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The Utility of Plasma CRH as a Predictor of Preterm Delivery

Departments of Endocrinology (W.J.I., T.C.R.P., M.J.E., J.H.L., R.A.D.), Christchurch Hospital and Obstetrics and Gynecology (L.H., R.R., P.S.B.), Christchurch Women’s Hospital, Christchurch, 8001 New Zealand

Address all correspondence to: Dr. M. Jane Ellis, Department of Endocrinology, Christchurch Hospital, Private Bag 4710, Christchurch, 8001 New Zealand. E-mail: jane.ellis{at}cdhb.govt.nz

Abstract

It has been suggested that CRH is a placental clock that controls the duration of pregnancy and that the timing of the rise in CRH may permit prediction of the onset of labor. We have performed a prospective longitudinal study, in 297 women, to examine the utility of a single second-trimester plasma CRH measurement to predict preterm delivery. Venous blood samples were taken at 4-weekly intervals, beginning at 16–20 wk gestation, until delivery for CRH and its binding protein. A time point at which a single plasma CRH test might give optimal data to predict preterm delivery was determined. Thirty-one subjects delivered prematurely (10.4%). Sampling for plasma CRH at 26 wk gestation seemed the optimal time point to maximize sensitivity and specificity of the test. The mean (± SD) plasma CRH in women at this gestation who eventually delivered after spontaneous labor within 1 wk of their due date (39–41 wk, n = 127) was 34.7 ± 27.0 pM. A plasma CRH of more than 90 pM at 26 wk gestation had a sensitivity of 45% and a specificity of 94% for prediction of preterm delivery. The positive predictive value was 46.7%. Calculation of free CRH did not improve these figures. In conclusion, a single measurement of plasma CRH, toward the end of the second trimester, may identify a group at risk for preterm delivery, but over 50% of such deliveries will be unpredicted. These data do not support the routine clinical use of plasma CRH as a predictor of preterm labor.

FOLLOWING THE ISOLATION and characterization of CRH in 1981 (1), it was soon discovered that CRH was detectable in human plasma during the third trimester of pregnancy (2). The CRH gene was shown to be expressed in the human placenta (3); and placental CRH secretion, the source of the elevated plasma levels. Several groups subsequently measured CRH in normal pregnancy (4, 5, 6, 7, 8). More marked elevation in maternal CRH was seen in abnormal pregnancy (9, 10, 11, 12). The discovery of a high-affinity binding protein for CRH (CRH-BP) (13) lead to the finding that levels fell during the third trimester of pregnancy (14), thereby increasing levels of free CRH in maternal plasma.

In 1995, McLean et al. (15) first coined the term: placental clock. They measured both CRH and CRH-BP in a large sample of women throughout pregnancy. They showed that women who delivered prematurely had an early rise in CRH, whereas women delivering post term had a later rise than those delivering at term. They postulated that the increase in CRH acted as a placental clock that controlled the length of human gestation (15). Further research has identified a number of mechanisms by which CRH may play a role in the initiation of labor (16). Several investigators have subsequently examined whether CRH, either alone or in combination with other clinical or biochemical measures, provides a useful predictor of preterm delivery (17, 18, 19, 20, 21).

Preterm labor and delivery remain a significant management problem, particularly with regard to the respiratory and neurological outcome of the infant. A simple biochemical test that might identify a group of women at high risk for preterm delivery would enable closer monitoring and timely intervention to optimize outcome. This would be particularly true if the test could be a single measurement rather than serial sampling. Our group has a well-established assay for the measurement of plasma CRH (22, 23) that has been extensively employed in the investigation of the human hypothalamic-pituitary-adrenal axis response to acute and chronic stress (24, 25, 26, 27). We aimed to determine whether the measurement of maternal CRH might result in a clinically useful diagnostic predictor of preterm delivery within our local population. CRH-BP was also measured to determine whether calculation of free CRH increased the diagnostic sensitivity.

In this study, we employed serial sampling, in a prospective longitudinal fashion, to derive an optimal time point for a single CRH measurement. In another report, we have described the pattern and timing of the rise in plasma CRH and unconjugated estriol in the preterm deliveries, compared with a similar number of term controls (28).

Materials and Methods

The study was carried out using a prospective longitudinal design. A total of 310 women were recruited through local midwives, private specialists, and the base hospital antenatal clinics in the early part of the second trimester. The Canterbury Ethics Committee approved the study.

