Key messages
1. We are unsure if high-protein formula affects malnutrition or obesity in infants.
2. Larger studies are needed to further evaluate the benefits and potential harms of the different types of formula.
3. Future research should focus on long-term growth and brain development.
What are high- and low-protein infant formulas?
Infant formulas have a similar nutritional content to breast milk, and contain ingredients such as cow's milk, fats, vitamins, proteins (such as whey or soy protein), and carbohydrates. Depending on the amount of protein they contain, formulas are categorized as low-protein (less than 1.8 g per 100 kcal), standard-protein, or high-protein (2.5 g or more per 100 kcal).
Why is it important to study infant formula?
Despite World Health Organization (WHO) recommendations, many full-term infants around the world are fed formula instead of breast milk. Some infant formulas contain more that the recommended amount of protein; they are designed to increase weight gain in infants during the first year of life. However, we do not know the effect of high-protein formula on malnutrition, overweight, or obesity during infancy.
What did we want to find out?
We wanted to find out whether high protein formula is better than standard or low protein formula for preventing:
1. malnutrition (low weight for age, low height for age, or low weight or height);
2. overweight or obesity (high weight for height); and
3. other unwanted events.
What did we do?
We searched for studies examining higher-protein formula compared with lower-protein formula in healthy infants of either sex, born at nine months of pregnancy and with normal birth weight and height.
We compared and summarized the results of the studies, and rated our confidence in the evidence based on factors such as study methods and sizes.
What did we find?
We found 11 eligible studies involving 1885 healthy, full-term, formula-fed infants. Seven studies (1629 infants) compared high-protein formula with standard-protein formula, and four studies (256 infants) compared standard-protein formula with low-protein formula. The biggest study included 1090 infants, and the smallest study included 20 infants. Ten studies were conducted in Europe and one in the USA. Most studies lasted approximately four months; only two studies lasted five years or more. Pharmaceutical companies funded all the studies.
Overall, we are unsure if feeding healthy infants high-protein formula compared to standard-protein formula has any effect on undernutrition, overweight, or obesity in the first year of life. We are unsure if feeding healthy infants standard-protein formula compared to low-protein formula has any effect on undernutrition in childhood. The occurrence of unwanted events in formula-fed infants may be unrelated to the protein content of the formula.
What are the limitations of the evidence
We are not confident about the evidence because the studies provided information in different ways, and the results varied considerably across studies. Moreover, some studies had many dropouts, which could have affected the results. Further research is likely to modify the results of this review.
How up to date is this evidence?
The evidence is current to October 2022.
We are unsure if feeding healthy infants high-protein formula compared to standard-protein formula has an effect on undernutrition, overweight, or obesity. There may be little or no difference in the risk of adverse effects between infants fed with high-protein formula versus those fed with standard-protein formula.
We are unsure if feeding healthy infants standard-protein formula compared to low-protein formula has any effect on undernutrition. There may be little or no difference in the risk of adverse effects between infants fed with standard-protein formula versus those fed with low-protein formula.
The findings of six ongoing studies and two studies awaiting classification studies may change the conclusions of this review.
Many infants are fed infant formulas to promote growth. Some formulas have a high protein content (≥ 2.5 g per 100 kcal) to accelerate weight gain during the first year of life. The risk-benefit balance of these formulas is unclear.
To evaluate the benefits and harms of higher protein intake versus lower protein intake in healthy, formula-fed term infants.
We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, OpenGrey, clinical trial registries, and conference proceedings in October 2022.
We included randomized controlled trials (RCTs) of healthy formula-fed infants (those fed only formula and those given formula as a complementary food). We included infants of any sex or ethnicity who were fed infant formula for at least three consecutive months at any time from birth. We excluded quasi-randomized trials, observational studies, and infants with congenital malformations or serious underlying diseases. We defined high protein content as 2.5 g or more per 100 kcal, and low protein content as less than 1.8 g per 100 kcal (for exclusive formula feeding) or less than 1.7 g per 100 kcal (for complementary formula feeding).
Four review authors independently assessed the risk of bias and extracted data from trials, and a fifth review author resolved discrepancies. We performed random-effects meta-analyses, calculating risk ratios (RRs) or Peto odds ratios (Peto ORs) with 95% confidence intervals (CIs) for dichotomous outcomes, and mean differences (MDs) with 95% CIs for continuous outcomes. We used the GRADE approach to evaluate the certainty of the evidence.
We included 11 RCTs (1185 infants) conducted in high-income countries. Seven trials (1629 infants) compared high-protein formula against standard-protein formula, and four trials (256 infants) compared standard-protein formula against low-protein formula. The longest follow-up was 11 years.
High-protein formula versus standard-protein formula
We found very low-certainty evidence that feeding healthy term infants high-protein formula compared to standard-protein formula has little or no effect on underweight (MD in weight-for-age z-score 0.05 SDs, 95% CI −0.09 to 0.19; P = 0.51, I2 = 61%; 7 studies, 1629 participants), stunting (MD in height-for-age z-score 0.15 SDs, 95% CI −0.05 to 0.35; P = 0.14, I2 = 73%; 7 studies, 1629 participants), and wasting (MD in weight-for-height z-score −0.12 SDs, 95% CI −0.31 to 0.07; P = 0.20, I2 = 94%; 7 studies, 1629 participants) in the first year of life.
We found very low-certainty evidence that feeding healthy infants high-protein formula compared to standard-protein formula has little or no effect on the occurrence of overweight (RR 1.26, 95% CI 0.63 to 2.51; P = 0.51; 1 study, 1090 participants) or obesity (RR 1.96, 95% CI 0.59 to 6.48; P = 0.27; 1 study, 1090 participants) at five years of follow-up.
No studies reported all-cause mortality.
Feeding healthy infants high-protein formula compared to standard-protein formula may have little or no effect on the occurrence of adverse events such as diarrhea, vomiting, or milk hypersensitivity (RR 0.93, 95% CI 0.76 to 1.13; P = 0.44, I2 = 0%; 4 studies, 445 participants; low-certainty evidence) in the first year of life.
Standard-protein formula versus low-protein formula
We found very low-certainty evidence that feeding healthy infants standard-protein formula compared to low-protein formula has little or no effect on underweight (MD in weight-for-age z-score 0.0, 95% CI −0.43 to 0.43; P = 0.99, I2 = 81%; 4 studies, 256 participants), stunting (MD in height-for-age z-score −0.01, 95% CI −0.36 to 0.35; P = 0.96, I2 = 73%; 4 studies, 256 participants), and wasting (MD in weight-for-height z-score 0.13, 95% CI −0.29 to 0.56; P = 0.54, I2 = 95%; 4 studies, 256 participants) in the first year of life.
No studies reported overweight, obesity, or all-cause mortality.
Feeding healthy infants standard-protein formula compared to low-protein formula may have little or no effect on the occurrence of adverse events such as diarrhea, vomiting, or milk hypersensitivity (Peto OR 1.55, 95% CI 0.70 to 3.40; P = 0.28, I2 = 0%; 2 studies, 206 participants; low-certainty evidence) in the first four months of life.