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Obstetrics & Gynecology 2003;101:557-564
© 2003 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Maternal Serum Corticotropin-Releasing Hormone at Midgestation in Hispanic and White Women

T. M. Siler-Khodr, PhD, G. Forthman, C. Khodr, S. Matyszczyk, Z. Khodr and G. Khodr, MD

From the University of Texas Health Science Center at San Antonio; and Southwest Genetics, P.A., San Antonio, Texas.

Address reprint requests to: Gabriel S. Khodr, MD, Southwest Genetics, P.A., 7711 Louis Pasteur, Suite 509, San Antonio, TX 78229; E-mail: swgene1{at}aol.com.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: Maternal circulating corticotropin-releasing hormone analysis at midgestation has been proposed as a parameter for the prediction of preterm birth. However, one recent study has reported that corticotropin-releasing hormone concentrations at midgestation differ in the black and white populations. These findings led us to investigate whether other populations have differing concentrations of maternal circulating corticotropin-releasing hormone that may require reference to specific population-based medians for optimal midgestational screening.

METHODS: In this study we have defined the mean and median concentrations of maternal circulating corticotropin-releasing hormone in Hispanic and white populations at each gestational week from 14 to 18 weeks of pregnancy, using a sensitive and specific radioimmunoassay.

RESULTS: Corticotropin-releasing hormone concentrations were found to be significantly lower in the Hispanic population as compared with whites at 16, 17, and 18 weeks’ gestation. The distribution of corticotropin-releasing hormone, expressed as multiples of the median (MoM) using the appropriate ethnicity-related median, was estimated for each gestational week and for each population. No differences were observed in the distribution of the ethnicity-adjusted MoM for Hispanics and whites.

CONCLUSION: These data demonstrate that ethnicity is a significant factor affecting corticotropin-releasing hormone concentrations at midgestation in the Hispanic and white populations. The use of ethnicity-specific medians to estimate the ethnicity-specific MoM for the corticotropin-releasing hormone concentrations may enhance the predictive value of midgestational maternal corticotropin-releasing hormone as a screening parameter for the prediction of preterm birth.

Corticotropin-releasing horne, a polypeptide hormone first characterized in hypothalamic extrcts,1 is produced by the placenta 2,3 secreted into the maternal circulation during normal preganct.4 The concetration in the maternal circulation during normal pregnancy increases exponentially form 15 weeks’s to 36 week’s gestation, attaining levels of 2000 pg/mL.5–7 A correlation of corticotropin-releasing hormone and gestational length has been demonstrated, which has led to the hypothesis that corticotropin-releasing hormone may act as a biological clock.8,9 Numerous investigators have observed an increased production of corticotropin-releasing hormone in certain complications of pregnancy, such as preterm birth and preeclampsia,10–15 yet it is not consistently increased in preterm birth associated with infection.12 Others have proposed that increased corticotropin-releasing hormone correlates with the level of maternal stress, which is inversely correlated with gestational length and fetal outcome.16–19 In these complications of pregnancy, in which an increase in maternal circulating corticotropin-releasing hormone has been noted, the increased corticotropin-releasing hormone precedes the clinical onset of the disease. Thus, it has been suggested that maternal circulating corticotropin-releasing hormone may be used as a predictive index of preterm birth not related to infection. Studies of maternal circulating corticotropin-releasing hormone in the early third trimester14,15,20 and at midgestation21–25 have been predictive for preterm birth in more than 25% of cases.

Although not presently used as a clinical screening test, its possible utility as such a tool, especially at mid-gestation, is currently under investigation. Analysis of maternal circulating corticotropin-releasing hormone at midgestation may allow time for interventions that will avert the negative outcome for these pregnancies.26,27 However, the use of corticotropin-releasing hormone as a predictive test has been complicated by the low, albeit measurable, levels of corticotropin-releasing hormone in maternal circulation at this stage of pregnancy and the presence of a circulation binding protein. To address this problem, we have developed and implemented a simple, sensitive method of measuring corticotropin-releasing hormone at midgestation in maternal serum and have demonstrated its effectiveness to predict preterm births at 15–18 weeks of pregnancy.7 Another important finding of these prior studies was the demonstration of a difference in the mean and the median corticotropin-releasing hormone concentration in the maternal circulation of black and white women at this stage of pregnancy. Using the race-specific medians determined from this group of matched normal-term and preterm births, the prediction of preterm birth with a sensitivity of 29% and 41% in the white and black populations, respectively, was observed.7

This difference in maternal circulating corticotropin-releasing hormone, as related to ethnicity in these populations, led us to realize the importance of establishing the appropriate median to be applied for corticotropin-releasing hormone screening in these populations. In the present study, we have estimated the circulating maternal corticotropin-releasing hormone at 14–18 weeks’ gestation in Hispanic and white women. The mean and median corticotropin-releasing hormone concentrations at each week of gestation are compared for these two populations. The ethnicity-specific medians at each week of midgestation are estimated in the Hispanic and white populations. The distribution pattern for corticotropin-releasing hormone at each gestational week for the His-panic and white populations, using the appropriate medians, are compared.


