Progress in perinatal mental health research

Perinatal psychiatric and substance use disorders are common, yet suboptimal treatment is frequent.¹ Underdiagnosis and undertreatment of perinatal psychiatric and substance use disorders is associated with poor maternal functioning, increased risk for adverse obstetrical and neonatal outcomes, and abnormal child socioemotional regulation including effects on cognitive and executive function and stress responsivity.^{2, 3} This special issue highlights the importance of the growing subspecialty of perinatal psychiatry with its rich cross-disciplinary approach bridging diverse specialties including obstetrics, neonatology, developmental pediatrics, child and adult psychiatry, psychology, psychiatric epidemiology, neuroscience, and more.

In this issue, several studies focus on risks associated with the development of perinatal psychiatric disorders or their relationship with a variety of maternal and infant outcomes. Johannsen et al. reported that the baseline risk of developing a mild to severe postpartum psychiatric episode was 6.9%, while for young mothers with a personal and family history of psychiatric disorders, the absolute risk rose to 21.6%, and rose further to 29.2% when information on high genetic liability to depression was added.⁴ While this risk calculation may not include all potential risk factors for an individual patient, these well-established personal risk factors when combined make it possible to identify a vulnerable group of women at significant risk for a postpartum psychiatric episode. Related, Schoretsanitis et al. reported that postpartum hemorrhage, which affects up to one-tenth of women giving birth, is a risk factor for the development of postpartum depression, a risk which was further increased in women with a history of depression or anxiety.⁵

Huizink et al. examined the normative courses of pregnancy-related anxiety in a large birth cohort.⁶ They identified two distinct trajectories of pregnancy-related anxiety, a low-symptom group (88.6%) with lower and slightly increasing levels of pregnancy-related anxiety, and a moderately high symptoms group (11.4%) who reported higher and slightly decreasing levels of anxiety. The presence of moderately high symptoms was correlated with several general risk factors for mental health disorders including a lower income, use of alcohol or smoking early in pregnancy, more early life adversities, younger age, primiparity, and single parenthood, among others. The authors suggest that women with high levels of pregnancy anxiety throughout pregnancy may need more clinical attention, as their symptoms may point to the presence of other mental health disorder risk factors, which together may negatively affect fetal and infant development and behavior.

A second group of studies focus on perinatal psychiatric disorder treatments. Research into the treatment of perinatal psychiatric disorders can focus on treatment efficacy in either the antenatal or postnatal periods, adverse treatment effects of in-utero or lactational exposure to the fetus/infant or adverse effects of undertreated or untreated psychiatric illness during gestation or in the postnatal period. Given the unique physiological state of each trimester and in the postnatal period, the risks and benefits for the maternal-infant dyad often change across pregnancy and the postpartum period. Thus, research across the perinatal period is critical to our practice of evidence-based medicine and the ability to share decision-making with our patients.

Research examining adverse fetal/infant effects from in-utero exposure is challenging as many studies lack adequate comparison groups and may be limited by sample size and in their ability to measure all potential confounding factors.^7-9 In some studies that demonstrate statistically significant differences between exposed and unexposed groups, the clinical significance of some findings may not be readily clear. In this special issue, Onken et al.¹⁰ examined the effects of maternal modafinil treatment on fetal development and neonatal growth outcomes and reported that in-utero exposure was associated with lower birth weight and neonatal head circumference but not with major congenital anomalies. This is the largest study of in-utero modafinil exposure published to date, an important analysis since previous study outcomes were mixed, with some notes concerning rates of clinically impactful major congenital anomalies and adverse growth outcomes.^{11, 12} Because research in this area has yet to definitively determine the risks of antenatal modafinil use, Onken et al. recommend that modafinil should not be used during pregnancy.

While not a treatment per se, the role of Mother-Baby units in the management of perinatal mental health disorders is an important adjunct to pharmacological approaches. In a systematic review, Adhikary et al.¹³ found that Mother-Baby units consistently improved mother-infant attachment and mental health outcomes. Another study conducted a randomized controlled trial of cognitive behavioral therapy using an online, peer-delivered approach.¹⁴ This unique approach resulted in statistically significant reductions in both depressive and anxiety symptoms and improved negative emotionality in infants. This intervention could lead to increased access to treatment for those experiencing perinatal mood and anxiety disorders.

