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Original Article |

Risk of Postpartum Depressive Symptoms With Elevated Corticotropin-Releasing Hormone in Human Pregnancy FREE

Ilona S. Yim, PhD; Laura M. Glynn, PhD; Christine Dunkel Schetter, PhD; Calvin J. Hobel, MD; Aleksandra Chicz-DeMet, PhD; Curt A. Sandman, PhD
[+] Author Affiliations

Author Affiliations: Departments of Psychology and Social Behavior (Dr Yim), and Psychiatry and Human Behavior (Drs Glynn, Chicz-DeMet, and Sandman), University of California, Irvine; Department of Psychology, University of California, Los Angeles (Dr Dunkel Schetter); Division of Maternal-Fetal Medicine, Cedars-Sinai Medical Center, Los Angeles, California (Dr Hobel); and Department of Psychology, Chapman University, Orange, California (Dr Glynn).


Arch Gen Psychiatry. 2009;66(2):162-169. doi:10.1001/archgenpsychiatry.2008.533.
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Context  Postpartum depression (PPD) is common and has serious implications for the mother and her newborn infant. A possible link between placental corticotropin-releasing hormone (pCRH) and PPD incidence has been hypothesized, but empirical evidence is lacking.

Objective  To determine whether accelerated increases in pCRH throughout pregnancy are associated with PPD symptoms.

Design  Pregnant women were recruited into this longitudinal cohort study. Blood samples were obtained at 15, 19, 25, 31, and 37 weeks' gestational age (GA) for assessment of pCRH, cortisol, and adrenocorticotropic hormone (ACTH). Depressive symptoms were assessed with a standardized questionnaire at the last 4 pregnancy visits and post partum.

Setting  Subjects were recruited from 2 southern California medical centers, and visits were conducted in research laboratories.

Participants  One hundred adult women with a singleton pregnancy.

Main Outcome Measure  Symptoms of PPD were assessed at a mean (SD) of 8.7 (2.94) weeks after delivery with the Edinburgh Postnatal Depression Scale.

Results  Sixteen women developed PPD symptoms. At 25 weeks' GA, pCRH was a strong predictor of PPD symptoms (R2 = 0.21; β = 0.46 [P < .001]), an effect that remained significant after controlling for prenatal depressive symptoms. No significant associations were found for cortisol and ACTH. Receiver operating characteristic curve analyses revealed that pCRH at 25 weeks' GA is a possible diagnostic tool (area under the curve, 0.78 [P = .001]). Sensitivity (0.75) and specificity (0.74) at the ideal cutoff point (pCRH, 56.86 pg/mL) were moderate. Growth curve analyses indicated that the trajectories of pCRH in women with PPD symptoms are significantly accelerated from 23 to 26 weeks' GA.

Conclusions  At a critical period in midpregnancy, pCRH is a sensitive and specific early diagnostic test for PPD symptoms. If replicated, these results have implications for the identification and treatment of pregnant women at risk for PPD.

Figures in this Article

Postpartum mood disorders range from the mild and common postpartum “blues” to much rarer incidences of severe postpartum psychosis.1 The most commonly studied postpartum mood disorder is postpartum depression (PPD), which is similar to major depressive disorder but has its onset within the first 4 weeks (International Statistical Classification of Diseases, 10th Revision)2 to 6 weeks (DSM-IV)3 after delivery. Postpartum depression not only influences the well-being of the new mother but also has adverse effects on the cognitive and behavioral development of her infant.4 Reports of PPD prevalence vary widely; a recent meta-analysis estimates it at 19.2% (7.1% for major PPD alone) within the first 3 months post partum.5

The high incidence and severe consequences of PPD make the identification of women at risk an important research goal. The most consistently identified risk factors include previous PPD; a history of depression, anxiety, stress, and depression during pregnancy; stressful life events; lack of social support; and low self-esteem6,7; however, these risk factors explain only a portion of the variance in the incidence of PPD. Endocrine risk factors for PPD have been identified as well, including changes in reproductive hormones during pregnancy, a history of premenstrual syndrome, and a history of oral contraceptive–induced mood changes.810

Little research interest has been directed toward the role of corticotropin-releasing hormone (CRH), a 41–amino acid neuropeptide central in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis,11 as a potential predictor of PPD.12 This is surprising because several lines of evidence suggest the possibility that increased CRH may be a risk factor for PPD. First, CRH plays an important role in the etiology of depression in the nonpregnant state.13 For example, depressed patients are more likely to have an increased number of hypothalamic CRH neurons, and these neurons tend to be hyperactive.14,15 This evidence has led to the development of a CRH hypothesis of depression, suggesting that the hyperactivity of CRH neurons and the HPA axis may trigger depressive symptoms.16

Second, pregnancy is characterized by marked changes in maternal HPA axis regulation. In the central nervous system, CRH is produced in the paraventricular nucleus of the hypothalamus and released into the median eminence, a local portal system connecting the hypothalamus with the pituitary, where CRH stimulates the release of adrenocorticotropic hormone (ACTH). Binding by ACTH causes the adrenal cortex to release the glucocorticoid cortisol.17 During pregnancy, CRH is also produced by the placenta and, unlike CRH of hypothalamic origin, is detectable in maternal peripheral blood.18,19 Placental (pCRH) and hypothalamic CRH are similar with regard to their structure, immunoreactivity, and bioactivity.20,21 However, in contrast to the role of cortisol in the negative feedback regulation of the HPA axis, cortisol stimulates CRH production in the placenta. As a result, levels of pCRH in maternal plasma increase exponentially throughout pregnancy18,22 and reach levels similar to those of hypothalamic CRH in the median eminence under conditions of acute stress.23 The sudden disappearance of the placenta after delivery results in a sharp drop of pCRH levels. The postpartum period is therefore characterized by pCRH withdrawal, resulting in transient suppression of hypothalamic CRH release and HPA axis dysregulation. It has been suggested that this may explain the occurrence of postpartum depressive disorders.2429

Finally, there are marked interindividual differences in the trajectories of pCRH throughout pregnancy.22 It has been demonstrated that accelerated trajectories of pCRH are associated with race/ethnicity30 and preterm birth22,3134; are implicated in pregnancy complications such as preeclampsia,3537 fetal growth retardation,38 and diminished umbilical artery blood flow39; and have consequences for the developing infant, including lower newborn physical and neuromuscular maturity40 and increased irritability.41 Because of the established association between CRH and depression, accelerated increases in pCRH throughout pregnancy may also serve as a potential early marker to identify women at high risk for PPD. It is the goal of the present study to address this possibility.

PARTICIPANTS

One hundred pregnant women with a singleton, intrauterine pregnancy were selected from a larger sample30,4042 that was recruited in a longitudinal study at Cedars-Sinai Medical Center and the University of California, Irvine, Medical Center. In this study, subjects with conditions known to affect HPA axis function, subjects with alcohol or other drug abuse within 6 months before the index pregnancy, and non–English-speaking subjects were excluded from participation.

