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Elevated Midpregnancy Corticotropin-Releasing Hormone Is Associated with Prenatal, But Not Postpartum, Maternal Depression

Connors Center for Women's Health and Gender Biology (J.W.R.-E.), Brigham and Women's Hospital, Departments of Epidemiology (J.W.R.-E., A.P.M.), Society, Human Development, and Health (R.J.W.), and Nutrition (M.W.G.), Harvard School of Public Health, Department of Obstetrics and Gynecology (M.R.H.), Beth Israel Deaconess Medical Center, Harvard Medical School, Division of Endocrinology (J.M.), Children's Hospital Boston, and Channing Laboratory (R.J.W.), Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215; and Department of Ambulatory Care and Prevention (J.W.R.-E., K.K., M.W.G.), Harvard Medical School and Harvard Pilgrim Health Care, Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Dr. Janet Rich-Edwards, Brigham and Women's Hospital, Connors Center for Women's Health, 1620 Tremont Street, Boston, Massachusetts 02215. E-mail: jr33{at}partners.org.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Elevated hypothalamic CRH has been implicated in melancholic major depression in nonpregnant individuals, but the role of placental CRH in maternal prenatal and postpartum depression is largely unexplored.

Objective: The objective of the study was to examine the association of maternal midpregnancy plasma CRH levels with prenatal and postpartum depression.

Participants: The study included 800 participants in Project Viva, a pregnancy and childhood cohort.

Methods: CRH levels were analyzed from blood samples obtained at mean 27.9 wk gestation (± 1.3 SD; range 24.6–37.4 wk) and were normalized on the logarithmic scale. Depression was assessed with the Edinburgh Postpartum Depression Scale (range 0–30 points) in midpregnancy and at 6 months postpartum. We used logistic regression to estimate the odds of scoring 13 or more points on the Edinburgh Postpartum Depression Scale as indicative of major or minor depression.

Results: Seventy (8.8%) and 46 (7.5%) women had prenatal and postpartum depression symptoms, respectively. Mean log CRH was 4.93 (± 0.62 SD). After adjusting for confounders, an SD increase in log CRH was associated with nearly 50% higher odds of prenatal depression symptoms (odds ratio 1.48, 95% confidence interval 1.14–1.93). Higher CRH levels during pregnancy were unassociated with greater risk of postpartum depressive symptoms. In fact, there was a suggestion that prenatal CRH levels might be inversely associated with risk of postpartum depressive symptoms (odds ratio 0.82, 95% confidence interval 0.58–1.15).

Conclusions: Elevated placental CRH levels in midpregnancy are positively associated with risk of prenatal depression symptoms but not postpartum depression symptoms.

	Introduction

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Prenatal and postpartum depression together affect roughly 15% of mothers (1) and may have serious consequences for the health and well-being of the entire family (2, 3, 4). Despite advances in understanding the causes of major depression, the particular triggers and hormonal profile of prenatal and postpartum depression are poorly understood.

Major depression is characterized by disordered hypothalamic-pituitary-adrenal (HPA) activity. Classic melancholic depression is associated with elevated levels of CRH in cerebrospinal fluid (5, 6). Pathology examinations report elevated CRH mRNA expression and CRH immunoreactivity in hypothalamic and brain stem nuclei of depressed suicides (7, 8, 9). Some (5, 10), but not all (11), studies have reported fewer CRH binding sites in the frontal cortex of suicides, consistent with CRH receptor down-regulation in response to excessive CRH expression.

During pregnancy the placenta contributes large amounts of CRH to maternal and fetal circulation. By 28–30 wk gestation, levels of CRH in peripheral maternal plasma reach those of the portal circulation between the hypothalamus and pituitary, although much of the CRH in maternal circulation is bound by CRH binding protein (12). Higher CRH levels in early and midpregnancy are associated with shorter gestation length, earning CRH the moniker the placental clock (13). CRH levels are elevated in pregnancies complicated by fetal physiological stressors, such as hypertensive disorders (14, 15, 16, 17, 18). The implications of placental CRH for onset of depression during and after pregnancy are largely unstudied.

To our knowledge, there is only one published study of CRH and prenatal depression. In a study of 59 adolescents, lower CRH in early pregnancy was associated with more depressive symptoms in late pregnancy; early pregnancy CRH levels accounted for 6% of the variance in depressive symptoms in early pregnancy and 11% in late pregnancy (19). In commenting on the contrast between their findings and the positive association of cerebrospinal CRH with major melancholic depression in adults, the authors speculated that the inverse association they observed might be a phenomenon unique to adolescent pregnancy. To our knowledge, no published data exist among adult pregnant women.