Research led by Rommel et al.¹⁵ examined if maternal genetic liability for major depression explains part of the association of antidepressant use in pregnancy with lower gestational age and birth weight. They confirmed that antidepressant use in pregnancy was associated with small reductions in gestational age and birth weight. However, they found that genetic liability for depression was not linearly associated with risk, so residual confounding was likely still present and that a potential confounder included depressive symptoms during pregnancy.

Given that pregnancies may be unintended and that most pregnancies may not be detected until organogenesis is well underway, prescribers should engage in pre-conception counseling with all patients who have the potential to become pregnant. In those shared decision-making conversations, in addition to the potential for treatment benefit, the risk of untreated psychiatric illness for the mother-infant dyad, as well as the known (and potential for currently unknown) risks of the treatment should be discussed and documented.

A final group of studies examined biological aspects in the pathophysiology of perinatal depression. Allopregnanolone has been under active study in the pathophysiology of perinatal depression^16-18 and allopregnanolone and its analog zuranolone have been developed in the United States for the treatment of postpartum depression.^19-21 Hare et al.²² reported unidirectional temporal associations between perinatal depression severity and allopregnanolone concentration, and specific associations between depression severity and allopregnanolone concentrations with postpartum structural changes in brain regions linked to emotion regulation and cognitive control. The research underscores the intricate interplay between perinatal depression severity, allopregnanolone concentrations, and postpartum gray matter volume, providing valuable insights into the neural mechanisms underlying perinatal depression and its potential implications for targeted interventions. Another study examined the association between perinatal depression and brain-derived neurotrophic factor (BDNF), which is involved in neuronal growth, neuronal differentiation, and synaptic plasticity and can be measured in peripheral blood, thought to be reflective of brain-tissue BDNF levels.²³ Jafarabady et al.²⁴ conducted a systematic review and meta-analysis on brain-derived neurotrophic factor levels in perinatal depression. The meta-analysis demonstrated a significant decrease in BDNF levels in both individuals with antepartum depression and postpartum depression.

Perinatal mental health research is important for several reasons. First and foremost, understanding the best treatment strategies during this crucial time period that optimize both parental and child outcomes is critical for reducing tragedies and minimizing the impact of perinatal mental illness. Second, identifying risk factors and biomarkers, particularly of individuals at elevated risk of later developing perinatal mental health disorders will eventually allow preventative rather than reactive clinical care. Finally, the timing of onset of perinatal mental health disorders is predictable which allows for study of the underlying pathophysiology as measurements of various biological processes can be taken prior to and after onset of the disorder. Identifying the biological processes underlying, for example, postpartum depression, is likely to lead to a greater understanding of major depression in general, and, in turn, lead to improved treatments and outcomes overall. This special issue demonstrates that progress is being made in perinatal mental health research. We look forward to seeing the clinical impact of these critical discoveries.

KMD receives research support from the National Institutes of Health. KMD also serves as a consultant to Sage Therapeutics, Biogen, Brii Biosciences, Gerbera Therapeutics, Neuroscience Software and Reunion Neuroscience. KMD served as a study principal investigator for contracted research awarded to the Feinstein Institutes for Medical Research from Sage Therapeutics, Nesos Corporation, Gerbera Therapeutics, Woebot Health and Premier Healthcare. JLP receives research support from the National Institutes of Health, Janssen Pharmaceuticals and Myriad Genetics. Dr. Payne has two patents: “Epigenetic Biomarkers of Postpartum Depression” and “Epigenetic Biomarkers of Premenstrual Dysphoric Disorder and SSRI Response.” Dr. Payne has Founder's Stock options in Dionysus Health. Dr. Payne has received consulting fees from SAGE Therapeutics, Biogen, Flo Health, and Brii Biosciences. She receives royalties from UpToDate and Elsevier. She has produced content for and received honoraria from Clinical Education Alliance, HMP Global, Med Learning Group and Medscape.