The present sample consisted of the 100 women with complete data for pCRH and depressive symptoms. Mean (SD) age at delivery was 31.2 (5.3) years. The ethnic composition was 54% non-Hispanic white, 22% Hispanic white, 12% Asian, 7% African American, and 5% multiethnic or other. Most women were married (79%), had graduated from high school (97%), and were college graduates (52%). The annual household income varied from $5000 to more than $100 000, and median income was in the range of $80 000 to $90 000. All pregnancies resulted in live births, and 53 girls and 47 boys were delivered. Deliveries were 72% vaginal and 28% cesarean section. Mean (SD) infant birth weight was 3514 (469) g (range, 2340-4450 g), and gestational length at term was 39.4 (1.3) weeks (range, 36.57-42.0 weeks). Because completion of the full study was an inclusion criterion, and because the last study visit occurred around 37 weeks' gestational age (GA), most women had full-term infants (97% had a gestational length >37 weeks), and no woman delivered before 36.6 weeks' GA. Most women had no previous live-born children (61%).

OVERALL PROCEDURE

Blood samples were obtained at a mean (SD) of 15.3 (0.92), 19.2 (0.72), 25.0 (0.94), 31.0 (0.76), and 36.7 (0.70) weeks' GA for assessment of pCRH, cortisol, and ACTH. Depressive symptoms were assessed at the last 4 time points during pregnancy and again at the postpartum visit (mean [SD], 8.7 [2.9] weeks). Written informed consent was obtained from all women before participation. This protocol was approved by the institutional review boards of the participating institutions.

HORMONE MEASURES

A 25-mL blood sample was obtained by antecubital venipuncture. Samples were drawn into chilled EDTA-treated test tubes (Vacutainers; Becton Dickinson and Company, Sumter, South Carolina) and spun for 15 minutes at 2000g. The plasma was then decanted into polypropylene tubes containing 500-kallikrein inhibitor units/mL of aprotinin (Sigma-Aldrich Corp, St Louis, Missouri) and stored at −70°C until assayed.

The concentration of total CRH was determined by means of radioimmunoassay using antiserum directed at human CRH (Bachem Peninsula Laboratories, San Carlos, California). Plasma samples (1-2 mL) were extracted with 3 volumes of ice-cold methanol, mixed, allowed to stand for 10 minutes at 4°C, and then centrifuged (20 minutes, 1700g, 4°C).43 The pellets were washed with 0.5 mL of methanol, and the combined supernatants dried in a concentrator (SpeedVac; Savant Instruments, Holbrook, New York). Reconstituted samples were incubated (100 μL/assay tube) with antiserum (100 μL/assay tube) for 48 hours at 4°C followed by an overnight incubation with iodine 125 –labeled CRH at 4°C. Labeled and unlabeled CRH samples were collected by means of immunoprecipitation, and the aspirated pellets were counted using a gamma counter (Isoflex; ICN Biomedical, Costa Mesa, California). Crossreactivity was less than 0.01 for ovine CRH, 36% for bovine CRH, and nondetectable for human ACTH. Intra-assay and interassay coefficients of variance were 5% and 15%, respectively. Using this technique, our laboratory has reliably detected pCRH at as early as 15 weeks' GA.30,4042

Plasma levels of ACTH were measured by a solid-phase 2-site immunoradiometric assay using human ACTH antibodies with nonsignificant cross-reactivity with β-endorphin and ACTH fragments, and with reported detection limits of 1.0 pg/mL (Nichols Institute Diagnostics, San Juan Capistrano, California) (to convert ACTH to picomoles per liter, multiply by 0.22). Briefly, 200-μL samples combined with 100 μL of ACTH-labeled antibody and a coated bead were incubated at room temperature for a mean (SD) of 20 (1) hours. The bound radiolabeled antibody complex was quantified using the gamma counter. Intra-assay and interassay coefficients of variation were 4.4% and 10.8%, respectively.

Plasma cortisol levels were determined using a competitive antibody-coated tube radioimmunoassay with reported sensitivity of 0.22 μg/dL (American Laboratory Products Company, Windham, New Hampshire) (to convert cortisol to nanomoles per liter, multiply by 27.588). Plasma samples (25 μL) were incubated with 500 μL of 125I-labeled cortisol in antibody-coated tubes for 45 minutes in a 37°C water bath. The aspirated radiolabeled antibody-bound labeled tubes were counted on a gamma counter. Cross-reactivities of the cortisol assay were less than 5% with 11-deoxycortisol, cortisone, and prednisone, and less than 1% with other steroids. Intra-assay and interassay coefficients of variation were 7% and 11%, respectively.

Concentrations of CRH, ACTH, and cortisol were interpolated from standard curves computed by a 4-parameter logistics program.44

ASSESSMENT OF DEPRESSIVE SYMPTOMS

Depressive symptoms were assessed 4 times during pregnancy with a 9-item version of the Center for Epidemiological Studies–Depression Scale (CES-D).45 On a 4-point scale, participants indicated how often they experienced a symptom during the past week. Because validation analyses show higher associations with the Structured Interview for DSM-III-R when items are rescored into a bivariate score,45 each item was scored 0 if option 0 or 1 was endorsed, and was scored 1 if option 2 or 3 was endorsed. Bivariate scores ranged between 0 and 9, with a suggested cutoff score of 4 or more. This scale has good internal consistency (Kuder-Richardson formula 20, 0.87), and the scores correlate highly with the original scale (r = 0.97).

At the postpartum visit, participants completed the 10-item Edinburgh Postnatal Depression Scale (EPDS),46 a scale specifically developed to assess postpartum depressive symptoms. Participants indicated how often they experienced a symptom in the past week on a 4-point scale. Total scores ranged from 0 to 30. A cutoff score of 10 or more has been suggested by the authors of the EPDS for studies including minor depression46 and has been confirmed in other studies.47 The scale has good reliability (split-half, 0.88; standardized α = .87).46

STATISTICAL ANALYSIS

All pCRH, cortisol, and ACTH levels were log transformed to reduce skewness. Pearson product moment correlations were performed to test for associations between relevant variables. The time of day of the blood draw was covaried when appropriate and in no case changed the significance of the results.

Variables that were significantly correlated with PPD symptoms were included in a stepwise linear regression model, and the model fit (adjusted R2), the change in R2, and the regression coefficient β are reported. Emerging significant predictors were included in a hierarchical linear regression model to assess the unique and separate contributions of each variable. A series of ancillary analyses (2-tailed, independent samples t tests and χ2 tests) revealed no evidence that sociodemographic (ethnicity, marital status, education, and household income) or pregnancy-related variables (birth weight, length of gestation, infant sex, mode of delivery, and parity) were significantly associated with PPD symptoms (for all associations, χ2 < 9.33 [P > .38] and t < 1.00 [P > .32]), with the exception of maternal age (t98 = 2.58 [P = .01]). Controlling for maternal age, however, did not change the significance of the results. At the postpartum visit, no association was found between the number of weeks since delivery and PPD symptoms (t = 1.33 [P = .19]).

The sample was then divided into women with and without PPD symptoms (Table 1 lists the sample characteristics). Receiver operating characteristic (ROC) curves were computed to assess sensitivity and specificity of relevant variables as potential diagnostic markers for PPD symptoms. For this analysis, non–log-transformed pCRH values were used to provide practical guidelines for actual pCRH cutoff scores. The areas under the ROC curve (AUCs) were computed to compare the usefulness of each diagnostic test. The AUC values can range from 0.5 to 1.0, with 1.0 indicating a perfect test. The Youden index (sensitivity + [specificity − 1]) was computed to obtain an optimal cutoff score. The Youden index can range from −1 to 1, with 1 indicating a perfect test.48,49 Positive and negative predictive values (PPV and NPV, respectively) were computed to express the probability that PPD is present when the test is positive (PPV) and absent when the test is negative (NPV) at the optimal cutoff.

