Anti-60-kDa Heat Shock Protein Antibodies in Fetal Serum: A Biomarker for Unexplained Small for Gestational Age Fetuses

<i>Introduction:</i> Small for gestational age (SGA) is an important problem affecting 10% of pregnancies and is associated with significant perinatal morbidity. In about 80% of cases, a probable etiology or a major risk factor can be identified. But almost 20% of SGA cases are considered unexplained. The 60-kDa heat shock protein (HSP60) is a highly immunogenic protein whose synthesis is greatly upregulated under nonphysiological conditions. Bacterial and human HSP60 share a high degree of sequence homology, and immunity to conserved epitopes may result in development of autoimmunity following a bacterial infection. We hypothesized that unexplained SGA could be the consequence of immune sensitization to human HSP60. <i>Methods:</i> Unexplained SGA fetuses were identified by ultrasound biometry with normal Doppler velocimetry and with no detectable maternal or fetal abnormalities. Fetal sera were obtained by cordocentesis performed for a karyotype analysis in cases of unexplained SGA (study group) or for screening of Rhesus incompatibility (control group). Fetal sera were tested for HSP60 antigen and for IgG and IgM anti-HSP60 by ELISA as well as for other immune and hematological parameters. <i>Results:</i> Maternal parameters were similar between the 12 study cases and the 23 control cases. The mean gestational age at cordocentesis was 29 weeks. IgM anti-HSP60 was detected in 12 cases (100%) and in no controls (p < 0.00017), while IgG anti-HSP60 was detected in 7 cases (58%) and only 1 control (p < 0.001). Three of the 4 cases with the highest IgM antibody levels died. There were no differences in fetal serum levels of HSP60 antigen or other immune and hematological markers between the two groups. <i>Conclusion:</i> Fetuses with unexplained SGA are positive for IgM and IgG antibody to human HSP60 and the specific IgM antibody level is predictive of fetal mortality. Detection of these antibodies indicates that a placental perturbation and a fetal autoimmune reaction to HSP60 are associated with this developmental delay.