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Original Studies |
Medical Research Council Group in Fetal and Neonatal Health and Development, Departments of Obstetrics and Gynecology and Physiology, University of Western Ontario, Lawson Research Institute, St. Joseph’s Health Center (C.K., M.M.R., L.W., E.B., A.D.B., J.R.G.C.), London, Ontario, Canada; and the Departments of Physiology and Obstetrics and Gynecology, University of Toronto (C.K., J.R.G.C.), Toronto, Ontario, Canada
Address all correspondence and requests for reprints to: Dr. Alan D. Bocking, Department of Obstetrics and Gynecology, St. Joseph’s Health Center, 268 Grosvenor Street, London, Ontario, Canada N6A 4V2.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In human pregnancy, CRH is produced by the placenta and fetal membranes in substantial amounts during the third trimester of pregnancy (4), giving rise to an increase in CRH concentrations in maternal peripheral plasma, particularly after 30 weeks gestation (5, 6). Recent studies have suggested that maternal plasma levels of CRH are elevated in women with preterm labor (7, 8, 9) and lower in those destined to give birth postterm (9).
The control of CRH production by the placenta is multifactorial. It has been shown recently in vitro that glucocorticoids stimulate the placental output of CRH, in contrast to the negative feedback of glucocorticoids on CRH expression at the hypothalamus (10). These glucocorticoids could be derived from the maternal adrenal gland or from the activated fetal adrenal gland (11). In maternal plasma, glucocorticoids are bound to corticosteroid-binding globulin, which is a glycoprotein that determines the availability of cortisol to target tissues (12).
In the present study we sought to evaluate maternal endocrine parameters that could potentially discriminate at hospital admission between women destined to give birth within 24 h from those who would not. We hypothesized specifically that maternal plasma CRH levels would be elevated in women giving birth within 24 h. We also examined other hormones of the hypothalamic-pituitary-adrenal-placental axis, including ACTH and cortisol, as well as corticosteroid-binding capacity (CBC) as a determinant of the bioavailability of cortisol. We compared these measurements in women with the diagnosis of threatened preterm labor with those in our own normal population who delivered at full term.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Twenty-eight low risk women were recruited from the antenatal clinics at St. Joseph’s Health Center (London, Canada) during the first trimester of pregnancy to establish normal values for maternal peripheral plasma concentrations of ACTH, cortisol, CBC, and CRH for our laboratory. Gestational age was assessed through determination of menstrual dates, early pelvic examination, and first or second trimester ultrasound. All of these women delivered healthy infants at a gestational age greater than 37 weeks (mean ± SEM, 39.8 ± 0.2 weeks) with Apgar scores greater than 7. The mean (±SEM) birth weight for these infants was 3525 ± 98 g.
Maternal blood samples were obtained at 20, 24, 28, 30, 32, 34, 36, and 38 weeks, at the time of regular prenatal visits, for a total of eight samples for each subject. Although we were not able in this study to control for the exact time of day of blood sample collection, in most women the samples were collected between 0900–1200 h. Five milliliters of peripheral blood were obtained by venipuncture into heparinized tubes and immediately centrifuged at 2500 rpm for 20 min at 4 C. The plasma was then divided into aliquots and stored at -80 C until assayed.
Preterm subjects
Two hundred and thirty-three women admitted to St. Joseph’s
Health Center between March 1994 and October 1995 with a diagnosis of
threatened preterm labor (regular uterine contractions, dilatation or
effacement of cervix, and/or ruptured membranes) and singleton
pregnancies between 24–36 completed weeks of gestation were enrolled
in the study. Women with multiple pregnancies, fetal anomalies,
diabetes mellitus, abruptio placenta, preeclampsia, cervical dilatation
more than 4 cm, intrauterine growth restriction, and clinical signs of
infection were excluded from the study. Pathological examination of
placental tissue was performed in those women who delivered preterm for
evidence of histological chorioamnionitis using the definition of acute
chorioamnionitis described by Blanc (13). This diagnosis of acute
chorioamnionitis relies primarily on establishing the presence of
polymorphonuclear leukocytes in the area of the placental chorionic
plate. Comprehensive demographic data were obtained for all subjects at
the time of enrollment, and information regarding birth outcome was
recorded in a database (Table 1
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RIAs
ACTH was measured using a commercial RIA kit (Incstar, Stillwater, MN) with the antibody characteristics described by the manufacturer and previously (14). The interassay coefficient of variation was 10.6%.