Table Graphic Jump LocationTable 1. Sample Characteristics for Women With and Without PPD Symptomsa

To estimate when differences in pCRH emerge as a predictor of PPD symptoms, multilevel modeling techniques (HLM 6)50 were used. First, an unconditional means model was computed to assess how much variance in pCRH can be attributed to between-subject (99.6%) and within-subject (0.4%) variation. Two unconditional growth models were then computed to assess the linear (coefficient, 18.48; SE, 1.07 [P < .001]) and quadratic (0.85; 0.13 [P < .001]) effects of time (level 1 predictor) on pCRH, which explained 68.9% and 80.4% of the variance, respectively. A comparison of the deviance scores revealed that the quadratic model fit the data significantly better than the linear model (χ23 = 137.04 [P < .001]). Postpartum depressive symptoms (coded 0 for no and 1 for yes) were then included as a level 2 predictor into a series of quadratic models that tested differences in the intercept and the instantaneous rate of change at each GA within the range of actual pCRH assessments available (12-39 weeks' GA). The error term was allowed to vary randomly in each equation.

DESCRIPTIVES

Consistent with earlier reports, pCRH increased significantly throughout pregnancy (F3.4,332.5 = 586.83 [P < .001]; η2 = 0.86). Likewise, significant increases in cortisol (F3.8,370.3 = 160.92 [P < .001]; η2 = 0.62) and ACTH (F3.5,351.4 = 186.63 [P < .001]; η2 = 0.65) were observed. Depressive symptoms did not change throughout pregnancy (F2.8,276.5 = 1.30 [P = .28]).

PREDICTORS OF PPD SYMPTOMS

At no time during pregnancy were any of the endocrine measures significantly associated with concurrent depressive symptoms (pCRH, r = 0.02 to r = 0.15 [P > .14 for all comparisons]; ACTH, r = −0.01 to r = −0.16 [P > .12 for all comparisons]; and cortisol, r = −0.002 to r = −0.06 [P > .53 for all comparisons]). However, when pCRH, ACTH, cortisol, and CES-D scores at each time point during pregnancy were correlated with PPD symp-toms (Table 2), significant correlations emerged for pCRH at 25 and 31 weeks' GA, for ACTH at 25 weeks' GA, and for CES-D scores at 19, 25, 31, and 37 weeks' GA. The 2 strongest associations (pCRH and CES-D scores at 25 weeks' GA) are depicted in Figure 1. These correlational analyses suggest no significant association between HPA axis hormones and depressive symptoms when assessed concurrently and provide evidence that HPA axis hormones (in midpregnancy) and depressive symptoms (throughout pregnancy) are significant predictors of PPD symptoms.

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Figure 1.

Relation of placental corticotropin-releasing hormone (CRH) (A) and Center for Epidemiological Studies–Depression (CES-D) scores (B) at 25 weeks' gestational age to scores on the Edinburgh Postnatal Depression Scale (EPDS).

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Table Graphic Jump LocationTable 2. Correlation Between pCRH, ACTH, and Cortisol Levels and CES-D Scores at Each GA With PPD Symptoms

To assess which variables are the strongest predictors of PPD symptoms, all variables that were significantly correlated with PPD symptoms (pCRH at 25 and 31 weeks' GA, ACTH at 25 weeks' GA, and CES-D scores at 19, 25, 31, and 37 weeks' GA) were included in a stepwise linear regression. Elevated pCRH at 25 weeks' GA emerged as the strongest predictor for PPD symptoms (step 1: R2 = 0.21; β = 0.46 [P < .001]). The prediction of PPD symptoms was improved by including CES-D scores at 25 weeks' GA into the model, accounting for 7% additional variance (step 2: βCRH = 0.42; βCES-D = 0.26 [P < .001]), whereas the influence of all other variables was not statistically significant. Because pCRH at 25 weeks' GA emerged as the best predictor, a hierarchical linear regression was performed to test the unique predictive value of pCRH on PPD symptoms after controlling for CES-D scores at this time point. After CES-D scores were entered into the model in step 1, pCRH was still a significant and independent predictor of PPD symptoms (step 2: R2 change = 0.17 [P < .001]). This further indicates that pCRH and CES-D scores explain different portions of the variance in the risk of developing PPD symptoms.

pCRH LEVELS AND CES-D SCORES AS DIAGNOSTIC TESTS FOR PPD SYMPTOMS

To test whether pCRH and CES-D scores at 25 weeks' GA may be useful diagnostic tests for PPD symptoms, the sample was divided into women with (n = 16) and without (n = 84) PPD symptoms. An ROC curve for pCRH was computed, and the AUC was 0.78 (95% confidence interval [CI], 0.65-0.91 [P = .001]), suggesting that at this time point pCRH is a moderate predictor of PPD (Figure 2A). The AUCs were lower at all other time points (15 weeks, 0.53 [P = .74]; 19 weeks, 0.62 [P = .14]; 31 weeks, 0.66 [P = .04]; 37 weeks, 0.61 [P = .17]). The optimal cutoff score for pCRH at 25 weeks' GA (Youden index, 0.51) was 56.86 pg/mL. At this cutoff, 75.0% of cases would have been correctly identified (sensitivity) (95% CI, 47.6%-92.6%), whereas in 23.8% of euthymic women PPD symptoms would have been falsely predicted (1 − specificity) (95% CI, 15.2%-34.4%). The PPV was 37.5% (95% CI, 21.1%-56.3%) and the NPV was 94.1% (85.6%-98.3%). Sensitivity and specificity for all possible cutoff scores are shown in Figure 2B.

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Figure 2.

Receiver operating characteristic (ROC) curve (A) and sensitivity and specificity at each possible cutoff point (B) for placental corticotropin-releasing hormone (CRH) at 25 weeks' gestation. The Youden index is calculated as sensitivity + (specificity − 1). Sensitivity indicates the probability that a case is correctly identified (true positive), and 1 − specificity is the probability that a nonsymptomatic subject is falsely identified as a case (false positive). AUC indicates the area under the ROC curve.

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The ROC analyses for CES-D scores at 25 weeks' GA showed that this measure was a similarly strong predictor of PPD symptoms (AUC = 0.77 [P = .001]; 95% CI, 0.65-0.89) (Figure 3A), confirming previous research that identified depression during pregnancy as an important predictor. In contrast to the ROC analyses for pCRH levels, the AUCs for depressive symptoms were significant for all other time points (19 weeks, 0.80 [P < .001]; 31 weeks, 0.71 [P = .009]; 37 weeks, 0.69 [P = .02]), suggesting that the predictive value of depressive symptoms is not specific to midpregnancy. At 25 weeks' GA, the optimal CES-D cutoff score (Youden index, 0.45) was 1.5. With this cutoff (ie, an actual score of ≥2 because CES-D scores have no decimals), 87.5% (95% CI, 61.6%-98.1%) of women with PPD symptoms would have been correctly identified; however, 42.9% (95% CI, 32.1%-54.1%) of women without future PPD symptoms would have been misclassified. The PPV was 28.0% (95% CI, 16.2%-42.5%) and the NPV was 96.0% (95% CI, 86.3%-99.4%). Sensitivity and specificity for all possible cutoff scores are shown in Figure 3B. At the ideal cutoff points, the CES-D is the more sensitive diagnostic test (CES-D score vs pCRH, 88% vs 75%), whereas pCRH is more specific (pCRH vs CES-D score, 76% vs 57%) for the detection of PPD symptoms.

