The Search for Postpartum Depression Biomarkers

The prevention of maternal psychiatric illness, particularly postpartum depression (PPD), has the potential to usher in far-reaching individual and societal consequences. A growing body of evidence suggests that maternal mental health significantly affects children’s physical, intellectual, and emotional development. PPD has been shown to result in lower IQ, slower language development, increased rates of attention-deficit/hyperactivity disorder, as well as an increased risk of behavioral issues and psychiatric illness in the exposed children.¹ Further, the Adverse Childhood Experiences (ACE) study² found a strong and graded relationship between exposure to abuse or household dysfunction during childhood that in turn was linked to multiple risk factors for the leading causes of death in adults. The ACE study screened for psychiatric disorders in the household, but many other ACEs can be linked to adverse maternal mental health, including substance abuse, divorce, and increased rates of abuse in the home.

In sum, targeting maternal mental health could improve both mental and physical outcomes for everyone in the home, and potentially improve outcomes for whole communities. While improving maternal mental health is bigger than preventing PPD, if we start with preventing PPD we can at least improve cognitive and mental health outcomes for both mothers and their children.

Risk Factors for Postpartum Depression

So how do we prevent PPD? One possibility is identifying markers or factors that are strongly predictive of PPD on an individual level, preferably prior to the onset of symptoms. These are collectively known as biomarkers: measurable substances whose presence is indicative or predictive of an illness’ onset and outcome.

PPD may be one of the easier psychiatric diseases to study, because you can identify the at-risk population and predict when the disease will occur. If you take 100 pregnant women, about 10 to 15 of them will become depressed in the first few weeks following childbirth. If those pregnant women have a history of a mood disorder and are not taking psychiatric medications the rate is even higher.^3-5 By following women through pregnancy while collecting potential biomarkers and then identifying who becomes ill postpartum, one can identify biomarkers that are predictive of later illness.

There are numerous factors associated with the development of PPD, at least on the group level. For example, having a psychiatric history prior to pregnancy, a family history of psychiatric illness including PPD, and being depressed in pregnancy are all associated with the development of PPD.⁶ These increase the odds of developing PPD, but the exact risk for a specific individual is difficult to quantify. The same can be said for various environmental risk factors, such as socioeconomic status, adverse life events, and obstetrical outcomes such as preterm birth.⁶ As mental health providers, we can screen for these factors in our patients and know that an individual is at an increased risk given her individual or family history, but we cannot predict whether she will develop PPD. More personalized prediction, however, may be possible.

Perhaps our most promising biomarker potential for PPD is epigenetics. Marrying environmental influences and gene function, epigenetics examines changes to DNA that do not alter the DNA sequence itself, but they do turn the function of the gene on or off. Much of the literature in this area has focused on DNA methylation, which can be altered by such environmental factors as stress, medication use, and hormones. Epigenetic alterations have the potential to explain some psychiatric illnesses, which could be the result of an underlying biological vulnerability that is triggered by environmental stressors. In the case of PPD, one possibility is that hormonal changes during pregnancy lead to epigenetic changes of particular genes that serve either as a marker for or as an underlying cause of PPD.

The Search for Personalized Biomarkers

My colleagues and I have published a series of studies identifying 2 epigenetic biomarkers of PPD. In our first publication, we initially identified genetic loci that were responsive to high dose estrogen in the mouse hippocampus.⁷ We cross-referenced these loci to DNA methylation differences in samples of blood from pregnant women with mood disorders, who were followed prospectively through pregnancy and postpartum.

The initial sample included pregnant women who were clinically well during pregnancy and either did or did not develop PPD. Two loci were identified at the HP1BP3 and TTC9B genes which, based on methylation differences, were able to correctly identify whether a woman did or did not develop PPD with an 87% accuracy.⁷ We then performed a replication analysis in women who were depressed during pregnancy and either continued to be depressed or recovered postpartum. Our biomarkers were again able to segregate PPD status with 88% accuracy.⁷ We then went on to replicate these results in an independent sample of 51 pregnant women with preexisting mood disorders, as well as in a sample of 240 pregnant women without a previous psychiatric diagnosis, with an accuracy of at least 80%.⁸ Most recently, our group again replicated the PPD prediction, but also found that we were also able to predict third trimester depression using blood samples from the first trimester.⁹

The exact functions of the TTC9B and HP1BP3 genes are currently unknown, but bioinformatics analysis suggests that both may be involved in mediating synaptic plasticity in the brain, and both have ties to estrogen signaling.⁷ Interestingly, mice without functioning HP1BP3 genes exhibit impaired maternal care, leading to a dramatic reduction in pup survival, indicating a role for the gene in maternal behavior.¹⁰ Further work on the functions of these 2 genes and their role in PPD may ultimately help elucidate the biological underpinnings of PPD.

Concluding Thoughts

What are the next steps? We are validating the biomarkers in a larger sample and examining what factors might be involved when there is a mismatch between what biomarkers predict and what actually happens from a psychiatric perspective postpartum.

The next important scientific step is to attempt the holy grail of psychiatry: a prevention study. Can PPD be prevented when a woman has the biomarkers in pregnancy or does having the biomarkers make the development of PPD inevitable? If PPD can be prevented, are there some interventions that are more effective than others?

Dr Payne is currently Associate Professor of Psychiatry and Director of the Johns Hopkins Women’s Mood Disorders Center at the Johns Hopkins School of Medicine, Baltimore, MD. Beginning September 1, She will become Professor of Psychiatry and Vice Chair of Research at the University of Virginia, Charlottesville, VA.

References

1. Grace SL, Evindar A, Stewart DE. The effect of postpartum depression on child cognitive development and behavior: a review and critical analysis of the literature. Arch Womens Ment Health. 2003;6(4):263-274.

2. Felitti VJ, Anda RF, Nordenberg D, et al. Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences (ACE) Study. Am J Prev Med. 1998;14(4):245-258.

3. Payne JL, Roy PS, Murphy-Eberenz K, et al. Reproductive cycle-associated mood symptoms in women with major depression and bipolar disorder. J Affect Disord. 2007;99(1-3):221-229.

4. Viguera AC, Tondo L, Koukopoulos AE, et al. Episodes of mood disorders in 2,252 pregnancies and postpartum periods. Am J Psychiatry. 2011;168(11):1179-1185.

5. Kimmel M, Hess E, Roy PS, et al. Family history, not lack of medication use, is associated with the development of postpartum depression in a high-risk sample. Arch Womens Ment Health. 2015;18(1):113-121.

6. Guintivano J, Manuck T, Meltzer-Brody S. Predictors of postpartum depression: a comprehensive review of the last decade of evidence. Clin Obstet Gynecol. 2018;61(3):591-603.

7. Guintivano J, Arad M, Gould TD, et al. Antenatal prediction of postpartum depression with blood DNA methylation biomarkers. Mol Psychiatry. 2014;19(5):560-567.

8. Osborne L, Clive M, Kimmel M, et al. Replication of epigenetic postpartum depression biomarkers and variation with hormone levels. Neuropsychopharmacology. 2016;41(6):1648-1658.

9. Payne JL, Osborne LM, Cox O, et al. DNA methylation biomarkers prospectively predict both antenatal and postpartum depression. Psychiatry Res. 2020;285:112711.

10. Garfinkel BP, Arad S, Neuner SM, et al. HP1BP3 expression determines maternal behavior and offspring survival. Genes Brain Behav. 2016;15(7):678-688.