An elevated fetal interleukin-6 concentration can be observed in fetuses with anemia due to Rh alloimmunization: implications for the understanding of the fetal inflammatory response syndrome

J Matern Fetal Neonatal Med. 2011 Mar;24(3):391-6. doi: 10.3109/14767058.2010.507294. Epub 2010 Aug 11.


Objective: The fetal inflammatory response syndrome (FIRS) has been described in the context of preterm labor and preterm prelabor rupture of the membranes and is often associated with intra-amniotic infection/inflammation. This syndrome is characterized by systemic fetal inflammation and operationally defined by an elevated fetal plasma interleukin (IL)-6. The objective of this study was to determine if FIRS can be found in fetuses with activation of their immune system, such as the one observed in Rh alloimmune-mediated fetal anemia.

Methods: Fetal blood sampling was performed in sensitized Rh-D negative women with suspected fetal anemia (n=16). Fetal anemia was diagnosed according to reference range nomograms established for the assessment of fetal hematologic parameters. An elevated fetal plasma IL-6 concentration was defined using a cutoff of >11 pg/ml. Concentrations of IL-6 were determined by immunoassay. Non-parametric statistics were used for analysis.

Results: (1) The prevalence of an elevated fetal plasma IL-6 was 25% (4/16); (2) there was an inverse relationship between the fetal hematocrit and IL-6 concentration -- the lower the hematocrit, the higher the fetal IL-6 (r=-0.68, p=0.004); (3) fetuses with anemia had a significantly higher plasma IL-6 concentration than those without anemia (3.74 pg/ml, interquartile range (IQR) 1.18-2.63 vs. 1.46 pg/ml, IQR 1.76-14.7; p=0.02); (4) interestingly, all fetuses with an elevated plasma IL-6 concentration had anemia (prevalence 40%, 4/10), while in the group without anemia, none had an elevated fetal plasma IL-6.

Conclusions: An elevation in fetal plasma IL-6 can be observed in a subset of fetuses with anemia due to Rh alloimmunization. This observation suggests that the hallmark of FIRS can be caused by non-infection-related insults. Further studies are required to determine whether the prognosis of FIRS caused by intra-amniotic infection/inflammation is different from that induced by alloimmunization.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adult
  • Anemia / blood
  • Anemia / congenital
  • Anemia / etiology*
  • Anemia / immunology
  • Comprehension
  • Cross-Sectional Studies
  • Female
  • Fetal Diseases / blood
  • Fetal Diseases / etiology*
  • Fetal Diseases / immunology
  • Fetus / blood supply
  • Hematocrit
  • Humans
  • Interleukin-6 / blood*
  • Osmolar Concentration
  • Pregnancy
  • Retrospective Studies
  • Rh Isoimmunization / blood
  • Rh Isoimmunization / complications*
  • Systemic Inflammatory Response Syndrome / blood
  • Systemic Inflammatory Response Syndrome / congenital*
  • Systemic Inflammatory Response Syndrome / etiology*
  • Systemic Inflammatory Response Syndrome / immunology


  • Interleukin-6