Place holder to copy figure label and caption
Figure 3.

Receiver operating characteristic (ROC) curve (A) and sensitivity and specificity at each possible cutoff point (B) for Center for Epidemiological Studies–Depression (CES-D) scores at 25 weeks' gestation. The Youden index and sensitivity and specificity are defined in the legend to Figure 2. AUC indicates the area under the ROC curve.

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TIME-SENSITIVE PERIODS FOR THE PREDICTION OF PPD SYMPTOMS

The analyses in the previous section suggest that the predictive value of pCRH for PPD symptoms may be limited to midpregnancy. With hierarchical linear modeling analyses, it is possible to model increases in pCRH throughout pregnancy and to estimate (1) the time range during which the instantaneous rate of change in pCRH predicts PPD symptoms and (2) the earliest time during gestation that differences in pCRH predict PPD symptoms. The growth curve analysis suggests that the instantaneous rate of changein pCRH in women with PPD symptoms is significantly accelerated from 23 to 26 weeks' GA (coefficients, 4.62-5.86; SE, 2.31-2.86 [P < .05 for all comparisons]), with a nonsignificant trend for weeks 22, 27, and 28 (P < .10 for all comparisons), compared with women without PPD symptoms (Figure 4). No differences in the instantaneous rate of change could be detected before 22 or after 28 weeks' GA. Significant differences in the levels of pCRH emerge at 18 weeks' GA (coefficient, 4.67; SE, 1.84 [P = .01]) and increase throughout pregnancy, with the greatest differences at 39 weeks' GA (coefficient, 38.79; SE, 4.43 [P < .001]). These data suggest that it is the rate of change in pCRH at about 25 weeks' GA, the time when differences in pCRH start to emerge, that makes some women more vulnerable to the development of PPD symptoms, and that pCRH in these women then remains at an accelerated trajectory until delivery.

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Figure 4.

Placental corticotropin-releasing hormone (CRH) across gestational ages in women with and without later postpartum depressive (PPD) symptoms. The gray shaded area indicates the gestational ages during which the instantaneous rate of change in placental CRH significantly predicts PPD symptoms (23-26 weeks' gestational age).

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These data are, to our knowledge, the first to suggest a sensitive period in midpregnancy during which pCRH, as measured in maternal plasma, is a moderate and independent predictor of PPD symptoms. We propose that pCRH during this period may serve as a sensitive and specific early diagnostic test to identify women at high risk for developing PPD symptoms. Our data also suggest that the predictive power of pCRH during this period can be further increased by assessing midpregnancy depressive symptoms.

Our data indicate that pCRH is a possible diagnostic tool to identify women at risk for the development of PPD symptoms. This is plausible from a neuroendocrine point of view. The postpartum period is characterized by a transient blunting of hypothalamic CRH secretion, which has been implicated in the pathophysiologic mechanisms of PPD.25,28 Consistent with this view, it has been shown that women who develop PPD show a more pronounced and longer-lasting suppression of ACTH responses to stimulation with exogenous (ovine) CRH within the first 12 weeks post partum, compared with women who remain euthymic.26 Our data now provide evidence that the HPA- placental system is already dysregulated during pregnancy among women at risk for PPD symptoms, such that they show accelerated pCRH increases. This is clinically relevant because the assessment of pCRH in maternal blood may provide a method to identify women at risk for PPD symptoms, months before symptoms occur.

Placental CRH in this study was a moderately sensitive and specific marker for PPD symptoms that allows for the correct identification of 75% of women with future PPD symptoms, and at the same time was characterized by a low misclassification rate (24%). The strength of pCRH as a diagnostic test for an early detection of PPD symptoms is indicated by an AUC of 0.78 at 25 weeks' GA. This association is high given that (1) a single endocrine marker was used to predict PPD symptoms and (2) the AUC for depressive symptoms, which are among the strongest and most consistently identified predictors of PPD in the previous literature,6,7 is almost identical (0.77).

Our data also show that elevated pCRH but not cortisol or ACTH is a significant predictor of PPD symptoms (except for a correlation between ACTH at 25 weeks' GA and PPD symptoms that did not remain significant in the regression analyses). Few studies have investigated the link between cortisol or ACTH during pregnancy and PPD symptoms. Results are mixed, but the clearest evidence for an existing association comes from studies that have assessed the stimulated activity of these hormones.26,5153 In our study, however, baseline measures of cortisol and ACTH were used, which may explain the lack of association we found.

Remarkably, pCRH is an independent predictor of PPD symptoms. Placental CRH at 25 weeks' GA has unique and significant predictive value for PPD symptoms, even after controlling for concurrent depressive symptoms. It indicates that assessing pCRH allows the identification of women at risk for developing PPD symptoms who would not be identified on the basis of self-reports of depressive symptoms during pregnancy. This is plausible because hormone measures are independent of a woman's willingness to disclose feelings of depression. Thus, the combined assessment of both markers may be an ideal strategy for identifying women at risk for the development of PPD symptoms.

Depressive symptoms at each time point during gestation are associated with PPD symptoms; however, the predictive value of pCRH for PPD symptoms is time sensitive and is maximized during midpregnancy (23-26 weeks' GA). The emergence of pCRH as a predictor of PPD symptoms around this time roughly coincides with a marked surge in pCRH.22,42 Detrimental influences at the time of this initial surge may slightly accelerate the exponential trajectory of pCRH, resulting in marked differences in pCRH toward the end of gestation. We do not know which factors may precipitate the surge in pCRH, but some evidence suggests an association between elevated cortisol early in pregnancy and increased pCRH late in pregnancy.42

To our knowledge, only one other study has addressed the link between pCRH and PPD symptoms, and that study suggests a lack of association.12 In that study, pCRH was assessed once within a wide range of GAs (24.6-37.4 weeks). Major changes occur in pCRH levels across pregnancy, and pCRH is characterized by significant individual differences.22 It is possible that we found an effect because we were able to take advantage of a longitudinal study design. In addition, PPD symptoms in our study were assessed nearer to parturition, at about 9 weeks after delivery, compared with 6 months post partum. These differences in timing may also explain, at least in part, our different results.

Although pCRH in our sample emerged as a strong predictor of PPD symptoms, at no time point was it associated with concurrent depressive symptoms. Two other studies have investigated this association: one suggested a positive correlation12 and the other suggested a negative correlation54 between pCRH and concurrent depressive symptoms. These conflicting results could be explained by differences in maternal age (in one of the studies, teenage pregnancies were studied54), GA at assessment, GA at delivery, and measures of depressive symptoms across studies.

There is clear evidence that pCRH predicts the length of gestation.22,3134 It is a strength of this study that our sample consists of women with full-term deliveries (except for 3 women who delivered between 36.5 and 37.0 weeks' GA), and that GAs at delivery were almost identical in women with and without PPD symptoms. Because pCRH predicts the length of gestation, and because we herein show that pCRH predicts PPD symptoms in a sample of women who delivered at full term, future research should investigate the link between pCRH and PPD symptoms in a sample including preterm deliveries.

