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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 9 4673-4677
Copyright © 2004 by The Endocrine Society

The Measurement of Maternal Plasma Corticotropin-Releasing Factor (CRF) and CRF-Binding Protein Improves the Early Prediction of Preeclampsia

P. Florio, A. Imperatore, F. Sanseverino, M. Torricelli, F. M. Reis, P. J. Lowry and F. Petraglia

Department of Pediatrics, Obstetrics, and Reproductive Medicine, University of Siena (P.F., A.I., F.M.R., F.S., M.T., F.P.), 53100 Siena, Italy; and School of Animal and Microbial Sciences, University of Reading (P.J.L.), Reading RG6 6AJ, United Kingdom

Address all correspondence and requests for reprints to: Dr. Felice Petraglia, Department of Pediatrics, Obstetrics, and Reproductive Medicine, University of Siena, Policlinico Le Scotte, Viale Bracci, 53100 Siena, Italy. E-mail: petraglia{at}unisi.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
In the present study we measured maternal plasma concentrations of two placental neurohormones, corticotropin-releasing factor (CRF) and CRF-binding protein (CRF-BP), in 58 at-risk pregnant women consecutively enrolled between 28 and 29 wk of pregnancy to evaluate whether their evaluation may predict third trimester-onset preeclampsia (PE). The statistical significance was assessed by t test. The cut-off points for defining altered CRF and CRF-BP levels for prediction of PE were chosen by receiving operator characteristics curve analysis, and the probability of developing PE was calculated for several combinations of hormone testing results. CRF and CRF-BP levels were significantly (both P < 0.0001) higher and lower, respectively, in the patients (n = 20) who later developed PE than in those who did not present PE at follow-up. CRF at the cut-off 425.95 pmol/liter achieved a sensitivity of 94.8% and a specificity of 96.9%, whereas CRF-BP at the cut-off 125.8 nmol/liter combined a sensitivity of 92.5% and a specificity of 82.5% as single markers for prediction of PE. The probability of PE was 34.5% in the whole study population, 93.75% when both CRF and CRF-BP levels were changed, and 0% if both hormone markers were unaltered. The measurement of CRF and CRF-BP levels may add significant prognostic information for predicting PE in at-risk pregnant women.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PREECLAMPSIA (PE) IS a multisystemic obstetric disease of unknown etiology and represents the main cause of maternal and neonatal morbidity and mortality (1). Over the last decade it has been shown that the human placenta has a main role in the events cascade leading to PE (1, 2), and the changes in placental hormones in the maternal circulation reflect a derangement of placental functions (1, 2, 3). Indeed, it has been hypothesized that levels of placental hormones in the maternal bloodstream may be considered preclinical manifestation of the earlier stages of the disease long before the onset of PE is diagnosed (2, 3).

Corticotropin-releasing factor (CRF) is a placental hormone whose maternal levels reach very high values in PE women (2, 3, 4, 5), and it may have a pathological role, through its activity in regulating blood flow throughout the human placenta (5).

In humans, the liver and placenta also secrete CRF-binding protein (CRF-BP) (6), a 37-kDa protein of 322 amino acids (7) that binds circulating CRF and modulates CRF actions on pregnant target tissues during pregnancy (8). Maternal plasma CRF and CRF-BP levels show inverse changes in the presence of hypertensive disorders of pregnancy: women with PE have the highest CRF and the lowest CRF-BP concentrations (5).

In the present study the probability of developing PE was evaluated at 28–29 wk gestation in at-risk patients affected by pregnancy-induced hypertension (PIH) by measuring maternal plasma CRF and CRF-BP levels and determining the positive and negative predictive values of CRF and CRF-BP cut-off points, chosen by receiver-operating characteristics (ROC) curve analysis.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

This was a prospective, controlled, hospital-based study including a group of pregnant women (n = 58) affected by PIH, consecutively enrolled between 28–29 wk of pregnancy at a university teaching hospital. Informed consent was obtained from all patients before inclusion in the study, for which local human investigation committee approval was obtained.

The main clinical and demographic characteristics of the study population are summarized in Table 1Go. It included nulliparous (n = 27) and multiparous (n = 31) women, of whom five (only two in the group developing third trimester PE) had a history of PE. Women with current medical complications, such as collagen vascular disease, thrombophilias, chronic hypertension, and diabetes mellitus, were not included.


