Protein Quality and Growth Monitoring Studies: Quality Factor Requirements for Infant Formula (2025)
Chapter: Appendix E: Modification of Infant Formula and Growth: A Scoping Review
Appendix E
Modification of Infant Formula and Growth:
A Scoping Review
ABSTRACT
Introduction
The aim of this scoping review is to report on the state of the science regarding methodologies for assessing the ability of infant formula to support normal human physical growth.
The research question examined in this scoping review is the following: In healthy full-term human infants <1 year of age, what is the availability of evidence assessing the impact of alternative formulas compared to standard formulas or human milk on physical infant growth outcomes? Sub-questions include the following:
- What study designs are used to examine this relationship?
- What types of formula alterations are being evaluated?
- What growth outcomes are reported?
- Do study designs and measures vary globally?
Methods
This scoping review was registered at Open Science Framework (Rozga et al., n.d.). It was conducted using the framework introduced by Arskey and O’Malley (2005) and developed by Levac et al. (2010), the Joanna Briggs Institute (Peters et al., 2020), and the Cochrane Collaboration (Higgins et al., 2024). The findings are reported according to the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist for scoping reviews (Moher et al., 2009).
Eligibility Criteria
Table E-1 lists the eligibility criteria. Studies were included if they included full-term healthy infants to investigate intake of formula with any compositional differences compared to standard formula or human milk. Studies were required to be published in 2000 or later to represent contemporary laboratory methods and infant formulas. Articles were required to be published in the English language due to resource constraints.
Information Sources
An information specialist designed the search strategies and searched MEDLINE, Cochrane CENTRAL, CINAHL, Cochrane Database of Systematic Reviews, Food Science Source, Embase, and Scopus on July 22, 2024. Table E-2 shows a sample search strategy for MEDLINE. Search results were managed and deduplicated by the information specialist using EndNote software (EndNote, 2013).
Article Selection
Article screening for eligibility criteria was conducted in two phases. In the first stage, titles and abstracts were uploaded using Rayyan software (Moher et al., 2009) and screened independently by two reviewers. In the second phase, the full texts were reviewed and screened against eligibility criteria by two independent reviewers. Any discrepancies in reviewer decisions were decided through discussion and reaching consensus or by a third reviewer.
Data Extraction
A template was designed to extract study characteristics and approved by an expert panel. Data were extracted to the standardized Excel sheet by one analyst and reviewed by a second. Data extracted from each article include bibliographic information, study design, details on the infant population, details on the composition of intervention and comparison infant formulas, and outcomes of physical growth that are reported.
| Category | Inclusion Criteria | Exclusion Criteria |
|---|---|---|
| Study participants | Human infants ≤12 months of age | Animal or in vitro studies; children >1 year of age at baseline |
| Health status of study participants | Studies that enroll full-term, healthy infants | Studies that exclusively enroll preterm or premature infants; infants with high birth weight or low birth weight or infants diagnosed with a disease or condition |
| Interventions/exposures | Cow’s milk–based, plant-based (e.g., soy, pea), or goat’s milk–based formula and partially hydrolyzed formula with any compositional differences from standard formulas | All other specialized formulas (formulas deemed exempt by U.S. Food and Drug Administration (FDA) such as fully hydrolyzed amino acid (AA) formulas or formulas for infants with metabolic diseases); toddler formulas. |
| Comparators | Infants fed standard infant formula or human milk or comparison to a national/international standard or reference, including z-scores | Specialized formulas (formulas deemed exempt by FDA such as fully hydrolyzed AA formulas or formulas for infants with metabolic diseases); toddler formulas |
| Outcomes | Primary outcomes: physical growth (e.g., length, weight, body mass index (BMI) z-score, head circumference); length-forage z-scores, or weight-for-age z-scores; weight for length Secondary outcomes: body composition, biomarkers of growth Co-variables: sex, ethnicity, socioeconomic status |
Fecal microbiota, metabolomics, neurodevelopment, other general health outcomes |
| Publication status | Articles published in peer-reviewed journals | Articles that have not been peer reviewed and are not published in peer-reviewed journals, including unpublished data, manuscripts, preprints, reports, abstracts, and conference proceedings |
| Category | Inclusion Criteria | Exclusion Criteria |
|---|---|---|