The extent to which CRH levels during pregnancy are associated with postpartum depressive symptoms is also of interest. Levels of CRH drop to undetectable amounts in maternal peripheral circulation within hours after delivery of the placenta (12). In the first 3 wk postpartum, the normal HPA axis is refractory to external CRH challenge (20). However, Magiakou et al. (20) demonstrated that women with symptoms of the postpartum blues or depression continued to have blunted ACTH responses to CRH challenge at 6 and 12 wk postpartum. This implicates a more profound or enduring HPA suppression in postpartum depression (20). We hypothesized that women with higher levels of placental CRH during pregnancy might have a more protracted postpartum refractory period and that this might be associated with postpartum depression symptoms.

The purpose of this study was to test the extent to which midpregnancy CRH levels were associated with midpregnancy and postpartum depressive symptoms in adults.

	Subjects and Methods

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We examined associations of CRH levels with depressive symptomatology in Project Viva, a prospective observational cohort study of pregnancy outcomes and maternal and child health. Project Viva participants were recruited between 1999 and 2002 at their first prenatal visit to one of eight obstetric practices associated with Harvard Vanguard Medical Associates, a large group practice in the Boston area. After enrollment, research assistants scheduled a follow-up meeting at the midpregnancy prenatal visit at which blood samples were routinely drawn for glucose tolerance testing (usually 26–28 wk gestation). As described previously, whole-blood samples were drawn into EDTA tubes, cooled, and later centrifuged, aliquotted, and stored in a –80 C freezer. We previously demonstrated the stability of CRH with this processing protocol (21).

CRH was assayed in maternal plasma as described elsewhere (22) with slight modification. Briefly, 0.5-ml plasma samples were thawed in an ice bath and centrifuged before extraction. The supernatant was mixed with 4 ml of TEAF [1000 ml distilled water plus 11.5 ml formic acid, titrated with triethylamine (to pH 3.2)] and 25 ml of 2% Triton X-100. A C18 Pak 1-g cartridge (Waters Association, Milford, MA) was prewashed with 10 ml acetonitrile, 10 ml TEAF-acetonitrile (2:3), and 10 ml TEAF. The diluted sample was loaded onto the C18 cartridge. After 1 ml of TEAF-propanol (1:1) was loaded to equilibrate the column, CRH was eluted with 3 ml TEAF-propanol (1:1). The eluted sample was lyophilized and either immediately assayed for CRH or stored at –80 C until assayed.

Lyophilized samples were reconstituted with RIA buffer supplied with the CRH RIA assay kit (Peninsula Laboratories Inc., San Carlos, CA) and assayed using the manufacturer's instructions. Data were analyzed using the log-logit method. Assay sensitivity was 40 pg/ml of plasma. The 37 samples less than 40 pg/ml were assigned 20 pg/ml. The assay had an interassay coefficient of variation of 32, 56, and 12% at plasma CRH values of 50, 250, and 500 pg/ml, respectively. After extraction, the interassay coefficient of variation was 7%, indicating that most of the assay variability occurred during plasma extraction.

Of 2128 participants who delivered a live infant, 1596 (75%) provided a midpregnancy blood sample for CRH analysis. Gestational length was determined using recalled last menstrual period corrected by ultrasound findings for 93 women whose estimates were 10 or more days discrepant. We excluded three samples drawn at less than 17 wk gestation length, one sample with low volume, and 540 samples that had been refrigerated for more than 25 h before being processed and frozen at the central research laboratory. After CRH analysis, 50 samples were excluded because of problems with the extraction process. Of the 1002 participants with eligible CRH results, 860 (86%) had completed a midpregnancy questionnaire that queried history of depression and current depressive symptoms with a 10-item Edinburgh Postpartum Depression Scale (EPDS). We excluded 60 women who were missing data on body mass index, income, or marital status, leaving 800 participants for the analysis of prenatal depression. At 6 months postpartum, 616 of these respondents (77%) completed a second EPDS and were included in the postpartum depression analysis.

