Early lean mass shapes long-term brain development in preterm infants

By Priyanjana Pramanik, MSc.Reviewed by Susha Cheriyedath, M.Sc.Nov 12 2025

A new study reveals that the quality of early growth, not just weight gain, influences long-term brain outcomes for extremely preterm infants, highlighting fat-free mass as a crucial marker of early developmental health.

Study: Fat-free mass is associated with neurodevelopment outcomes in extremely preterm infants up to 3 years of age. Image Credit: Ratchat / Shutterstock

In a recent study published in the journal Pediatric Research, researchers investigated whether early body composition at term-equivalent age is associated with neurodevelopmental outcomes until the age of three for extremely preterm infants. They found that children with higher fat-free mass (FFM) showed better neurodevelopmental outcomes in terms of motor, language, and cognitive skills up to the age of three. This suggests that monitoring FFM in early life could support long-term brain development and guide targeted nutritional care for preterm children.

Risks and Nutritional Challenges in Extreme Prematurity

Extremely preterm infants, who are born before 28 weeks’ gestation, remain at high risk for mortality and long-term neurological impairment despite significant advances in neonatal care. Although survival rates have improved, these infants often face growth and nutritional challenges that can impact brain development.

Limitations of Traditional Growth Indicators

Adequate early nutrition is crucial for optimal neurodevelopment; however, defining effective nutritional strategies remains challenging due to the lack of precise markers of nutritional adequacy. Human milk is known to support better neurodevelopmental outcomes, yet even with improved feeding practices, many extremely preterm infants still experience growth faltering and malnutrition.

Body Composition as a Qualitative Growth Marker

Recent technological advances, such as air displacement plethysmography, now allow accurate assessment of infant body composition, distinguishing FFM from fat mass (FM). FFM reflects muscle, organs, and brain tissue and is therefore considered a more meaningful indicator of nutritional quality and organ growth than total weight gain.

Rationale for Studying FFM and Long-Term Outcomes

Previous research by this group linked greater FFM at term-equivalent age with larger brain volume in preterm infants, but the long-term neurodevelopmental impact of FFM gains has not been fully explored. In this study, researchers aimed to determine whether early body composition, particularly FFM, predicts neurodevelopmental performance up to three years of age in extremely preterm infants.

Study Cohort and Inclusion Criteria

The study included 105 infants born before 28 weeks’ gestation at a hospital in Vienna. Infants with intraventricular hemorrhage greater than grade II, congenital abnormalities, or metabolic disorders were excluded. Body composition was measured at term-equivalent age using air displacement plethysmography, a validated and non-invasive method.

Growth Measures and Stability Requirements

Measurements were performed only on clinically stable infants without respiratory support, and Z-scores were calculated using sex- and gestational-age-specific reference data. Growth faltering was evaluated using changes in weight, length, or head circumference Z-scores between birth and term-equivalent age.

Assessment of Neurodevelopmental Trajectories

Neurodevelopmental outcomes were assessed at one, two, and three years of age using the Bayley Scales of Infant Development, Third Edition (Bayley-III), evaluating cognitive, language, and motor skills. Standard definitions were used to classify the severity of developmental delay.

Longitudinal Data Collection and Morbidity Tracking

Detailed anthropometric data were collected longitudinally, along with neonatal morbidities such as retinopathy of prematurity, necrotizing enterocolitis, and bronchopulmonary dysplasia.

Nutritional Management and Statistical Methods

Nutritional management was conducted according to established guidelines, prioritizing mother’s milk, donor milk, or formula as needed. Statistical analyses, including Pearson correlations and multivariate linear regressions, were adjusted for confounders such as gestational age, illness severity, and sex.

Infant Characteristics and Body Composition Profiles

Of 139 screened infants, 105 extremely preterm infants were included in the analysis, with most receiving an exclusively human milk diet. The median gestational age was 26.1 weeks, and the median birthweight was 770 g. Body composition was measured at a median of 41.2 weeks postmenstrual age, revealing a median FFM Z-score of minus 1.5 and FM Z-score of 1.0.

Patterns in Bayley-III Neurodevelopment Scores

Developmental scores on the Bayley-III were mostly normal at one year but showed mild impairment across cognitive, language, and motor domains at two and three years. Infants with lower Bayley-III scores (<85) consistently had lower FFM and FM Z-scores, with the strongest differences seen for FFM.

Independent Associations Between FFM and Development

Correlation and regression analyses confirmed a significant independent positive association between higher FFM Z-scores and better Bayley-III outcomes across all domains at one and three years, and in most domains at two years. Each one standard deviation increase in FFM corresponded to roughly a four-point improvement in Bayley-III scores. FM and anthropometric Z-score changes, such as head circumference, weight, and length, showed some unadjusted associations but no independent association with neurodevelopmental outcomes.

Nutrition Pathways and Parenteral Feeding Effects

A longer duration of parenteral nutrition was independently associated with poorer motor and language scores, particularly at two and three years of age, suggesting adverse nutritional or metabolic effects from prolonged intravenous feeding.

Clinical Implications of FFM for Brain Development

This study found that FFM at term-equivalent age was an independent predictor of better cognitive, language, and motor development through three years in extremely preterm infants. In contrast, fat mass and conventional growth measures were not associated with neurodevelopment, highlighting that qualitative growth, lean tissue accretion, matters more than overall weight gain.

Strengths, Limitations, and Need for Targeted Trials

The findings support current concepts that individualized nutrition, aimed at achieving adequate protein and energy intake and timely enteral feeding, may help promote FFM gains and brain development. However, the study did not directly measure nutritional intake or test specific feeding strategies. Strengths include a large, homogeneous cohort of extremely preterm infants, the high follow-up rate, and standardized Bayley-III assessments. Limitations include a lack of detailed nutritional intake data and the observational design, which precludes causal inference.

Future Directions for Body Composition–Guided Care

The study supports the use of routine body composition monitoring as a clinical tool to guide tailored nutrition and potentially improve neurodevelopmental outcomes. Future randomized trials should test targeted nutritional strategies to enhance FFM in this vulnerable group.