   MATERIALS AND METHODS
TOP
ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Serum samples (n = 1069), which were previously collected by venipuncture from patients in the San Antonio area having serum collected at midgestation for triple screens between 1998 and 1999 and stored at -20C, were used for these studies. The patient population was approximately 50% Hispanic, 40% white, 8% black, and 2% other. Only sera obtained from singleton pregnancies, dated by midgestational ultrasound, were analyzed. Gestational age, as estimated by ultrasound measurement, was grouped by week 14, 15, 16, 17, or 18, each week including the 0–6 days of that gestational week. Data analysis was based on serum samples from 618 Hispanic and 451 white patients during the 14–18 weeks of gestation. Table 1Go lists, by gestational age, the number of samples for Hispanics and whites that were analyzed in this study. Because a sufficient number of sera from black and other ethnicities were not available, these groups were not analyzed. Patient identifiers were not available, and pregnancy outcomes are not known. This study was approved by the Institutional Review Board.


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  		Table 1. Maternal Circulating Weight-Adjusted Corticotropin-Releasing Hormone Concentrations
 
The corticotropin-releasing hormone in the sera was first extracted from its binding protein using methanol. Duplicate aliquots of serum (500 µL) were mixed with methanol (3.5 mL). After centrifugation at 1000 g for 10 minutes, the methanol fraction containing the corticotropin-releasing hormone was dried using a Savant (Holbrook, NY) Speed-Vac. In each extraction, two control sera with a known amount of corticotropin-releasing hormone were also extracted to determine the recovery for each extraction set. The average extraction efficiency using this method was 84 ± 1%. The duplicate extracted corticotropin-releasing hormone aliquots for each patient and the control sera were then assayed for corticotropin-releasing hormone using a highly specific and sensitive radioimmunoassay. This extraction method provides for a higher recovery than the Sep-Pak C-18 (Millipore, Marlboro, MA) extraction method and yields similar values for corticotropin-releasing hormone in maternal blood.7,21 The higher recovery is of value for midgestational corticotropin-releasing hormone measurement, because it allows for a lower limit of detection, which is important for precise measurement of the lower concentrations of corticotropin-releasing hormone at midgestation. The recovery and stability of endogenous and exogenous corticotropin-releasing hormone in maternal blood processed and stored as serum was established and validated as described in our prior studies.21 We continue to determine the stability of corticotropin-releasing hormone in stored maternal serum samples by direct comparison with previous analyses of fresh samples and have now documented the stability of corticotropin-releasing hormone in maternal serum stored at -20C as long as 3 years (the longest point determined to date).

The corticotropin-releasing hormone radioimmunoassay used a sensitive and specific method similar to that reported by Sorem et al,7 but the samples were extracted as described above. Antiserum (a gift from Dr. Chrousos, National Institutes of Health, Bethesda, Maryland) was used at a final concentration of 1/250,000. Radio-iodinated Tyr-corticotropin-releasing hormone was prepared by the method of Hunter and Greenwood,28 and 10 pg was added to each tube. Standard corticotropin-releasing hormone was purchased from Sigma Chemical Co. (St. Louis, MO). The concentrations were corrected for water content. After a 3-day incubation with antiserum, labeled corticotropin-releasing hormone was added, and the incubation continued for 3 additional days. Bound and free hormones were separated using second antibody conjugated magnetic beads (Poly-Science Inc., Warrington, PA). Assay sensitivity (the concentration at ±2 standard deviations of the maximum binding) was approximately 7 pg/mL after correction of extraction loss. Intra-assay and interassay coefficients of variation were 3% and 5%, respectively.

Both the mean and median values for corticotropin-releasing hormone of Hispanic and white populations at each gestational week were calculated and compared across each gestational week, as well as by ethnicity. Two-way analysis of variance was used to analyze both the raw data and the log-transformed data. Using either method, a significant interaction was observed, but with the log-transformed data a greater significance was found. One-way analysis of variance was performed within each ethnic group to determine the effect of gestational age. For both ethnic groups, the one-way analysis of variance was significant, and the Bonferroni-adjusted Student t test was performed to identify specific gestational age–related differences with a given ethnicity. To compare the effect of ethnicity at each gestational age, unpaired Student t tests were performed. These same data were adjusted for maternal weight by multiplying the maternal corticotropin-releasing hormone concentration by the maternal weight for each patient, and the Hispanics and whites at each gestational week were compared. Statistical analysis was then applied with these data as described above. Correlation of maternal weight and circulating corticotropin-releasing hormone was also studied using linear regression analysis. The log-regressed medians were used to calculate the multiples of the median (MoM) for each subject and the distribution of MoM, using integrals of 0.25 MoM, was calculated. The distribution for Hispanics and whites was compared using {chi}2 analysis. For each statistical analysis, a P value less than .05 was considered significant.