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  		TABLE 1. Clinical characteristics of patients with PIH and patients with PIH who developed third trimester PE

 
PIH was defined by the presence of hypertension (≥140/90 mm Hg blood pressure level confirmed by two measurements at least 6 h apart) alone, occurring de novo after the 20th wk of pregnancy (9). The screening tools evaluated in enrolled women affected by PIH through the present study were maternal plasma CRF and CRF-BP and the third-trimester onset of PE, defined as 300 mg or more urinary protein excretion/24 h and blood pressure of 140/90 mm Hg or higher, first diagnosed after 20 wk gestation (9).

Blood samples were drawn from the anticubital vein with a polypropylene syringe and a butterfly needle, and then transferred to chilled tubes containing EDTA (10 mg/ml blood) and aprotinin [50 µl/tube from a solution of 20,000 IU/ml, Trasylol 100,000 kallikrein inactivator units (KIU); Bayropharm, Milan, Italy]. The tubes were immediately centrifuged at 4 C (3000 x g for 10 min), and plasma samples were stored at –20 C until assay.

CRF assay

Maternal plasma samples were submitted to an extraction procedure as previously described (5). The acid extraction method we used to strip CRF from the CRF-BP allowed us to measure total CRF (10). Briefly, cyclohexyl columns (500 mg; Bondelut, AnalyLichem International, Arbor City, CA) were washed with methanol (0.5 ml) and a 2-ml mixture of formic acid plus triethylamine and 0.2% ß-mercaptoethanol (pH 3) and loaded slowly into the column. The peptide was finally eluted with a mixture of 75% acetonitrile, 25% triethylamine, and 0,2% mercaptoethanol (2 ml). The final recovery of the peptide evaluated with cold (100 ng) or labeled (125I) CRF was 85%. All extracted samples were then dried in a speed vacuum concentrator (Savant, Hicksville, NJ). All reagents were purchased from Sigma-Aldrich Corp. (St. Louis, MO).

Each dried sample was redissolved in buffer (0,1% BSA, 0.05% Triton X-100, and PBS, pH 7.3), and CRF concentrations were measured by RIA in duplicate at two different dilutions. Rabbit antirat CRF serum was used at a final dilution of 1:770,000. Synthetic human CRF (J. Rivier, The Salk Institute, La Jolla, CA) was used to prepare the standard curve. The tracer ([125I]human CRF) was purchased from NEN Life Science Products (Boston, MA). The entire reagent was diluted in buffer. The characteristics of the RIA had been described previously. The limit of detection was 15 pmol/liter, and the intraassay coefficient of variation was 4.0%. The final results are expressed as picomoles per liter.

CRF-BP assay

CRF-BP levels were measured by a specific RIA, as previously described (5). Purified recombinant CRF-BP was radioiodinated by the glucose oxidase/lactoperoxidase method and was separated on a 90 x 1-cm bed of Sephacryl S200 developed with 0.05 ml/liter phosphate buffer, pH 7.4, containing 0.5% BSA and 0.1% sodium azide at a flow rate of 3 ml/h, with fractions collected every 20 min. Only a radiolabel constituting the peak eluting with a kAV of 0.46 was used as tracer for the CRF-BP RIA. Seventy-nine percent of the radioactivity from these peak fractions was precipitable by the addition of an excess of the rabbit antibody raised against recombinant CRF-BP, as used in the RIA. The immunoassay was performed essentially as previously described (5). Briefly, CRF-BP stocks (3.28 mg/liter) were prepared in aliquots of 0.5 ml in sheep serum and stored frozen at –20 C. Assay standards were prepared by dilution of stock aliquots in 0.05 mol/liter phosphate buffer, pH 7.4, containing 0.5% (wt/vol) BSA and 0.1% (wt/vol) sodium azide to obtain a range of concentrations from 0.9–464 mg/liter. To 50 ml of the above buffer were added 50 ml standard or a column fraction, 100 ml tracer containing 20,000 cpm [125I]CRF-BP, and 100 ml rabbit anti CRF-BP antibody diluted 4000-fold in the same buffer. Standard and samples were prepared in duplicate, and the assay was incubated for 16 h at 4 C before separation. Separation was achieved by a precipitating antibody consisting of 10% sheep antirabbit antiserum directed against the Fc fragment containing 0.5% (vol/vol) normal rabbit serum and 4% polyethylene glycol 6000 (Sigma-Chimica, Milan, Italy). Inclusion of human CRF in standards or in human plasma samples in concentrations ranging from 1.6–25 mg/liter had no effect on CRF-BP measurement (10). The assay sensitivity was 3.125 nmol/liter. Samples were assayed within the assay, and the intraassay coefficient of variation was 7%. The final results are expressed as nanomoles per liter.