After written informed consent, blood samples for CRH and CRH-BP were drawn every 4 wk, beginning from 16–20 wk gestation, until delivery. Data were collected concerning maternal health during pregnancy, onset of labor, and timing of delivery. Gestational dating was determined using menstrual histories or, when these were unreliable, by ultrasonographic scanning.

Assays

All samples from individual subjects were assayed in a single assay. Plasma CRH was measured by a modification of an RIA previously described (23). The CRH was extracted into 3 vol methanol, and extracts were dried and reconstituted in assay buffer equivalent to sample volume. Values therefore reflect total CRH, comprising the free fraction and that bound to the plasma CRH-BP. The antiserum (A12) was raised against a fragment of human/rat CRH (CRH_3–21) in rabbits held in the Christchurch School of Medicine animal facility. Intraassay coefficients of variation of extracted samples (n = 12) were 7% (1050 pM), 3.2% (105 pM), and 13.4% (25 pM); and interassay coefficients of variation were 7.8%, 10%, and 30% (n = 35–45) at the same concentrations of CRH.

CRH-BP was measured by RIA. Recombinant human (rh) CRH-BP and rabbit antiserum BP.I (raised against rhCRH-BP) were gifts from Professor P. J. Lowry, University of Reading. Iodination was performed using 0.5 mCi Na¹²⁵I in the presence of 5 µg chloramine T in 25 µl 0.5 M phosphate buffer, pH 7.5, for 90 sec, followed by the addition of 0.5 mg BSA and 1 mg methionine in 250 µl 0.05-M phosphate buffer, pH 7.5. The resulting mixture was loaded onto a 30-cm Sephacryl S200 column equilibrated with assay buffer [0.05 M phosphate buffer with 0.1% alkaline-treated casein, 0.1% Triton x100 and 0.02 M NaN₃, pH 7.5 (22)] and eluted at 3 ml/h. The fraction containing the first peak of radioactivity was used in the assay. Fifty microliters of rhCRH-BP standards (20–5000 pM) or plasma samples, diluted 9-fold in assay buffer, were incubated with 150 µl antiserum (1:6000) for 72 h at 4 C, followed by addition of 100 µl [¹²⁵I]rhCRH-BP (3000 cpm) for a further 72 h at 4 C. Bound and free [¹²⁵I]rhCRH-BP were separated using Sac-cell, Donkey-Anti Rabbit (IDS Ltd., Bolden, UK). Serial dilutions of plasma samples showed parallel displacement compared with standard rhCRH-BP. The analytical sensitivity and ED₅₀ of the standard curve were 4 pM and 95 pM, respectively. Intraassay coefficients of variation (n = 21) were 8.3% (314 pM), 7.5% (143 pM), and 9.0% (44 pM); and interassay coefficients of variation (n = 21 assays) were 12.9%, 8.8%, and 13.6%, respectively.

Statistical analysis

For each subject, a linear equation was fitted using the least-squares method to log-transformed CRH (total) data from three or more samples. A derived value for plasma CRH could therefore be calculated at any gestational age beyond the initial time point for each subject. We analyzed derived CRH levels at 24, 26, and 28 wk gestation to determine whether measurement of a single CRH level would provide a clinically useful diagnostic test. This preliminary analysis indicated that the 26-wk value was the best discriminator of preterm delivery. The normal range for plasma CRH at 26 wk gestation, in women delivering within 1 wk of their due date, was calculated by taking the mean CRH level ± 2 SD in this group. Because the data failed to satisfy parametric assumptions, two-way ANOVA on ranks was employed to examine whether the 26-wk CRH level was significantly different between term (39–41 wk gestation), preterm (<37 wk gestation), or postterm (>41 wk gestation) subjects. The preterm group was further subdivided into those women who entered a spontaneous labor and those who had an obstetric intervention. Post hoc analysis was carried out using Dunn’s test, examining all pairwise comparisons. The sensitivity, specificity, and positive predictive value of a raised 26-wk plasma CRH level were calculated.

Using the equations calculated on each individual’s longitudinal data, we examined the slope of the curve, to determine whether the rate of rise in CRH differed between the groups. One-way ANOVA was employed to compare the slope of the CRH curves between the spontaneous and interventional preterm groups and the term controls.

Values of free CRH were calculated from the total CRH and the CRH-BP levels using a dissociation-constant value of 0.17 nM (29) for binding of rhCRH-BP and human CRH. Log-transformed free CRH data for individual women were fitted to a linear equation as before.