   RESULTS
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The mean concentration of maternal circulating corticotropin-releasing hormone at 14–18 weeks’ gestation for Hispanic and white women is shown in Figure 1Go. The concentration of maternal circulating corticotropin-releasing hormone was higher in white women than in Hispanic women, which was significant at 14 (P < .035), 16 (P < .001), 17 (P < .001), and 18 (P < .010) weeks’ gestation. Corticotropin-releasing hormone increased with continuing gestation in both populations. A significantly higher concentration of corticotropin-releasing hormone was observed in the white women at gestational weeks 17 and 18 as compared with weeks 14 and 15 (P < .02, P < .005, respectively) and for 18 versus 16 weeks (P < .005). For Hispanics, corticotropin-releasing hormone increased across gestational age, having significantly higher concentrations at 15, 17, and 18 weeks as compared with 14 weeks (P < .04, P < .01, P < .001, respectively). No correlation of maternal weight with the circulating maternal corticotropin-releasing hormone concentrations at midgestation for either Hispanic or white populations (r2 = .016 and .0239, respectively; P > .05) was observed. Similarly, the product of maternal weight and corticotropin-releasing hormone concentration did not alter the observed difference in corticotropin-releasing hormone as related to ethnicity (Table 1Go).



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  		Figure 1. Average maternal circulating corticotropin-releasing hormone (CRH) (mean ± standard error of the mean) for gestational weeks 14–18 for Hispanic(diamonds) and white (squares) women. a, P < .035; b, P < .001; c, P < .010.

Siler-Khodr. Midgestational CRH and Ethnicity. Obstet Gynecol 2003.

 
The median concentration of maternal circulating corticotropin-releasing hormone for gestational weeks 14, 15, 16, 17, and 18 is shown in Figure 2Go. The median corticotropin-releasing hormone concentration for His-panic women was significantly less than that for white women. The median concentration was less than the average corticotropin-releasing hormone at each week of gestation and for each ethnicity. The log-regressed median for each ethnic group and at each week of gestation was used to calculate the MoM at each gestational week and for each ethnicity. The frequency distributions by ethnic group at each week of gestation are given in Table 2Go. The pattern of distribution for the MoM for each week of gestation and for each ethnicity was similar ({chi}2 > 0.80). The composite distribution pattern for the MoM of Hispanic and white women at 14–18 weeks of pregnancy is shown in Figure 3Go. For both ethnic groups, approximately 73.8% of the population had MoM of <1.5, and 82.5% were <1.75% when the appropriate gestational age–ethnicity-adjusted medians were used to calculate the MoM. A bimodal trend of distribution of corticotropin-releasing hormone was noted (ie, a number of higher MoM was observed in both Hispanic and white populations). The mean value for corticotropin-releasing hormone, which is higher than the median value at each gestational age for each ethnic group, reflects this bimodal distribution having a higher MoM component.



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  		Figure 2. Median value for maternal circulating corticotropin-releasing hormone (CRH) for gestational weeks 14–18 for Hispanic (diamonds) and white (squares) women. The log-regressed median across these gestational weeks is shown (solid lines). The number of patients for each ethnicity at each gestational week is given.

Siler-Khodr. Midgestational CRH and Ethnicity. Obstet Gynecol 2003.

 

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  		Table 2. Distribution of Corticotropin-Releasing Hormone (Multiples of the Median) for Hispanic and White Women at Midgestation
 


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  		Figure 3. Percent frequency for a range of multiples of the median (MoM) for maternal circulating corticotropin-releasing hormone (after normalization to the log-regressed median at each gestational week for the respective ethnic groups) (Hispanic, diamonds; white, squares).

Siler-Khodr. Midgestational CRH and Ethnicity. Obstet Gynecol 2003.

 

