Review
Depression in new mothers is common in many cultures, affecting anywhere from 10% to 20% of postpartum women. In some high-risk populations, the percentage can even be as high as 40% or 50%
Inflammation and depression
In recent years, researchers in the field of PNI have found that inflammation is involved in the pathogenesis of depression. Maes and colleagues first documented that mothers with the postpartum blues had higher levels of inflammation than mothers who did not
When researchers first identified inflammation as increasing the risk of depression, most considered it an independent risk factor along with several others. The other risk factors included psychosocial stress, a broad category that included significant life changes, lack of social support, marital difficulties, infant illness or prematurity, and low income. Psychological trauma, another risk factor, includes current trauma or a history of trauma, which creates a vulnerability to future stressors even when there are no current symptoms. Sleep disturbance and pain are physical stressors that are common among new mothers and increase the risk of depression. The model portrayed on Figure
Risk Factors for Depression in New Mothers – Old Paradigm
Risk Factors for Depression in New Mothers – Old Paradigm. depicts six risk identified risk factors for depression in new mothers: stress, sleep disturbance, pain, inflammation, psychological trauma, and a history of abuse depression or trauma.
More recent research, however, suggests a new paradigm for understanding depression. PNI researchers have found that physical and psychosocial stressors (i.e., all the risk factors for depression) increase inflammation
Risk Factors for Depression in New Mothers – New Paradigm
Risk Factors for Depression in New Mothers – New Paradigm. depicts five risk factors for depression in new mothers (stress, sleep disturbance, pain, psychological trauma and a history of abuse or trauma) with inflammation as the underlying risk factor.
Puerperal women are especially vulnerable because their inflammation levels rise significantly during the last trimester of pregnancy – a time when they are also at high risk for depression. Moreover, common experiences of new motherhood, such as sleep disturbance, postpartum pain, psychological stress, and trauma also increase inflammation. Physical and psychosocial risk factors for depression are still important to identify. The old paradigm identifies the known causes of depression in new mothers.
The new paradigm moves the field forward and provides an answer to the next question: why? Why would psychosocial risk factors, such as lack of social support or marital strife or stress, increase the risk of depression? Why would depression be more likely in women who are sleep deprived or who have experienced trauma or pain? The new paradigm provides perspective on the mechanism by which previously identified risk factors increase risk. It also guides practitioners in their intervention efforts and suggests that targeting inflammation may increase women's resilience to other stressors.
Breastfeeding and depression in mothers
Breastfeeding also has an important role to play in mothers' postpartum mental health. Groër and Davis noted that "breastfeeding confers some psychoneuroimmunological benefits to mothers" (p. 599) in part because of its impact on stress
Method of literature review
The studies cited below were assembled from a wide variety of sources. Literature searches on PubMed and PsychInfo were conducted on depression, postpartum/postnatal depression, depression and inflammation, proinflammatory cytokines, pain, sleep disturbances, HPA dysfunction and depression, trauma, omega-3 fatty acids, inflammation and depression. In addition, several key PNI and psychiatry journals were manually searched for relevant articles including
Physical and psychological stressors that increase inflammation and risk of depression
