In the mystery of postpartum depression, the immune system offers clues
For decades scientists have been trying to solve the mystery of postpartum depression, including why it strikes some women and not others. The illness - marked by intense feelings of sadness and even thoughts of harming a child or oneself - can be devastating to mothers, newborns and entire families.
Now, emerging research may hold answers. Although postpartum depression has commonly been linked to the hormonal fluctuations of pregnancy, scientists say that the immune system may play a much larger role than previously known.
The findings have the potential to profoundly change how doctors diagnose and treat pregnancy-related depression. Most important, the research could one day identify mothers most at risk, so that support and treatment could begin before symptoms occur.
The focus on the link between immune health and postpartum depression is part of a seismic change happening in the study of psychiatric illnesses. Scientists around the world are finding that underlying autoimmune and inflammatory processes can have a profound impact on the brain and may be more common than previously believed in patients with a variety of neuropsychiatric conditions, including major depression.
Scientists have found that motherhood causes such dramatic remodeling of the brain that many researchers now consider it to be "like another critical period of brain development, like early life or adolescence," said Benedetta Leuner, associate professor of psychology at Ohio State University.
These brain changes may be a key to understanding both nurturing maternal behavior and how pregnancy-related depression can develop. And many experts believe that increasing awareness of the biological mechanisms of postpartum depression can help combat the all-too-commonplace stigma and shame that often accompany it.
The biological toll of pregnancy-related depression
Many mothers experience the "baby blues," a period of sadness, irritability and crying spells that typically lasts a few days following childbirth. But an estimated 1 in 5 women - about 700,000 Americans a year - experience a more severe, prolonged and debilitating depression during or after pregnancy, marked by intense feelings of hopelessness, disinterest and, in rare cases, psychosis. (Scientists prefer the term "peripartum depression" or PPD because about a third of the cases begin during pregnancy.)
The feelings can persist for weeks, months or even years, and can hamper parent-infant bonding and caretaking. It is also a leading cause of preventable maternal mortality: Suicide accounts for 20 percent of postpartum deaths.
Earlier this year, the Food and Drug Administration for the first time approved a pill to specifically treat the condition. The drug, sold under the brand name Zurzuvae, is a neuroactive steroid that mimics a natural metabolite of the hormone progesterone.
The drug is widely viewed as a game changer in helping women cope, but it doesn't solve the problem of identifying those at highest risk of PPD. Nor is it, along with standard therapy and antidepressants, expected to work on every woman.
"We do not know how to treat it as well as we should," said Tsachi Ein-Dor, an associate professor of psychology at Reichman University in Israel.
An immune response to pregnancy and parenthood
Increasingly, scientists are finding that shifting hormones are not the whole picture in PPD. The immune system also fluctuates in its activity during pregnancy.
"Immune changes are one of the most important changes that have to occur in order to essentially, you know, tolerate a visitor in your body for nine months," said Kathryn Lenz, an associate professor of psychology at Ohio State University.
During the first trimester, there is increased inflammation to assist the implantation of the embryo. By the second trimester, the immune system shifts to an anti-inflammatory state to prevent an attack on the rapidly growing fetus. In the third trimester and as labor approaches, the immune system rapidly ramps up and reenters a pro-inflammatory state to promote uterine contractions and the birth of the child.
Scientists already know that with prolonged inflammation and immune activity, inflammatory cytokines from the body can pass into the brain, triggering neuroinflammation and ultimately affecting brain areas involved in depression.
Pregnancy-related depression may represent an especially potent example of an inflammatory subtype of depression due to the profound changes in immune activity during and after pregnancy, said Lena Brundin, professor of neurodegenerative science at Van Andel Institute.
In one recent study of 165 postpartum women, Brundin and her colleagues found that increased inflammatory cytokines in the blood were associated with increased risk for severe and suicidal PPD.
In another study, scientists found that certain immune cells that are suppressed during pregnancy do not rebound properly after childbirth in women who developed PPD.
"If you look at the ways their immune systems change, it's not so simple as saying there's more or less inflammation," said Lauren Osborne, associate professor of obstetrics and gynecology at Weill Cornell Medicine and the study's lead author. "It's that there's this dysregulation all over."
Disruption of sleep and elevated stress - which are common in mothers nurturing a newborn - also are known to impact the immune system and increase inflammation. The link between stress and the immune system may also help explain why parents who do not directly experience pregnancy and childbirth can develop PPD. About 1 in 10 fathers develop PPD, as do some parents who adopt.
The motherhood brain
Pregnancy affects not only the immune system in the body but also the brain's resident immune cells - the microglia. Microglia are essential for sculpting brain circuits and may help prime a mother's brain for motherhood.
