Fetal growth restriction and small for gestational age : antenatal identification, outcomes and the maternal gut microbiota

Background Fetal growth restriction (FGR) affects approximately 5-10% of pregnancies and is a major determinant of adverse perinatal outcomes. In most cases, FGR is caused by placental insufficiency. While the pathophysiological mechanisms underlying placental abnormalities in FGR pregnancies have partly been established, several aspects remain unexplained. FGR is defined as the failure of a fetus to reach its growth potential due to a pathological process; however, as fetal growth potential is difficult to determine, small for gestational age (SGA) is often used as a proxy. Antenatal screening strategies aim to identify small fetuses and distinguish constitutionally small fetuses from pathologically growth restricted fetuses to reduce adverse outcomes. Evaluating perinatal outcomes in antenatally identified versus unidentified SGA/FGR pregnancies, assessing potential inequalities in identification, and exploring novel etiological pathways may to improve care and advance knowledge in this field. Methods Population-based register data from computerized maternity and delivery records in the Stockholm region were cross-linked with national Swedish health and population registers. Logistic regression analyses were used to assess associations between antenatal identification of SGA/FGR and adverse perinatal and childhood outcomes, including analyses conducted separately for early- and late-onset FGR. Socioeconomic and demographic factors were examined using both conventional and intersectional models to evaluate potential inequalities in antenatal identification. In addition, data from the Swedish Maternal Microbiome Cohort, including fecal samples collected in early and late pregnancy and detailed questionnaire data, were used to investigate associations between maternal gut microbiota composition and SGA or FGR birth. Results A substantial proportion of SGA pregnancies remained unidentified antenatally. Unidentified SGA fetuses had a markedly increased risk of stillbirth compared with identified SGA fetuses, whereas identified SGA fetuses had a higher risk of severe childhood outcomes. Antenatal identification of early-onset FGR was associated with a reduced risk of stillbirth, but an increased risk of severe newborn distress and adverse childhood outcomes. Identification of late-onset FGR was associated with an increased risk of severe childhood outcomes, while no clear association with stillbirth was observed. No indicators of low socioeconomic status or foreign background were associated with failure to identify SGA antenatally. Maternal gut microbiota composition in both early and late pregnancy was associated with SGA and FGR births, with more pronounced alterations, including a significant microbial shift, observed in FGR pregnancies. Conclusions In a setting using risk-based antenatal screening for SGA, a large proportion of SGA pregnancies remained unidentified, and non-identification was associated with a substantially increased risk of stillbirth. The beneficial effect of antenatal identification was more evident for early-onset FGR, whereas identification of late-onset FGR was not associated with a corresponding reduction in stillbirth risk. In contrast, antenatal identification was associated with increased risks of severe childhood outcomes across both early- and late-onset FGR, highlighting the complexity of clinical management in these pregnancies. To reduce potentially preventable stillbirths, improved antenatal identification of SGA/FGR is required, together with more refined risk stratification and management strategies, particularly for late-onset FGR. Although socioeconomic disadvantages and a foreign background were hypothesized to contribute to identification failure, no such associations were observed, indicating that other, currently unknown or overlooked risk factors need to be identified. The observed associations between maternal gut microbiota composition and SGA/FGR births suggest a potential role of maternal microbiota in the pathophysiology of fetal growth restriction. List of scientific papers I. Hertting E, Herling L, Lindqvist PG, Wiberg-Itzel E. Importance of antenatal identification of small for gestational age fetuses on perinatal and childhood outcomes: A register-based cohort study. Acta Obstet Gynecol Scand. 2024;103(1):42-50. https://doi.org/10.1111/aogs.14697 II. Hertting E, Herling L, Lindqvist PG, Wiberg-Itzel E. Antenatal identification of early- and late-onset fetal growth restriction and the possible impact of the introduction of cerebroplacental ratio: Effect on perinatal and childhood outcome. PloS one. 2025;20(6):e0325906. https://doi.org/10.1371/journal.pone.0325906 III. Hertting E, Herling L, Lindqvist PG, Wiberg-Itzel E. The importance of socioeconomic factors on antenatal identification of small for gestational age pregnancies: Exploring health inequalities in the antenatal care in Sweden. Acta Obstet Gynecol Scand. 2026;105(1):125-35. https://doi.org/10.1111/aogs.70091 IV. Hertting E, Antony AT, Herling L, Lindqvist PG, Wiberg-Itzel E, Hugerth L. Associations between gut microbiota composition in early and late pregnancy and small for gestational age or growth restricted births: a nested case-control study. [Manuscript]