There are 2 notable limitations to this study. First, our assessment of PPD symptoms relies on a self-report questionnaire and not on a clinical diagnosis. However, validation studies of the EPDS with the same cutoff score used in our report document a high sensitivity (DSM-III criteria, 100%55 and Research Diagnostic Criteria, 89%56) and specificity (DSM-III and Research Diagnostic Criteria, 82%55,56) of this measure. Because of the quality of this measure, we are fairly confident that our results reflect clinically significant symptoms of depression. We acknowledge, however, the importance of replicating our findings using further diagnostic instruments. Second, although we controlled for depressive symptoms in the index pregnancy, we did not have information about a lifetime history of depression. Although it is reasonable to assume that the effects of current depressive symptoms would be much stronger than any additional variance explained by a history of depression, the general importance of this variable as a predictor of PPD is evident.6,7 Future research, ideally prospective in nature, is needed to explain the importance of this variable.

Our study has important clinical and theoretical implications. If our results are replicable, it may be considered useful to implement a pCRH PPD screen into standard prenatal care. Because blood draws to screen for gestational diabetes are typically performed at 24 to 28 weeks' GA,57 a potential PPD screen could be completed at the same time. In addition, a better understanding of the role of pCRH in the pathophysiologic mechanism leading to PPD may contribute to the development of preventions targeted at this rather common disorder.

Correspondence: Ilona S. Yim, PhD, Department of Psychology and Social Behavior, 3340 Social Ecology II, University of California, Irvine, Irvine, CA 92697-7085 (ilona.yim@uci.edu).

Submitted for Publication: March 7, 2008; final revision received July 15, 2008; accepted September 10, 2008.

Financial Disclosure: None reported.

Funding/Support: This study was supported by the US Public Health Service (National Institutes of Health) research awards HD28413 and HD51852 from the National Institute of Child Health and Human Development (Dr Sandman).

Previous Presentation: Portions of the data in this manuscript were presented at the Fifth International Congress on Developmental Origins of Health and Disease; November 7, 2007; Perth, Australia.

Additional Information: Dr Hobel holds the Miriam Jacobs Chair in the Division of Maternal-Fetal Medicine at Cedars-Sinai Medical Center.

