Higher versus lower protein intake in formula‐fed term infants

Background 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. Objectives To evaluate the benefits and harms of higher protein intake versus lower protein intake in healthy, formula‐fed term infants. Search methods We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, OpenGrey, clinical trial registries, and conference proceedings in October 2022. Selection criteria 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). Data collection and analysis 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. Main results 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. Authors' conclusions 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.