Results

A total of 297 women completed the study and were included in the final analysis. Of these, 31 delivered before 37 wk gestation, therefore giving a preterm delivery rate of 10.4% in the study population. Serial data points for plasma CRH in the 297 women are shown in Fig. 1. There was an overrepresentation of high plasma CRH levels throughout the study period in the women who eventually delivered prematurely, but with considerable overlap demonstrated. A total of 127 women delivered after spontaneous labor, within 1 wk of their expected dates, and were defined as the term controls.

View larger version (24K): [in this window] [in a new window]   Figure 1. Serial individual data points for maternal CRH during 2nd and 3rd trimester of pregnancy. , Preterm delivery (<37 wk gestation); •, delivery at more than 37 wk gestation. Note log scale for y-axis.

Figure 2 outlines the derived 26-wk CRH values (mean ± SEM) in the women who delivered at term (34.7 ± 2.4 pM), compared with those who delivered prematurely and those who delivered more than 7 d after their due date (post term, 29.1 ± 4.1 pM, n = 28). There was a significant difference between the groups (P < 0.001 by ANOVA). Post hoc analysis revealed that both preterm subgroups (spontaneous, 98.1 ± 17.2 pM; intervention, 110 ± 25.2 pM) were higher than the term and postterm groups, but not significantly different from each other. There was no difference in the 26-wk CRH level between those who delivered at term vs. those delivering post term.

View larger version (17K): [in this window] [in a new window]   Figure 2. Individual (•) and mean ± SEM () maternal CRH levels at 26 wk gestation, in groups delivering prematurely (<37 wk gestation), within 1 wk of their due date (term) or post term (>41 wk gestation). The value for 26-wk plasma CRH was derived by individually fitted equations for each subject.

View larger version (25K): [in this window] [in a new window]   Figure 3. Mean ± SD level of CRH-BP in women delivering within 1 wk of their due date, pooled at 10-d intervals (•). Individual data points for women with preterm deliveries (<37 wk) are also plotted ().

This study provides comprehensive prospective data on a large cohort of pregnant women, with respect to plasma concentration of CRH and CRH-BP. In addition, we have examined the clinical utility of the measurement of a single plasma CRH level, toward the end of the second trimester, as a diagnostic predictor of preterm labor. Our results in the group as a whole are similar to those reported by other investigators (15). The longitudinal nature of our data is a strength of this study and it allowed the slope of the individual CRH curves to be calculated. The analysis did not reveal any slope difference between the groups, indicating a left shift, but similar rate of change, in the preterm deliveries. Our data also provides a normal range for plasma CRH in women who deliver at term, at a specific time point during the late second trimester. This then allows the calculation of sensitivity and specificity of a raised CRH at this time point. Further analysis could enable such a normal range to be calculated for any gestational point from approximately 20 wk. Our data do not lend strong support for the routine use of late second- trimester CRH as a clinical screen for preterm delivery, although the positive predictive value was higher than previously observed using a combination of CRH, -fetoprotein and clinical risk factors (20). The concurrent measurement of CRH-BP and CRH in our study allowed estimation of free CRH levels; however, this did not seem to improve specificity or sensitivity for predicting preterm deliveries when compared with use of total CRH values.

Risk factors for preterm delivery include previous preterm delivery, infection, smoking, uterine abnormalities, multiple gestation, polyhydramnios, and such demographic variables as extremes of maternal age, social class, race, and low body weight (30). Other biochemical markers used in an attempt to improve the prediction of preterm labor include estriol (31), activin (21), cytokines (32), fibronectin (33), collagenase (34), and tissue inhibitors of metalloproteinases (35). To date, there has been no test, either alone or in combination, that has provided a clinically useful predictor of preterm delivery (20, 36).

Our results are in general agreement with those of McLean et al. (15), who first proposed the hypothesis of the placental clock controlling the length of human gestation, and with other studies examining the relationship between plasma CRH and preterm labor. Even taking a single derived time point for plasma CRH at 26 wk gestation, those pregnancies destined to result in preterm delivery generally had raised CRH levels. Considerable overlap was observed, however. The subgroup of women who delivered after obstetric intervention included a number with antenatal complications known to be associated with a raised CRH level (9, 11). Small numbers of twin pregnancies and preterm deliveries after obstetric intervention do not allow determination of whether CRH is a better predictor in these situations than in spontaneous singleton labor. In contrast to the McLean study, those women delivering more than 1 wk post term had levels similar to those of the term controls. No other investigators have taken the mathematical approach of interpolating a CRH value at a fixed time point. Several studies report their findings based on a single sample taken over a range of gestations in a cross-sectional manner (18, 20, 37), or use up to three individual points per subject (38). This approach may explain why our results show a higher sensitivity than previously reported for CRH alone (18, 20, 21).