Brockington  I Postpartum psychiatric disorders. Lancet 2004;363 (9405) 303- 310
PubMed Link to Article
World Health Organization, International Statistical Classification of Diseases, 10th Revision (ICD-10).  Geneva, Switzerland World Health Organization1992;
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC American Psychiatric Association1994;
Grace  SLEvindar  AStewart  DE The effect of postpartum depression on child cognitive development and behavior: a review and critical analysis of the literature. Arch Womens Ment Health 2003;6 (4) 263- 274
PubMed Link to Article
Gavin  NIGaynes  BNLohr  KNMeltzer-Brody  SGartlehner  GSwinson  T Perinatal depression: a systematic review of prevalence and incidence. Obstet Gynecol 2005;106 (5, pt 1) 1071- 1083
PubMed Link to Article
Beck  CT Predictors of postpartum depression: an update. Nurs Res 2001;50 (5) 275- 285
PubMed Link to Article
Robertson  EGrace  SWallington  TStewart  DE Antenatal risk factors for postpartum depression: a synthesis of recent literature. Gen Hosp Psychiatry 2004;26 (4) 289- 295
PubMed Link to Article
Bloch  MDaly  RCRubinow  DR Endocrine factors in the etiology of postpartum depression. Compr Psychiatry 2003;44 (3) 234- 246
PubMed Link to Article
Bloch  MRotenberg  NKoren  DKlein  E Risk factors for early postpartum depressive symptoms. Gen Hosp Psychiatry 2006;28 (1) 3- 8
PubMed Link to Article
O’Hara  MWSchlechte  JALewis  DAVarner  MW Controlled prospective study of postpartum mood disorders: psychological, environmental, and hormonal variables. J Abnorm Psychol 1991;100 (1) 63- 73
PubMed Link to Article
Vale  WRivier  CBrown  MRSpiess  JKoob  GSwanson  LBilezikjian  LBloom  FRivier  J Chemical and biological characterization of corticotropin releasing factor. Recent Prog Horm Res 1983;39245- 270
PubMed
Rich-Edwards  JWMohllajee  APKleinman  KHacker  MRMajzoub  JWright  RJGillman  MW Elevated midpregnancy corticotropin-releasing hormone is associated with prenatal, but not postpartum, maternal depression. J Clin Endocrinol Metab 2008;93 (5) 1946- 1951
PubMed Link to Article
Nemeroff  CBVale  WW The neurobiology of depression: inroads to treatment and new drug discovery. J Clin Psychiatry 2005;66 ((suppl 7)) 5- 13
PubMed Link to Article
Raadsheer  FCHoogendijk  WJStam  FCTilders  FJSwaab  DF Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology 1994;60 (4) 436- 444
PubMed Link to Article
Raadsheer  FCvan Heerikhuize  JJLucassen  PJHoogendijk  WJTilders  FJSwaab  DF Corticotropin-releasing hormone mRNA levels in the paraventricular nucleus of patients with Alzheimer's disease and depression. Am J Psychiatry 1995;152 (9) 1372- 1376
PubMed
Bao  AMMeynen  GSwaab  DF The stress system in depression and neurodegeneration: focus on the human hypothalamus. Brain Res Rev 2008;57 (2) 531- 553
PubMed Link to Article
Smith  SMVale  WW The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci 2006;8 (4) 383- 395
PubMed
Sasaki  ALiotta  ASLuckey  MMMargioris  ANSuda  TKrieger  DT Immunoreactive corticotropin-releasing factor is present in human maternal plasma during the third trimester of pregnancy. J Clin Endocrinol Metab 1984;59 (4) 812- 814
PubMed Link to Article
Shibasaki  TOdagiri  EShizume  KLing  N Corticotropin-releasing factor–like activity in human placental extracts. J Clin Endocrinol Metab 1982;55 (2) 384- 386
PubMed Link to Article
Petraglia  FFlorio  PNappi  CGenazzani  AR Peptide signaling in human placenta and membranes: autocrine, paracrine, and endocrine mechanisms. Endocr Rev 1996;17 (2) 156- 186
PubMed
Florio  PZatelli  MCReis  FMdegli Uberti  ECPetraglia  F Corticotropin releasing hormone: a diagnostic marker for behavioral and reproductive disorders? Front Biosci January2007;12551- 560
PubMed Link to Article
McLean  MBisits  ADavies  JWoods  RLowry  PSmith  R A placental clock controlling the length of human pregnancy. Nat Med 1995;1 (5) 460- 463
PubMed Link to Article
Lowry  PJ Corticotropin-releasing factor and its binding protein in human plasma. Ciba Found Symp 1993;172108- 128
PubMed
Hochberg  ZPacak  KChrousos  GP Endocrine withdrawal syndromes. Endocr Rev 2003;24 (4) 523- 538
PubMed Link to Article
Chrousos  GPTorpy  DJGold  PW Interactions between the hypothalamic-pituitary-adrenal axis and the female reproductive system: clinical implications. Ann Intern Med 1998;129 (3) 229- 240
PubMed Link to Article
Magiakou  MAMastorakos  GRabin  DDubbert  BGold  PWChrousos  GP Hypothalamic corticotropin-releasing hormone suppression during the postpartum period: implications for the increase in psychiatric manifestations at this time. J Clin Endocrinol Metab 1996;81 (5) 1912- 1917
PubMed
Halbreich  U The association between pregnancy processes, preterm delivery, low birth weight, and postpartum depressions: the need for interdisciplinary integration. Am J Obstet Gynecol 2005;193 (4) 1312- 1322
PubMed Link to Article
Vitoratos  NPapatheodorou  DCKalantaridou  SNMastorakos  G “Reproductive” corticotropin-releasing hormone. Ann N Y Acad Sci 2006;1092310- 318
PubMed Link to Article
Kammerer  MTaylor  AGlover  V The HPA axis and perinatal depression: a hypothesis. Arch Womens Ment Health 2006;9 (4) 187- 196
PubMed Link to Article
Glynn  LMSchetter  CDChicz-DeMet  AHobel  CJSandman  CA Ethnic differences in adrenocorticotropic hormone, cortisol and corticotropin-releasing hormone during pregnancy. Peptides 2007;28 (6) 1155- 1161
PubMed Link to Article
Hobel  CJDunkel-Schetter  CRoesch  SCCastro  LCArora  CP Maternal plasma corticotropin-releasing hormone associated with stress at 20 weeks' gestation in pregnancies ending in preterm delivery. Am J Obstet Gynecol 1999;180 (1, pt 3) S257- S263
PubMed Link to Article
Leung  TNChung  TKMadsen  GLam  PKSahota  DSmith  R Rate of rise in maternal plasma corticotrophin-releasing hormone and its relation to gestational length. BJOG 2001;108 (5) 527- 532
PubMed
Holzman  CJetton  JSiler-Khodr  TFisher  RRip  T Second trimester corticotropin-releasing hormone levels in relation to preterm delivery and ethnicity. Obstet Gynecol 2001;97 (5, pt 1) 657- 663
PubMed Link to Article
Wadhwa  PDGarite  TJPorto  MGlynn  LChicz-DeMet  ADunkel-Schetter  CSandman  CA Placental corticotropin-releasing hormone (CRH), spontaneous preterm birth, and fetal growth restriction: a prospective investigation. Am J Obstet Gynecol 2004;191 (4) 1063- 1069
PubMed Link to Article