   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
These data demonstrate that the concentration of maternal circulating corticotropin-releasing hormone at mid-gestation in Hispanic women is significantly less than that in white women. This differential was observed from 14 weeks of pregnancy. Adjustment for maternal weight at the time of corticotropin-releasing hormone sampling did not alter the differences observed between Hispanic and white women. In a previous study, an ethnicity-related difference in maternal circulating corticotropin-releasing hormone at midgestation for black and white women was reported.21 That study used a nested case-control design containing two groups, pre-term and term births, matched by ethnicity.21 We performed the corticotropin-releasing hormone measurements for that study using the same method we used in the present report. In that previous study, it was found that black women had lower concentrations of circulating corticotropin-releasing hormone than white women. The sample analysis began at 15 weeks, and the number of samples was too small to allow for valid statistical comparison at weekly intervals. Thus, it was not possible to discern when a significant difference in corticotropin-releasing hormone between black and white women first occurred. However, the importance of adjusting for ethnicity at each gestational week, when determining the MoM for corticotropin-releasing hormone at midgestation, could be appreciated by the enhanced sensitivity of this parameter for prediction of preterm birth in the black population, which was 41% in this study. In other reports, in which ethnicity-adjusted medians were not used, the sensitivity of corticotropin-releasing hormone for predicting preterm birth was 28%.25 We are presently studying the value of applying ethnicity-adjusted median for the prediction of preterm birth to our population. An influence of ethnicity has been reported for other hormonal parameters as well. Other studies comparing a hormonal parameter by ethnicity have demonstrated significant differences. Both the medians for free ßhCG and PAPP-A were shown to be significantly increased in Afro-Caribbean women as compared with white women, and this difference was not related to maternal weight.29

The simplicity of this assay method (ie, methanol extraction of the corticotropin-releasing hormone from serum or plasma, its high recovery, and consistent reproducibility) makes this method easily applicable to clinical screening. Methods using C-18 separation of corticotropin-releasing hormone and corticotropin-releasing hormone binding protein are much more labile and tedious, yielding lower recovery with more variability. The higher recovery with methanol extraction also provides for greater sensitivity with this method and allows for greater precision and accuracy in the quantitation of the lower concentration of corticotropin-releasing hormone during the midgestational period. Thus, the methanol extraction procedure described herein is well suited for screening of corticotropin-releasing hormone in midgestation pregnancies and has now been implemented in a number of laboratories.

A significant difference for circulating corticotropin-releasing hormone in the white and Hispanic populations was first noted at 14 weeks’ gestation. Further studies, throughout the second half of pregnancy, are needed to determine whether ethnicity-related differences continue to term. The reason for the observed differences is unclear at this time. The regulation of placental corticotropin-releasing hormone is thought to be stimulated by glucocorticoids during pregnancy.30–32 However, this hypothesis is based on data obtained primarily from cell culture studies of third trimester tissues. Whether the feed-forward action of cortisol on corticotropin-releasing hormone production is operative at midgestation has yet to be determined. We have compared maternal circulating cortisol concentrations in Hispanic and white women at midgestation and have observed a higher concentration of cortisol in Hispanic women (unpublished data, Ruiz and Siler-Khodr), yet as shown in this study, corticotropin-releasing hormone concentrations are lower. This finding of a lower concentration of corticotropin-releasing hormone in the His-panic population at midgestation indicates that a negative-feedback activity is functioning at this stage of gestation. In addition, we have demonstrated that corticotropin-releasing hormone production from fresh placental tissue is not stimulated by glucocorticoids in the absence of high concentrations of estrogen–progester-one.33,34 Thus, we propose that at midgestation the negative-feedback activity of glucocorticoids is still active and that higher maternal cortisol in the Hispanic population effects a negative-feedback activity on placental corticotropin-releasing hormone production at midgestation, resulting in the lower circulating concentrations of corticotropin-releasing hormone. This hypothesis is also supported by the observation that an increase in corticotropin-releasing hormone after betamethasone treatment occurs in pregnancies of more than 30 weeks’ gestation,35 suggesting that a switch to the feed-forward action of glucocorticoids occurs around this time of gestation.

The possible use of corticotropin-releasing hormone as a predictor for preterm birth has been proposed by a number of investigators. It was first suggested on the basis of increased maternal circulating corticotropin-releasing hormone during the third trimester of pregnancies ending in preterm birth.14,15,20 However, to date an established intervention procedure for preterm birth has yet to be applied in practice. The value of analyzing maternal circulating corticotropin-releasing hormone concentrations at midgestation is two-fold. First, it allows time for intervention, and second, blood samples for triple screens are already routinely collected at this stage of pregnancy.21–25 In three different studies, the sensitivity of midgestational corticotropin-releasing hormone screening to predict preterm birth was 25–41%.21,23,25 In light of these findings, further studies using appropriate norms are needed to estimate the true predictive value of corticotropin-releasing hormone midgestational screening for preterm birth. The sensitivity and the predictive value of this parameter for prediction of preterm birth might be increased if corticotropin-releasing hormone measurements are done with a very sensitive procedure and MoM are calculated with medians adjusted for the ethnicity of the patient. The procedure used in this report has overcome limited assay sensitivity and provides reliable norms for Hispanic and white populations. Further studies using the appropriate norms should better define the positive predictive index and limit the false positives for midgestational screening of maternal circulating corticotropin-releasing hormone to predict preterm birth.


   Footnotes
 
doi: 10.1016/S0029-7844(02)03072-7

Received May 15, 2002. Received in revised form September 5, 2002. Accepted September 12, 2002.


   REFERENCES
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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