Expression of mRNA linked to fetal death risk

Expression of mRNA linked to fetal death risk | Image Credit: © kieferpix - © kieferpix - stock.adobe.com.

Placental interleukin 6 and vascular endothelial growth factor receptor 2 messenger RNA (mRNA) expression is significantly increased in the placenta of fetal death, according to a recent study published in the American Journal of Obstetrics & Gynecology.

Preventable causes of fetal death

Of the 2 million fetal deaths reported globally per year, over 80% occur at the end of pregnancy.² Experts have hypothesized many of these cases are caused by known maternal, placental, and fetal risk factors, with approximately 60% of unexplained fetal deaths caused by a failure to identify risk factors.¹

“Placental lesions associated with fetal death are extremely varied, and poorly defined, and their relation to pathologic processes leading to fetal death are difficult to evaluate,” wrote investigators.

To evaluate gene expression levels in sphingosine 1-phosphate (S1P) metabolism and signaling, which has been linked to pregnancy complications and inflammation, investigators conducted a retrospective case-control study. Ten patients diagnosed with antepartum fetal death after 30 weeks of pregnancy were included in the analysis.

Study design and methodology

Fetal death, defined by Apgar scores of 0 at 1 and 5 minutes and no signs of life, was reported as antepartum when occurring during pregnancy and before labor onset. Delivery was performed between 4 and 24 hours after antepartum fetal death diagnosis in all patients.

Microsoft Excel software (Microsoft Corporation, Redmond, WA) database was assessed for maternal demographics, as well as medical and obstetrical history. Placental samples were obtained using systematic sampling techniques and evaluated for macroscopic and microscopic aspects. Four or more blocks were submitted for each sample.

Investigators described any gross lesions found and measured the percentage of total placental volume. Histological evaluation was performed in sampled lesions.

The MagCore Total RNA FFPE One-Step Kit (RBC Bioscience Corp, New Taipei City, Taiwan) was used to extract total RNA from the samples for reverse transcription to complementary DNA. Real-time polymerase chain reaction was used to quantify mRNA expression.

Key findings and implications

Of covariates, only gestational age at delivery and birthweight significantly differed between groups. Patients with fetal death reported significantly increased mRNA expression of interleukin 6 vs controls, but lower activin A. No significant differences were observed in transforming growth factor β1.

Similarly, similar vascular endothelial growth factor levels were reported between groups, though cases with fetal death had significantly increased vascular endothelial growth factor receptor 2 vs controls. Fetal death cases also had reduced expression for ATP-binding cassette transporters P-glycoprotein and breast cancer resistance protein.

Investigators also reported significant differences in S1P receptors 1, 3, and 4, involved in S1P signaling. These receptors had increased expression in fetal death cases, alongside the enzyme sphingosine kinase 2 responsible for S1P production. Other S1P receptors and sphingosine kinases did not significantly differ between groups.

“In conclusion, the present study shows a decreased expression of regulatory factors… implicated in fetal protection, as well as a dysregulation in the S1P signaling pathway, involved in inflammation and fibrosis, confirming an inflammatory state and impaired fetal protection mechanisms in placentas of pregnancies ended in fetal death,” wrote investigators.

References

1. Nardi E, Seidita I, Abati I, et al. The placenta in fetal death: molecular evidence of dysregulation of inflammatory, proliferative, and fetal protective pathways. Am J Obstet Gynecol. 2025;232:328.e1-9. doi:10.1016/j.ajog.2024.06.011
2. Lawn JE, Blencowe H, Waiswa P, et al. Stillbirths: rates, risk factors, and acceleration towards 2030. Lancet. 2016;387(10018):587-603. doi:10.1016/S0140-6736(15)00837-5