To understand the role of inflammation in depression, it's helpful to first review the normal physiologic response to stress. When faced with a threat, human bodies have a number of interdependent mechanisms in place designed to preserve our lives. The sympathetic nervous system responds by releasing catecholamines (norepinephrine, epinephrine, and dopamine). The hypothalamic-pituitary-adrenal (HPA) axis also responds: the hypothalamus releases corticotrophin releasing hormone (CRH), the pituitary releases adrenocorticotropin hormone (ACTH), and the adrenal cortex releases cortisol, a glucocorticoid. The immune system responds by increasing production of proinflammatory cytokines, which increase inflammation. Cytokines are proteins that regulate immune response. Proinflammatory cytokines help the body heal wounds and fight infection by stimulating an inflammatory response
Maes and colleagues described the interrelatedness of these systems and noted that inflammation influences levels of serotonin and catecholamines, and has an impact on the HPA axis, which controls cortisol levels
(1) Immune and HPA dysfunction in depression
Depression is also related to some distinct abnormalities in the immune system and HPA axis. I will describe the immune effects first. For many years, researchers considered depression to be primarily immunosuppressive in that they observed that depressed people had fewer lymphocytes and the natural killer cells (NK) had lower cytotoxicity
The proinflammatory cytokines that researchers identified most consistently as being elevated in depression are interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and more recently, interferon-γ (IFN-γ)
Depression can also influence the systems that normally keep inflammation in check, such as the HPA axis. Cortisol is anti-inflammatory and is generally secreted when inflammation levels get too high. However, depressed people either have abnormally low levels of cortisol or they become less sensitive to cortisol. In either case, cortisol fails to restrain the inflammatory response. In one recent study of 72 women, depressed women had higher levels of IL-6 and TNF-α in response to an acute stressor than women who weren't depressed
(2) Depression, inflammation and preterm birth
Depression poses another health risk to puerperal women – increased risk of preterm birth. Several researchers have noted that depression and posttraumatic stress disorder increase risk of preterm birth, and inflammation may explain why
In a prospective cohort study of 681 women, the rate of spontaneous preterm birth for depressed women was more than twice that of women who were not depressed (9.7% vs. 4%; OR: 3.3)
The proinflammatory cytokines IL-6, IL-8, and TNF-α ripen the cervix before birth and these are also elevated when women are under stress. In a study of 30 pregnant women, Coussons-Read and colleagues found that TNF-α and IL-6 levels were significantly higher, and the anti-inflammatory cytokine IL-10 was significantly lower, in mothers who were stressed compared with mothers who weren't
Inflammation may also explain another set of findings regarding preterm birth. In a study of 291 low-income pregnant women, participants were randomly assigned to receive either DHA-enriched eggs or regular eggs that they were to consume daily during the last trimester of their pregnancy
(3) Physical and psychological stressors
As described in the previous section, human bodies are designed to respond a certain way when they are threatened. These threats can be physical or psychological; the physiological response is the same. Moreover, some types of stressors have both physical and psychological elements. Three stressors – sleep disturbance, pain, and trauma – are particularly relevant to new mothers. Studies that examine these stressors with regard to inflammation are described below.
(a) Sleep disturbances and fatigue
Sleep disturbances and fatigue are physical and psychological stressors that increase the risk of depression. Fatigue and sleep problems are often overlooked or minimized because they are so common in new mothers. But fatigue is often of great concern to mothers, and quantity and quality of sleep can alter stress both immune function and emotional well-being
Sleep disturbance and depression are also mutually maintaining conditions: sleep disturbance can cause depression and depression causes sleep disturbances. Ross et al. noted that several factors suggest a relationship between sleep problems and depression in postpartum women
1) Insomnia is a significant risk for new-onset depression;
2) Sleep disturbances are common in most psychiatric disorders;
3) Treatments that manipulate sleep and circadian rhythms can be used to treat mood disorders.
