OBSTETRICS Fetal hemoglobin and ␣ 1 -microglobulin as first- and e second-trimester predictive biomarkers for pr Ulrik Dolberg Anderson, MD; Magnus G. Olsson, PhD; Sigurbjörg Rutardóttir, MSc; Magnus Centlow, PhD; Karl Heby Kristensen, MD, PhD; Per Erik Isberg, BSc; Baskaran Thilaganathan, MD, PhD; Bo Åkerström, PhD; Stefan R. Hansson, MD, PhD OBJECTIVE: The aim of this study was to evaluate fetal hemoglobin (HbF) and ␣ 1 -microglobulin (A1M) in maternal serum as first-trimester biomarkers for preeclampsia (PE). STUDY DESIGN: The design was a case-control study. We included 96 patients in the first trimester of pregnancy (60 with PE and 36 controls). Venous serum samples were analyzed for HbF and total hemoglobin (Hb) by enzyme-linked immunosorbent assay and for A1M by radioim- munoassay. Sensitivity and specificity was calculated by logistic regres- sion and receiver operating characteristic curve analysis. RESULTS: The HbF/Hb ratio and A1M concentration were sig elevated in serum from women with subsequent development ofPE (P ⬍ .0001). The optimal sensitivity and specificity was o the biomarkers in combination; 69% sensitivity for a 5% rate and 90% sensitivity for a 23% screen positive rate. CONCLUSION: The study suggests that HbF/Hb ratio in combination with A1M is predictive biomarkers for PE. Key words: ␣ 1 -microglobulin, first-trimester biomarker, free hemoglobin, prediction preeclampsia Cite this article as: Anderson UD, Olsson MG, Rutardóttir S, et al. Fetalhemoglobin and ␣ 1 -microglobulin as first- and early second-trimester predictive biomarkers for preeclampsia. Am J Obstet Gynecol 2011;204:520.e1-5. P reeclampsia (PE) affects up to 7% of all pregnancies and is an important factor of maternal morbidity and mor- tality. 1,2 The clinical manifestations of PE appear in the second to third trimes- ter. Early-onset PE, the more severe form,appears before a gestational age (GA) of 34 weeks. 2,3 The symptoms and objective findings are often diverse, such as headache, blurry vision, epigastralgia, and edema. Hypertension and protein- urea are not only hallmarks of the disease but are also integral to the diagnosis. 4 Clinically, PE spans vary broadly, from mild caseswith few subjective symp- toms, only mild hypertension and little proteinurea, to life-threatening cases with severe hypertension and marked proteinureaoftencomplicatedwith some degree of renalfailure and the worst cases with seizures. Although there are clinical parameters used for diagnosing PE and a very clear definition of the diagnosis, there are still some difficulties in predicting which pa- tients will develop the most severe cases of the disease. Neither the amount of proteinurea nor the level of hypertension is a very good predictor for, for example, HELLP syndrome or eclampsia. 5,6 Due to the fact that there are no estab- lished biomarkers for predicting and/or diagnosing PE, greatefforthaslately been put into this field. However, finding a good biomarker is a major challenge. Many of the suggested markers need to be combined with each other and/or evaluated in combination with Doppler ultrasound to improve the diagnostic ac- curacy. To date, several have been sug- gested, but none are accepted as being useful biomarkers for the clinical predic tion or diagnosis of PE. 7-20 Two antian- giogenic factors are promising, showing a significant association with PE: soluble fms-like tyrosine kinase 1 (sFlt) and sol- uble endoglin. 8,14,15,17,21,22 These mark- ers have been shown to be particularly useful in the second and third trimester but their value in the first trimester is s to be determined. Our recent studies have indicated the involvement of hemoglobin (Hb)-in- duced oxidative stress in the develop- ment of PE. Increased local synthesis of fetalHb (HbF) by cells in the placenta was indicated by an up-regulation of th HbF genes and the accumulation of HbF in the term PE placenta. 23 Free Hb, ie, outside the red blood cell, and its meta olites heme and iron induce oxidative stress by formation of reactive oxygen species. 24 In fact,free heme, bilirubin, and biliverdinhave been identified among 14 metabolites in a metabolomi signatureof PE using first-trimester plasma. 20 The oxidative stress may dam- age the blood-placenta barrier, leading to leakage of HbF into the maternal cir- culation and eventually cause elevated From the Department of Obstetrics and Gynecology, Clinical Sciences (Drs Anderson, Centlow, and Hansson); the Division of Infection Medicine (Drs Olsson and Åkerström and Ms Rutardóttir); and the Department of Statistics (Mr Isberg), Lund University Hospital, Lund University, Lund and the Department of Obstetrics and Gynecology, Malmö University Hospital, Malmö (Dr Kristensen), Sweden, and the Division of Clinical Development Sciences, Department of Obstetrics and Gynaecology, St Georges University of London, London, England, UK (Dr Thilaganathan). Received Aug. 29, 2010; revised Nov. 8, 2010; accepted Jan. 26, 2011. Reprints: Ulrik Dolberg Anderson, MD, Lund University, Tornavägen 10, 221 84 Lund, Sweden. ulrik.dolberg_anderson@med.lu.se. 0002-9378/$36.00 © 2011 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2011.01.058 Research www. AJOG .org 520.e1 American Journal of Obstetrics & Gynecology JUNE 2011