Natural copper isotopic abnormity in maternal serum at early pregnancy associated to risk of spontaneous preterm birth

Spontaneous preterm birth (SPB) has drawn public attention due to its increasing incidence and adverse effects on fetal growth. Effect of copper (Cu) imbalance in maternal bodies on the risk of SPB remains a subject of debate, and the related mechanisms are still unraveled. Here we applied natural stable copper isotopes to explore the underlying association and mechanism of copper imbalance with SPB using a nested case-control study. We collected maternal sera at the early pregnancy stage and then measured their copper isotopic ratio (⁶⁵Cu/⁶³Cu, expressed as δ⁶⁵Cu) as well as physiological and biochemical indexes from women with and without delivering SPB. We found that SPB cases had no significant difference in serum copper level from their controls, but their serum copper was significantly isotopically heavier than the controls (δ⁶⁵Cu value = 0.15 ± 0.34 ‰ versus −0.15 ± 0.17 ‰, P = 0.0149). Compared with the controls with lower δ⁶⁵Cu values, the crude odds ratio (OR) associated with SPB risk increased to 4.00 (95 % confidence interval (CI): 1.37–11.70) and the adjusted OR reached up to 11.35 (95 % CI: 1.35–95.60). Furthermore, via the copper isotopic fractionation, we revealed that dietary intake and blood ceruloplasmin may play more important roles than blood lipids and mother-to-child transmission in the copper imbalance associated with SPB. Further studies will be needed to understand the mechanisms of isotope fractionation related to reproductive health.