Objective:

To investigate the association of low maternal serum isthmin-2 (ISM2) levels in the first trimester with the risk of preeclampsia (PE) and fetal growth restriction (FGR).

Approach:

• Study Design: Analyzed samples from 3 prospective pregnancy cohorts, including the POPS study with 4,512 nulliparous patients, measuring 2,904 maternal serum proteins at approximately 12 weeks.
• Outcomes Evaluated: Four outcomes were assessed: PE without FGR, FGR without PE, PE with FGR, and a composite of any of the three outcomes.
• Statistical Analysis: Compared ISM2 with established placental biomarkers and evaluated its association with uterine artery blood flow.
• Functional Studies: Investigated ISM2 expression and function using human trophoblast stem cells and placental organoids.

Key Findings:

• Low ISM2 levels at 12 weeks were associated with all four outcomes: PE without FGR, FGR without PE, PE with FGR, and a composite of any of the three outcomes.
• ISM2 showed greater discrimination for composite outcomes compared to five established placental biomarkers.
• Lower ISM2 at 12 weeks was associated with greater uterine artery resistance at 20 weeks.
• In the IMPACT study, lower ISM2 levels were observed in those who experienced PE complicated by preterm birth or FGR.

Limitations:

• The study focused on northern European cohorts, requiring validation in other populations.
• The reasons for lower ISM2 levels in patients who developed PE or FGR were not determined.
• Mechanisms underlying the effects of ISM2 on trophoblast invasion and migration remain unknown.

Conclusion:

Low ISM2 in the first trimester had the strongest association with subsequent PE and/or FGR among the proteins studied.

Sources:

• Nature Medicine