Ahmed  IGlynn  BPPerkins  AVCastro  MGRowe  JMorrison  ELinton  EA Processing of procorticotropin-releasing hormone (pro-CRH): molecular forms of CRH in normal and preeclamptic pregnancy. J Clin Endocrinol Metab 2000;85 (2) 755- 764
PubMed
Goland  RSConwell  IMJozak  S The effect of pre-eclampsia on human placental corticotrophin-releasing hormone content and processing. Placenta 1995;16 (4) 375- 382
PubMed Link to Article
Florio  PImperatore  ASanseverino  FTorricelli  MReis  FMLowry  PJPetraglia  F The measurement of maternal plasma corticotropin-releasing factor (CRF) and CRF-binding protein improves the early prediction of preeclampsia. J Clin Endocrinol Metab 2004;89 (9) 4673- 4677
PubMed Link to Article
Goland  RSJozak  SWarren  WBConwell  IMStark  RITropper  PJ Elevated levels of umbilical cord plasma corticotropin-releasing hormone in growth-retarded fetuses. J Clin Endocrinol Metab 1993;77 (5) 1174- 1179
PubMed
Giles  WBMcLean  MDavies  JJSmith  R Abnormal umbilical artery Doppler waveforms and cord blood corticotropin-releasing hormone. Obstet Gynecol 1996;87 (1) 107- 111
PubMed Link to Article
Ellman  LMDunkel Schetter  CHobel  CJChicz-DeMet  AGlynn  LMSandman  CA Timing of fetal exposure to stress hormones: effects on newborn physical and neuromuscular maturation. Dev Psychobiol 2008;50 (3) 232- 241
PubMed Link to Article
Davis  EPGlynn  LMDunkel Schetter  CHobel  CChicz-Demet  ASandman  CA Corticotropin-releasing hormone during pregnancy is associated with infant temperament. Dev Neurosci 2005;27 (5) 299- 305
PubMed Link to Article
Sandman  CAGlynn  LSchetter  CDWadhwa  PGarite  TChicz-DeMet  AHobel  C Elevated maternal cortisol early in pregnancy predicts third trimester levels of placental corticotropin releasing hormone (CRH): priming the placental clock. Peptides 2006;27 (6) 1457- 1463
PubMed Link to Article
Linton  EAPerkins  AVHagan  PPoole  SBristow  AFTilders  FCorder  RWolfe  CD Corticotrophin-releasing hormone (CRH)-binding protein interference with CRH antibody binding: implications for direct CRH immunoassay. J Endocrinol 1995;146 (1) 45- 53
PubMed Link to Article
Rodbard  DHutt  D Statistical analysis of radioimmunoassays and immunoradiometric (labeled antibody) assays. Rodbard  DHutt  DProceedings, Symposium on Radioimmunoassays and Related Procedures in Medicine. Vol 1. Vienna, Austria International Atomic Energy Agency1974;165- 192
Santor  DACoyne  JC Shortening the CES-D to improve its ability to detect cases of depression. Psychol Assess 1997;9 (3) 233- 243
Link to Article
Cox  JLHolden  JMSagovsky  R Detection of postnatal depression: development of the 10-item Edinburgh Postnatal Depression Scale. Br J Psychiatry June1987;150782- 786
PubMed Link to Article
Matthey  SHenshaw  CElliott  SBarnett  B Variability in use of cut-off scores and formats on the Edinburgh Postnatal Depression Scale: implications for clinical and research practice. Arch Womens Ment Health 2006;9 (6) 309- 315
PubMed Link to Article
Hilden  JGlasziou  P Regret graphs, diagnostic uncertainty and Youden's index. Stat Med 1996;15 (10) 969- 986
PubMed Link to Article
Youden  WJ Index for rating diagnostic tests. Cancer 1950;3 (1) 32- 35
PubMed Link to Article
Raudenbush  SWBryk  ASCheong  YFCongdon  RT  Jr HLM 6: Hierarchical Linear Modeling.  Lincolnwood, IL Scientific Software International2004;
Nierop  ABratsikas  AZimmermann  REhlert  U Are stress-induced cortisol changes during pregnancy associated with postpartum depressive symptoms? Psychosom Med 2006;68 (6) 931- 937
PubMed Link to Article
Handley  SLDunn  TLWaldron  GBaker  JM Tryptophan, cortisol and puerperal mood. Br J Psychiatry 1980;136498- 508
PubMed Link to Article
Okano  TNomura  J Endocrine study of the maternity blues. Prog Neuropsychopharmacol Biol Psychiatry 1992;16 (6) 921- 932
PubMed Link to Article
Schmeelk  KHGranger  DASusman  EJChrousos  GP Maternal depression and risk for postpartum complications: role of prenatal corticotropin-releasing hormone and interleukin-1 receptor antagonist. Behav Med 1999;25 (2) 88- 94
PubMed Link to Article
Harris  BHuckle  PThomas  RJohns  SFung  H The use of rating scales to identify post-natal depression. Br J Psychiatry 1989;154813- 817
PubMed Link to Article
Murray  LCarothers  AD The validation of the Edinburgh Postnatal Depression Scale on a community sample. Br J Psychiatry 1990;157288- 290
PubMed Link to Article
Hollander  MHPaarlberg  KMHuisjes  AJ Gestational diabetes: a review of the current literature and guidelines. Obstet Gynecol Surv 2007;62 (2) 125- 136
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Relation of placental corticotropin-releasing hormone (CRH) (A) and Center for Epidemiological Studies–Depression (CES-D) scores (B) at 25 weeks' gestational age to scores on the Edinburgh Postnatal Depression Scale (EPDS).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Receiver operating characteristic (ROC) curve (A) and sensitivity and specificity at each possible cutoff point (B) for placental corticotropin-releasing hormone (CRH) at 25 weeks' gestation. The Youden index is calculated as sensitivity + (specificity − 1). Sensitivity indicates the probability that a case is correctly identified (true positive), and 1 − specificity is the probability that a nonsymptomatic subject is falsely identified as a case (false positive). AUC indicates the area under the ROC curve.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Receiver operating characteristic (ROC) curve (A) and sensitivity and specificity at each possible cutoff point (B) for Center for Epidemiological Studies–Depression (CES-D) scores at 25 weeks' gestation. The Youden index and sensitivity and specificity are defined in the legend to Figure 2. AUC indicates the area under the ROC curve.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Placental corticotropin-releasing hormone (CRH) across gestational ages in women with and without later postpartum depressive (PPD) symptoms. The gray shaded area indicates the gestational ages during which the instantaneous rate of change in placental CRH significantly predicts PPD symptoms (23-26 weeks' gestational age).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Sample Characteristics for Women With and Without PPD Symptomsa
Table Graphic Jump LocationTable 2. Correlation Between pCRH, ACTH, and Cortisol Levels and CES-D Scores at Each GA With PPD Symptoms