| Date of publication | January 2000 until the search date of June 23, 2024 | Articles published prior to January 2000 or after search date of June 23, 2024 |
| Language of publication | Articles published in English | Articles published in languages other than English |
| Study design | Randomized controlled trials; nonrandomized controlled trials, including quasi-experimental and controlled before-and-after studies; observational studies; prospective cohort studies; retrospective cohort studies; meta-analyses; systematic reviews; case-control studies | Editorials Narrative reviews Abstracts/conference abstracts Study protocols |
| Country | Studies conducted in high-income countries, based on the United Nations (UN) Human Development Index | Studies conducted outside of high-income countries, based on the UN Human Development Index |
| # | Query |
|---|---|
| S22 | S21 AND DT 20000101-20250101 |
| S21 | S20 AND LA English |
| S20 | S19 NOT PT (comment or editorial or news or newspaper article) |
| S19 | S18 NOT ((MH “Animals”) NOT ((MH “Humans”) AND (MH “Animals”))) |
| S18 | S9 AND S14 AND S17 |
| S17 | S15 OR S16 |
| S16 | TI (infant* OR newborn* OR neonat*) OR AB (infant* OR newborn* OR neonat*) OR CI (infant* OR newborn* OR neonat*) |
| S15 | MH (Infant OR “Infant, Newborn”) |
| S14 | S10 OR S11 OR S12 OR S13 |
| S13 | TI (length OR “head circumference” OR “body circumference” OR height OR anthropometric*) OR AB (length OR “length-for-age” OR LAZ OR “weight-for-length” OR “head circumference” OR “body circumference” OR height OR anthropometric*) OR CI (length OR “head circumference” OR “body circumference” OR height OR anthropometric*) |
| S12 | TI (“body mass” OR BMI OR bodyweight OR body weight OR “weight gain” OR weighed OR “weight-for-age” OR “z-score” OR WAZ) OR AB (“body mass” OR BMI OR bodyweight OR body weight OR “weight gain” OR weighed OR “weight-for-age” OR “z-score” OR WAZ) OR CI (“body mass” OR BMI OR bodyweight OR body weight OR “weight gain” OR weighed OR “weight-for-age” OR “z-score” OR WAZ) |
| S11 | TI (“body composition” OR “air displacement plethysmography” OR “dual-energy x-ray absorptiometry” OR “bioelectrical impedance” OR “skinfold thickness”) OR AB (“body composition” OR “air displacement plethysmography” OR “dual-energy x-ray absorptiometry” OR “bioelectrical impedance” OR “skinfold thickness”) OR CI (“body composition” OR “air displacement plethysmography” OR “dual-energy x-ray absorptiometry” OR “bioelectrical impedance” OR “skinfold thickness”) |
| S10 | MH (“infant, newborn/gd”) |
| S9 | S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 |
| S8 | TI (“human-identical milk” OR “human milk based protein” OR “human milk oligosaccharides” OR “manufactured human milk”) OR AB (“human-identical milk” OR “human milk based protein” OR “human milk oligosaccharides” OR “manufactured human milk”) OR CI (“human-identical milk” OR “human milk based protein” OR “human milk oligosaccharides” OR “manufactured human milk”) |
| # | Query |
|---|---|
| S7 | TI (((plant OR soy OR pea OR oat OR oats) N1 (formula OR formulas)) AND infant) OR AB (((plant OR soy OR pea OR oat OR oats) N1 (formula OR formulas)) AND infant) OR CI (((plant OR soy OR pea OR oat OR oats) N1 (formula OR formulas)) AND infant) |
| S6 | TI (((goat OR cow OR bovine) N1 (formula OR formulas or milk)) AND infant) OR AB (((goat OR cow OR bovine) N1 (formula OR formulas or milk)) AND infant) OR CI (((goat OR cow OR bovine) N1 (formula OR formulas or milk)) AND infant) |
| S5 | TI ((milk OR whey OR casein OR dairy OR “partially hydrolyzed” OR “partially hydrolysed” OR “amino acid*”) N1 (formula OR formulas)) OR AB ((milk OR whey OR casein OR dairy OR “partially hydrolyzed” OR “partially hydrolysed” OR “amino acid*”) N1 (formula OR formulas)) OR CI ((milk OR whey OR casein OR dairy OR “partially hydrolyzed” OR “partially hydrolysed” OR “amino acid*”) N1 (formula OR formulas)) |
| S4 | TI ((regular OR standard*) N1 (formula OR formulas)) OR AB ((regular OR standard*) N1 (formula OR formulas)) OR CI ((regular OR standard*) N1 (formula OR formulas)) |
| S3 | TI (“formula-fed” OR “fed formula” OR “fed formulas” OR “formula feeding” OR “feeding formula” OR “feeding formulas” OR “formula diet” OR “based formula” OR “based formulas” OR “formula milk”) OR AB (“formula-fed” OR “fed formula” OR “fed formulas” OR “formula feeding” OR “feeding formula” OR “feeding formulas” OR “formula diet” OR “based formula” OR “based formulas” OR “formula milk”) OR CI (“formula-fed” OR “fed formula” OR “fed formulas” OR “formula feeding” OR “feeding formula” OR “feeding formulas” OR “formula diet” OR “based formula” OR “based formulas” OR “formula milk”) |
| S2 | TI (infant N1 (formula OR formulas)) OR AB (infant N1 (formula OR formulas)) OR CI (infant N1 (formula OR formulas)) |
| S1 | MH (“Infant Formula”) |
Synthesis of Results
The study selection process is documented in a PRISMA flowchart (EndNote, 2013). Characteristics and results of included studies are narratively described, and results are also represented in charts, figures, and a heat map. As is customary with scoping reviews, critical appraisal of study quality was not conducted.
