Depressive symptoms and proinflammatory cytokines across the perinatal period in African American women.

http://informahealthcare.com/pog ISSN: 0167-482X (print), 1743-8942 (electronic) J Psychosom Obstet Gynaecol, 2014; 35(1): 8–15 ! 2014 Informa UK Ltd. DOI: 10.3109/0167482X.2013.868879

ORIGINAL ARTICLE

Emma Robertson Blackmore1,2, Susan W. Groth3, Ding-Geng (Din) Chen3,4, Michelle A. Gilchrist1, Thomas G. O’Connor1, and Jan A. Moynihan1 1

Department of Psychiatry, University of Rochester Medical Center, Rochester, NY, USA, 2Department of Psychiatry, University of Florida College of Medicine, Jacksonville, FL, USA, 3School of Nursing and University of Rochester Medical Center, Rochester, NY, USA, and 4Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY, USA Abstract

Keywords

Background: Comparatively few studies have examined the biological mechanisms that may underlie the reported racial disparities in antenatal and postpartum depression. Objective: To examine the associations among race, depressive symptoms and the proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-a across the perinatal period in a diverse sample of healthy pregnant women at elevated psychosocial risk. Methods: 171 subjects were enrolled. Women were interviewed and blood samples drawn at 18 and 32 weeks gestation and 6 weeks and 6 months postpartum. Depressive symptoms were measured using the Edinburgh Postnatal Depression Scale. Serum levels of IL-6 and TNF-a were assayed using high sensitivity enzyme-linked immunosorbent assay kits. Results: Compared with non-African American (AA) women, AA women had significantly higher levels of IL-6 (est. diff ¼ 0.521, p ¼ 0.02, confidence interval (CI): 0.088–0.954) but not TNF-a across all time points (est. diff ¼ 0.060, p ¼ 0.80, CI: 0.517 to 0.397). IL-6 was not associated with depressive symptoms but differences in IL-6 were accounted for by greater Body Mass Index in AA women. Conclusions: Compared with non-AA women, AA women entered pregnancy with elevated inflammatory cytokine levels that persisted across the perinatal period. This group difference in inflammation did not suggest increased risk for depression, but suggests other implications for long-term health.

Antenatal depression, depression, obesity, postpartum depression, proinflammatory cytokines, race

Introduction The identification and treatment of depression during pregnancy or the postpartum period is a significant clinical concern for both women and health care providers [1]. Available data suggest that African American (AA) women have higher rates of both antenatal and postpartum depression [2–8] compared with non-AA women, even after controlling for sociodemographic and behavioral factors [9]. However, AA women are typically under-represented in perinatal studies [10], and key variables that may account for racial differences in depression rates, particularly biological mechanisms, are not well studied or understood [10]. Experiencing psychological stress during pregnancy is associated with elevated hypothalamo–pituitary–adrenal (HPA) axis reactivity [11], increased inflammation [12] and Address for correspondence: Emma Robertson Blackmore, PhD, Department of Psychiatry, University of Rochester Medical Center, 580 W 8th Street, Tower 2, 6th Floor, Suite 6015, Jacksonville, FL 32209, USA. Tel: 904 244 9611. Fax: 904 244 9234. Email: [email protected]

History Received 26 February 2013 Revised 18 November 2013 Accepted 20 November 2013

has been shown to partially mediate the effects of inflammation on adverse obstetric outcomes [13]. However, ‘‘psychological stress’’ is a broad term that encompasses a range of distinct phenotypes, including stress, anxiety and depression. Focusing on more narrowly defined phenotypes will allow us to examine whether there are differential effects of stress, anxiety or depression on immune, endocrine and nervous system functions that are central to successful pregnancy outcomes [13,14]. In this study, we focus on depressive symptoms occurring during pregnancy and the postpartum period, the pathophysiology of which remains unclear. Current research focuses on four main areas: genetic vulnerability, the HPA axis, steroid hormones and, our particular interest, psychoneuroimmunology. There is growing evidence supporting the role of inflammation in the development of depression occurring outside of the perinatal period [15,16]; associations between elevated levels of the proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-a and onset of depression have been reported in some [17] but not all studies [18,19]. Although data on racial differences are very limited,

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Depressive symptoms and proinflammatory cytokines across the perinatal period in African American women


