Objective
The aim of this study was to evaluate fetal hemoglobin (HbF) and α 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 radioimmunoassay. Sensitivity and specificity was calculated by logistic regression and receiver operating characteristic curve analysis.
Results
The HbF/Hb ratio and A1M concentration were significantly elevated in serum from women with subsequent development of PE ( P < .0001). The optimal sensitivity and specificity was obtained using the biomarkers in combination; 69% sensitivity for a 5% screen positive 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.
Preeclampsia (PE) affects up to 7% of all pregnancies and is an important factor of maternal morbidity and mortality. The clinical manifestations of PE appear in the second to third trimester. Early-onset PE, the more severe form, appears before a gestational age (GA) of 34 weeks. The symptoms and objective findings are often diverse, such as headache, blurry vision, epigastralgia, and edema. Hypertension and proteinurea are not only hallmarks of the disease but are also integral to the diagnosis. Clinically, PE spans vary broadly, from mild cases with few subjective symptoms, only mild hypertension and little proteinurea, to life-threatening cases with severe hypertension and marked proteinurea often complicated with some degree of renal failure 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 patients 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.
Due to the fact that there are no established biomarkers for predicting and/or diagnosing PE, great effort has lately 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 accuracy. To date, several have been suggested, but none are accepted as being useful biomarkers for the clinical prediction or diagnosis of PE. Two antiangiogenic factors are promising, showing a significant association with PE: soluble fms-like tyrosine kinase 1 (sFlt) and soluble endoglin. These markers have been shown to be particularly useful in the second and third trimester, but their value in the first trimester is still to be determined.
Our recent studies have indicated the involvement of hemoglobin (Hb)-induced oxidative stress in the development of PE. Increased local synthesis of fetal Hb (HbF) by cells in the placenta was indicated by an up-regulation of the HbF genes and the accumulation of HbF in the term PE placenta. Free Hb, ie, outside the red blood cell, and its metabolites heme and iron induce oxidative stress by formation of reactive oxygen species. In fact, free heme, bilirubin, and biliverdin have been identified among 14 metabolites in a metabolomic signature of PE using first-trimester plasma. The oxidative stress may damage the blood-placenta barrier, leading to leakage of HbF into the maternal circulation and eventually cause elevated levels in the maternal plasma or serum. Indeed, increased levels of HbF, total Hb, and markers for oxidative stress, as well as the heme-scavenger and antioxidant endogenous protein α 1 -microglobulin (A1M), were found to be elevated at term in both plasma and placenta from women with PE.
The aim of the present study was to measure the concentrations of HbF, total Hb, and A1M in first-trimester serum samples to evaluate their value as predictive biomarkers for PE.
Materials and Methods
Patients and demographics
The study was designed as a case-control study. Originally a total of 100 women were included in the study. Exclusion criteria were diabetes, prepregnancy hypertension, and premature delivery. Four controls were excluded due to these criteria, as 2 had type 1 diabetes and 2 others had essential hypertension. In the end a total of 96 women were included, 60 women who subsequently developed PE (cases) and 36 with normal uncomplicated pregnancies (controls). Characteristics are shown in Table 1 . Of the 60 cases, 20 cases delivered at a GA of <37+0 weeks, of which 7 delivered <34+0 weeks. All controls delivered >37+0 weeks.
| Demographic | Normal pregnancy, control (n = 36) | PE (n = 60) |
|---|---|---|
| GA at delivery a | 39.9 (39.5–40.3) | 36.8 (35.7–37.8) |
| GA at sampling, wk b | 12.9 (12.2–13.6) | 14.1 (13.5–14.7) |
| Birthweight, g c | 3484 (3281–3687) | 2752 (2484–3019) |
| Ethnicity d | ||
| Caucasian | 29 | 31 |
| Asian | 4 | 11 |
| Afro-Caribbean | 2 | 15 |
| Mixed | 1 | 4 |
| Preterm e | 0 (0%) | 20 (33.3%) |
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