Cortisol was measured by RIA after extraction with diethyl ether. For each sample, 25 µL plasma were extracted; duplicate assays were performed using aliquots of a different volume. The antibody characteristics have been reported previously (14). The interassay coefficient of variation was 11%.
CBC was determined using the saturation binding assay of Ballard et al. (15) as modified by us (16). For the assay, 25 µL maternal plasma were used in the presence of 32 ng cortisol to achieve saturation.
CRH was measured after extraction of plasma with 4 vol ice-cold methanol (17). After the addition of methanol, samples were mixed and incubated for 15 min at 4 C, then centrifuged at 2000 x g for 20 min at 4 C. The supernatants were poured into a second set of tubes. The pellets were washed with 0.5 mL ice-cold methanol and centrifuged at 2000 x g for 15 min at 4 C. The supernatants were pooled and dried under air on a heating block at 40 C. The extracts were then dissolved in 1 mL 0.05 mol/L phosphate buffer, pH 7.3, containing 5.8 g/L NaCl, 9.5 g/L ethylenediamine tetraacetate, 1.0 g/L NaN3, and 1 mL/L Triton. Aliquots of the reconstituted extracts were assayed for CRH in duplicate. For the RIA, CRH antibody (50 µL; dilution, 1:6000) raised in a rabbit against human CRH (Cedarlane, Belmont, CA) was added to the samples and standards (0–5000 pg/mL) in a volume of 200 µL. Incubations were conducted for 24 h at 4 C. Then, 10,000 cpm [125I]CRH (DuPont-New England Nuclear Research Products, Wilmington, DE) were added to the samples, which were incubated for an additional 48 h at 4 C. Bound and free fractions were separated using a donkey second antibody (50 µL; Sac-Cel, IDS, Boldon Business Park, Tyne and Wear, UK). After further incubation for 20 min at room temperature, 1 mL distilled water was added to the samples. These were centrifuged at 2000 x g for 20 min at room temperature, the supernatant was aspirated, and the radioactivity was counted.
Human CRH (Peninsula Laboratories, Belmont, CA) was used as a reference
standard. CRH was added to plasma from nonpregnant women in known
different concentrations and processed as described above. The mean
recovery of added CRH over the concentration range 250-2000 pg/mL was
88.8 ± 2.0% (SEM). The sensitivity of the CRH assay
was 20 pg/mL. The intra- and interassay coefficients of variation were
12% and 6.5%, respectively. There was no detectable (<0.01%)
cross-reactivity of human ACTH or 
MSH with the human CRH
antiserum.
Data analysis and statistical methods
Results for all hormones were not available for all subjects at all gestational ages due to occasional insufficient aliquots or technical difficulties. Differences in the mean values of ACTH, cortisol, CBC, cortisol/CBC ratio, and CRH with advancing gestational age (20, 24, 28, 30, 32, 34, 36, and 38 weeks) in normal subjects was sought by one-way repeated measures ANOVA, followed by post-hoc Student-Newman-Keuls test.
The women with threatened preterm labor were stratified into the
following three gestational age groups: 24–28, 28–32, and 32–36
weeks gestation; within groups, they were divided into those that
delivered less than or equal to 24 h or greater than 24 h
from the time of admission. For normal subjects at each of the three
gestational ages (24–28, 28–32, and 32–36 weeks), the values for the
two blood samples obtained were averaged to allow comparison with the
preterm labor subjects. Differences in hormone concentrations in
maternal plasma between the study groups (delivery 
24 h, delivery
>24 h, and normal subjects) were assessed by ANOVA, followed by
Students-Newman-Keuls post-hoc test. Results are expressed
as the mean ± SEM. Statistical significance level was
set at P < 0.05.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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ACTH levels increased progressively during normal pregnancy from
47.3 ± 3.4 pg/mL (n = 24) at 20 weeks gestation to 57.5
± 4.3 pg/mL (n = 22) at 38 weeks gestation. The mean values for
the eight different gestational ages were statistically different
(P < 0.0001; Fig. 1).