DOI: 10.3109/0167482X.2013.868879

depressed AA women had increased inflammation compared with depressed non-AA women in one study [20]. Whether proinflammatory cytokines might also be associated with depression in the perinatal period is an important hypothesis that has only recently attracted systematic attention; evidence for an association is mixed, and differs in the ante- and postpartum periods. Studies of concurrent antenatal depressive symptoms and IL-6 report positive [21,22] and negative [23,24] associations; studies of antenatal depressive symptoms and TNF-a report marginal [21] or no association [23–25]. Findings in the postpartum period are slightly more consistent, with several reports linking blues and mild depressive symptoms with elevated IL-6 [26,27] and TNF-a levels [26]. The possibility that race differences in perinatal depression may be explained by race differences in proinflammatory cytokines is an important hypothesis, but not one that has been systematically examined, because few studies have had adequate numbers of minority participants. Data from a sample of 187 pregnant AA women [25] indicated that IL-6 and IL-1b were positively and significantly correlated with antenatal depressive symptoms, but TNF-a was not. We build on and extend these studies by examining whether the reported racial differences in perinatal depression are explained by racial differences in proinflammatory cytokines. In summary, the literature suggests that AA women may be at increased risk of perinatal depression and also may have elevated inflammation. The current study has several key methodological advantages over prior studies in this area, including a prospective longitudinal design covering the perinatal period, a focus on depressive symptoms, and a recruitment strategy that oversampled minority participants at elevated risk for perinatal depression. Across four occasions of measurement, we tested the hypothesis that there are racial differences in perinatal depression and inflammation, and that race differences in inflammation account for the reported differences in depression. We also considered the impact of maternal anxiety, which is often comorbid with depression, in addition to other potential confounding factors, including Body Mass Index (BMI) and psychosocial risk. A secondary aim was to examine race differences in obstetrical outcomes and determine whether these are explained by race differences in proinflammatory cytokines in pregnancy.

Methods Design and study participants The data are derived from a prospective, longitudinal cohort study of women receiving obstetrical care from a hospitalbased practice serving a predominantly low-income minority population. The primary aim of the study was to examine the relationship between cytokines and depressive symptoms across the perinatal period in a normal (i.e. non-diseased) population. Therefore, we excluded women with medical conditions that could elevate proinflammatory cytokines levels and potentially confound the relationship being tested. These included autoimmune disorders such as type 1 diabetes, rheumatoid arthritis and multiple sclerosis. Furthermore, significantly elevated levels of IL-6 and TNF-a in pregnancy have been linked with adverse obstetric outcomes such as premature labor and delivery, premature rupture of membranes

IL-6 and perinatal mood

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(PROM) and preeclampsia [28–30]. Therefore, we excluded women considered at increased risk of these adverse obstetric outcomes and only included women considered low to medium obstetric risk by the medical team. Using standardized definitions (National Institutes of Health (NIH), American Congress of Obstetricians and Gynecologists (ACOG)), high obstetric risk referred to an increased likelihood of maternal or fetal complications due to various factors, including young or old maternal age, more than one fetus, experiencing previous problems in pregnancy (preeclampsia, stillbirth and multiple miscarriages), or prenatal drug or alcohol use. Consequently, the inclusion criteria were women aged 19–34 years old with a confirmed singleton pregnancy less than 18 weeks gestation at enrollment, considered low to medium obstetric risk by the medical team, fluent in English and able to provide informed consent. Exclusion criteria were current or past psychotic symptoms, a diagnosis of bipolar disorder or schizophrenia and pregnancies determined to be medically high-risk. To reduce bias and potential confounds we only included pregnancies that resulted in live births, and excluded infants who were deemed low birth weight (52500 g) or premature (gestational age at birth 537 weeks) from inferential analysis. The study was approved by the University of Rochester Institutional Review Board, and written informed consent was obtained from each research participant following an explanation of the study procedures. Nursing staff in the clinic provided an overview of the study to all clinic attendees who met initial inclusion criteria and asked if they were interested in learning more about the study. Given that the rate of antenatal depression is 13% [9], it was necessary to employ a sampling strategy (oversampling) that would enable us to obtain sufficient variability in depressive symptoms, and adequate numbers of depressed women across the perinatal period. Due to the longitudinal design of the study and the natural course of the illness, initial depression status and symptom patterns were expected to change over time. A screening interview was conducted with all women during which the Edinburgh Postnatal Depression Scale (EPDS) [31] was administered. The EPDS is a 10-item self-report questionnaire and is the most widely used and validated screening tool for depressive symptoms in pregnant and postpartum women [32]. Validation studies have shown that a score of 13 on the EPDS identifies women with a diagnosis of major depression [32,33]. At initial screening (mean gestational age 8.3 weeks), we enrolled women scoring below 7 on the EPDS who were considered non-depressed and those with a score of 12 who were considered depressed. Study team members met with 397 pregnant women who met initial eligibility criteria and expressed an interest in participating. After receiving a full explanation of the study procedures, 214/397 (53.9%) women consented to participate. A further 35 women (35/214, 16%) were excluded after the first interview because they had at least one exclusion criteria that was not previously detected, suffered a perinatal loss, changed obstetrics provider or were lost to contact prior to the clinical interview assessment. A further eight women were excluded following subsequent interviews revealing the presence of psychotic features or drug abuse that had not been previously disclosed or identified. The final

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E. R. Blackmore et al.

sample included 171 women. Data were collected between May 2007 and April 2011.


