Small for Gestational Age sub-groups have differential morbidity, growth and neurodevelopment at age 2: the INTERBIO-21st Newborn Study

Small for Gestational Age (SGA) is a complex perinatal syndrome associated with increased neonatal morbidity, mortality, and impaired childhood growth and neurodevelopment. Current classifications rely primarily on birth weight, which does not capture the heterogeneity of the condition nor predict long-term health outcomes. Here we aim to identify and characterise distinct SGA sub-groups and assess their neonatal and early childhood health trajectories. To refine the classification of SGA by identifying sub-groups based on maternal, fetal, and environmental factors and evaluating their associations with neonatal morbidity, growth, and neurodevelopment at age 2. Prospective Cohort Study. In six countries worldwide, between 2012 and 2018, the INTERBIO-21st Study enrolled SGA and non-SGA newborns defined by the <10th centile of international standards with moderate (≥3rd to <10th centile) and severe (<3rd centile) SGA sub-groups; we assessed their growth, health, nutrition, motor development, and neurodevelopment up to age 2. We used 2-step cluster analysis to identify SGA sub-groups, and a probabilistic approach to choose the optimal sub-group model based on a statistical measure of fit. We performed logistic regression analysis (OR; 95% CI) to assess health and development outcomes among sub-groups using the non-SGA as reference group, adjusting for key confounders. We enrolled 5153 non-SGA and 1549 SGA newborns: moderate (≥3rd to <10th centile) SGA=947 and severe (<3rd centile) SGA=602). We identified nine SGA sub-groups: 'no main condition detected' (29.0%); 'previous low birth weight (LBW)/preterm birth (PTB)' (14.6%); 'severe maternal disease' (12.0%); 'maternal short stature (11.6%); 'hypertensive disorders' (9.6%); 'extrauterine infection' (6.8%); 'previous miscarriage(s)' (6.5%); 'smoking' (5.2%), and 'maternal under-nutrition' (4.7%). Severe SGA newborns in the 'severe maternal disease' (OR: 3.2; 95% CI, 1.8-6.0), 'previous LBW/PTB' (OR: 2.8; 95% CI, 1.6-4.8), and 'smoking' (OR: 5.4; 95% CI, 1.3-21.8) sub-groups had increased risk of neonatal and long-term morbidity, and low anthropometric measures at age 2 as compared to the non-SGA group. Moderate SGA newborns in the "hypertensive disorders" sub-group had increased risk of neonatal morbidity (OR: 2.6; 95% CI, 1.5-4.6), and higher odds of scoring <10th centile of normative values in language (OR: 3.5; 95%CI, 1.0-12.0) and positive behavior (OR: 2.2; 95%CI, 1.1-4.5). The 'severe maternal disease' sub-group had also higher risk of deficit (<10th centile of normative values) in language (OR: 5.7; 95%CI, 1.3-24.8), positive behavior (OR: 3.4; 95%CI, 1.5-7.6). SGA comprises heterogeneous sub-groups with distinct patterns of neonatal morbidity, postnatal growth, and neurodevelopmental outcomes up to age 2.