Cortisol levels increased slightly during normal pregnancy from
191.3 ± 15.1 ng/mL (n = 25) at 20 weeks gestation to
231.5 ± 10.9 ng/mL (n = 23) at 38 weeks gestation, although
this was not statistically significant (Fig. 1).
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). There was no change in the
cortisol/CBC ratio with advancing gestation from the value of 0.57
± 0.04 at 20 weeks.
Peripheral plasma CRH levels increased markedly during normal pregnancy
from 62.2 ± 6.3 pg/mL (n = 25) at 20 weeks gestation to
1449.3 ± 240.8 pg/mL (n = 22) at 38 weeks gestation. The
mean maternal CRH concentrations were significantly greater than
measurements at previous gestational ages from 32 weeks onward
(P < 0.0001; Fig. 1).
Preterm labor subjects
The mean gestational ages at the time of admission within the
three gestational age groupings of 24–28, 28–32, and 32–36 weeks
gestation were similar for women who gave birth within 24 h of
blood sampling and those who gave birth at greater than 24 h
(Table 1).
Of those women admitted with threatened preterm labor and intact
membranes, 48% gave birth prematurely (<37 weeks), and 96% of those
with ruptured membranes delivered at less than 37 weeks (Table 2). Overall, 21% of women with intact
membranes gave birth less than 24 h and 24% gave birth less than
48 h from admission. The percentages of women with ruptured
membranes giving birth within 24 and 48 h were 57% and 65%,
respectively. Because of the small numbers of women who gave birth
between 24–48 h of admission, we chose a threshold of delivery within
24 h of blood sampling for our analysis.
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Overall, mean maternal peripheral plasma CRH was significantly higher
(P < 0.05) in women who gave birth at 24 h or
less (1343.3 ± 143.9 pg/mL; n = 81) compared to those giving
birth at more than 24 h (714.5 ± 64.8 pg/mL; n = 144)
and those in normal subjects (445.3 ± 41.0 pg/mL; n = 28).
In women with ruptured membranes, maternal CRH concentrations were
greater (P < 0.05) in those giving birth within
24 h (1541.5 ± 173.6 pg/mL; n = 56) than in those who
did not (831.8 ± 134.9 pg/mL; n = 41). At both 28–32 and
32–36 weeks, plasma CRH was significantly higher (P <
0.05) in women who gave birth at 24 h or less [990.1 ±
307.6 pg/mL (n = 10); 1707.3 ± 177.7 pg/mL (n = 56)]
compared to those who gave birth at more than 24 h as well as
those in normal subjects. There was no difference in maternal plasma
CRH concentrations between groups at 24–28 weeks gestation (Fig. 2).
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).
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).
The ratio of maternal plasma cortisol/CBC between 24 and 36 weeks
gestation was significantly higher in women giving birth within 24
h (0.65 ± 0.04; n = 82) than in those who did not
(0.55±.0.02; n = 136) or in normal subjects (0.57 ± 0.01;
n = 68). At both 24–28 and 28–32 weeks, the cortisol/CBC ratio
was higher in women giving birth within 24 h [0.75 ± 0.07
(n = 14) and 0.89 ± 0.02 (n = 11)] than in women who
did not or in normal subjects (Fig. 3).
Between 32–36 weeks, the cortisol/CBC ratio was also significantly
higher in women giving birth at 24 h or less (0.58 ± 0.03;
n = 57) than in those who did not (0.48 ± 0.03; n =
58), but was not different from that in the normal subjects (0.56
± 0.03; n = 23).
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).