Procedure and measures The women were interviewed on four separate occasions: twice in pregnancy at approximately 18 and 32 weeks gestation and twice in the postpartum period at 6 weeks and 6 months. All assessments were conducted by highly trained clinical interviewers, and participants completed a battery of questionnaires and a clinical diagnostic interview for mood disorders [34] at each assessment. Interviews took place in the Clinical Research Center, located within the same hospital from which they received their obstetric care; blood samples were also obtained during these assessments. Detailed clinical, medical and sociodemographic data were obtained from interview and medical notes. Depressive symptomatology was assessed using the EPDS. Clinical diagnoses of current depression and history of depressive episodes were obtained through the mood episodes section of the Structured Clinical Interview for DSM [34]. Anxiety symptoms were assessed using the 20-item state subscale of the State-Trait Anxiety Inventory [35], a widely used measure of anxiety in pregnancy in obstetric and psychological settings. The sample was divided into two groups based on self-reported race. Those women who identified themselves as being of AA race, including those who identified themselves as biracial that included AA, were classified as AA (n ¼ 81). The remaining 90 women identified themselves as a racial group that was not of AA descent (non-AA group). Laboratory procedures and cytokine analysis Blood was collected into vacutainer tubes (BD Diagnostics, Franklin Lakes, NJ) via conventional venipuncture. Blood was centrifuged at 1000 g for 10 min within 15 min of collection, and serum was stored at 80 C until assayed. In order to ensure that elevated cytokines levels were not due to an underlying medical condition or infection, women were asked prior to the blood draw if they had been ill recently, the nature of any illness and any medications that they had taken. Women who had been febrile, experienced a cold or flu or were taking medications for these were asked to return a week later, or when asymptomatic, to provide blood and complete assessments; medical chart data were also reviewed for evidence of illness. Serum levels of IL-6, IL-1b and TNF-a and were assayed by enzyme-linked immunosorbent assay using high-sensitivity kits purchased from R&D Systems, Inc. (Minneapolis, MN); however, levels of IL-1b were undetectable in all subjects, and so we consider only IL-6 and TNF-a in analyses below. The kits were used according to manufacturer’s standard protocols with the standard curve run on each 96-well assay plate. Samples were run in duplicate. Absorbance was read at 490 nm with 650 nm wavelength correction within 30 min after development using an automated Opsys MR Microplate Reader (Thermo Labsystems, Chantilly, VA). The minimum detectable limit for IL-6 is 0.039 and 0.106 pg/ml for TNF-a. The intra-assay variability for both cytokines was 4% and the inter-assay CV was 55%.

J Psychosom Obstet Gynaecol, 2014; 35(1): 8–15

Covariates Based on previous findings in the literature and recent reviews [36], we included the following as covariates: age, BMI at initial intake examination in the first trimester (calculated using the standard formula kg/m2), years of education, Medicaid status, marital status, sleep (the total number of hours slept in a typical night) assessed through the Pittsburgh Sleep Quality Index [37] and the time of the blood draw. Number of hours of sleep and the time of the blood draw were included to control for circadian rhythm. Data analysis The study was designed to have 80% power to detect a mean difference of half of a standard deviation (two-tailed) or an effect size of 0.5 based on a sample of 128 women. First, we tested whether the 90 women who self-identified as Caucasian or Hispanic, i.e. the non-AA group, differed in terms of EPDS scores or proinflammatory cytokine levels. Fifty-one women identified themselves as Caucasian (51/90, 57%) and 39 as of Hispanic descent (including biracial) (39/ 90, 33%). Analysis of variance (ANOVA) showed that there was no significant difference for any measure at any of the four time points studied between Caucasian and Hispanic women (details available from first author). Therefore, we combined these subjects into a ‘‘non-AA’’ group. Treating the two groups under comparison as independent, we used 2 analysis for categorical variables and t-tests and ANOVA were conducted for continuous variables. Continuous symptom (EPDS) scores were used in analyses. A linear mixed-effects model to incorporate the repeated-measures from the four data points was used to test the outcome measures of IL-6 and TNF-a for AA and non-AA women, as well as to model these outcome measures, adjusting for associated risk factors listed in Table 1. This model is superior for modeling correlated repeated-measures to include fixed-effects and random-effects components and can easily deal with missing values [38]. In the data analysis, we first examined the interaction between time and race to test the different trends for IL-6 and TNF-a between the two groups. As this interaction was shown to be not statistically significant, we then fitted a reduced linear mixed-effects model with just the main effects of time and race.

