Perinatal Depression

Abstract

Purpose of review:

Perinatal depression is a common and debilitating complication of pregnancy and childbirth. Recent studies have elucidated relationships between acute birth events on depression risk, and novel treatments for postpartum depression have been discovered and approved. This article reviews current understandings about birth events on depression, new screening standards, and novel treatments for postpartum depression.

Recent findings:

Pain, analgesia, and depression are complex traits that are inter-related in during and after pregnancy. Certain individuals may benefit more than others from addressing pain and suffering around childbirth. Exposures to general anesthesia or post-dural puncture headache are associated with postpartum depression symptoms, although a causal relationship is unlikely. Brexanolone, ketamine and its related compounds, and non-pharmacologic options offer new or alternative therapies for depression, although safety information for some of these treatments in pregnancy and lactation are needed. Maternal health bundles call for close attention to perinatal mental health screening with validated instruments, and for timely treatment referrals in the “fourth trimester.”

Summary:

Clinical monitoring and timely treatment of depression in the perinatal and postpartum periods is critical for maternal postpartum health and recovery. Perinatal specialists and researchers should continue to focus on tailored treatments specific to this special population.

INTRODUCTION

Perinatal depression is depression – a mood disorder that causes persistent feelings of sadness and loss of interest – that occurs during or after pregnancy(1). Depression affects mental and physical performance and can result in significant emotional, relationship, and physical problems. Immediately after birth, it is normal for new mothers to experience a short period of exhaustion, worry, or other mild mood changes that accompanies adjustment to life with a newborn (i.e., “baby blues”)(2, 3). If these mood changes and anxiety persist beyond two weeks after birth, or become severe, a new mother may have depression. When depression manifests in the postpartum period two or more weeks after delivery, it is termed postpartum depression (PPD)(2). The American College of Obstetricians and Gynecologists (ACOG) has defined the first 12 weeks after delivery as a “fourth trimester” during which attention to mental health is important(24, 25). The perinatal anesthesiologist is concerned with both short- and long-term consequences of birth stressors and events for new mothers. This article will review new developments and understandings about pain, analgesia, and acute labor events on PPD risk and disease progression, as well as current postpartum PPD monitoring and treatment modalities.

EPIDEMIOLOGY

PPD is common, affecting 1 in 7 women who give birth, and first-time mothers are at 7.3 times higher risk for PPD(4). Women who have had PPD in the past have a 50% chance of experiencing it again in a future pregnancy(4). Infants of mothers with PPD are at risk for insecure attachments; children of mothers with PPD are at risk for cognitive delays, adolescent behavior problems, or future mood disorders(5, 6). Suicide, which can result from psychosis or unaddressed depression, is a common cause of maternal death worldwide(7). Because it is so common, debilitating, and with risk for serious maternal and child consequences, PPD remains a significant individual and societal health problem that demands rigorous clinical and research attention.

LABOR PAIN, ANALGESIA, AND DEPRESSION

Labor/perinatal pain, labor analgesia, and PPD have been linked in observational studies, although results have been conflicting(8). Some studies have found a protective relationship between improved pain management and/or labor analgesia and PPD(9–10,11**–13), while others have found no relationship(14), or potentially harmful relationships when plans and expectations for labor analgesia utilization do not meet reality(15). One study found genetic associations between clinical perinatal pain and depression, suggesting a potential biological explanation for these findings(16). Most observational studies have had limitations including small sample sizes, focus on labor analgesia utilization rather than pain, and incomplete confounding assessment(17**, 18). Some recent studies are limited by their use of population methodologies to answer questions about individual-level risk, e.g., analyses of administrative data lacking clinical detail and validation; systematic reviews, meta-analyses(19). Studies that ask simple questions about the use vs. non-use of labor analgesia on risk for PPD overlook the complexity of patient and medical decision-making around labor analgesia utilization; these complex factors that influence use or non-use of analgesia can independently associate with PPD risk, or can affect mediating factors that lead to PPD. Pain and depression are complex traits, and future studies should no longer focus on use vs. non-use of labor analgesia, but rather should examine pain and complex intermediating factors, including individual and cultural factors influencing pain/suffering experiences, that may either protect against or predispose toward risk for PPD. These types of studies remain important as they will address knowledge gaps around individualized pain management and childbirth experience and may lead to new methods or discoveries for PPD risk assessment and treatment.

