Small for gestational age subgroups have differential morbidity, growth, and neurodevelopment at age 2: the INTERBIO-21st Newborn Study

Background: Small for gestational age is a complex perinatal syndrome associated with increased neonatal morbidity, mortality, and impaired childhood growth and neurodevelopment. Current classifications rely primarily on birthweight, which does not capture the heterogeneity of the condition nor predict long-term health outcomes. Here we aim to identify and characterize distinct small for gestational age subgroups and assess their neonatal and early childhood health trajectories.

Objective: To refine the classification of small for gestational age by identifying subgroups based on maternal, fetal, and environmental factors and evaluating their associations with neonatal morbidity, growth, and neurodevelopment at age 2.

Study Design: Prospective cohort study. In six countries worldwide, between 2012 and 2018, the INTERBIO-21st Study enrolled small for gestational age and non-small for gestational age newborns defined by the <10th centile of international standards with moderate (≥third–<10th centile) and severe (<third centile) small for gestational age subgroups; we assessed their growth, health, nutrition, motor development, and neurodevelopment up to age 2. We used 2-step cluster analysis to identify small for gestational age subgroups, and a probabilistic approach to choose the optimal subgroup model based on a statistical measure of fit. We performed logistic regression analysis (odds ratio; 95% confidence interval) to assess health and development outcomes among subgroups using the non-small for gestational age as reference group, adjusting for key confounders.

Results: We enrolled 5153 non-small for gestational age and 1549 small for gestational age newborns: moderate (≥third–<10th centile) small for gestational age=947 and severe (<third centile) small for gestational age=602. We identified 9 small for gestational age subgroups: “no main condition detected” (29.0%); “previous low birthweight or preterm birth” (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 undernutrition” (4.7%). Severe small for gestational age newborns in the “severe maternal disease” (odds ratio, 3.2; 95% confidence interval, 1.8–6.0), “previous low birthweight or preterm birth” (odds ratio, 2.8; 95% confidence interval, 1.6–4.8), and “smoking” (odds ratio, 5.4; 95% confidence interval, 1.3–21.8) subgroups had increased risk of neonatal and long-term morbidity and low anthropometric measures at age 2 as compared to the non-small for gestational age group. Moderate small for gestational age newborns in the “hypertensive disorders” subgroup had increased risk of neonatal morbidity (odds ratio, 2.6; 95% confidence interval, 1.5–4.6) and higher odds of scoring <10th centile of normative values in language (odds ratio, 3.5; 95% confidence interval, 1.0–12.0) and positive behavior (odds ratio, 2.2; 95% confidence interval, 1.1–4.5). The “severe maternal disease” subgroup had also higher risk of deficit (<10th centile of normative values) in language (odds ratio, 5.7; 95% confidence interval, 1.3–24.8) and positive behavior (odds ratio, 3.4; 95% confidence interval, 1.5–7.6).

Conclusion: Small for gestational age comprises heterogeneous subgroups with distinct patterns of neonatal morbidity, postnatal growth, and neurodevelopmental outcomes up to age 2.