Statistical analysis

After a normality test showed that the CRF and CRF-BP levels were normally distributed, data were expressed as the mean ± SE, and statistical significance was assessed by t test and the Pearson’s correlation coefficient. Statistical significance was assumed whenever P < 0.05.

The cut-off points for defining altered serum CRF and CRF-BP levels for prediction of PE were chosen by ROC curve analysis (11, 12). Using the best cut-offs indicated by the ROC analysis, positive and negative predictive values with their respective 95% confidence bounds were calculated for all possible combinations of hormone results. The probability of developing preeclampsia after having positive results for none, one, or both hormone tests (according the chosen cut-off points) was thus estimated and compared with the pretest probability, defined as the prevalence of PE in the whole group of patients (13).


   Results
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 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Clinical findings

Patients who later developed PE delivered at a significantly (P < 0.0001) lower (34.2 ± 0.6 wk) gestational age than those who did not present PE at follow-up (gestational age, 39.08 ± 0.4 wk; Table 1Go). Furthermore, PE newborns had a significantly (P < 0.0001) lower (2302 ± 115.8 g) birth weight and a significantly (P < 0.0001) longer duration (54.6 ± 15.28 d) in the neonatal intensive care unit than PIH women who did not develop PE (birth weight, 3344 ± 66.31 g; neonatal intensive care unit stay, 4.9 ± 0.21 d; Table 1Go).

CRF and CRF-BP levels

CRF and CRF-BP levels were measurable in all samples evaluated. Mean ± SE CRF levels in the patients who later developed PE (525.69 ± 18.6 pmol/liter; n = 20) were significantly (P < 0.0001) higher than in those who did not present PE at follow-up (405.04 ±.6.3 pmol/liter; Fig. 1AGo), whereas maternal plasma levels of CRF-BP in the group of patients who developed PE were significantly (P < 0.0001) lower (81.74 ± 10.32 nmol/liter) than in those who did not (167.02 ± 6.13 nmol/liter; Fig. 1BGo). A significant (P < 0.0001) inverse (Pearson r = –0.653) correlation was found between maternal plasma CRF and CRF-BP concentrations (Fig. 2Go).



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  		FIG. 1. CRF (A) and CRF-BP (B) levels were significantly higher in patients with PIH who developed PE than in those who did not present PE at follow-up (PIH). The bars represent the mean ± SE. *, P < 0.0001 (by t test).

 


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  		FIG. 2. Correlation between CRF and CRF-BP levels in maternal plasma. A significant inverse linear correlation was found in the whole study population (r = –0.653; P < 0.0001).

 
CRF at the cut-off 425.95 pmol/liter achieved a sensitivity of 94.8% and a specificity of 96.9% as single marker for prediction of PE (area under the ROC curve, 0.99). CRF-BP at the cut-off 125.8 nmol/liter combined a sensitivity of 92.5% and a specificity of 82.5% for the prediction of preeclampsia (area under the ROC curve, 0.931).

Twenty of 58 patients developed PE (Table 1Go), making an overall prevalence of the disease in our population of 34.5% [95% confidence interval (CI), 22.2–42.7%; Table 2Go and Fig. 3Go]. This was the predicted probability of developing PE before the hormone measurement was performed (pretest probability). With respect to the performance of CRF and CRF-BP measurements in predicting PE, if only CRF was available, the positive predictive value was 82.0% (95% CI, 66.4–97.6%), and the negative predictive value was 97.14% (95% CI, 91.6–100%), respectively. If only CRF-BP measurement was available, its positive and negative predictive values were 80.0% (95% CI, 63,1–97.1%) and 89.5% (95% CI, 79.8–99.2%), respectively (Table 2Go and Fig. 3Go). If both CRF and CRF-BP levels were modified (i.e. according to the cut-offs indicated by the ROC curve analysis), the probability of developing PE was 93.75% (95% CI, 81.9–100%). If both hormones were unaltered, the probability of developing PE (100 – negative predictive value) was 0% (95% CI, 0–3%; Table 2Go and Fig. 3Go). However, if only one hormone was positive and the other was negative, the probability of preeclampsia was 66.6% (95% CI, 29–100%); if only CRF was high and CRF-BP was unaltered, the probability was 25% (95% CI, 0–67%; Table 2Go).


