without lipids.
The primary outcome measure of average weight growth velocity during the first 21 days of intervention was similar in both groups, just above 18 g/kg/day, in line with recommendations,24 and similar to growth rates observed in a study with other lipid-containing HMFs.25 Average weight-for-age z-scores and percentages of infants with a weight <10th percentile were stable during the first 28 days of intervention in both groups, suggesting that accumulation of postnatal growth deficit could be prevented in most infants with routine use of HMF.26 This contrasts with the findings of Martin et al, who observed that the proportion of ELBW infants with a weight <10th percentile increased from 18% at birth to 75% at 28 days of life, despite growth velocity rates above 15 g/kg/day and HMF.27
The comparable growth rates of test and control groups might come from the relatively small difference in protein content (0.2 g/100 mL fortified HM) between study HMFs.1 28 29 Other studies in preterm infants did not show improved growth comparing HMFs with different protein levels (1.8 g vs 1.0 g per 100 mL HM,30 31 pointing towards a ceiling effect for enteral protein supply). Increasing protein intake enhances protein accretion and clinical outcome such as weight gain in a linear dose–response manner. It is hypothesised that beyond a so-called ‘beneficial upper limit’, higher protein intakes do not yield further improvements in clinical outcome32
More studies have compared HMFs with varying protein and lipid levels in preterm infants.20 33–36 Rigo et al compared a new fortifier adding 0.7 g fat (including 6.3 mg DHA) and 1.4 g partially hydrolysed protein to 100 mL of HM, to an isocaloric fortifier with 0.0 g fat and 1.0 g extensively hydrolysed protein. Average weight growth velocity in the new fortifier group was 18.3 g/kg/day compared with 16.8 g/kg/day in controls.25 Notably, the growth rate observed in their new fortifier group was similar to those of both groups in the current study. Another study compared a liquid HMF with a higher protein content (and ARA and DHA) to a traditional powder HMF in VLBW infants. Those who completed a 2-week intervention period showed no differences in weight, length, HC or knee–heel length gains.37 This is in contrast to a study investigating the same liquid versus powder HMF, which showed significantly higher length growth in the liquid group.18
The novel HMF tested in this study contains components that may have benefits for preterm infants. First, it contains lipids at the expense of carbohydrates, reducing osmolality compared with the conventional HMF. The osmolality of the novel HMF fortified to HM of 410 mOsm/kg is well below the maximum tolerable level of 450–500 mOsm/kg indicated in recent reviews.33 38 Second, the novel HMF includes DHA and ARA in equal amounts. A balanced DHA and ARA supplementation is needed for optimal infant growth and cognitive development.2 13 14 Moreover, the DHA and ARA are partially bound to phospholipids, which are more efficiently absorbed by preterm infants than triglyceride-bound DHA,34 and possibly more efficiently incorporated in body tissues.35 36 Furthermore, the novel HMF contains medium-chain triglycerides, an easily absorbable source of energy,39 and anhydrous milk fat with 38% of palmitic acid at the beta-position. Benefits of beta-palmitate are improved fat and calcium absorption and softer stools.40 41 Finally, it contains extensively hydrolysed proteins, in line with clinicians’ preferences.1 Recently, Doshi et al showed decreased levels of faecal calprotectin in preterm infants after using a HMF with hydrolysed protein, suggesting that intestinal inflammation may be lower compared with fortifiers containing intact protein.42
Overall, AEs reported in this study were typical for preterm infants and no clinically relevant differences in AEs were observed between groups. Hence, there are no safety concerns for the use of this novel HMF in VLBW infants. The low incidence of necrotising enterocolitis, a condition often linked with preterm enteral nutrition, in this study (test: 2.9% and control: 6.9%) is reassuring. Furthermore, it is encouraging that the incidence of gastrointestinal SAEs was lower in test compared with control infants. We hypothesise that this is related to the lower osmolality of the novel HMF.
In the first week of the intervention, a higher percentage of infants with vomiting was reported for test versus control. Vomiting was not defined a priori and was assessed according to local investigators’ judgement. This led to high inter-hospital variability in its recording with incidence ranging from 8% to 91% between sites. In the centre with a significant diffrence between groups, it was due to the joint recording of vomiting and aspirates. Their reports of vomiting should be best interpreted as a combination of ‘spitting up/posseting’ and true vomiting. Overall, infants with vomiting had on average <1 vomiting episode per day. No subject terminated the study prematurely due to vomiting, while all infants grew adequately. We therefore consider these findings as not clinically relevant.
Strengths of our study include the randomised controlled trial design, strict blinding and a relatively large study group. Nine hospitals in four European countries participated, with variations in fortification approaches and standard clinical care. This enhances external validity of the results, as it mimics reality. The study included infants who were fed with their own mother’s milk, donor human milk and/or preterm formula, reflecting reality as a mother’s own milk is not always available in sufficient amounts.