In a review of polysomnographic studies of postpartum women, Ross et al. noted that there are differences in REM latency for women at risk for postpartum depression or who have current postpartum depression – reduced REM latency, increased total sleep time during pregnancy and decreased total sleep time postpartum
Sleep disturbances and fatigue too are related to cytokine levels. When proinflammatory cytokine levels are high, fatigue increases. Moreover, the body experiences disturbed sleep as a physiological stressor
Another study examined the role of the proinflammatory cytokine IL-1β in postpartum women
In a study of women four to six weeks postpartum, Groër and colleagues found that mothers' fatigue levels correlated with their levels of stress and depression
In a more recent study of 200 women at 4 to 6 weeks postpartum, Groër and Morgan found that depressed mothers reported more fatigue and daytime sleepiness than non-depressed mothers
In summary, sleep disturbances and fatigue are physical stressors that increase the risk of depression. The relationship between sleep problems and proinflammatory cytokines appears to be bidirectional: sleep disturbances increase cytokines and cytokines increase sleep disturbance by delaying sleep onset, increasing daytime fatigue, and perpetuating the cycle of disturbed sleep and inflammation. Motivala and colleagues hypothesized that interventions that target disordered sleep may also lower inflammation, thereby lowering the risk of depression
(b) Pain
Pain is another physical and psychological stressor related to increased inflammation and the risk of depression. Pain and depression are highly co-morbid conditions and may have a common etiology
The relationship between pain and inflammation also appears to be bidirectional. When a woman experiences pain, stress hormones and levels of proinflammatory cytokines increase. High levels of proinflammatory cytokines, in turn, increase pain. Cytokines (especially IL-1) are stimulated by Substance P. Substance P is the neuropeptide that is high in patients with pain. In one study, patients with major depression or posttraumatic stress disorder were compared to healthy controls (n = 101)
Sleep disturbances can also increase pain. An example of the relationship between disrupted sleep and pain is in the chronic pain syndrome fibromyalgia. While this is a controversial diagnosis in some circles, researchers have noted that patients with fibromyalgia have a number of physiologic abnormalities that cannot be influenced by patient report. These include increases in Substance P (up to three times as much compared to healthy controls), decreases in serotonin and the serotonin metabolite 5-HIAA in the cerebral spinal fluid, abnormal brain activation patterns, and of relevance to the present discussion, abnormal sleep patterns
An interesting exception to the pain-sleep disturbance phenomenon is co-sleeping. Polysomnographic studies of breastfeeding mothers who are sleeping next to their babies for all or part of the night indicate that the mothers spend less time in deep sleep than mothers who are not co-sleeping. Despite significantly decreased slow-wave sleep, co-sleeping mothers do not appear to report an increase in body pain
Pain can be a potent trigger for depression in postpartum women. A common type of pain in the first few weeks after birth is nipple pain. A study of 113 breastfeeding women (48 with nipple pain, 65 without) demonstrated that women with pain were significantly more likely to be depressed than women without pain (38% vs. 14%)
Unfortunately, nipple pain appears to be common, even among educated, middle-class women – the group most likely to breastfeed. In one study in Minneapolis, Minnesota, an astonishing 50% of women had nipple pain at five weeks
In summary, postpartum pain is a common experience among women who have recently given birth
(c) Current trauma or history of trauma
Psychological trauma can also have an impact on depression and cytokine levels. Like depression, posttraumatic stress disorder (PTSD) is a dysregulation of a normal stress response. Cortisol levels can be abnormally high or low. Previous studies found that people with PTSD had abnormally low cortisol levels. When cortisol is not there to inhibit the inflammatory response system, people who have PTSD have increased cytokine activity
According to the
PTSD can be caused by a pre-existing trauma, such as sexual assault or natural disaster. Or it can be caused by the birth itself. In a review of the literature, Beck found that the rates of women who met full criteria for PTSD following birth ranged from 1.5% to 6%
1) The impact of highly stressful births on breastfeeding
Women may also have experiences that are highly stressful, while not leading to PTSD
2) Prior history of depression or trauma
A woman with a history of depression or trauma is often more vulnerable to current life stresses. One way that that vulnerability manifests is a more rapid inflammatory response to current stressors. This effect has been noted in both human and animal research. For example, in an animal study, prior exposure to a stressor (in this case, inescapable foot shock) led to a hypersensitivity of the inflammatory response system and more rapid release of proinflammatory cytokines when exposed to a subsequent stressor
Kiecolt-Glaser and colleagues also noted that stress and depression appear to prime the inflammatory response so that it is more reactive to subsequent stressors
Implications: goals of prevention and treatment
A PNI approach suggests two important and related goals for the prevention and treatment of depression in new mothers: reduce maternal stress and reduce maternal inflammation. These recommendations are described below.
(1) Reduce maternal stress
Since physical and psychological stressors trigger the inflammatory response system, the first goal for preventing or treating depression is to reduce maternal stress. And one important way to do this is for health care providers to encourage mothers to breastfeed, and to support ongoing breastfeeding relationships.