Results
The database searches identified 4,927 unique articles; 235 full texts were reviewed against eligibility criteria, and 143 articles were included (see Figure E-1) (Abrahamse-Berkeveld et al., 2024; Abrams et al., 2015; Ahrens et al., 2018; Alexander et al., 2016; Alliet et al., 2022; Andres et al., 2012; Ashley et al., 2012; Ben et al., 2004; Billeaud et al., 2014, 2022; Breij et al., 2019; Bruzzese et al., 2009; Camier et al., 2021; Cekola et al., 2015; Cesare Marincola et al., 2016; Chouraqui et al., 2008; Civardi et al., 2017; Collell et al., 2016; Costalos et al., 2008; Czerkies et al, 2018; Davis et al., 2008; Demmelmair et al., 2022; Escribano et al., 2012; Estorninos et al., 2022; Fanaro et al., 2005; Fleddermann et al., 2014, 2017, 2018; Fusch et al., 2001; Gale et al., 2012; Gianni et al., 2018; Gibson et al., 2009; Gil-Campos et al., 2012; Giovannini et al., 2013; Haschke et al., 2014; He et al., 2022; Hedrick et al., 2021; Hegar et al., 2008; Hernell and Lönnerdal,, 2002; Heubi et al., 2000; Hoffman et al., 2008, 2019; Holscher et al., 2012; Inostroza et al., 2014; Jankiewicz et al., 2023; Jaramillo-Ospina et al., 2022; Jasani et al., 2017; Jiang et al., 2022; Jinno et al., 2020; Jochum et al., 2023; Johnston et al., 2015; Kantaras et al., 2024; Karaglani et al., 2020; Koletzko et al., 2009; Koo et al., 2003; Kouwenhoven et al. 2020, 2021a,b; Kuehn et al., 2022; Lambidou et al., 2021; Lasekan et al., 2006, 2011, 2014, 2022; Li, F., et al., 2019; Li, X., et al. 2019; Liang et al., 2024; Lien et al., 2004; Liotto et al., 2018; Litmanovitz et al., 2013; Lonnerdal et al., 2016; López-Velázquez et al., 2013; Mackey et al., 2013; Makrides et al., 2000, 2005; Maldonado et al., 2012, 2019; Marriage et al., 2015; Martin et al., 2014; Meli et al., 2014; Milani et al., 2023; Morris et al., 2000; Mugambi et al., 2012; Neumer et al., 2021; Nieto-Ruiz et al., 2019; Oropeza-Ceja et al., 2021; Parschat et al., 2021; Pastor et al., 2006; Patro-Gołąb et al., 2016; Petersen et al., 2020; Picaud et al., 2020; Piemontese et al., 2011; Plaza-Diaz et al., 2023; Puccio et al., 2007, 2017; Putet et al., 2016; Radke et al., 2017; Räihä et al., 2002; Rao et al., 2009; Ren et al., 2022; Rigo et al., 2019; Rodriguez-Herrera et al., 2019; Román et al., 2020; Rozé et al., 2012; Rzehak et al., 2009; Sandström et al., 2008; Scalabrin et al., 2012; Schmelzle et al., 2003; Sepúlveda-Valbuena et al., 2021; Shahramian et al., 2018; Shen et al., 2021; Singhal et al., 2010; Szajewska and Chmielewska, 2013; Szajewska et al., 2015, 2017; Takahashi et al., 2023; Teoh et al., 2022; Timby et al., 2014; Tinghäll Nilsson et al., 2023, 2024; Tonon et al., 2021; Totzauer et al., 2018; Trabulsi et al., 2011; Troesch et al., 2019; Turck et al., 2006; Udell et al., 2005; Vandenplas et al., 2020; Veereman-Wauters et al., 2011; Vendt et al., 2006; Vlieger et al., 2009; Wang, L., et al., 2019; Wang, Y., et al., 2021; Weizman and Alsheikh, 2006; Wu et al., 2017; Xia et al., 2021; Xu et al., 2015; Yang et al., 2022; Yeiser et al., 2016; Yin et al., 2023; Zhang et al., 2023; Zhou et al., 2014; Ziegler et al., 2007, 2015). The 143 articles had 16 sys-
NOTES: CINAHL = Cumulative Index to Nursing and Allied Health Literature; n = number; SR = systematic reviews.
tematic reviews (Abrams et al., 2015; Gale et al., 2012; Jankiewicz et al., 2023; Jasani et al., 2017; Liang et al., 2024; Makrides et al., 2005; Milani et al., 2023; Mugambi et al., 2012; Patro-Gołąb et al., 2016; Rao et al., 2009; Ren et al., 2022; Szajewska et al., 2015, 2017; Udell et al., 2005; Wang, L., et al., 2019; Zhang et al., 2023), four pooled studies (Alexander et al., 2016; Camier et al., 2021; Czerkies et al., 2018; Haschke et al., 2014), and 115
primary studies published in 125 articles (see Figure E-2). Three articles reported results of the EU Childhood Obesity Study (Collell et al., 2016; Escribano et al., 2012; Koletzko et al., 2009), four articles reported results of the BeMIM study (Demmelmair et al., 2022; Fleddermann et al., 2014, 2017, 2018), Kouwenhoven et al. (2020, 2021a,b) reported results of one study in three articles, and Tinghäll Nilsson et al. (2023, 2024) reported results of one study in two articles. Among the 115 primary studies (123 articles), 108 studies (116 articles) were randomized controlled trials (RCTs) (Abrahamse-Berkeveld et al., 2024; Ahrens et al., 2018; Alliet et al., 2022; Ashley et al., 2012; Ben et al., 2004; Billeaud et al., 2014; Breij et al., 2019; Bruzzese et al., 2009; Cekola et al., 2015; Cesare Marincola et al., 2016; Chouraqui et al., 2008; Civardi et al., 2017; Collell et al., 2016; Costalos et al., 2008; Davis et al., 2008; Demmelmair et al., 2022; Escribano et al., 2012; Estorninos et al., 2022; Fanaro et al., 2005; Fleddermann et al., 2014, 2018; Fusch et al., 2001; Gianni et al., 2018; Gibson et al., 2009; Gil-
NOTES: NRCTs = nonrandomized controlled trials; RCTs = randomized controlled trials.