Results Sociodemographic and clinical characteristics of the sample As shown in Table 1, the overall sample was predominantly single, received Medicaid and had a high school education or less. Almost half reported a history of depression, and 57% were classified as overweight or obese according to BMI in early pregnancy. Retention within the study was relatively high for a sample at elevated psychosocial risk, with 91% of women completing both pregnancy assessments and 58% completing both postpartum assessments. We examined whether race or depression status influenced the number of study assessments completed; AA women completed a significantly larger number of study assessments compared with non-AA women (t(169) ¼ 2.32, p50.02, mean difference ¼ 0.35,


DOI: 10.3109/0167482X.2013.868879

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Table 1. Sociodemographic, clinical and obstetric characteristics of the sample and grouped by AA and non-AA women. Overall sample (n ¼ 171)


Variable Age Ethnicity Education Years completed Marital status Single Cohabiting/married Received Medicaid First trimester BMI (kg/m2) Underweight (518.5) Normal (18.5–24.9) Overweight (25.0–29.9) Obese (430) Previous history of depression EPDS score 18 Weeks 32 Weeks 6 Weeks postpartum 6 Months postpartum Visits completed 18 Weeks 32 Weeks 6 Weeks postpartum 6 Months postpartum Age at first pregnancy Primigravid Low birth weight baby (LBW) 52500 g Baby birth weight (in grams) Excluding LBW N ¼ 148 Premature birth 537 weeks gestation Gestational Age (weeks) Excluding premature births N ¼ 140 Caesarean Section performed

24.5 (3.6) 19–34

AA subjects (n ¼ 81)

Non-AA subjects (n ¼ 90)

M, SD, range or N (%) 24.4 (3.5) 19–34 24.4 (3.2) 19–34 81/171 (47) 90/171 (53)

12.8 (2.4) 11–34

12.1 (1.4) 8–16

13.4 (2.6) 8–26

91 80 118 28.1 9 64 39 59 83

62 19 40 30.0 4 23 15 39 40

29 61 58 26.4 5 41 24 20 43

7.4 6.2 4.4 4.6

(53) (47) (69) (7.5) 13–49.4 (5) (37) (23) (35) (49) (6.03) 0–23 (5.5) 0–24 (4.7) 0–23 (4.9) 0–18

7.1 6.6 3.9 4.3

(77) (23) (49) (8.1) 13–49.4 (5) (28) (19) (48) (49) (5.9) (6.2) (4.2) (5.0)

0–20 0–24 0–15 0–18

7.6 5.9 5.1 5.0

(32) (68) (64) (6.5) 16.6–45.6 (6) (45) (27) (22) (48) (6.2) (4.8) (5.2) (4.8)

p Value 0.86 0.001 0.001 0.17 0.001

0.83 0.8

0–23 0–20 0–23 0–18 0.02

171/171 (100) 156/171 (91) 101/134 (75) 83/134 (62) 19.4 (3.9) 11–34 47 (28) 13/161 (8) 3402.2 469.7 2505–4735 21/161 (13) 39.4 1.0 38–42 55/161 (34)

95% confidence interval (CI) 0.05–0.65). Depression status at 18 weeks gestation was not associated with the number of study assessments completed (t(169) ¼ 1.43, p40.15, mean difference ¼ 0.27, 95% CI 0.64 to 0.10). As shown in Table 1, compared with non-AA women, AA women were significantly more likely to be single, to have completed fewer years of education, were more likely to be multigravid, have a higher BMI and were significantly younger at their first pregnancy. Rates of depression within the sample Using a cut-off score of 13, 25% (n ¼ 43) of the overall sample had an EPDS score indicative of major depression on at least one of the two interview occasions during pregnancy and 6% (n ¼ 11) had EPDS scores indicative of major depression in the postpartum period. Analysis by race showed similar rates of antenatal depression (AA n ¼ 21/81, 26% versus non-AA 22/90, 24%; X ¼ 0.02 (1), p40.89; 95% CI 0.92, 0.46–1.84); 13% of AA women (7/54) and 8% of nonAA women (4/48) had scores indicative of depression in the postpartum period (X2 ¼ 0.57, p40.45; 95% CI 0.92, 0.46–1.84). The mixed-effects model analysis showed that EPDS scores across time did not differ between the two groups ( ¼ 0.16, p40.80, CI: 1.60 to 1.29).

81/81 (100) 73/81 (90) 57/69 (83) 47/69 (68) 18.5 (3.7) 11–31 13 (16) 9/13 (69) 3342.7 487.9 2505–4680.0 13/21 (62) 39.4 1.0 38–42 27/80 (34)

90/90 (100) 83/90 (92) 44/65 (68) 36/65 (55) 20.2 (4.0) 13–34 34 (38) 4/13 (31) 3457.1 448.4 2505.0–4735.0 8/21 (38) 39.5 0.9 38–41 28/81 (35)

