Early Pregnancy Oxylipins Point to Distinct Inflammatory and Oxidative Stress Signals in Fetal Growth Restriction

Highlights

• In early pregnancy, specific urinary oxylipins were associated with small-for-gestational-age (SGA) birth, supporting a link between lipid mediator imbalance and impaired fetal growth.
• A urinary thromboxane-related metabolite showed the clearest association with SGA birth, while urinary isoprostanes tracked with an early-pregnancy growth-restriction phenotype.
• Late-pregnancy growth restriction and early-pregnancy growth restriction appeared to have different biomarker signatures, suggesting biologically distinct pathways.
• Associations with large-for-gestational-age (LGA) birth did not remain significant after false discovery rate correction.

Background

Fetal growth restriction remains one of the most consequential problems in obstetrics. Infants who are born small for gestational age face higher risks of stillbirth, perinatal morbidity, neurodevelopmental impairment, and long-term cardiometabolic disease. Yet in day-to-day practice, clinicians still struggle to identify which pregnancies are at risk early enough to intervene effectively. Standard tools such as fundal height screening, ultrasound biometry, and Doppler assessment can detect established growth problems, but they do not fully solve the challenge of early prediction.

That gap has renewed interest in biologic markers that reflect the processes driving abnormal placentation and fetal growth. Oxylipins are a broad class of lipid mediators derived from polyunsaturated fatty acids. They include enzymatically generated products, such as thromboxane metabolites, and non-enzymatic products of lipid peroxidation, such as isoprostanes. Because these molecules sit at the intersection of inflammation, oxidative stress, and vascular signaling, they are attractive candidates for studying the pathogenesis of fetal growth restriction.

The central idea behind this study is clinically important: if a measurable biomarker profile is already abnormal at around 10 weeks of gestation, well before most cases of growth restriction are apparent, then that profile may help identify women and pregnancies at risk much earlier than current approaches allow.

Study design

This was a case-cohort study that evaluated 901 pregnancies with measured early-pregnancy oxylipins. Plasma and urine samples were collected at approximately 10 weeks of gestation. The investigators quantified 24 oxylipins and examined their associations with two primary birth outcomes: SGA birth and LGA birth.

As a secondary analysis, they also studied ultrasound-based fetal growth phenotypes. These phenotype definitions are especially valuable because they go beyond the final birthweight label and attempt to separate pregnancies with early-onset versus late-onset growth restriction based on longitudinal growth patterns.

The analytic approach also accounted for multiple testing using false discovery rate correction, which is essential in biomarker studies that examine many correlated lipid mediators. In practical terms, this means that only the more robust associations should be interpreted as likely signals rather than chance findings.

Key findings

1) A thromboxane-related urinary metabolite was associated with SGA birth

The strongest primary result was a urinary metabolite of the pro-inflammatory thromboxane A2 pathway. Higher levels of this biomarker were associated with higher odds of SGA birth, with an odds ratio of 1.43 and a 95% confidence interval of 1.20 to 1.72. This is a clinically meaningful signal because thromboxane is linked to vasoconstriction, platelet activation, and inflammatory signaling, all of which are biologically plausible contributors to impaired placental perfusion and restricted fetal growth.

Importantly, this was an early-pregnancy measurement, which increases its potential value for prediction. A biomarker detected at 10 weeks gestation may reflect upstream maternal-placental physiology long before the fetus has clearly fallen off its growth trajectory.

2) The biomarker signal differed by fetal growth restriction phenotype

When the investigators moved beyond the broad SGA label and examined ultrasound-based phenotypes, the associations became more informative. The thromboxane-related metabolite was most strongly linked to a late-pregnancy growth-restriction phenotype. That pattern suggests that this pathway may be particularly relevant to growth failure that becomes more apparent later in gestation, potentially when placental reserve is increasingly stressed.

By contrast, urinary isoprostanes were associated with an early-pregnancy growth-restriction phenotype. Isoprostanes are widely recognized markers of oxidative stress and lipid peroxidation, so this result points toward early redox imbalance as a possible contributor to a more severe or earlier-onset form of growth restriction. One example was a 5-series isoprostane, which was associated with higher odds of early-pregnancy growth restriction compared with appropriate-for-gestational-age birth, with an odds ratio of 2.22 and a 95% confidence interval of 1.34 to 3.69.

This phenotype-specific pattern matters. Clinically, SGA is often treated as a single endpoint, but the biology is likely more heterogeneous. Early-onset restriction usually reflects more profound placental dysfunction, while late-onset restriction may involve subtler placental insufficiency, maternal vascular disease, or inflammatory dysregulation that emerges later. The oxylipin findings are consistent with that framework.