Campos et al., 2022; Giovannini et al., 2013; Haschke et al., 2014; He et al., 2022; Hedrick et al., 2021; Hegar et al., 2008; Heubi et al., 2000; Hoffman et al., 2008, 2019; Holscher et al., 2012; Inostroza et al., 2014; Jaramillo-Ospina et al., 2022; Jiang et al., 2022; Johnston et al., 2015; Kantaras et al., 2024; Karaglani et al., 2020; Koletzko et al., 2009; Koo et al., 2003; Kouwenhoven et al. 2020, 2021a,b; Kuehn et al., 2022; Lambidou et al., 2021; Lasekan et al., 2006, 2011, 2014, 2022; Li, F., et al., 2019; Li, X., et al. 2019; Lien et al., 2004; Liotto et al., 2018; Litmanovitz et al., 2013; Lonnerdal et al., 2016; López-Velázquez et al., 2013; Mackey et al., 2013; Makrides et al., 2000; Maldonado et al., 2012, 2019; Marriage et al., 2015; Martin et al., 2014; Meli et al., 2014; Morris et al., 2000; Neumer et al., 2021; Nieto-Ruiz et al., 2019; Oropeza-Ceja et al., 2021; Parschat et al., 2021; Petersen et al., 2020; Picaud et al., 2020; Rigo et al., 2019; Rodriguez-Herrera et al., 2019; Román et al., 2020; Rozé et al., 2012; Rzehak et al., 2009; Sandström et al., 2008; Scalabrin et al., 2012; Schmelzle et al., 2003; Sepúlveda-Valbuena et al., 2021; Shahramian et al., 2018; Shen et al., 2021; Singhal et al., 2010; Szajewska et al., 2017; Takahashi et al., 2023; Teoh et al., 2022; Timby et al., 2014; Tinghäll Nilsson et al., 2023, 2024; Tonon et al., 2021; Totzauer et al., 2018; Trabulsi et al., 2011; Troesch et al., 2019; Turck et al., 2006; Vandenplas et al., 2020; Veereman-Wauters et al., 2011; Vendt et al., 2006; Vlieger et al., 2009; Wang, Y., et al., 2021; Wu et al., 2017; Xia et al., 2021; Xu et al., 2015; Yang et al., 2022; Yeiser et al., 2016; Yin et al., 2023; Zhou et al., 2014; Ziegler et al., 2015); of these, 62 studies (70 articles) included a nonrandomized human milk–fed arm (Abrahamse-Berkeveld et al., 2024; Ahrens et al., 2018; Alliet et al., 2022; Ben et al., 2004; Breij et al., 2019; Cesare Marincola et al., 2016; Collell et al., 2016; Davis et al., 2008; Demmelmair et al., 2022; Escribano et al., 2012; Fleddermann et al., 2014, 2018; Gianni et al., 2018; Giovannini et al., 2013; He et al., 2022; Holscher et al., 2012; Inostroza et al., 2014; Jaramillo-Ospina et al., 2022; Koletzko et al., 2009; Kuehn et al., 2022; Lambidou et al., 2021; Lasekan et al., 2022; Li, X., et al. 2019; Liang et al., 2024; Liotto et al., 2013; Litmanovitz et al., 2013; López-Velázquez et al., 2013; Mackey et al., 2013; Makrides et al., 2000; Marriage et al., 2015; Martin et al., 2014; Meli et al., 2014; Nieto-Ruiz et al., 2019; Oropeza-Ceja et al., 2021; Parschat et al., 2021; Petersen et al., 2020; Picaud et al., 2020; Piemontese et al., 2011; Plaza-Diaz et al., 2023; Putet et al., 2016; Radke et al., 2017; Räihä et al., 2002; Rodriguez-Herrera et al., 2019; Román et al., 2020; Rzehak et al., 2009; Sandström et al., 2008; Scalabrin et al., 2012; Sepúlveda-Valbuena et al., 2021; Shahramian et al., 2018; Shen et al., 2021; Singhal et al., 2010; Takahashi et al., 2023; Teoh et al., 2022; Timby et al., 2014; Tinghäll Nilsson et al., 2023, 2024; Totzauer et al., 2018; Trabulsi et al., 2011; Troesch et al., 2019; Vandenplas et al., 2020; Veereman-Wauters et al., 2011; Wang, Y., et al., 2021; Wu et al., 2017; Xia et al., 2021; Yin et al., 2023; Zhou et al., 2014; Ziegler et al., 2015), three were non-
randomized controlled trials (Billeaud et al., 2022; Hernell and Lönnerdal, 2002; Jochum et al., 2023), and four were prospective cohort studies (Andres et al., 2012; Jinno et al., 2020; Pastor et al., 2006; Tonon et al., 2021).