References

Brockington  I Postpartum psychiatric disorders. Lancet 2004;363 (9405) 303- 310
PubMed Link to Article
World Health Organization, International Statistical Classification of Diseases, 10th Revision (ICD-10).  Geneva, Switzerland World Health Organization1992;
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC American Psychiatric Association1994;
Grace  SLEvindar  AStewart  DE The effect of postpartum depression on child cognitive development and behavior: a review and critical analysis of the literature. Arch Womens Ment Health 2003;6 (4) 263- 274
PubMed Link to Article
Gavin  NIGaynes  BNLohr  KNMeltzer-Brody  SGartlehner  GSwinson  T Perinatal depression: a systematic review of prevalence and incidence. Obstet Gynecol 2005;106 (5, pt 1) 1071- 1083
PubMed Link to Article
Beck  CT Predictors of postpartum depression: an update. Nurs Res 2001;50 (5) 275- 285
PubMed Link to Article
Robertson  EGrace  SWallington  TStewart  DE Antenatal risk factors for postpartum depression: a synthesis of recent literature. Gen Hosp Psychiatry 2004;26 (4) 289- 295
PubMed Link to Article
Bloch  MDaly  RCRubinow  DR Endocrine factors in the etiology of postpartum depression. Compr Psychiatry 2003;44 (3) 234- 246
PubMed Link to Article
Bloch  MRotenberg  NKoren  DKlein  E Risk factors for early postpartum depressive symptoms. Gen Hosp Psychiatry 2006;28 (1) 3- 8
PubMed Link to Article
O’Hara  MWSchlechte  JALewis  DAVarner  MW Controlled prospective study of postpartum mood disorders: psychological, environmental, and hormonal variables. J Abnorm Psychol 1991;100 (1) 63- 73
PubMed Link to Article
Vale  WRivier  CBrown  MRSpiess  JKoob  GSwanson  LBilezikjian  LBloom  FRivier  J Chemical and biological characterization of corticotropin releasing factor. Recent Prog Horm Res 1983;39245- 270
PubMed
Rich-Edwards  JWMohllajee  APKleinman  KHacker  MRMajzoub  JWright  RJGillman  MW Elevated midpregnancy corticotropin-releasing hormone is associated with prenatal, but not postpartum, maternal depression. J Clin Endocrinol Metab 2008;93 (5) 1946- 1951
PubMed Link to Article
Nemeroff  CBVale  WW The neurobiology of depression: inroads to treatment and new drug discovery. J Clin Psychiatry 2005;66 ((suppl 7)) 5- 13
PubMed Link to Article
Raadsheer  FCHoogendijk  WJStam  FCTilders  FJSwaab  DF Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology 1994;60 (4) 436- 444
PubMed Link to Article
Raadsheer  FCvan Heerikhuize  JJLucassen  PJHoogendijk  WJTilders  FJSwaab  DF Corticotropin-releasing hormone mRNA levels in the paraventricular nucleus of patients with Alzheimer's disease and depression. Am J Psychiatry 1995;152 (9) 1372- 1376
PubMed
Bao  AMMeynen  GSwaab  DF The stress system in depression and neurodegeneration: focus on the human hypothalamus. Brain Res Rev 2008;57 (2) 531- 553
PubMed Link to Article
Smith  SMVale  WW The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci 2006;8 (4) 383- 395
PubMed
Sasaki  ALiotta  ASLuckey  MMMargioris  ANSuda  TKrieger  DT Immunoreactive corticotropin-releasing factor is present in human maternal plasma during the third trimester of pregnancy. J Clin Endocrinol Metab 1984;59 (4) 812- 814
PubMed Link to Article
Shibasaki  TOdagiri  EShizume  KLing  N Corticotropin-releasing factor–like activity in human placental extracts. J Clin Endocrinol Metab 1982;55 (2) 384- 386
PubMed Link to Article
Petraglia  FFlorio  PNappi  CGenazzani  AR Peptide signaling in human placenta and membranes: autocrine, paracrine, and endocrine mechanisms. Endocr Rev 1996;17 (2) 156- 186
PubMed
Florio  PZatelli  MCReis  FMdegli Uberti  ECPetraglia  F Corticotropin releasing hormone: a diagnostic marker for behavioral and reproductive disorders? Front Biosci January2007;12551- 560
PubMed Link to Article
McLean  MBisits  ADavies  JWoods  RLowry  PSmith  R A placental clock controlling the length of human pregnancy. Nat Med 1995;1 (5) 460- 463
PubMed Link to Article
Lowry  PJ Corticotropin-releasing factor and its binding protein in human plasma. Ciba Found Symp 1993;172108- 128
PubMed
Hochberg  ZPacak  KChrousos  GP Endocrine withdrawal syndromes. Endocr Rev 2003;24 (4) 523- 538
PubMed Link to Article
Chrousos  GPTorpy  DJGold  PW Interactions between the hypothalamic-pituitary-adrenal axis and the female reproductive system: clinical implications. Ann Intern Med 1998;129 (3) 229- 240
PubMed Link to Article
Magiakou  MAMastorakos  GRabin  DDubbert  BGold  PWChrousos  GP Hypothalamic corticotropin-releasing hormone suppression during the postpartum period: implications for the increase in psychiatric manifestations at this time. J Clin Endocrinol Metab 1996;81 (5) 1912- 1917
PubMed
Halbreich  U The association between pregnancy processes, preterm delivery, low birth weight, and postpartum depressions: the need for interdisciplinary integration. Am J Obstet Gynecol 2005;193 (4) 1312- 1322
PubMed Link to Article
Vitoratos  NPapatheodorou  DCKalantaridou  SNMastorakos  G “Reproductive” corticotropin-releasing hormone. Ann N Y Acad Sci 2006;1092310- 318
PubMed Link to Article
Kammerer  MTaylor  AGlover  V The HPA axis and perinatal depression: a hypothesis. Arch Womens Ment Health 2006;9 (4) 187- 196
PubMed Link to Article
Glynn  LMSchetter  CDChicz-DeMet  AHobel  CJSandman  CA Ethnic differences in adrenocorticotropic hormone, cortisol and corticotropin-releasing hormone during pregnancy. Peptides 2007;28 (6) 1155- 1161
PubMed Link to Article
Hobel  CJDunkel-Schetter  CRoesch  SCCastro  LCArora  CP Maternal plasma corticotropin-releasing hormone associated with stress at 20 weeks' gestation in pregnancies ending in preterm delivery. Am J Obstet Gynecol 1999;180 (1, pt 3) S257- S263
PubMed Link to Article
Leung  TNChung  TKMadsen  GLam  PKSahota  DSmith  R Rate of rise in maternal plasma corticotrophin-releasing hormone and its relation to gestational length. BJOG 2001;108 (5) 527- 532
PubMed
Holzman  CJetton  JSiler-Khodr  TFisher  RRip  T Second trimester corticotropin-releasing hormone levels in relation to preterm delivery and ethnicity. Obstet Gynecol 2001;97 (5, pt 1) 657- 663
PubMed Link to Article
Wadhwa  PDGarite  TJPorto  MGlynn  LChicz-DeMet  ADunkel-Schetter  CSandman  CA Placental corticotropin-releasing hormone (CRH), spontaneous preterm birth, and fetal growth restriction: a prospective investigation. Am J Obstet Gynecol 2004;191 (4) 1063- 1069
PubMed Link to Article
Ahmed  IGlynn  BPPerkins  AVCastro  MGRowe  JMorrison  ELinton  EA Processing of procorticotropin-releasing hormone (pro-CRH): molecular forms of CRH in normal and preeclamptic pregnancy. J Clin Endocrinol Metab 2000;85 (2) 755- 764
PubMed
Goland  RSConwell  IMJozak  S The effect of pre-eclampsia on human placental corticotrophin-releasing hormone content and processing. Placenta 1995;16 (4) 375- 382
PubMed Link to Article
Florio  PImperatore  ASanseverino  FTorricelli  MReis  FMLowry  PJPetraglia  F The measurement of maternal plasma corticotropin-releasing factor (CRF) and CRF-binding protein improves the early prediction of preeclampsia. J Clin Endocrinol Metab 2004;89 (9) 4673- 4677
PubMed Link to Article
Goland  RSJozak  SWarren  WBConwell  IMStark  RITropper  PJ Elevated levels of umbilical cord plasma corticotropin-releasing hormone in growth-retarded fetuses. J Clin Endocrinol Metab 1993;77 (5) 1174- 1179
PubMed
Giles  WBMcLean  MDavies  JJSmith  R Abnormal umbilical artery Doppler waveforms and cord blood corticotropin-releasing hormone. Obstet Gynecol 1996;87 (1) 107- 111
PubMed Link to Article
Ellman  LMDunkel Schetter  CHobel  CJChicz-DeMet  AGlynn  LMSandman  CA Timing of fetal exposure to stress hormones: effects on newborn physical and neuromuscular maturation. Dev Psychobiol 2008;50 (3) 232- 241
PubMed Link to Article
Davis  EPGlynn  LMDunkel Schetter  CHobel  CChicz-Demet  ASandman  CA Corticotropin-releasing hormone during pregnancy is associated with infant temperament. Dev Neurosci 2005;27 (5) 299- 305
PubMed Link to Article
Sandman  CAGlynn  LSchetter  CDWadhwa  PGarite  TChicz-DeMet  AHobel  C Elevated maternal cortisol early in pregnancy predicts third trimester levels of placental corticotropin releasing hormone (CRH): priming the placental clock. Peptides 2006;27 (6) 1457- 1463
PubMed Link to Article
Linton  EAPerkins  AVHagan  PPoole  SBristow  AFTilders  FCorder  RWolfe  CD Corticotrophin-releasing hormone (CRH)-binding protein interference with CRH antibody binding: implications for direct CRH immunoassay. J Endocrinol 1995;146 (1) 45- 53
PubMed Link to Article
Rodbard  DHutt  D Statistical analysis of radioimmunoassays and immunoradiometric (labeled antibody) assays. Rodbard  DHutt  DProceedings, Symposium on Radioimmunoassays and Related Procedures in Medicine. Vol 1. Vienna, Austria International Atomic Energy Agency1974;165- 192
Santor  DACoyne  JC Shortening the CES-D to improve its ability to detect cases of depression. Psychol Assess 1997;9 (3) 233- 243
Link to Article
Cox  JLHolden  JMSagovsky  R Detection of postnatal depression: development of the 10-item Edinburgh Postnatal Depression Scale. Br J Psychiatry June1987;150782- 786
PubMed Link to Article
Matthey  SHenshaw  CElliott  SBarnett  B Variability in use of cut-off scores and formats on the Edinburgh Postnatal Depression Scale: implications for clinical and research practice. Arch Womens Ment Health 2006;9 (6) 309- 315
PubMed Link to Article
Hilden  JGlasziou  P Regret graphs, diagnostic uncertainty and Youden's index. Stat Med 1996;15 (10) 969- 986
PubMed Link to Article
Youden  WJ Index for rating diagnostic tests. Cancer 1950;3 (1) 32- 35
PubMed Link to Article
Raudenbush  SWBryk  ASCheong  YFCongdon  RT  Jr HLM 6: Hierarchical Linear Modeling.  Lincolnwood, IL Scientific Software International2004;
Nierop  ABratsikas  AZimmermann  REhlert  U Are stress-induced cortisol changes during pregnancy associated with postpartum depressive symptoms? Psychosom Med 2006;68 (6) 931- 937
PubMed Link to Article
Handley  SLDunn  TLWaldron  GBaker  JM Tryptophan, cortisol and puerperal mood. Br J Psychiatry 1980;136498- 508
PubMed Link to Article
Okano  TNomura  J Endocrine study of the maternity blues. Prog Neuropsychopharmacol Biol Psychiatry 1992;16 (6) 921- 932
PubMed Link to Article
Schmeelk  KHGranger  DASusman  EJChrousos  GP Maternal depression and risk for postpartum complications: role of prenatal corticotropin-releasing hormone and interleukin-1 receptor antagonist. Behav Med 1999;25 (2) 88- 94
PubMed Link to Article
Harris  BHuckle  PThomas  RJohns  SFung  H The use of rating scales to identify post-natal depression. Br J Psychiatry 1989;154813- 817
PubMed Link to Article
Murray  LCarothers  AD The validation of the Edinburgh Postnatal Depression Scale on a community sample. Br J Psychiatry 1990;157288- 290
PubMed Link to Article
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