Between 24–36 weeks gestational age, of those women giving birth
within 24 h, maternal CRH was significantly higher in women
without placental signs of infection than in those with evidence of
histological chorioamnionitis (Table 4).
This difference was not evident at 24–28 weeks, but was significant at
28–32 and 32–36 weeks. In those women giving birth greater than
24 h from admission, maternal CRH concentrations were higher when
there was no histological evidence of chorioamnionitis at birth than in
those with infection (809.5 ± 125.6 vs. 490.3 ±
57.0 pg/mL), although this was not statistically significant. There was
no difference in the concentrations of other hormones measured between
women with or without placental signs of infection.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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One limitation of this study is the different time of day that blood sampling was carried out, although this reflects normal clinical practice. In the preterm labor subjects, blood was collected at the time of admission to hospital regardless of the time of day, whereas in the normal subjects, the majority of blood samples were drawn between 0900–1200 h. We chose 24 h as our threshold for time of delivery because antenatal glucocorticoid administration for fetal lung maturity has been shown to have a beneficial effect beyond that time period. When 48 h was used as the threshold, the results were very similar. It will be important to examine the predictive value of these measurements in larger studies in relation to different intervals of blood sampling to delivery. This information will be of potential benefit for clinical decision making regarding the use of tocolytic agents, glucocorticoids, and/or admission to hospital.
In this study we have confirmed that ACTH concentrations in maternal peripheral plasma increase during normal pregnancy similar to the results of previous studies, but remain within the range of levels seen in nonpregnant women (18, 19, 20). It has been observed previously that plasma ACTH concentrations are not suppressible by therapeutic dexamethasone administration in human pregnancy (20, 21), raising the possibility of a source for circulating ACTH levels other than the pituitary during pregnancy, such as the placenta (22). Glucocorticoids, which suppress the secretion of pituitary ACTH, have no effect on the release of ACTH by the placenta (23), indicating that there is no negative feedback inhibition of glucocorticoids on ACTH secretion from placental cells.
There was no change in cortisol concentrations in maternal plasma in our normal subjects between 20–38 weeks gestation. Previous studies have shown that cortisol levels increase between 12–26 weeks gestation, with no subsequent changes (19), although Scott et al. (24) found an increase of about 40% in cortisol levels between 12–16 and 36–38 weeks gestation.
Mean maternal plasma cortisol concentrations were higher in women giving birth within 24 h, suggesting that cortisol might play a role in the mechanism of preterm labor in some women. Mazor et al. (25) also observed higher plasma cortisol levels in women in threatened preterm labor who delivered prematurely than in those who delivered at term, which is consistent with maternal hypercortisolemia being important in preterm labor. It would be of interest to measure free cortisol concentrations in a similar group of women to further investigate this relationship, although in this study, we have examined the ratio of cortisol to CBC as an indirect measure of free cortisol.
In this longitudinal study, maternal plasma CBC increased significantly between 20–38 weeks gestational age in normal pregnancy. Moore et al. (26) reported that CBC levels begin to increase by 9 weeks gestation, after which a threshold of endogenous estrogen is surpassed, and CBC levels increase in a linear fashion until 18 weeks gestation. In another study using cross-sectional measurements, CBC was found to increase during pregnancy, but this was not statistically significant (27).
The ratio of total plasma cortisol to CBC provides, indirectly, information about the available bioactive free cortisol. We observed that in normal pregnant women this ratio stays relatively constant at approximately 0.57 during the course of pregnancy between 20–38 weeks gestation. In contrast, with threatened preterm labor between 24–36 weeks gestation, the cortisol/CBC ratio is significantly elevated in women destined to give birth within 24 h compared to that in women who do not or that in normal pregnant women. This elevated ratio in women giving birth prematurely provides further evidence that levels of maternal plasma cortisol may play an important role in the pathogenesis of preterm labor in some women. Recent studies have shown that during in vitro culture of human placental tissue, glucocorticoids up-regulate CRH gene expression (28, 29). We have also shown recently that clinical administration of glucocorticoids for fetal lung maturity leads to elevated maternal plasma CRH levels (30).
