Aetiologically-Based Small for Gestational Age Phenotypes Have Differential Morbidity, Growth and Neurodevelopment at Age 2: The INTERBIO-21 <sup>st</sup> Newborn Study

Background: Small for Gestational Age (SGA) is increasingly recognised as a complex perinatal syndrome that requires phenotypic classification. Methods: In six countries worldwide, between 2012 and 2018, the INTERBIO-21 st Study enrolled SGA and non-SGA newborns, and assessed their size, health, nutrition, and motor development at ages 1 and 2, and neurodevelopment at age 2. We used 2-step cluster analysis to identify novel, aetiologically-based, SGAphenotypes, and a probabilistic approach to choose the optimal subgroup model based on a statistical measure of fit. We performed logistic regression analysis to assess phenotype-health outcome associations. Findings: 6702 newborns were included in the analysis: moderate (≥3 rd to <10 th centile) SGA=947; severe (<3 rd centile) SGA=602, and non-SGA=5153. Cluster analysis identified nine maternally-related SGA phenotypes: ‘no main condition detected’ (29·0%); ‘previous low birth weight (LBW)/preterm newborn’ (14·6%); ‘severe disease’ (12·0%); ‘short stature (11·6%); ‘hypertensive disorders’ (9·6%); ‘extrauterine infection’ (6·8%); ‘previous miscarriage(s)’ (6·5%); ‘smoking’ (5·2%, and ‘nutrition’ (4·7%). Severe SGA newborns in the ‘severe disease’ (OR: 3·2; 95% CI, 1·8-6·0), ‘previous LBW/preterm newborn’ (OR: 2·8; 95% CI, 1·6-4·8), and ‘smoking’ (OR: 5·4; 95% CI, 1·3-21·8) phenotypes had increased risk of neonatal and long-term morbidity, and low anthropometric measures at age 2. The ‘severe disease’ phenotype was also associated with higher odds of scoring <10th centile of normative values in language (OR: 5·7; 95%CI, 1·3-24·8), positive behaviour (OR: 3·4; 95%CI, 1·5-7·6), walking alone (β: 1·6; 95%CI, 0·4-2·7) and crawling milestones (β: 1·3; 95%CI, 0·4-2·2). Moderate SGA newborns in the “hypertensive disorders” phenotype had increased risk of neonatal morbidity (OR: 2·6; 95% CI, 1·5-4·6), and higher odds of scoring <10 th centile of normative values in language (OR: 3·5; 95%CI, 1·0-12·0) and positive behaviour (OR: 2·2; 95%CI, 1·1-4·5). Interpretation: SGA consists of aetiologically-based phenotypes with markedly differential patterns of neonatal morbidity, and growth and neurodevelopment up to age 2. Funding: The Bill & Melinda Gates FoundationDeclaration of Interest: ATP is supported by the Oxford Partnership Comprehensive Biomedical Research Centre with funding from the NIHR Biomedical Research Centre funding scheme. The views expressed herein are those of the authors and not necessarily those of the NHS, NIHR, Department of Health or any of the other funders. ATP is a Senior Advisor of Intelligent Ultrasound. All other authors declare no competing interests.Ethical Approval: INTERBIO-21st was approved by the Oxfordshire Research Ethics Committee, institutional research ethics committees and corresponding regional authorities