LC-HRMS Reveals Lipid Clues to Fetal Overgrowth

Babies who are large for their gestational age (LGA) are often born to mothers who seem perfectly healthy by standard measures, which makes it hard for doctors to spot the risk ahead of time using the usual clinical checks. To dig deeper, researchers looked at whether the makeup of fats (lipids) in mothers' blood during the second trimester could reveal hidden risk, even in women who appeared healthy. They did this by comparing blood samples from mothers who had LGA babies against those who didn't, drawing from a larger, ongoing study following pregnant women over time. The blood samples were analyzed using liquid chromatography and high-resolution mass spectrometry (LC-HRMS) to separate and identify different fat molecules with high precision. A paper based on this research was published in the journal iScience.¹

Why Do Some Babies Still End Up Large for Their Gestational Age Even When the Mother Appears Metabolically Healthy by Standard Measures?

Babies born large for their gestational age face a higher risk of developing heart and blood vessel problems later in life, even into adulthood. This is thought to happen because the conditions inside the womb during pregnancy can leave a lasting mark on how the body handles metabolism, with effects that can remain for a lifetime.^2-5Looking at this from a whole-life perspective, catching the problem early and stepping in during pregnancy offers a key opportunity to break this cycle of metabolic risk before it gets passed down and takes hold. We already know that certain factors raise the risk of a baby growing too large in the womb, including high blood sugar in the mother, obesity before pregnancy, and gaining too much weight during pregnancy. These factors seem to work mainly by increasing the amount of sugar and fat that crosses the placenta from mother to baby.^6-8Even so, LGA still happens in as many as 15% of pregnancies where the mother has a normal weight and normal blood sugar levels,^9,10 which, in the opinion of the paper’s authors, “represent an apparently metabolically healthy phenotype, suggesting that even apparently healthy women may harbor underlying metabolic abnormalities that drive excessive fetal growth through mechanisms not captured by conventional clinical screening.”¹

Can Blood Lipid Biomarkers Improve Prediction of LGA Risk Beyond What Standard Clinical Factors Alone Can Identify?

The study first tested its approach on a group of 135 participants, then checked whether the findings held up in a separate, later group of 66 participants to make sure the results were not a fluke. Using statistical modeling that looks at multiple factors together, researchers pinpointed 11 fat-related compounds in the blood, mostly different types of lipids, that were linked to a higher risk of having a baby that is LGA. When these blood markers were combined with standard clinical information doctors already collect, the predictions became noticeably more accurate than using the clinical information alone.¹

“These findings,” write the authors of the paper,¹ “suggest that metabolic alterations are detectable before clinical manifestations become apparent and support serum lipidomic profiling as a complementary approach for early risk stratification in pregnancies traditionally considered low risk.”

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References

1. Wang, J.; Gong, Y.; Yue, T. et al. Second Trimester Serum Lipidomics Predicts Large-for-Gestational-Age Infants in Apparently Metabolically Healthy Pregnancies. iScience 2026, 29 (8), 116994. DOI: 10.1016/j.isci.2026.116994
2. Zhao, Y.; Li, D. Z. Born Large for Gestational Age: Not Just Bigger. Am J Obstet Gynecol. 2023, 228 (3), 366-367. DOI: 10.1016/j.ajog.2022.11.1285
3. Wikström, I.; Axelsson, O.; Bergström, R. et al. Traumatic Injury in Large-for-Date Infants. Acta Obstet Gynecol Scand. 1988, 67 (3), 259-264. DOI: 10.3109/00016348809004216
4. Oral, E.; Cağdaş, A.; Gezer, A. et al. Perinatal and Maternal Outcomes of Fetal Macrosomia. Eur J Obstet Gynecol Reprod Biol. 2001, 99 (2), 167-171. DOI: 10.1016/s0301-2115(01)00416-x
5. International Association of Diabetes in Pregnancy Study Group (IADPSG) Working Group on Outcome Definitions; Feig, D. S.; Corcoy, R.; Jensen, D. M. et al. Diabetes in Pregnancy Outcomes: A Systematic Review and Proposed Codification of Definitions. Diabetes Metab Res Rev. 2015, 31 (7), 680-690. DOI: 10.1002/dmrr.2640
6. McGrath, R. T.; Glastras, S. J.; Hocking, S. L. et al. Large-for-Gestational-Age Neonates in Type 1 Diabetes and Pregnancy: Contribution of Factors Beyond Hyperglycemia. Diabetes Care 2018, 41 (8), 1821-1828. DOI: 10.2337/dc18-0551
7. Pedersen, J. Weight and Length at Birth of Infants of Diabetic Mothers. Acta Endocrinol (Copenh). 1954, 16 (4), 330-342. DOI: 10.1530/acta.0.0160330
8. Choudhury, A.A.; Devi Rajeswari, V. Gestational Diabetes Mellitus - A Metabolic and Reproductive Disorder.Biomed Pharmacother Biomedicine Pharmacother. 2021, 143, 112183. DOI: 10.1016/j.biopha.2021.112183
9. Monod, C.; Kotzaeridi, G.; Linder, T. et al. Maternal Overweight and Obesity and its Association with Metabolic Changes and Fetal Overgrowth in the Absence of Gestational Diabetes Mellitus: A Prospective Cohort Study. Acta Obstet Gynecol Scand. 2024, 103 (2), 257-265. DOI: 10.1111/aogs.14688
10. Song, X.; Shu, J.; Zhang, S. et al. Pre-Pregnancy Body Mass Index and Risk of Macrosomia and Large for Gestational Age Births with Gestational Diabetes Mellitus as a Mediator: A Prospective Cohort Study in Central China. Nutrients 2022, 14 (5), 1072. DOI: 10.3390/nu14051072