Articles were published 2000–2024 with a stable increase in publications over time (see Figure E-3). The greatest number of studies were conducted in the United States (Andres et al., 2012; Ashley et al., 2012; Cekola et al., 2015; Davis et al., 2008; Hedrick et al., 2021; Heubi et al., 2000; Hoffman et al., 2008, 2019; Holscher et al., 2012; Johnston et al.,
2015; Koo et al., 2003; Kuehn et al., 2022; Lasekan et al., 2006, 2011, 2014, 2022; Lien et al., 2004; Mackey et al., 2013; Marriage et al., 2015; Yeiser et al., 2016; Ziegler et al., 2007, 2015), followed by Italy (Ben et al., 2004; Bruzzese et al., 2009; Cesare Marincola et al., 2016; Civardi et al., 2017; Fanaro et al., 2005; Gianni et al., 2018; Giovannini et al., 2013; Kantaras et al., 2024; Liotto et al., 2018; Meli et al., 2014; Puccio et al., 2007, 2017; Räihä et al., 2002; Rodriguez-Herrera et al., 2019), Spain (Collell et al., 2016; Gil-Campos et al., 2012; Maldonado et al., 2012, 2019; Nieto-Ruiz et al., 2019; Pastor et al., 2006; Plaza-Diaz et al., 2023; Rodriguez-Herrera et al., 2019; Román et al., 2020; Sepúlveda-Valbuena et al., 2021), Germany (Escribano et al., 2012; Fusch et al., 2001; He et al., 2022; Jochum et al., 2023; Koletzko et al., 2009; Kouwenhoven et al. 2020, 2021a,b; Lambidou et al., 2021; Parschat et al., 2021; Petersen et al., 2020; Picaud et al., 2020; Radke et al., 2017; Rzehak et al., 2009; Schmelzle et al., 2003), and China (Ben et al., 2004; Jiang et al., 2022; Li, F., et al., 2019; Li, X., et al. 2019; Lonnerdal et al., 2016; Shen et al., 2021; Wang, Y., et al., 2021; Wu et al., 2017; Xia et al., 2021; Xu et al., 2015) (see Figure E-4). Studies were funded by industry (100 studies) (Abrahamse-Berkeveld et al., 2024; Ahrens et al., 2018; Alliet et al., 2022; Andres et al., 2012; Ashley et al., 2012; Ben et al., 2004; Billeaud et al., 2014, 2022; Breij et al., 2019; Bruzzese et al., 2009; Cekola et al., 2015; Cesare Marincola et al., 2016; Civardi et al., 2017; Costalos et al., 2008; Davis et al., 2008; Demmelmair et al., 2022; Fleddermann et al., 2014, 2018; Gianni et al., 2018; Gibson et al., 2009; Gil-Campos et al., 2012; Giovannini et al., 2013; He et al., 2022; Hedrick et al., 2021; Hegar et al., 2008; Heubi et al., 2000; Hoffman et al., 2008, 2019; Holscher et al., 2012; Inostroza et al., 2014; Jaramillo-Ospina et al., 2022; Jochum et al., 2023; Johnston et al., 2015; Kantaras et al., 2024; Karaglani et al., 2020; Koo et al., 2003; Kouwenhoven et al. 2020, 2021a,b; Kuehn et al., 2022; Lambidou et al., 2021; Lasekan et al., 2006, 2011, 2014, 2022; Li, F., et al., 2019; Li, X., et al. 2019; Lien et al., 2004; Liotto et al., 2018; Lonnerdal et al., 2016; Makrides et al., 2000; Maldonado et al., 2012, 2019; Marriage et al., 2015; Meli et al., 2014; Morris et al., 2000; Neumer et al., 2021; Nieto-Ruiz et al., 2019; Oropeza-Ceja et al., 2021; Parschat et al., 2021; Pastor et al., 2006; Peters et al., 2020; Picaud et al., 2020; Piemontese et al., 2011; Plaza-Diaz et al., 2023; Puccio et al., 2017; Putet et al., 2016; Räihä et al., 2002; Rodriguez-Herrera et al., 2019; Román et al., 2020; Rozé et al., 2012; Rzehak et al., 2009; Sandström et al., 2008), the government (18 studies) (Andres et al., 2012; Escribano et al., 2012; Hernell and Lönnerdal, 2002; Jiang et al., 2022; Koletzko et al., 2009; Kouwenhoven et al. 2020, 2021a,b; Makrides et al., 2000; Neumer et al., 2021; Nieto-Ruiz et al., 2019; Oropeza-Ceja et al., 2021; Pastor et al., 2006; Rzehak et al., 2009; Singhal et al., 2010; Totzauer et al., 2018; Wu et al., 2017; Xu et al., 2015), and a university (one
study) (Sepúlveda-Valbuena et al., 2021), and some received funding from multiple sources (see Figure E-5).
Study Populations in Primary Studies
Most studies had a population size of 100–500 participants (84 studies) (see Figure E-6). All studies except one reported an equal distribution of boys and girls, and 25 studies did not report the proportion of girls and boys. Twenty-one studies reported race/ethnicity; 10 were conducted in the United States and 11 (14 articles) were conducted outside of the United States (Alliet et al., 2022; He et al., 2022; Jochum et al., 2023; Kouwenhoven et al. 2020, 2021a,b; Piemontese et al., 2011; Puccio et al., 2007; Putet et al., 2016; Román et al., 2020; Scalabrin et al., 2012; Teoh et al., 2022; Tinghäll Nilsson et al., 2023; Zhou et al., 2014) (see Figure E-7).
