Psychiatric disorders during pregnancy represent a major public health concern because of their prevalence and persistence into the postpartum period (1
). Public health and clinical concerns about prenatal psychiatric disturbance are most acute for minority women of lower socioeconomic status who exhibit increased prevalence of depressive symptoms (3
). For example, a large-scale study of low income minority pregnant women reported that 29.3% (7
) had experienced a traumatic event; another study of a similar population reported rates of post traumatic stress disorder (PTSD) to be 7.7% (8
). Markedly elevated rates of co-morbid depression (42.2% and 66.7%) and anxiety disorders (any anxiety disorder 35.1%, panic disorder 36.4%) were found in studies by Loveland Cook et al (8
) and Smith et al. (7
The pathophysiology underlying mood changes throughout the perinatal period is not fully understood. Potential mechanisms currently being investigated include genetic vulnerability (9
), disruption of the HPA axis (10
), sensitivity to changes in levels of steroid hormones (11
) and other markers of stress including sleep disruption (13
). In the current paper, we consider the hypothesis that prenatal mood disorders may be associated with cytokines (low molecular weight, circulating messenger proteins) that often promote inflammation (i.e., proinflammatory cytokines), specifically Tumor Necrosis Factor (TNF)-α and Interleukin (IL)-6.
Although IL-6 and TNF-α are both involved in immune responses, hematopoeisis, and inflammation, they are distinct proteins with their own characteristic functional properties (15
). These cytokines are secreted by monocytes/macrophages within the immune system and other organs. However, TNF-α can be produced by some T helper, Th 1cells, whereas IL-6 is produced by Th 2 cells. Further, IL-6 is, notably, secreted by adipocytes and endothelial cells. Although both IL-6 and TNF-α are important components of acute phase responses to a variety of challenges, there are a number of studies that report low correlations between these two cytokines (16
A growing body of literature suggests that proinflammatory cytokines may be causally associated with psychiatric symptoms (20
). Evidence for this derives from several sources involving non-pregnant samples. First, exposure to psychosocial stressors, including marital difficulties and childhood maltreatment, is associated with inflammation and proinflammatory cytokine production (22
). Second, illnesses characterized by chronic inflammatory responses are also associated with depression (25
). Third, the administration of cytokines such as IFN-α to treat infectious diseases or cancer often results in patients exhibiting ‘sickness behaviors’ analogous to depressive symptoms; these symptoms ceased when treatment was stopped, and the symptoms were attenuated with antidepressant treatment (26
). A recent meta-analysis found that compared to control subjects, patients with major depression had significantly higher concentrations of IL-6 and TNF-α (29
); associations with other cytokines were not significant. Studies of cytokines and anxiety symptoms are fewer and focus particularly on PTSD (30
), but also provide robust evidence that compared to controls, subjects with PTSD have significantly increased levels of serum IL-6 (32
) and TNF-α (33
It is not yet clear whether the link between psychiatric symptoms and proinflammatory cytokines reported outside of the perinatal period exists during pregnancy, or how this may help to explain prenatal mood disorders. Pregnancy is characterized by substantial alterations in endocrine and immune measures with obvious functional importance (35
), and these pregnancy-related changes may disguise or confound a link with psychiatric symptoms. Available data indicating such relationships are limited, but suggestive. Coussons-Read et al (36
) reported a significant association between elevated psychosocial stress scores and higher levels of IL-6 and TNF-α measured in the first and third trimesters. Christian et al (38
) did not find a significant association between perceived stress and either IL-6 or TNF-α at 15 weeks gestation, but did report that depressive symptoms were significantly and positively associated with IL-6 and marginally with TNF-α. More work is clearly needed to determine if a link exists, whether or not it is evident throughout pregnancy, and which symptom patterns are most closely associated with cytokine production. Accordingly, the central aim of this short-term longitudinal study is to investigate the link between psychiatric symptoms and proinflammatory cytokines in a sample of pregnant women using a broad index of psychiatric symptoms.
Considerable evidence associates psychiatric symptoms and stress with low birth weight, premature labor and delivery, and pregnancy complications (39
). Therefore, if there is a link between prenatal psychiatric symptoms and inflammation, as we hypothesized and studies of non-pregnant women document, then that raises the possibility that symptoms may predict obstetric outcomes via their association with cytokine production. That follows reports in the obstetrics literature that inflammation in pregnancy predicts poor obstetric outcomes (48
). We consider this an exploratory hypothesis because a very substantial number of individuals with pregnancy complications may be needed to detect this mediation (in contrast to the numbers needed to detect associations between symptoms and cytokines, the central aim of the paper).
In summary, the current study was designed to extend the limited research on psychiatric symptoms and proinflammatory cytokines in women with a normal pregnancy. We do this by a) focusing on a broad set of psychiatric dimensions (depression, anxiety and trauma) and targeting proinflammatory cytokines most reliably assessed in the clinical literature (IL-6 and TNF-α); b) including women at high psychosocial risk, who are typically under-represented in the literature; and c) assessing women in two occasions of measurement, during the 2nd and 3rd trimesters, to try to account for the changing nature of both symptoms and cytokines across pregnancy.