(a) The adaptiveness of breastfeeding
When breastfeeding is going well, it protects mothers from stress
Another study compared stress levels of three groups of women: women who were exclusively breastfeeding (n = 84), women who were exclusively feeding infant formula (n = 99), and non-postpartum healthy volunteers (n = 33)
A study of 43 breastfeeding women found that both breastfeeding and holding their babies without breastfeeding significantly decreased ACTH, plasma cortisol, and salivary free cortisol
Exclusive breastfeeding also increases the effectiveness of the mothers' immune system
Breastfeeding and stress in babies
Breastfeeding not only reduces stress for mothers; it also lowers stress that babies experience when their mothers are depressed. Jones et al. compared the infants of four groups of women: depressed mothers who were either breast or bottle feeding, and non-depressed mothers who were either breast or bottle feeding
The researchers found that the babies of the depressed/non-breastfeeding mothers had the abnormal pattern of right-frontal asymmetry
In summary, breastfeeding protects maternal mood by lowering stress. When stress levels are lower, the mother's inflammatory response system will not be activated, thereby lowering her risk of depression. However positive these results, I must issue one caveat: they only apply when breastfeeding is going well. As noted earlier, when breastfeeding that is not going well, particularly if there is pain, it becomes a trigger to depression rather than something that lessens the risk. Mothers' mental health is yet another reason to intervene quickly when breastfeeding difficulties arise.
(b) Exercise and depression
Another way mothers can reduce stress is to exercise, which has also been found to alleviate depression. In a Finnish population study (n = 3,403), men and women who exercised two to three times a week experienced significantly less depression, anger, cynical distrust, and stress than men and women who exercised less frequently
The efficacy of exercise was also demonstrated in a randomized trial of patients with major depressive disorder. In this study, 156 patients with major depression (>50 years old) were randomized into one of three treatment groups: aerobic exercise alone, sertraline (antidepressant) alone, and a combination of exercise and sertraline
In summary, by linking stress and depression, the PNI framework provides a rationale for why exercise would be an effective intervention for depression – something practitioners can share with mothers. The goal is improved mental health, not weight loss (although some might occur). Depressed mothers need this information because exercise is often the very last thing they feel like doing. But exercise is an effective technique for both decreasing their risk of depression and helping them cope with the stresses and strains of early motherhood.
(2) Reduce inflammation
The second recommendation is for mothers to reduce inflammation. As described earlier, psychosocial and physical risk factors for depression increase inflammation, which increases depression risk. One way to decrease inflammation is through consumption of long-chain omega-3 fatty acids. Omega-3s show promise in the treatment of mood disorders according to a 2006 expert panel convened by the American Psychiatric Association
(a) Long-chain omega-3 fatty acids and depression
Over the past 100 years, the diet of people in many Western cultures has changed substantially. Some have theorized that these changes could explain the increase in depression during this same time period
(i) Anti-inflammatory activity of omega-3s
Omega-3s are powerful anti-inflammatories and lower proinflammatory cytokines. In a large population study, high levels of omega-3s (ALA, EPA and DHA) were related to lower levels of the proinflammatory cytokines IL-1α, IL-1β, IL-6, and TNF-α and higher levels of anti-inflammatory cytokines such as IL-10. For people with low levels of omega-3s, the opposite was true: these people had high levels of proinflammatory cytokines and low levels of anti-inflammatory cytokines
In a study of older adults, the combination of depression and higher omega-6: omega-3 ratios dramatically increased levels of proinflammatory cytokines (IL-6 & TNF-α) beyond the individual contribution of either variable alone. The authors noted that a diet with a high ratio of omega-6s:omega-3s increases the risk of both depression and diseases related to chronic inflammation including heart disease, diabetes and cancer
EPA and DHA may also increase resilience to stress by regulating and attenuating the stress response. Maes and colleagues noted that an imbalance of omega-6s:omega-3s leads to an overproduction of proinflammatory cytokines in response to psychological stress