Food and Drug Administration (FDA) Requirements Reported in Primary Studies
FDA’s Code of Federal Regulations (Title 21) report quality factors for infant formulas (FDA and HHS, n.d.). Table E-3 lists 19 quality standards and the number of studies reporting them in and outside of the United States. Only two studies reported all 19 quality standards (Rigo et al., 2019; Zhou et al., 2014). Of the 22 studies conducted in the United States, 55 percent (12 studies) (Cekola et al., 2015; Haschke et al., 2014; Johnston et al., 2015; Koo et al., 2003; Kuehn et al., 2022; Lasekan et al., 2006, 2011, 2014, 2022; Marriage et al., 2015; Yeiser et al., 2016; Ziegler et al., 2015) met at least 13 of the 19 standards; 61 percent (57 out of 93 studies) of those conducted outside the United States met this criterion (see Figure E-8). The least frequently reported standards among studies in the United States were head circumference z-score (3 studies (14 percent)) (Cekola et al., 2015; Kuehn et al., 2022; Lasekan et al., 2006) and weight-
| Variables | Number of Studies in U.S. | Number of Studies Conducted Outside of the U.S. |
|---|---|---|
| Number of Articles; Number of Studies | 22; 22 | 101; 93 |
| Infants Enrolled by 15 Days of Life | 17 (77%) | 44 (47%) |
| Exclusive Formula Feeding (for intervention and control/standard groups) | 22 (100%) | 82 (88%); 6 NR |
| Equal to or More Than 15 Weeks of Intervention (not an age, a duration) | 18 (82%) | 72 (77%); 1 NR |
| Standard Formula Comparator | 21 (95%) | 78 (84%) |
| Time of Growth Measurement Performance (3 or more within 1 month = 1) | 6 (27%) | 5 (5%) |
| Number of Time Points (equal or more than 6 = 2) | 6 (27%) | 27 (29%) |
| Weight Reported | 21 (95%) | 93 (100%) |
| Weight Statistical Significance Reported | 16 (73%) | 83 (89%) |
| Weight Z-Score Reported | 4 (18%) | 59 (63%) |
| Length Reported | 20 (91%) | 84 (90%) |
| Length Statistical Significance Reported | 16 (73%) | 74 (79%) |
| Length Z-Score Reported | 6 (27%) | 57 (61%) |
| Head Circumference Reported | 19 (86%) | 78 (85%) |
| Head Circumference Statistical Significance Reported | 14 (64%) | 70 (76%) |
| Head Circumference Z-Score Reported | 3 (14%) | 50 (54%) |
| Weight/Length Z-Score Reported | 3 (14%) | 30 (33%) |
| Formula Intake Reported | 18 (82%) | 65 (70%) |
| AEs/Tolerance Variables Reported | 21 (95%) | 80 (86%) |
| Attrition of Subjects Reported | 20 (91%) | 84 (90%) |
| Not FDA Requirement—Biomarkers Reported | 14 (64%) | 46 (50%) |
NOTES: AEs = adverse events, FDA = U.S. Food and Drug Administration; NR = not reported; U.S. = United States.
NOTE: FDA = U.S. Food and Drug Administration.
for-length (3 studies (14 percent)) (Cekola et al., 2015; Davis et al., 2008; Kuehn et al., 2022). Among studies outside of the United States, the least frequently reported standard was three reported growth measurements with 1 month (5 studies (5 percent)) (He et al., 2022; Li, X., et al., 2019; Rigo et al., 2019; Totzauer et al., 2018; Zhou et al., 2014).
Infant Formula Modifications Evaluated in Primary Studies
Types of infant formula included cow (111 studies), plant/other (2 studies) (Gianni et al., 2018; Gibson et al., 2009), soy (2 studies) (Andres et al., 2012; Hoffman et al., 2008), and goat (4 studies) (He et al., 2022; Xu et al., 2015; Yin et al., 2023; Zhou et al., 2014). All goat-based studies
were conducted outside of the United States. Eighteen studies evaluated partially hydrolyzed formulas (Ahrens et al., 2018; Ben et al., 2004; Billeaud et al., 2022; Cekola et al., 2015; Fusch et al., 2001; Holscher et al., 2012; Jochum et al., 2023; Kantaras et al., 2024; Kuehn et al., 2022; Lasekan et al., 2006; Picaud et al., 2020; Rigo et al., 2019; Román et al., 2020; Rzehak et al., 2009; Schmelzle et al., 2003; Wang, Y., et al., 2021; Yang et al., 2022). The formula modifications included protein amount (Ahrens et al., 2018; Billeaud et al., 2022; Collell et al., 2016; Davis et al., 2008; Demmelmair et al., 2022; Escribano et al., 2012; Fleddermann et al., 2014, 2017, 2018; He et al., 2022; Hedrick et al., 2021; Inostroza et al., 2014; Jinno et al., 2020; Koletzko et al., 2009; Kouwenhoven et al. 2020, 2021a,b; Lasekan et al., 2006; Li, F., et al., 2019; Lien et al., 2004; Liotto et al., 2018; Lonnerdal et al., 2016; Martin et al., 2014; Neumer et al., 2021; Oropeza-Ceja et al., 2021; Petersen et al., 2020; Picaud et al., 