0.004 0.001 0.16 0.14 0.23 0.51 0.91

Change in cytokine levels across time and between races Analyses showed no relationship between any of the sociodemographic factors and TNF-a; BMI (p50.001) and number of years of education (p50.05) were positively and negatively related to IL-6, respectively, at each time point. The mean levels of IL-6 and TNF-a at each time point and by race groups are shown in Table 2 and are illustrated in Figures 1 and 2. To test statistical significance, the mixed-effects model was employed. We first tested the interaction between time and race, and found that the interaction was not statistically significant for both IL-6 (p ¼ 0.72) and TNF-a (p ¼ 0.43). Then, a reduced model with main effects was used. This mixed-effects model revealed differences in levels of IL-6 between AA and non-AA women across the four time points (est. diff ¼ 0.52, p ¼ 0.02, CI: 0.09–0.95, Figure 1), with AA women exhibiting higher levels. There was no statistically significant time trend (p ¼ 0.11). Given the race differences in psychosocial risk and in BMI (Table 1) that are related to inflammation and might mediate this effect, we re-examined the race effect after accounting for possible confounding factors. After controlling for BMI, the effect of race was non-significant ( ¼ 0.02, p ¼ 0.24).

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Table 2. Mean (SD) levels of proinflammatory cytokines IL-6 and TNF-a across the perinatal period grouped by ethnicity (raw data). Pregnancy

Postpartum

18 weeks Cytokine IL-6 TNF-a

32 weeks

6 weeks

6 months

AA n ¼ 81

Non-AA n ¼ 90

AA n ¼ 73

Non-AA n ¼ 83

AA n ¼ 69

Non-AA n ¼ 65

AA n ¼ 69

Non-AA n ¼ 65

2.49 (1.85) 1.16 (2.33)

1.81 (1.33) 0.99 (1.38)

2.69 (2.02) 1.24 (1.91)

2.37 (1.46) 1.21 (1.30)

2.61 (2.41) 2.13 (3.29)

2.19 (1.72) 2.74 (4.80)

2.54 (2.22) 1.56 (1.57)

1.86 (1.46) 1.87 (1.73)


Table 3. Main findings from the analyses. AA women had significantly higher levels of IL-6, but not TNF-a, across all four time points compared with non-AA women After controlling for BMI the effect of race on IL-6 levels was not significant EPDS scores were not significantly different between AA and non-AA women, across time There was no significant association between either IL-6 or TNF-a, depression and race across time There were no significant differences between racial groups and obstetric outcomes. However, AA women did have babies that were on average 115 g smaller than babies born to non-AA women Antenatal levels of IL-6 and TNF-a were not associated with gestational age or birthweight for either racial group

Figure 1. Mean IL-6 levels across time by race. Ns for each point. 18 weeks ¼ 171, 32 weeks ¼ 156, 6 weeks postpartum ¼ 101, and 6 months postpartum ¼ 83.

maternal anxiety symptoms as the phenotype and found similar results: there was no relationship between anxiety and race ( ¼ 0.58, p40.70); neither IL-6 nor TNF-a was associated with anxiety across the four time points. Factors associated with birth outcomes

Figure 2. Mean TNF-a levels across time by race. Ns for each point. 18 weeks ¼ 171, 32 weeks ¼ 156, 6 weeks postpartum ¼ 101 and 6 months postpartum¼83.

Similar analysis was conducted for TNF-a across all time points and we found that there was no statistical significant race group effect (est. diff ¼ 0.060, p ¼ 0.80, CI: 0.517 to 0.397, Figure 2); however, there was a significant time trend ( ¼ 0.46, p50.001, CI: 0.19–0.73, Figure 2); TNF-a significantly increased until parturition (Figure 2). Cytokine levels, depressive symptoms and race Analyses using the mixed-effects model indicated that neither IL-6 ( ¼ 0.05, p ¼ 0.23) nor TNF-a ( ¼ 0.03, p ¼ 0.7) was associated with depression and race across the four time points. Due to the comorbidity of anxious and depressive symptoms, we controlled for the effects of maternal anxiety on depression, cytokines and race. We then ran models using

As shown in Table 1, one-way ANOVA indicated that birth weight was non-significantly lower in AA compared with non-AA women (3342.7 g (487.9) versus 3457.1 g (448.4), respectively (F(1,147) ¼ 2.21, p40.14; est. diff ¼ 114.4, 95% CI 255.8 to 26.95), and gestational age was nonsignificantly shorter (39.3 (1.1) versus 39.9 (1.2) weeks for non-AA versus AA mothers (F(1,139) ¼ 0.82, p40.37; est. diff ¼ 0.1, 95% CI 0.39 to 0.19). Gestational age was not associated with antenatal levels of IL-6 (F(1) ¼ 2.15, p ¼ 0.15) or TNF-a (F(1) ¼ 0.82, p ¼ 0.37) and race. Birth weight was not associated with antenatal levels of IL-6 (F(1) ¼ 2.21, p ¼ 0.14) or TNF-a (F(1) ¼ 0.43, p ¼ 0.51) and race. BMI was not related to gestational age for either race (AA r ¼ 0.16, p ¼ 0.17, non-AA r ¼ 0.13, p ¼ 0.27); however, BMI was significantly correlated with baby weight in the non-AA women (r ¼ 0.31, p50.05) but not the AA women (r ¼ 0.19, p ¼ 0.12). Table 3 provides a summary of the main findings from the analyses.

