Papageorghiou Aris T, Restrepo-Méndez María C, McGready Rose, Barros Fernando C, Nosten Francois, Munim Shama, Ochieng Roseline, Craik Rachel, Barsosio Hellen C, Berkley James A, Carvalho Maria, Fernandes Michelle, Ismail Leila Cheikh, Lambert Ann, Norris Shane A, Ohuma Eric O, Stein FRCPsych Alan, Tshivuila-Matala Chrystelle O O, Winsey Adele, Bhutta Zulfiqar A, Kennedy Stephen H, Villar Jose
Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford, UK; Oxford Maternal & Perinatal Health Institute, Green Templeton College, University of Oxford, Oxford, UK.
Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford, UK; Oxford Maternal & Perinatal Health Institute, Green Templeton College, University of Oxford, Oxford, UK.
Am J Obstet Gynecol. 2025 May 23. doi: 10.1016/j.ajog.2025.05.017.
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-21 Study enrolled SGA and non-SGA newborns defined by the <10 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 (≥3 to <10 centile) SGA=947 and severe (<3 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 <10 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 (<10 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.
小于胎龄儿（SGA）是一种复杂的围产期综合征，与新生儿发病率、死亡率增加以及儿童期生长和神经发育受损有关。目前的分类主要依赖出生体重，这既无法体现该病症的异质性，也不能预测长期健康结局。在此，我们旨在识别并描述不同的SGA亚组，并评估其新生儿期和幼儿期的健康轨迹。
通过基于母亲、胎儿和环境因素识别亚组，并评估其与2岁时新生儿发病率、生长和神经发育的关联，来完善SGA的分类。
前瞻性队列研究。在2012年至2018年期间，全球六个国家的INTERBIO-21研究纳入了根据国际标准百分位数＜10定义的SGA和非SGA新生儿，分为中度（≥第3至＜第10百分位数）和重度（＜第3百分位数）SGA亚组；我们评估了他们直至2岁时的生长、健康、营养、运动发育和神经发育情况。我们使用两步聚类分析来识别SGA亚组，并采用概率方法根据拟合的统计量选择最佳亚组模型。我们进行逻辑回归分析（OR；95%CI），以非SGA作为参照组，对关键混杂因素进行调整，评估亚组间的健康和发育结局。
我们纳入了5153名非SGA新生儿和1549名SGA新生儿：中度（≥第3至＜第10百分位数）SGA = 947名，重度（＜第3百分位数）SGA = 602名）。我们识别出九个SGA亚组：“未检测到主要病症”（29.0%）；“既往低出生体重（LBW）/早产（PTB）”（14.6%）；“严重母体疾病”（12.0%）；“母体身材矮小”（11.6%）；“高血压疾病”（9.6%）；“宫外感染”（6.8%）；“既往流产”（6.5%）；“吸烟”（5.2%），以及“母体营养不足”（4.7%）。与非SGA组相比，“严重母体疾病”（OR：3.2；95%CI，1.8 - 6.0）、“既往LBW/PTB”（OR：2.8；95%CI，1.6 - 4.8）和“吸烟”（OR：5.4；95%CI，1.3 - 21.8）亚组中的重度SGA新生儿发生新生儿期和长期发病的风险增加，且2岁时人体测量指标较低。“高血压疾病”亚组中的中度SGA新生儿发生新生儿发病的风险增加（OR：2.6；95%CI，1.5 - 4.6），语言（OR：3.5；95%CI，1.0 - 12.0）和积极行为（OR：2.2；95%CI, 1.1 - 4.5）得分低于标准值第10百分位数的几率更高。“严重母体疾病”亚组在语言（OR：5.7；95%CI，1.3 - 24.8）、积极行为（OR：3.4；95%CI，1.5 - 7.6）方面出现缺陷（低于标准值第10百分位数）的风险也更高。
SGA由异质性亚组组成，在新生儿发病率、出生后生长以及直至2岁时的神经发育结局方面具有不同模式。
