Fetal-origin cells in maternal circulation correlate with placental dysfunction, fetal sex, and severe hypertension during pregnancy

J Reprod Immunol. 2024 Mar:162:104206. doi: 10.1016/j.jri.2024.104206. Epub 2024 Jan 20.


Fetal microchimerism (FMc) arises when fetal cells enter maternal circulation, potentially persisting for decades. Increased FMc is associated with fetal growth restriction, preeclampsia, and anti-angiogenic shift in placenta-associated proteins in diabetic and normotensive term pregnancies. The two-stage model of preeclampsia postulates that placental dysfunction causes such shift in placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFLt-1), triggering maternal vascular inflammation and endothelial dysfunction. We investigated whether anti-angiogenic shift, fetal sex, fetal growth restriction, and severe maternal hypertension correlate with FMc in hypertensive disorders of pregnancy with new-onset features (n = 125). Maternal blood was drawn pre-delivery at > 25 weeks' gestation. FMc was detected by quantitative polymerase chain reaction targeting paternally inherited unique fetal alleles. PlGF and sFlt-1 were measured by immunoassay. We estimated odds ratios (ORs) by logistic regression and detection rate ratios (DRRs) by negative binomial regression. PlGF correlated negatively with FMc quantity (DRR = 0.2, p = 0.005) and female fetal sex correlated positively with FMc prevalence (OR = 5.0, p < 0.001) and quantity (DRR = 4.5, p < 0.001). Fetal growth restriction no longer correlated with increased FMc quantity after adjustment for correlates of placental dysfunction (DRR = 1.5, p = 0.272), whereas severe hypertension remained correlated with both FMc measures (OR = 5.5, p = 0.006; DRR = 6.3, p = 0.001). Our findings suggest that increased FMc is independently associated with both stages of the two-stage preeclampsia model. The association with female fetal sex has implications for microchimerism detection methodology. Future studies should target both male and female-origin FMc and focus on clarifying which placental mechanisms impact fetal cell transfer and how FMc impacts the maternal vasculature.

Keywords: Fetal microchimerism; Fetal sex; Hypertensive disorders of pregnancy; Placental dysfunction; Placental growth factor; Two-stage model of preeclampsia.

MeSH terms

  • Biomarkers / metabolism
  • Female
  • Fetal Growth Retardation
  • Humans
  • Hypertension*
  • Male
  • Placenta / metabolism
  • Placenta Growth Factor / metabolism
  • Pre-Eclampsia*
  • Pregnancy
  • Pregnancy Proteins* / metabolism
  • Vascular Endothelial Growth Factor Receptor-1


  • Placenta Growth Factor
  • Pregnancy Proteins
  • Vascular Endothelial Growth Factor Receptor-1
  • Biomarkers