Discussion The adverse long-term effects of experiencing perinatal depression have been well documented for both maternal and child outcomes [39–44], and some studies [3–9] have suggested that this risk may be elevated in AA women. This study examined the relationship between depressive symptoms and the proinflammatory cytokines IL-6 and TNF-a in AA and non-AA women across four time points in pregnancy and the postpartum period.



DOI: 10.3109/0167482X.2013.868879

In the sample as a whole, women reported higher rates of depressive symptoms during pregnancy compared with other studies, reflecting the increased psychosocial risks in the population from which we drew our sample and the fact that we oversampled for depressive symptoms at the initial screen [5,35]. A quarter of women had scores indicative of major depression on at least one occasion during (mid to late) pregnancy [32,33] compared with the 10–15% reported in general populations [45] but there were no apparent racial differences. Our finding of higher rates of depression in pregnancy compared with the postpartum period is consistent with other reports [46], but does not yet have a clear explanation. Literature outside of the perinatal period suggests that depressed AA subjects may have increased inflammation [20], but whether this relationship extended to the perinatal period is unclear. We found that AA women had significantly elevated levels of IL-6 across the four time points compared with non-AA women. However, elevated IL-6 was not significantly associated with depressive symptoms, but was reliably associated with BMI and number of years of education. The lack of a robust link between proinflammatory cytokines and depression is noteworthy, given the adequate sample size to detect small/modest effects and the methodological strength of the prospective longitudinal design. To date, the evidence linking proinflammatory cytokines and perinatal depression remains equivocal. However, the depression-cytokine hypothesis is just one aspect of a complex array of interacting mechanisms that are independently associated with both depression and pregnancy [14]. Researchers need to consider the complex interplay between behavioral phenotypes and the immune, neuroendocrine and nervous systems within the perinatal period [14]. The more novel finding, that AA women had elevated IL-6, has several clinical implications. Increased IL-6 has been linked with adverse obstetric outcomes, including pre-eclampsia, low birth weight and PROM [28–30,47–49]. However, we found no association between proinflammatory cytokines and birth outcomes. More broadly defined psychological distress and elevated proinflammatory markers have, however, been linked with shortened gestational age [13]. More research is needed to examine whether distinct psychological phenotypes (stress, anxiety or depression) exert differential effects on pregnancy outcomes [14]. Although racial disparities in birth outcomes are well documented [50], we found no significant group differences in rates of prematurity, low birth weight, caesarean section or other complications. However, this may reflect the fact that the sample was considered low to medium obstetric risk at recruitment. Racial differences in IL-6 levels across time were accounted for by BMI; this is not surprising given that IL-6 is secreted by adipose cells [47]. AA women had a significantly higher prepregnancy BMI than non-AA women, and the obesity rates reported in this sample are higher than have been previously reported (e.g. 48% compared with approximately 33%) [51]. Obesity is a clinical concern, not only for women who become pregnant, but also for long-term health outcomes, and may be

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particularly salient for AA women [51]. These figures clearly demonstrate the need for interventions to address obesity in low-income minority populations. The study had several limitations: we excluded medically high-risk pregnancies and women with severe psychiatric conditions, for whom the psychiatric symptoms and proinflammatory cytokine link may be most easily detected. That was because of our interest in assessing race, symptoms and cytokines in a non-diseased sample. In addition, our assessment of cytokines was limited, but did focus on those most researched in the literature on stress and psychopathology. We oversampled for depressive symptoms at the initial assessment to ensure adequate numbers of depressed women. Finally, we employed the social and self-construction of race but did not include a formal measure of perceived racial discrimination. Offsetting these limitations were several strengths, including multiple assessments across the perinatal period and a sampling frame that targeted a relatively large, ethnically diverse sample of women. Comparisons between racial groups were strengthened by the fact that the groups were relatively homogenous in terms of psychosocial risk factors for depression. The study showed, in this community sample of predominantly low-income women at increased risk for depression, that the course of the proinflammatory cytokines IL-6 and TNF-a was similar for both AA and non-AA women, but AA women entered pregnancy with higher levels of inflammation that persisted into the postpartum period. Increased BMI accounted for the elevated IL-6 levels seen in AA women. Further research is required to develop interventions to reduce obesity and subsequent adverse health conditions associated with increased inflammation in low-income women of childbearing age.

Declarations of interest The authors report no declarations of interest.