Within our cohort, we have examined whether concurrent measurement of plasma estriol and CRH would provide a more effective biochemical screen for preterm delivery. This was not the case, because plasma uE3 related more to days of gestation than to time before delivery; and there was no difference between plasma uE3 levels in the preterm singleton pregnancies, compared with term controls at equivalent gestation (28). Twin pregnancies did demonstrate a significantly early elevation, relative to singleton controls; however, this is likely to relate to placental and fetal adrenal mass rather than to preterm gestation, because it was not significant when compared with twin controls.

The current study was not designed to investigate the mechanism by which CRH may play a role in the initiation of labor and delivery. Several investigators have examined this in detail (16). First, CRH increases the production of PGs, known to stimulate myometrial contraction, from the placenta and fetal membranes (39). Second, CRH may modulate the maturation of the fetal hypothalamic pituitary adrenal axis, resulting in fetal cortisol and DHEA production. Cortisol plays an important function in the regulation of PG-synthesizing enzymes and also further enhances placental CRH expression (40). Third, CRH has been demonstrated to be a potent vasodilator and may be involved as a regulator of placental vascular tone (41, 42). Finally, CRH may interact directly with specific myometrial receptor subtypes that are up-regulated during pregnancy (43). CRH may have a dual role, by facilitating myometrial quiescence during pregnancy, followed by augmentation of PG and oxytocin- induced contractility during labor (16).

With the sensitivity and positive predictive value for a 26-wk gestation CRH being less than 50%, the implication is that there are a number of other factors involved in the initiation of preterm labor and delivery. One such possibility is maternal infection, which has been implicated in up to 30% of preterm labors (44) and seems not to be associated with an elevation in maternal CRH (12). The subgroup of women who went into spontaneous preterm labor included seven subjects with premature rupture of membranes, a risk factor for intrauterine infection. Unfortunately, we do not have complete placental and amniotic histology on our group, to determine with accuracy the number of preterm deliveries with inflammatory changes suggestive of infection. One might postulate, however, that spontaneous labor resulting from a maternal infection is unlikely to be associated with a preset shortening of the duration of gestation (And early elevation in plasma CRH) as per the placental clock hypothesis. Another factor involved in up to 15% of preterm labor is a deficiency in the enzyme choriodecidual 15-hydroxy-PG dehydrogenase (45). This enzyme deficiency results in an inability of the fetal membranes to metabolize PGs, resulting in the exposure of the myometrium to PG E2 that may initiate contractions (45).

In summary, we have performed a longitudinal study of serial CRH and CRH-BP measurement during human pregnancy, established a reference range for a single plasma CRH in the latter part of the second trimester (26 wk gestation), and examined the utility of this measurement to predict preterm delivery. We find that less than half of preterm deliveries were anticipated by a CRH level above the normal range for women who eventually deliver within a week of their due date. Furthermore, though the specificity of the test is 94%, over half of the women who had an elevated CRH at 26 wk did not deliver prematurely. We conclude that the performance characteristics of a late second-trimester measurement of plasma CRH alone as a diagnostic predictor of prematurity are insufficient to recommend in routine clinical practice. This does not rule out the possibility that a 26-wk plasma CRH level may prove to be useful in combination with other clinical and biochemical parameters.

Acknowledgments

We thank Angela Howe and Sara Raudsepp for valuable work in recruitment and patient data management and assistance with hormone assays, respectively. The cooperation of midwives and blood collection staff at the various hospitals and clinics is appreciated.

Footnotes

This work was supported in part by The Health Research Council of New Zealand, The Canterbury Medical Research Foundation, and Canterbury Health Ltd.

¹ Present address: Department of Medicine, University of Melbourne, St. Vincent’s Hospital, 41 Victoria Parade, Fitzroy VIC 3065, Australia.

² Present address: Department of Pathology, University of Cambridge, Cambridge CB2 1TN, United Kingdom.

Abbreviations: CRH-BP, CRH-binding protein; rh, recombinant human.

Received May 17, 2001.

Accepted August 24, 2001.

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