(ii) Omega-3s in population studies
Population studies have provided support for the efficacy of omega-3s in preventing depression and other mental health problems by demonstrating that populations who naturally consume more omega-3s in their diets (usually by eating fatty coldwater fish, e.g. such as salmon or mackerel) have lower rates of a variety of mental health problems. For example, populations with higher levels of EPA and DHA in their diets had lower levels of major depression, bipolar disorder, and future suicide risk
(iii) Treatment with EPA and DHA
Positive findings have been noted in randomized clinical trials, where researchers have given either EPA/DHA supplements or a placebo to people currently receiving treatment for unipolar or bipolar depression. When EPA was added to patients' normal regimen of antidepressants, EPA made the antidepressants more effective in treating depression than the placebo
In a recent review, EPA had efficacy in the treatment of depression in four of the six studies reviewed
A preliminary study demonstrated that EPA and DHA may have efficacy in the treatment of postpartum depression. The study was limited, however, by a small sample, no control group, and subjects who were not blind to the treatment condition. This study was intriguing, however, because depression decreased 48% to 51% in the eight-week study period
(iv) DHA in the perinatal period
During the perinatal period, DHA appears to be particularly important
DHA appears to have a role in the prevention of depression, but according to two recent reviews, has no efficacy in treatment of depression when used alone
DHA may have another effect that could help prevent depression postpartum. In a study of infant sleep, mothers with high levels of DHA during pregnancy had babies who exhibited a more mature sleep pattern in the first few days of life
(v) Sources of EPA and DHA
As the previously cited studies indicate, women are often deficient in long-chain omega-3 fatty acids during the perinatal period. However, pregnant or breastfeeding women often need to limit the amount of fish they eat, the prime source of EPA and DHA, because of contaminants in seafood. Fortunately, there are a alternative sources of EPA and DHA that are tested for contaminants and are contaminant free. A listing of sources of EPA/DHA that are tested for contaminants can be seen in Additional file
Sources of EPA/DHA that are tested for contaminants
Click here for file
(b) Other anti-inflammatory treatments for depression
In addition to omega-3s, several standard treatments for depression are also anti-inflammatory. For example, the herbal antidepressant St. John's wort has long been known to be anti-inflammatory
One could even argue that cognitive therapy is anti-inflammatory. Two recent studies have demonstrated that negative beliefs, such as hostility, can increase the levels of proinflammatory cytokines – especially IL-6
Conclusion
Recent research has identified inflammation as a key factor in depression, and inflammatory response system is triggered by both physical and psychological stress. Postpartum women are particularly at risk because their inflammation levels are naturally elevated in the last trimester of pregnancy, and this elevation continues through the postpartum period. Two approaches may prevent depression or reduce its severity: lowering maternal stress and reducing inflammation. Breastfeeding has been shown to reduce stress and protect maternal mood. Breastfeeding also reduces stress of babies of depressed mothers and protects them from the harmful effects of maternal depression. Treatment approaches that are anti-inflammatory have efficacy in treating depression. These include EPA and DHA, exercise, cognitive therapy, herbal anti-depressants such as St. John's wort, and standard antidepressants. Research is needed to assess if anti-inflammatory approaches used proactively can prevent depression from occurring in the first place.
Abbreviations
ALA: α-linolenic acid
COX-2: cyclooxygenase-2
CRP: C-reactive protein
DHA: docosahexaenoic acid
EEG: electroencephalogram
EPA: eicosapentaenoic acid
HPA: hypothalamic-pituitary-adrenal axis
ICAM: intercellular adhesion molecule
IL-1β: Interleukin-1beta
IL-6: Interleukin-6
IL-10: Interleukin-10
IFN-γ: Interferon-γ
IRS: inflammatory response system
PNI: psychoneuroimmunology
PTSD: posttraumatic stress disorder
SSRI: selective serotonin reuptake inhibitor
TNF-α:Tumor Necrosis Factor-alpha
Competing interests
The author worked briefly in 2006 as a consultant and continuing education provider for Martek Biosciences Corporation. This paper was written independent of that work and was completed several months after the consulting agreement ended.