2020; Plaza-Diaz et al., 2023; Putet et al., 2016; Räihä et al., 2002; Rigo et al., 2019; Román et al., 2020; Timby et al., 2014; Tinghäll Nilsson et al., 2023, 2024a; Totzauer et al., 2018; Trabulsi et al., 2011; Turck et al., 2006; Wu et al., 2017; Xu et al., 2015; Zhou et al., 2014), amino acid (AA) modification (Davis et al., 2008; Demmelmair et al., 2022; Fleddermann et al., 2014, 2017, 2018; Jinno et al., 2020; Johnston et al., 2015; Kouwenhoven et al. 2020, 2021a,b; Kuehn et al., 2022; Lasekan et al., 2022; Lien et al., 2004; Petersen et al., 2020; Räihä et al., 2002; Sandström et al., 2008; Sepúlveda-Valbuena et al., 2021; Tonon et al., 2021; Xu et al., 2015), fat amount (Ashley et al., 2012; Ben et al., 2004; Cesare Marincola et al., 2016; Demmelmair et al., 2022; Fleddermann et al., 2014, 2017, 2018; Gianni et al., 2018; Hegar et al., 2008; Jinno et al., 2020; Lambidou et al., 2021; Liotto et al., 2018; Meli et al., 2014; Morris et al., 2000; Neumer et al., 2021; Nieto-Ruiz et al., 2019; Pastor et al., 2006; Schmelzle et al., 2003; Wang, Y., et al., 2021; Xu et al., 2015; Zhou et al., 2014), fat type (Abrahamse-Berkeveld et al., 2024; Andres et al., 2012; Ben et al., 2004; Billeaud et al., 2014, 2022; Breij et al., 2019; Cesare Marincola et al., 2016; Civardi et al., 2017; Demmelmair et al., 2022; Fleddermann et al., 2014, 2017, 2018; Fusch et al., 2001; Gianni et al., 2018; Gibson et al., 2009; Hedrick et al., 2021; Hoffman et al., 2008, 2019; Jaramillo-Ospina et al., 2022; Jiang et al., 2022; Jinno et al., 2020; Johnston et al., 2015; Koo et al., 2003; Li, X., et al. 2019; Litmanovitz et al., 2013; Makrides et al., 2000; Meli et al., 2014; Morris et al., 2000; Nieto-Ruiz et al., 2019; Petersen et al., 2020; Schmelzle et al., 2003; Sepúlveda-Valbuena et al., 2021; Shen et al., 2021; Teoh et al., 2022; Timby et al., 2014; Xia et al., 2021; Xu et al., 2015; Yeiser et al., 2016; Zhou et al., 2014), micronutrients (Ashley et al., 2012; Davis et al., 2008; Hedrick et al., 2021; Hoffman et al., 2008; Mackey et al., 2013; Xu et al., 2015; Zhou et al., 2014), lactose free (Heubi et al., 2000; Lasekan 2006, 2011, 2014), prebiotics (Ahrens et al., 2018; Alliet et al., 2022; Ashley et al., 2012; Bruzzese et al., 2009; Cesare Marincola et al., 2016; Chouraqui
et al., 2008; Civardi et al., 2017; Costalos et al., 2008; Estorninos et al., 2022; Fanaro et al., 2005; Fusch et al., 2001; Giovannini et al., 2013; Hoffman et al., 2019; Jochum et al., 2023; Kuehn et al., 2022; Lambidou et al., 2021; Lasekan et al., 2022; Li, X., et al. 2019; López-Velázquez et al., 2013; Marriage et al., 2015; Meli et al., 2014; Neumer et al., 2021; Nieto-Ruiz et al., 2019; Parschat et al., 2021; Picaud et al., 2020; Piemontese et al., 2011; Puccio et al., 2007, 2017; Radke et al., 2017; Rigo et al., 2019; Rodriguez-Herrera et al., 2019; Román et al., 2020; Rozé et al., 2012; Scalabrin et al., 2012; Schmelzle et al., 2003; Sepúlveda-Valbuena et al., 2021; Shahramian et al., 2018; Szajewska et al., 2017; Teoh et al., 2022; Tonon et al., 2021; Veereman-Wauters et al., 2011; Vlieger et al., 2009; Wang, Y., et al., 2021; Xu et al., 2015; Yang et al., 2022; Yeiser et al., 2016; Ziegler et al., 2007), and probiotics (Cekola et al., 2015; Gibson et al., 2009; Gil-Campos et al., 2012; Holscher et al., 2012; Inostroza et al., 2014; López-Velázquez et al., 2013; Maldonado et al., 2012, 2019; Martin et al., 2014; Meli et al., 2014; Nieto-Ruiz et al., 2019; Plaza-Diaz et al., 2023; Puccio et al., 2007; Radke et al., 2017; Rozé et al., 2012; Sepúlveda-Valbuena et al., 2021; Szajewska et al., 2017; Vendt et al., 2006;Vlieger et al., 2009; Wang, L., et al., 2019; Weizman and Alsheikh, 2006) (see Figure E-9).
Outcomes Reported in Primary Studies
The most frequently reported outcome was weight, followed by length and head circumference (see Figure E-10 and Table E-4). The least frequently reported outcomes were body composition (lean and fat mass) and body mass index. Z-scores were far less frequently reported (e.g., weight 18 percent) for studies inside than outside of the United States (e.g., weight 63 percent). A wide variety of biomarkers were reported, including bone mineral, gut microbiome, and developmental values. The most frequently reported biomarkers with nutrition related (AAs, iron, and carotenoids), and the least frequently reported were bone mineral status values.