Research in rats found that late in pregnancy and postpartum, there is a marked decrease in microglia in the brain, particularly in areas important for maternal care and mood regulation. This decline in microglia may help initiate maternal behavior.
In a 2023 study, Ohio State researchers reported that female rats could be induced to care for another rat's pups after their microglia were artificially depleted to emulate the state of a pregnant rat's brain.
But preliminary data suggest that the brains of stressed rat moms look different. Stressed rats may have more inflammatory microglia in their brains than unstressed moms, suggesting that elevated microglia could contribute to PPD symptoms.
A metabolite called kynurenine may be another related factor in PPD. Kynurenine helps give our brain and body energy, particularly when it is under stress or when the immune system is activated, at the expense of producing serotonin, a neurotransmitter related to mood.
The energy production has another cost: Like a "nuclear reactor," it creates waste, and these metabolic byproducts of kynurenine can create "wear and tear on our brain," said Ein-Dor, who has written about the possible link between kynurenine and PPD.
The placenta, a new organ grown wholesale for pregnancy, is also replete with immune activity and enzymes that also promote more kynurenine production.
Prolonged inflammation and stress may shift the metabolic balance toward more kynurenine and can activate microglia, contributing to PPD.
Predicting pregnancy-related depression before it happens
For now, why some women get PPD and others don't remains a mystery.
Liza Amichay, now 39 and living in Israel, said she had three relatively easy births, and often felt like Wonder Woman as she balanced the demands of work, playdates for her three sons and a busy household.
But when she was seven months pregnant with her fourth son, something changed. Amichay, a school counselor, said she started crying a lot, feeling exhausted and overwhelmed. It only worsened when her child was born. She was hospitalized for two months after feeling suicidal despite trying numerous medical treatments.
"Every morning when I opened my eyes, I was crying," Amichay said. "Every night, I was hoping to die."
To help women like Amichay, researchers are working to find biomarkers and develop tests to detect changes in the immune system and kynurenine that could signal risk and potentially allow doctors to start treatment before peripartum symptoms develop.
In a 2022 study, Brundin and her colleagues collected blood samples from 114 women and evaluated their depression symptoms each trimester and following childbirth. Higher levels of specific inflammatory cytokines, IL-1β and IL-6, were associated with more severe depressive symptoms through and after pregnancy.
Crucially, analyzing blood samples for a combination of cytokines and kynurenine metabolites during the second trimester had a greater than 99 percent probability of predicting depression in the third trimester. This study was a proof of concept, and more work remains to be done before such a biomarker test can be used in the clinic.
Ein-dor is working on a longitudinal study on 200 heterosexual couples and collecting saliva samples to see if gene expression changes could predict the onset of PPD.
Building "a screening tool or predictive tool would allow us to assess risk groups," Ein-dor said. And if researchers can find "the exact dysregulations, then we can begin developing treatments, which would be much more effective than we have today."
Translating the research into tools for diagnosis and treatment remains challenging. Targeting inflammation during pregnancy is complicated because the immune system plays a vital role in healthy pregnancy. There is also the challenge of ensuring treatments are safe for the developing fetus and during breastfeeding.
There are ways mothers themselves can try to decrease inflammation through lifestyle changes, such as increasing exercise, shifting to a less inflammatory diet with fewer processed foods and refined carbohydrates and improving sleep.
But a need for more potent, targeted therapies remains. "Even if we try, we might not be successful to modulate some inflammation ourselves," Brundin said.
Reducing the stigma
Experts and patients say that the emerging biological understanding of pregnancy-related depression has already had an impact in destigmatizing pregnancy-related depression. "Saying that it's something biological - I think people are relieved by that and they feel less at fault," Osborne said.
Wendy Davis, who experienced PPD with her first child in 1994 and now is executive director of the nonprofit Postpartum Support International, said the new research may already help mothers with pregnancy-related depression who often blame themselves.
"Think back to the mom who thought: 'I'm embarrassed. I'm ashamed. I can't tell anybody because I think it's my fault,'" Davis said. "No, that's not it. You are a person made up of this unique set of biology and psychology."
Amichay now lectures about her experiences with PPD alongside Ein-dor, her former college tutor, who teaches about its biological underpinnings. She has gone back to working full time and coaches mothers who are facing mental health challenges.
Amichay said she was amazed when she first learned about Ein-dor's research into the biological basis of PPD. "This is a revelation," she said. "It could save so many lives."
Postpartum Support International offers resources, support groups and experts. The National Maternal Mental Health Hotline offers free confidential support before, during and after pregnancy 24/7 in English and Spanish. Call or text 1-833-TLC-MAMA (1-833-852-6262).
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