Women completed the prenatal EPDS as part of a longer written questionnaire close to the time of the midpregnancy blood draw and the postpartum EPDS as part of a longer questionnaire at 6 months after delivery. Eighty-five percent returned the prenatal questionnaire on the same day as the blood draw, 3% returned the questionnaire 2–6 d before or after the blood draw, 3% returned the questionnaire more than 1 wk before the blood draw, and 9% returned it more than 1 wk after the blood draw. We chose the EPDS because it is the only self-reported depression scale that has been validated for prenatal and postpartum use (23, 24). The EPDS focuses on cognitive and affective symptoms of depression, avoiding the loss of specificity that occurs with the inclusion of physical symptoms (such as fatigue and physical discomfort) common to normal pregnancy and the postpartum period (2, 25). A postpartum EPDS score of 13 or more points on its 0–30 scale indicates probable major depression (26). Although the appropriate EPDS threshold to indicate prenatal depression is debated, we used the cut point of 13 or more to indicate probable depression during pregnancy and the postpartum, consistent with previous work in our cohort (27) and other large cohorts that collected EPDS data prenatally and postnatally (28).

We obtained data from electronic medical records regarding pregnancy complications and medication prescriptions from 91 d before the last menstrual period through 6 months postpartum. We searched for the use of 29 commonly used antidepressants during pregnancy and 6 months postpartum. Because pregnancy complications or antidepressant use might affect CRH levels, we also conducted secondary sensitivity analyses to determine whether excluding women with pregnancy complications (specifically, preeclampsia, gestational hypertension, or gestational diabetes) or antidepressant use would change our findings. The study protocol was approved by the governing Institutional Review Board at Harvard Pilgrim Health Care.

Data analysis

We conducted our analyses using the Statistical Analysis System (SAS 9.01; SAS Institute, Cary, NC). We log transformed CRH values to induce normality.

We used analysis of covariance to estimate mean log CRH levels by participant characteristics, adjusted for maternal age and gestation length in weeks at blood draw. We used logistic regression to estimate odds ratios of depression associated with a SD increase in log CRH levels. In model building, we included demographic factors (age, race/ethnicity, annual household income, marital status, parity) that were associated with depressive symptoms in Project Viva in previous analysis (27). For postpartum depression, we also adjusted for whether the birth had been preterm (<37 wk gestation). Addition of maternal education, prepregnancy body mass index, or offspring birth weight to these multivariate models made no further change to the point estimates of the association between log CRH and depressive symptoms; thus, these covariates were not included.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Plasma CRH levels ranged from 20.00 to 2118 pg/ml, with a mean (SD) of 170 (164) pg/ml. Log CRH ranged from 3.0 to 7.7 log pg/ml, with a mean of 4.9 (0.6) log pg/ml. As expected, adjusted log CRH levels were positively correlated with gestational age at the blood draw (r = 0.29; P < 0.0001) and were inversely associated with total gestation length (r = –0.17; P < 0.0001).

Table 1 displays the mean log CRH in midpregnancy by maternal characteristics. Midpregnancy plasma CRH levels, adjusted for gestation length at blood draw, were positively associated with maternal age. After further adjustment for maternal age, higher household income appeared to be associated with higher CRH levels in midpregnancy, although maternal education was not. Half of the cohort was parous; CRH levels did not vary by parity. Midpregnancy CRH levels were higher in pregnancies that resulted in preterm deliveries.

View larger version (7K): [in this window] [in a new window]   FIG. 1. Adjusted odds ratios and 95% confidence intervals for risk of prenatal and postpartum depression symptoms per SD increase in midpregnancy log CRH, Project Viva, adjusted for gestational length in weeks at blood draw, maternal age, maternal race/ethnicity, household income, parity, marital status, and (for postpartum depression symptoms) preterm delivery.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Women with prenatal depression symptoms had higher levels of plasma CRH at midpregnancy than women without depression symptoms. These observations are consistent with reports of elevated cerebrospinal CRH levels in major depression in nonpregnant individuals (5, 6), which drop with clinical recovery (29). Because most CRH circulating in maternal plasma is bound to CRH binding protein (30), the extent to which placental CRH has access to the maternal brain is unknown. At least two mechanisms could explain our observed positive association of CRH with prenatal depression symptoms. Placental CRH may indeed have a direct impact on maternal affect, as does hypothalamic CRH in nonpregnant melancholic depressives. Alternatively, prenatal depressive symptoms might be associated with pregnancy complications, such as hypertensive disorders, that are associated with elevated CRH levels. If mothers felt depressed after learning they had a pregnancy complication, then the association between CRH and maternal depression could be spurious. However, we observed that placental CRH was positively related with prenatal depressive symptoms among women without gestational diabetes or hypertensive disorders of pregnancy.

Our finding of a positive association of CRH levels with prenatal depression stands in contrast to the only other published report of CRH during pregnancy, a small study (n = 59) that reported an inverse association of CRH levels with maternal depressive symptoms among teen mothers (19). The conflicting results of our studies may be due to chance, the different age of the populations, different measures of depression, or possibly different forms of prenatal depression. Although subtypes of prenatal depression have yet to be described, prenatal depression may comprise both a melancholic HPA hyperarousal syndrome and an atypical HPA hypoarousal syndrome, as is recognized for major depression in nonpregnant adults (12).