References 1. Byatt N, Moore Simas TA, Lundquist RS, et al. Strategies for improving perinatal depression treatment in North American outpatient obstetric settings. J Psychosom Obstet Gynaecol 2012; 33:143–61. 2. Beck CT. Predictors of postpartum depression: an update. Nurs Res 2001;50:275–85. 3. Chaudron LH, Szilagyi PG, Tang W, et al. Accuracy of depression screening tools for identifying postpartum depression among urban mothers. Pediatrics 2010;125:e609–17. 4. Goyal D, Gay C, Lee KA. How much does low socioeconomic status increase the risk of prenatal and postpartum depressive symptoms in first-time mothers? Womens Health Issues 2010;20: 96–104. 5. Rich-Edwards JW, Kleinman K, Abrams A, et al. Sociodemographic predictors of antenatal and postpartum depressive symptoms among women in a medical group practice. J Epidemiol Community Health 2006;60:221–7. 6. Segre LS, O’Hara MW, Arndt S, et al. The prevalence of postpartum depression: the relative significance of three social status indices. Soc Psychiatry Psychiatr Epidemiol 2007;42: 316–21. 7. Yonkers KA, Ramin SM, Rush AJ, et al. Onset and persistence of postpartum depression in an inner-city maternal health clinic system. Am J Psychiatry 2001;158:1856–63.


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8. Orr ST, Blazer DG, James SA. Racial disparities in elevated prenatal depressive symptoms among black and white women in eastern North Carolina. Ann Epidemiol 2006;16:463–8. 9. Gavin AR, Melville JL, Rue T, et al. Racial differences in the prevalence of antenatal depression. Gen Hosp Psychiatry 2011;33: 87–93. 10. Ross LE, Campbell VL, Dennis C-L, et al. Demographic characteristics of participants in studies of risk factors, prevention and treatment of postpartum depression. Can J Psychiatry 2006;51: 704–10. 11. Parker VJ, Douglas AJ. Stress in early pregnancy: maternal neuroendocrine-immune responses and effects. J Reprod Immunol 2010; 85:86–92. 12. Coussons-Read ME, Okun ML, Nettles CD. Psychosocial stress increases inflammatory markers and alters cytokine production across pregnancy. Brain Behav Immunol 2007;21: 343–50. 13. Coussons-Read ME, Lobel M, Carey JC, et al. The occurrence of preterm delivery is linked to pregnancy-specific distress and elevated inflammatory markers across gestation. Brain Behav Immun 2012;26:650–9. 14. Dunkel Schetter C. Psychological science on pregnancy: stress processes, biopsychosocial models, and emerging research issues. Annu Rev Psychol 2011;62:531–58. 15. Raison CL, Miller AH. Is depression an inflammatory disorder? Curr Psychiatry Rep 2011;13:467–75. 16. Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 2009;65:732–41. 17. Dowlati Y, Herrmann N, Swardfager W, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry 2010;67: 446–57. 18. Berk M, Wadee AA, Kuschke RH, et al. Acute phase proteins in major depression. J Psychosom Res 1997;43:529–34. 19. Marques-Deak AH, Neto FL, Dominguez WV, et al. Cytokine profiles in women with different subtypes of major depressive disorder. J Psychiatr Res 2007;41:152–9. 20. Deverts DJ, Cohen S, DiLillo VG, et al. Depressive symptoms, race, and circulating C-reactive protein: the coronary artery risk development in young adults (CARDIA) study. Psychosom Med 2010;72:734–41. 21. Christian LM, Franco A, Glaser R, et al. Depressive symptoms are associated with elevated serum proinflammatory cytokines among pregnant women. Brain Behav Immun 2009;23: 750–4. 22. Azar R, Mercer D. Mild depressive symptoms are associated with elevated C-reactive protein and proinflammatory cytokine levels during early to midgestations: a prospective pilot study. J Womens Health 2013;22:385–9. 23. D’Anna KL, Hoffman MC, Coussons-Read M, et al. Interactions between the hypothalamic pituitary-axis and immune system predict maternal depression during pregnancy. Brain Behav Immun 2011;25:S179–242. 24. Robertson Blackmore E, Moynihan JA, Rubinow DR, et al. Psychiatric symptoms and proinflammatory cytokines in pregnancy. Psychosom Med 2011;73:656–63. 25. Cassidy-Bushrow AE, Peters RM, Johnson DA, et al. Association of depressive symptoms with inflammatory biomarkers among pregnant African-American women. J Reprod Immunol 2012;94: 202–9. 26. Boufidou F, Lambrinoudaki I, Argeitis J, et al. CSF and plasma cytokines at delivery and postpartum mood disturbances. J Affect Disord 2009;115:287–92. 27. Maes M, Lin AH, Ombelet W, et al. Immune activation in the early puerperium is related to postpartum anxiety and depressive symptoms. Psychoneuroendocrinology 2000;25:121–37. 28. Saito S. Cytokine network at the feto-maternal interface. J Reprod Immunol 2000;47:87–103. 29. Santhanam U, Avila C, Romero R, et al. Cytokines in normal and abnormal parturition: elevated amniotic fluid interleukin-6 levels in


30.