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  		TABLE 2. Prediction of PE in women with PIH using maternal plasma CRF and CRF-BP levels

 


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  		FIG. 3. Probability of developing PE among all patients (pretest probability) and after different test results (posttest probability). Data are reported as percentages, and the error bars indicate the 95% CI for each probability.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Several in vitro studies have demonstrated that CRF exerts a vasodilator effect in a number of species through relaxation of the vascular smooth muscle (14, 15, 16). However, CRF can also act through specific receptors located on endothelial (17, 18) and endothelial smooth muscle (19) cells, modulating peripheral vascular resistance by endothelium-dependent (activation of nitric oxide pathway) and endothelium-independent (direct stimulation of vascular smooth muscle relaxation) mechanisms (20). In pregnant women the placenta is the main source of CRF, as supported by undetectable levels of circulating CRF levels in nonpregnant women, which increase exponentially during gestation in maternal and fetal circulation and in amniotic fluid (4). Elevated concentrations were also found in the third trimester of a small group suffering from PIH (21).

Pregnancy is associated with decreased peripheral vascular resistance (22, 23), and in this context CRF has been postulated to have a significant physiological role as a local regulator of vascular tone (4), because placental vasculature cannot autoregulate (22, 23, 24, 25). Indeed, CRF induced vasodilatation of the human fetal placental circulation at concentrations comparable to plasma CRF levels found in the maternal and fetal circulations and activating different pathways (26, 27).

In the present study we found that in women with PIH, maternal plasma CRF levels are significantly increased only in those who later progressed to PE, compared with those who did not develop the disease. Taken together, these findings lead us to suggest that increased CRF levels in hypertensive disorders of pregnancy may be a placental compensatory response to guarantee adequate perfusion of the feto-placental unit, because CRF may be secreted into the fetal-placental circulation and travel to its site of action through the placental vascular system.

In the present study we also found in women with PIH that CRF-BP levels were significantly low in patients who progressed to PE. CRF-BP may be involved in the paracrine regulation of vasodilator CRF effects, perhaps in preventing CRF actions in human placenta (4). In this regard, the reduced secretion of CRF-BP may enhance and amplify the effects of CRF by increasing its biologically active free amounts; the decrease in CRF-BP levels was inversely correlated with the increase in CRF-BP concentrations. Because CRF exerts vasodilator and hypotensive effects, the increased active free levels may be viewed as a compensatory response to PIH and PE.

Although it is not clear whether these changes in maternal plasma are primary or secondary to PIH, their detection may have clinical usefulness, because these changes have been detected before the development of PE. Predicting PE remains a difficult task even though an array of clinical, biochemical, and biophysical tests have been proposed (2, 3, 24). Because none of the current methods combines accuracy, reproducibility, and simplicity to become a universal predictive marker of PE, there continues to be a compelling demand for new markers and new algorithms that extract the best information from current screening methods. Indeed, the prevention of PE would mean a big step forward in prenatal medicine, avoiding the maternal and fetal complications associated with the gestational diseases. Secondary prevention (i.e. before emergence of the clinically recognizable disease) is possible if methods of early detection are available (2, 3, 24).

In the present study the clinical usefulness of CRF and CRF-BP measurements for predicting the development of PE in a selected groups of at-risk pregnant women (as affected by PIH) was evaluated. We found that CRF and CRF-BP are reliable predictive markers of PE in our high risk population. In fact, although CRF measurement was more sensitive than CRF-BP, combining both hormones improved the predictive value of the test, resulting in a higher positive (93.75%) predictive value if both were altered, but a higher negative (100%) predictive value if both were normal. In addition, measuring CRF and CRF-BP levels yielded a positive, but also a negative, predictive value that differs materially from the overall prevalence of PE in the study population. This is an important point of discussion because the use of tests that achieve a high negative predictive value (100%) may prevent unnecessary hospitalization and testing, eliminating unnecessary interventions and providing reassurance for the patient.

Our data give support to a stepwise strategy for predicting PE, moving from simple screening tests (such as blood pressure measurement) to more specific and sophisticated tests that can be applied to selected patients following a sequential algorithm. In our example, hormone markers were used for fine-tuning the prediction of PE in patients with increased blood pressure, which has been used as a first step screening test for the general population. As the probability of preeclampsia was remarkably higher among women with positive (100%) than in women with negative (0%) double-hormone tests, it can be concluded that CRF and CRF-BP measurements may add significant prognostic information for predicting preeclampsia among at-risk women.


   Footnotes
 
Abbreviations: CI, Confidence interval; CRF, corticotropin-releasing factor; CRF-BP, corticotropin-releasing factor-binding protein; PE, preeclampsia; PIH, pregnancy-induced hypertension; ROC, receiving operator characteristics.

Received February 4, 2004.

Accepted June 14, 2004.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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