Other researchers have noted an association between late pregnancy CRH levels and maternal anxiety (31). In particular, CRH levels were associated with maternal pregnancy-related anxiety regarding the pregnancy outcome, although CRH was unrelated to more global-state anxiety. It is possible that pregnancy complications, such as the hypertensive disorders, might explain both elevated CRH and heightened maternal anxiety regarding pregnancy outcomes. Nevertheless, it is noteworthy that anxiety is frequently comorbid with melancholic depression (32), lending support to the suggestion that CRH might be associated with both maternal anxiety and melancholic-type depression in pregnancy.

We had hypothesized that prenatal CRH levels would be associated with higher risk of postpartum depression. However, our data suggest that higher CRH levels in pregnancy may be associated with reduced risk of postpartum depression symptoms; this is a post hoc observation that should be treated with caution. Kammerer et al. (33) suggested that prenatal depression symptoms more closely resemble the symptoms of insomnia, anorexia, and anxiety of melancholic depression, whereas postpartum depression may be more atypical in manifestation, with symptoms of lethargy, hypersomnia, and hyperphagia. Our data may be consistent with this view, to the (unknown) extent that high prenatal CRH levels are analogous to HPA hyperarousal typical of melancholia and low prenatal CRH levels may presage a postpartum hypothalamic-pituitary hypoarousal characteristic of atypical depression.

Our study had several limitations. Clinical depression and the timing of its onset are diagnosed only by psychiatric interview. Unfortunately, that gold standard of diagnosis was impractical for this large study. Our reliance on a single administration of the EPDS in midpregnancy and a second at 6 months postpartum probably caused us to miss some short-lived depressive episodes. The result of this misclassification of depression status, presumably random with respect to CRH levels, which were unknown to the mothers, is likely to bias our results toward the null. CRH during pregnancy does not have diurnal rhythm (20), so our results could not be confounded by blood drawing at different times of day. Finally, without serial measures of CRH and maternal mood, we cannot tell whether depression precipitated a rise in CRH levels or whether elevated CRH levels caused the depressive symptoms. This is an important question to resolve.

It would be useful to replicate these studies in adolescents and adults in a longitudinal cohort with serial measures of CRH and tools to characterize depression subtype. Because several antidepressants lower cerebrospinal CRH levels in nonpregnant adults (34), it would be interesting to measure the response of maternal peripheral CRH levels to antidepressant treatment during pregnancy. This is particularly relevant because new antidepressants specifically targeting CRH activity are being developed: CRH receptor type 1 antagonists are in clinical trials for the treatment of anxiety and depression in nonpregnant adults (35), and one open-label trial has demonstrated reduced anxiety and depression in patients with major depression (36).

Placental CRH levels are inversely associated with length of gestation (13), although it is not clear whether this association is causal. Thus, caution may be warranted in considering the use of antidepressants that could affect maternal-placental CRH dynamics. Indeed, the CRH antagonist antalarmin delays the onset of parturition in sheep (37). On the other hand, a number of studies have reported shorter gestations among women taking selective serotonin reuptake inhibitors during pregnancy (38, 39, 40, 41, 42). Although selective serotonin reuptake inhibitors reduce cerebrospinal CRH in nonpregnant individuals (43), their impact on placental CRH is untested.

Elucidation of the hormonal correlates of prenatal depression may help to identify women at especially high risk of depression during pregnancy as well as develop antidepressants designed specifically for prenatal depression. Because the CRH molecule appears to be a placental reaction to physiological stress, it is important to consider both the psychological impact on the mother and the physiological impact on the pregnancy of any drugs that interfere with placental CRH production or action.

	Acknowledgments

 
We are grateful for the advice of Dr. Hadine Joffe regarding antidepressant use during pregnancy.

	Footnotes

 
This work was supported by Grant R01 MH068596 from the National Institute of Mental Health.

Disclosure Statement: J.W.R.-E., A.P.M., K.K., M.R.H., J.M., R.J.W., and M.W.G. have nothing to declare.

First Published Online February 26, 2008

Abbreviations: EPDS, Edinburgh Postpartum Depression Scale; HPA, hypothalamic-pituitary-adrenal; TEAF, distilled water plus formic acid, titrated with triethylamine.

Received November 15, 2007.

Accepted February 15, 2008.

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