In this study we have confirmed that plasma CRH increases markedly between 20 and 38 weeks gestation (5, 6, 31) in normal pregnancy and that maternal plasma CRH levels are elevated in association with preterm labor (7, 8, 9). Our study is the first, however, that describes the use of maternal plasma CRH as a diagnostic tool to distinguish women in threatened preterm labor at different gestational ages destined to give birth within 24 h from those who will not. Of note, is that in women who give birth within 24 h, maternal plasma CRH levels are significantly higher than in those women who do not give birth within 24 h between 28–36 weeks gestation, whereas at 24–28 weeks there was no difference between the study groups. Our findings are in contrast to those of Berkowitz et al. (32), who concluded from a cross-sectional study in a largely Hispanic population that maternal CRH levels are not an important predictor of preterm birth. It is of note that these investigators did not control for the presence or absence of histological chorioamnionitis.
Interestingly, we found that in those women who gave birth within 24 h and in whom there was a histological diagnosis of placental chorioamnionitis, CRH was not elevated compared to that in women without placental signs of infection. This lack of elevation of CRH in women with histological chorioamnionitis was present in women with both intact and ruptured membranes. This suggests that in women with placental infection there are other mechanisms that lead to labor, such as release of bacterial endotoxins and cytokines resulting in increased PG production in the amnion and decidua (33). Our results are in agreement with the data of Warren et al. (8), who noted that in women with preterm labor and associated clinical or placental signs of infection, there was no elevation of maternal plasma CRH. In contrast, Petraglia et al. (34) found that in the presence of microbial invasion of the amniotic cavity, preterm labor was associated with a significant elevation of CRH in maternal plasma and placenta. These discrepancies may be due to the use of different definitions of infection. In the present study we looked at histological signs of infection only, excluding women with clinical signs of infection from study, whereas Petraglia et al. (34) looked at microbial invasion of the amniotic cavity, and Warren et al. (8) studied patients with both clinical and histological signs of infection. It is possible that infection with associated cytokine release may either directly stimulate placental CRH production (35), or if the infection is severe enough, destruction of the chorionic trophoblast cells (36) may cause a decrease in placental CRH production. Maternal plasma CRH levels would therefore represent a balance between these two competing actions.
There is considerable evidence that placental CRH plays an important role in the development of human term and preterm labor. In vitro studies have shown that CRH stimulates placental PG output (10), and CRH receptors have been found in human myometrium (37). Placental CRH presumably then synergizes with PGs and oxytocin to enhance myometrial activity (38), which, in turn, would eventually lead to preterm labor. Increased fetal and/or maternal bioavailable cortisol levels could also stimulate placental CRH production, which, in turn, would increase PG output, eventually leading to preterm labor. The interaction between cortisol and CRH, therefore, plays a central role in the genesis of preterm birth in some women. CRH-binding protein is also known to influence the availability of CRH to act on target tissues (17), and it would be of interest to make measurements of CRH-binding protein in future studies to further investigate the mechanism(s) underlying preterm labor.
In summary, we have shown that plasma CRH is elevated between 28–36 weeks of pregnancy in women with threatened preterm labor destined to give birth within 24 h of admission and that the plasma cortisol/CBC ratio is also elevated in these same women between 24–36 weeks gestation. The ratio of cortisol/CBC and/or CRH measured in maternal peripheral plasma may be useful markers for determining which patients are in true active preterm labor. The ability to identify at the time of presentation to the hospital women who are going to give birth within a defined period of time from those who will not would be an important addition to current clinical management. The present study provides a rationale for proceeding with a prospective study to determine the positive and negative predictive values of these measurements in clinical practice. Such studies, however, will require characterizing initially the normal gestational age specific values for CRH levels between 28–36 weeks gestation to determine the most appropriate cut-off threshold for this potentially useful diagnostic test.
Received August 18, 1997.
Revised January 12, 1998.
Accepted January 28, 1998.
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37 weeks) for those
with intact and ruptured membranes at the time of admission to hospital
with threatened preterm labor