Pooled Studies
Four pooled analyses studies met criteria and were included in this scoping review (Alexander et al., 2016; Camier et al., 2021; Czerkies et al., 2018; Haschke et al., 2014). Three evaluated protein amount modification (Alexander et al., 2016; Camier et al., 2021; Haschke et al., 2014) in infant formula. Haschke et al. (2014) conducted a pooled analysis of three studies; one study was included in this scoping review (Inostroza et al., 2014), and two studies were excluded (conference abstracts). Alexander et al. (2016) pooled individual data from 11 RCTs. Five of the 11 RCTs
are included in this scoping review (Chouraqui et al., 2008; Gibson et al., 2009; Meli et al., 2014; Puccio et al., 2007; Putet et al., 2016), and six were excluded (publication date, population, and reported outcomes). Camier et al. (2021) pooled results from two cohorts with multiple publications. The investigative purposes of the articles included in the in this pooled analysis were outside the scope of this scoping review and therefore not included. Czerkies et al. (2018) conducted a pooled analysis that included seven clinical trials to evaluate the effectiveness of partially hydrolyzed formulas compared to standard formulas on growth and stools (Czerkies et al., 2018). Four studies from pooled analysis were included in this scoping review; three studies were excluded because they were conference
NOTES: BMI = body mass index; U.S. = United States.
| Number of Studies in U.S. Reporting Significance | Number of Studies in U.S. Reporting Statistically Significant Results | Number of Studies Conducted Outside of the U.S. Reporting Significance | Number of Studies Conducted Outside of the U.S. Reporting Statistically Significant Results | |
|---|---|---|---|---|
| Weight z-score at 4 months | 8 | 0 | 39 | 4 |
| Weight at 4 months | 13 | 0 | 45 | 3 |
| Weight z-score at the end of the study | 8 | 1 | 57 | 5 |
| Length at 4 months | 12 | 0 | 39 | 3 |
| Head circumference at 4 months | 11 | 0 | 39 | 1 |
| Weight z-score by sex/gender at the end of the study | 7 | 2 | 9 | 3 |
| Weight z-score by race/ethnicity at the end of the study | 1 | 0 | 1 | 0 |
NOTES: U.S. = United States.
proceedings (Cekola et al., 2015; Chouraqui et al., 2008; Meli et al., 2014; Puccio et al., 2007).
Systematic Reviews
Sixteen systematic reviews met criteria and were included in this scoping review (see Table E-5) (Abrams et al., 2015; Ahrens et al., 2018; Alexander et al., 2016; Alliet et al., 2022; Andres et al., 2012; Bruzzese et al., 2009; Gale et al., 2012; Jankiewicz et al., 2023; Jasani et al., 2017; Jiang et al., 2022; Liang et al., 2024; Makrides et al., 2005; Milani et al., 2023; Mugambi et al., 2012; Patro-Gołab et al., 2016; Rao et al., 2009; Ren et al., 2022; Szajewska et al., 2015, 2017; Udell et al., 2005; Wang, L., et al., 2019; Zhang et al., 2023). The majority of the systematic reviews searched at least two databases (with the exception of two: Gale et al., 2012; Makrides et al., 2005), conducted risk of bias assessments of included articles (with the exception of two: Makrides et al., 2005; Udell et al., 2005), and conducted meta-analyses (with the exception of two: Abrams et al., 2015; Szajewska et al., 2015). Only three systematic reviews evaluated the certainty of evidence for each reported outcome (Jasani et al., 2017; Liang et al., 2024; Mugambi et al., 2012). Years of publication were 2005–2024. Topics included amount and type of fat (Jasani et al., 2017; Makrides et al., 2005; Udell et al., 2005; Zhang et al., 2023), pre-, pro-, and postbiotics (Liang et al., 2024; Mugambi et al., 2012; Rao et al., 2009; Szajewska et al., 2015), protein (Abrams et al., 2015; Milani et al., 2023; Patro-Gołab et al., 2016; Ren et al., 2022), fermentation (Szajewska et al., 2015), nucleotides (Wang, L., et al., 2019), goat milk (Jankiewicz et al., 2023), and formula compared to human milk (Gale et al., 2012).
| Author | Year | Number of Articles | 2 or More Databases | ROB | COE | Meta-Analysis |
|---|---|---|---|---|---|---|
| Fat | ||||||
| Makrides et al. (2005) | 2005 | 14 | 0 | 0 | 0 | 1 |
| Udell et al. (2005) | 2005 | 5 | 1 | 0 | 0 | 1 |
| Jasani et al. (2017) | 2017 | 15 | 1 | 1 | 1 | 1 |
| Zhang et al. (2023) | 2023 | 16 | 1 | 1 | 0 | 1 |
| Pre- or Probiotics | ||||||
| Rao et al. (2009) | 2009 | 11 | 1 | 1 | 0 | 1 |
| Mugambi et al. (2012) | 2012 | 23 | 1 | 1 | 1 | 1 |
| Szajewska et al. (2013) | 2013 | 9 | 1 | 1 | 0 | 1 |
| Liang et al. (2024) | 2024 | 9 | 1 | 1 | 1 | 1 |
| Formula vs. Human Milk | ||||||
| Gale et al. (2012) | 2012 | 15 | 0 | 1 | 0 | 1 |
| Protein | ||||||
| Abrams et al. (2015) | 2015 | 6 | 1 | 1 | 0 | 0 |
| Patro-Gołab et al. (2016) | 2016 | 12 | 1 | 1 | 0 | 1 |
| Ren et al. (2022) | 2022 | 19 | 1 | 1 | 0 | 1 |
| Milani et al. (2023) | 2023 | 5 | 1 | 1 | 0 | 1 |
| Fermentation | ||||||
| Szajewska et al. (2017) | 2015 | 5 | 1 | 1 | 0 | 0 |
| Nucleotides | ||||||
| Wang et al. (2019) | 2019 | 8 | 1 | 1 | 0 | 1 |
| Goat Milk | ||||||
| Jankiewicz et al. (2023) | 2023 | 4 | 1 | 1 | 0 | 1 |
NOTE: COE = certainty of evidence; ROB = risk of bias.
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