31.

32.

33.

34.

35.

36.

37.

38. 39.

40.

41.

42.

43.

44.

45. 46.

47.

48.

49.

50. 51.

women with premature rupture of membranes associated with intrauterine infection. Cytokine 1991;3:155–63. Gomez R, Ghezzi F, Romero R, et al. Premature labor and intra-amniotic infection. Clinical aspects and role of the cytokines in diagnosis and pathophysiology. Clin Perinatol 1995;22: 281–342. Cox JL, Holden JM, Sagovsky R. Detection of postnatal depression. Development of the 10-item Edinburgh Postnatal Depression Scale. Br J Psychiatry 1987;150:782–6. Murray D, Cox J. Screening for depression during pregnancy with the Edinburgh depression scale (EPDS). J Repro Infant Psychol 1990;8:99–107. Murray L, Carothers AD. The validation of the Edinburgh Postnatal Depression Scale on a community sample. Br J Psychiatry 1990;157:288–90. First M. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, ResearchVersion, Patient Edition with Psychotic Screen (SCID-I/P W/PSY SCREEN). New York: Biometrics Research, New York State Psychiatric Institute; 2002. Spielberger CD. State-trait anxiety inventory: a comprehensive bibliography. Palo Alto, CA: Consulting Psychological Press; 1984. O’Connor MF, Bower JE, Cho HJ, et al. To assess, to control, to exclude: effects of biobehavioral factors on circulating inflammatory markers. Brain Behav Immun 2009;23:887–97. Buysse DJ, Reynolds CF, III, Monk TH, et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989;28:193–213. Chen DG, Peace KE. Clinical Trial Data analysis using R. New York: Chapman and Hall/CRC Biostatistics Series; 2010. O’Connor TG, Heron J, Golding J, et al. Maternal antenatal anxiety and children’s behavioural/emotional problems at 4 years. Report from the Avon Longitudinal Study of Parents and Children. Brit J Psychiatry 2002;180:502–8. Hay DF, Pawlby S, Sharp D, et al. Intellectual problems shown by 11-year-old children whose mothers had postnatal depression. J Child Psychol Psychiatry 2001;42:871–89. Halligan SL, Herbert J, Goodyer I, et al. Disturbances in morning cortisol secretion in association with maternal postnatal depression predict subsequent depressive symptomatology in adolescents. Biol Psychiatry 2007;62:40–6. Grote NK, Bridge JA, Gavin AR, et al. A meta-analysis of depression during pregnancy and the risk of preterm birth, low birth weight, and intrauterine growth restriction. Arch Gen Psychiatry 2010;67:1012–24. Robertson E, Grace S, Wallington T, et al. Antenatal risk factors for postpartum depression: a synthesis of recent literature. Gen Hosp Psychiatry 2004;26:289–95. Meltzer-Brody S. New insights into perinatal depression: pathogenesis and treatment during pregnancy and postpartum. Dialogues Clin Neurosci 2011;13:89–100. O’Hara MW, Swain AM. Rates and risks of postpartum depression – a meta-analysis. Int Rev Psychiatry 1996;8:37–54. Heron J, O’Connor TG, Evans J, et al. The course of anxiety and depression through pregnancy and the postpartum in a community sample. J Affect Disord 2004;80:65–73. Greenberg AS, Obin MS. Obesity and the role of adipose tissue in inflammation and metabolism. Am J Clin Nutr 2006;83(suppl): 461S–5S. Xiao JP, Yin YX, Gao YF, et al. The increased maternal serum levels of IL-6 are associated with the severity and onset of preeclampsia. Cytokine 2012;60:856–60. Xie C, Yao MZ, Liu JB, et al. A meta-analysis of tumor necrosis factor-alpha, interleukin-6, and interleukin-10 in preeclampsia. Cytokine 2011;56:550–9. Martin JA, Hamilton BE, Ventura SJ, et al. Births: final data for 2010. National Vital Statistics Reports. 2012;61:1–72. Hinkle S, Sharma A, Kim S, et al. Prepregnancy obesity trends among low-income women, United States, 1999–2008. Mat Child Health 2012;16:1339–48.

DOI: 10.3109/0167482X.2013.868879


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ä Current knowledge on the subject African American (AA) women have been suggested to be at increased risk of depression during the perinatal period. Patients with depression have elevated levels of IL-6 and TNF-a, but it is not clear if this relationship extends to the perinatal period and whether there are racial differences.


ä What this study adds AA women had similar rates of antenatal depression, but higher rates of postpartum depression compared with nonAA women. AA women entered pregnancy with elevated IL-6 levels that persisted across the perinatal period, but this was not associated with depressive symptoms. The difference in IL-6 levels was likely driven by increased BMI in AA women which has implications for the long-term health outcomes of these women.

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