An important limitation is that the intervention period had a minimum duration of 21 days, which is relatively short. Data were available for a longer period, but only for a subset of the population. This hindered evaluation of growth during a longer time frame. Also, no data on individual HM composition were available. It is known that there is large variation in the composition of HM between mothers,10–12 and that donor milk on average has a different composition to own mother’s milk, including lower protein and LCPUFA levels.28 43 No blood sampling was done to analyse fatty acid profiles, which would have provided valuable insights into the LCPUFA status. Finally, the PP approach instead of the intention to treat approach could be questioned. The PP population was, by design, the primary dataset for the efficacy analyses, as it is the preferred approach in non-inferiority trials believed to lead to more conservative conclusions.21 However, analysis in the PP population can lead to biased estimates of the treatment effect, as non-compliant subjects are removed from the comparison. In a sensitivity analysis, non-inferiority was confirmed in the ASR population indicating robustness of our conclusions. In addition, comparison of the baseline covariates between the PP and ASR population showed similar characteristics in both population arms, which confirms the balance of randomisation was not severely influenced by excluding non-adhering participants in the PP population, although this cannot be fully ruled out.
In summary, in a population of VLBW infants, we observed that a novel multicomponent HMF containing LCPUFA and well-absorbable fats appears to support adequate postnatal growth and to be safe and well-tolerated.
Data availability statement
Data are available upon reasonable request. Reasonable requests for access to the data that support the findings of this study will be considered by contacting the Sponsor. Qualified researchers are required to submit a research proposal which is subject to a critical appraisal of compliance with the Danone Nutricia Research (DNR) Clinical Study Data Sharing policy and approved by a dedicated DNR review committee. Proposals should be directed to datasharing.clinicalresearchnutricia@danone.com. To gain access, data requestors will need to sign a data access agreement. Data are available for the period defined in the data access agreement.
Ethics statements
Patient consent for publication
Ethics approval
The study was approved by Ethics Review Boards of participating centres/countries: UK National Health Service Health Research Authority National Research Ethics Service (London Riverside Research Ethics Committee) (IRAS ID 232768; REC Reference 17/LO/1947; Protocol No. EBB16GL06402) and was adopted onto the National Institute for Health Research Clinical Research Network portfolio (CPMS ID 37339). Medical Ethical Committee of the Free University Medical Center in Amsterdam (Reference 2017.422 - NL61360.029.17), the federal state Ethical Committee of Bayern (reference no: 17057), Ethical Committee of the Otto von Guericke University Magdeburg at the Medical Faculty and University Clinic Magdeburg (reference no: 160/17), Committee for the Protection of Persons East IV hosted by the University Hospitals of Strasbourg (id IDCRB 2017-A02278-45). Participants gave informed consent to participate in the study before taking part.
References
Footnotes
X @neonataldoc, @drpaulclarke
Presented at These data were previously presented in abstract form at the 54th Annual Meeting of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), Copenhagen, Denmark, June 2022.
Collaborators RENOIR Study Group: Blandine Pastor-Diez (Neonatal Intensive Care Unit, Hôpital Croix-Rousse, Hospices civils de Lyon, Lyon, France and Laboratoire CarMen, INSERM, INRA, Université Claude Bernard Lyon1, Pierre-Bénite, France), Marion Masclef-Imbert (Neonatal Intensive Care Unit, Hôpital Croix-Rousse, Hospices civils de Lyon, Lyon, France and Laboratoire CarMen, INSERM, INRA, Université Claude Bernard Lyon1, Pierre-Bénite, France), Karen Wells (Neonatal Intensive Care Unit, St. Peter's Hospital, Ashford & St. Peter's Hospitals NHS Foundation Trust, Chertsey, UK), Samantha Claire (Neonatal Intensive Care Unit, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK), Amy Nichols (Neonatal Intensive Care Unit, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK), Marieke Hemels (Department of Neonatology, Isala Women and Children’s hospital, Zwolle, Netherlands), Astrid Giezen (Department of Neonatology, Isala Women and Children’s hospital, Zwolle, Netherlands), Mariëtte Schoorlemmer (Department of Neonatology, Isala Women and Children’s hospital, Zwolle, Netherlands), Annemiek de Lange (Department of Neonatology, Emma Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands), Adel Szakacs-Fusch (Department of Pediatrics, Paracelsus Medical School and Nuernberg General Hospital, Nuernberg, Germany), Appolline Wittwer (Neonatology Department, Maternite Regionale, CHRU Nancy, Nancy, France), Sabine Guignon (Neonatology Department, Maternite Regionale, CHRU Nancy, Nancy, France).
Contributors J-CP, PRR, PC, MMvW, RAvL, RB, EvW-K, CF and JMH were responsible for the conceptualisation of the study and conducting the investigation. EvdH and AG were involved in designing the study methodology and protocol. PC was the UK national coordinating investigator and assisted development of patient-facing documentation and achievement of UK ethics approvals. J-CP, EvdH, AG and AB were involved in the writing of the original manuscript draft. All authors were involved in the writing, review and editing of the final manuscript and all approved the final version. JCP is the
author responsible for the overall content as the guarantor.
Funding The study Sponsor, Nutricia Research B.V., provided the funding to conduct the study.This work was supported by Nutricia Research B.V.
Competing interests EvdH, AG and AB are employees of Danone Nutricia Research, Utrecht, The Netherlands. PC declares unrestricted research funding paid to his employing institution (NNUHFT) by Danone Early Life Nutrition, and conference travel and accommodation reimbursements received from Nutricia and Nestle in 2018–19. The remaining authors have no conflicts of interest relevant for this study to declare.
Provenance and peer review Not commissioned; externally peer-reviewed.
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