3) LGA associations were not robust after multiple-testing correction

Although the investigators also evaluated LGA birth, the associations did not remain significant after false discovery rate correction. That negative result is informative. It suggests that the early-pregnancy oxylipin signals identified here may be more closely tied to constrained fetal growth than to fetal overgrowth, rather than simply reflecting nonspecific disturbance in pregnancy metabolism.

For clinicians, this is useful because it argues against interpreting oxylipin changes as a generic marker of abnormal fetal size. Instead, the data point toward a more specific relationship with growth restriction phenotypes.

4) What the effect sizes mean

The reported odds ratios are not trivial. An OR of 1.43 for the thromboxane-related metabolite indicates a meaningful increase in SGA odds associated with the biomarker signal. The stronger OR of 2.22 for one urinary isoprostane in early-pregnancy growth restriction suggests an even larger association, although effect size alone should not be mistaken for immediate clinical utility. Biomarker performance in practice depends on calibration, discrimination, reproducibility, and whether the marker adds value beyond established clinical risk factors.

At present, these oxylipins should be viewed as hypothesis-generating and potentially useful for risk stratification research, not as stand-alone clinical tests.

Expert commentary

This study is notable for several reasons. First, it measured biomarkers very early in gestation, when preventive strategies would have the greatest chance of changing outcome. Second, it focused on mechanistically relevant lipid mediators rather than broad inflammatory markers that may be less specific. Third, it used longitudinal ultrasound data to separate fetal growth restriction into phenotypes, which is a more biologically informed approach than birthweight alone.

The biology is also plausible. Thromboxane A2 is a potent vasoconstrictor and platelet activator, and a shift toward thromboxane signaling may reflect endothelial dysfunction or placental vascular maladaptation. Isoprostanes, meanwhile, are products of oxidative injury to lipids and are widely used as markers of oxidative stress. Pregnancy requires a finely tuned balance between pro- and anti-inflammatory activity as well as controlled oxidative signaling. If that balance is disturbed early, placental development may be affected in ways that later manifest as restricted fetal growth.

At the same time, several limitations should temper enthusiasm. This was an observational biomarker study, so it cannot establish causality. Residual confounding is possible, particularly from maternal comorbidity, nutrition, medications, smoking, or other exposures that influence both lipid mediators and fetal growth. A single early-pregnancy blood and urine sample may not fully capture dynamic changes across gestation. In addition, biomarker panels can yield false-positive findings without careful correction, which is why replication in independent cohorts is essential.

Generalizability may also be limited. Biomarker distributions can vary by population, assay platform, and specimen handling. Before oxylipins can be considered for routine screening, investigators will need to show that the findings reproduce across diverse populations and that they improve prediction beyond established clinical models such as maternal risk factors, uterine artery Doppler studies, and fetal biometry.

Still, the study offers an important translational clue: fetal growth restriction may not be a single biologic entity. Different lipid mediator patterns may point to different pathophysiologic routes, which in turn could support more individualized prevention strategies. That concept is especially compelling if future work can link these biomarkers to pathways that are modifiable, such as aspirin responsiveness, dietary fatty acid balance, antioxidant status, or vascular health.

Conclusion

Early-pregnancy oxylipin profiles were associated with SGA birth, and the associations varied by fetal growth restriction phenotype. A thromboxane-related urinary metabolite aligned most strongly with late-pregnancy growth restriction, while urinary isoprostanes were associated with an early-pregnancy restriction phenotype. These findings strengthen the case that inflammation and oxidative stress are not just background features of pregnancy, but potentially measurable contributors to pathologic fetal growth. The work is promising for early prediction research, but clinical implementation will require replication, standardization, and proof of added value over current obstetric assessment.

Funding and clinicaltrials.gov

Funding details were not stated in the abstract or PubMed record reviewed. No clinicaltrials.gov registration was listed in the citation provided.

References

1. Ferguson KK, Welch BM, Stevens DR, Bommarito PA, Milne GL, Meeker JD, Edin ML, Zeldin DC, Cantonwine DE, McElrath TF. Early pregnancy oxylipin markers of inflammation and oxidative stress are associated with small-for-gestational-age birth and specific phenotypes of fetal growth restriction. Am J Obstet Gynecol. Published online 2026. PMID: 42035818.
2. American College of Obstetricians and Gynecologists. Fetal Growth Restriction. Practice Bulletin No. 227. Obstet Gynecol. 2021.