RELATIONSHIP WITH POSTPARTUM RECOVERY

Depression can negatively affect overall postpartum recovery and well-being after childbirth(20). Depression, anxiety, and psychological measures are commonly measured psychosocial subdomains for postpartum recovery(21**). Higher acute postpartum pain has been linked with lower exclusive breastfeeding quality and rates, and higher depression scores(22*). Conversely, enhanced recovery protocols after cesarean delivery can help discharge patients sooner without affecting rates of PPD(23**). For many women, postpartum mood and mental health is an important aspect of functional recovery after pregnancy and childbirth that should be routinely assessed and treated.

ACUTE ANSTHESIA EVENTS AND DEPRESSION

Post-Dural Puncture Headache (PDPH) has been suggested to increase the risk for PPD, as well as post-traumatic stress disorder, chronic headache, chronic back pain, and reduced breastfeeding(26, 27). However, these studies have been limited by small sample sizes or have used administrative data with potentially limited accuracy for PDPH codes – it is possible that non-PDPH postpartum headache (e.g., migraine, tension headache, cluster headache) is coded as PDPH(28). Although causal relationship between PDPH and PPD is not currently established, best practice recommendations(29–31) underscore close follow-up and timely treatment of PDPH to improve symptoms and reduce risk for any adverse events.

General anesthesia for cesarean delivery was found to have increased odds of severe postpartum depression requiring hospitalization(32). However, general anesthesia is rarely used for cesarean delivery and typically used in cases of emergency events where there is no time to induce neuraxial anesthesia, or when neuraxial anesthesia is contraindicated or cannot be achieved for other reasons. However, the authors raised interesting points about the effects of anesthetics on mental health. Given the potential beneficial effects of some anesthetics (e.g., ketamine) on mental health, continuing research on potential interactions between anesthetic agents and post-operative psychological and neurocognitive effects in general is needed.

MONITORING AND TREATMENTS

Monitoring for depression during and after pregnancy is part of postpartum maternal mental health safety bundles(3, 5, 33, 34). The American College of Obstetricians and Gynecologists (ACOG) has reinforced the concept of the “fourth trimester” and advocated for a new paradigm of postpartum care, part of which includes recognition of mental health challenges that accompany this period(24, 25). National Institute for Health and Care Excellence (NICE) and ACOG recommend screening for postpartum depression at least once during the perinatal period for depression and anxiety symptoms, using a standardized, validated tool(4, 35). Positive screens should then be followed by appropriate referrals to behavioral health, social workers or consult liaison psychiatrists for further evaluation and care. In the peri-delivery period, anesthesiologists may be asked to evaluate patients with pain or other conditions/concerns, which may or may not be accompanied by tearfulness, anger, or moodiness. In these evaluations, the perinatal anesthesiologist should consider screening and appropriate referrals, through partnering closely with the patient and the primary obstetrician team.

Brexanolone is the first treatment specifically for PPD that was approved by the Federal Drug Administration in March 2019(36*, 37**). It is also known as allopregnanolone, and is classified as a neurosteroid antidepressant that works as a positive allosteric modulator of synaptic and extrasynaptic GABA receptors. A proposed mechanism of PPD involves fluctuations in neuroactive steroids, and brexanolone is thought to act by enhancing GABA activity, although its precise mechanism remains unknown. In two multicenter double-blind randomized placebo-controlled phase 3 trials, brexanolone resulted in significant and clinically meaningful reduction in depression scores(38). It works rapidly (within 48 hours) to reduce symptoms in major depressive disorder. However, it is costly, delivered by 60-hour intravenous infusion, and requires inpatient monitoring with pulse oximetry due to potential side effects of sedation and loss of consciousness. Brexanolone represents a potentially revolutionary option for PPD because it confers a faster treatment response than typical selective serotonin reuptake inhibitors or other drugs. This episodic control of depression can also allow for engagement in long-term psychiatric treatments, resulting in improved maternal-infant bonding and promoting a return to non-depressed functioning. Although brexanolone is a novel and promising treatment for severe PPD, monitoring, cost, and side effect constraints may potentially limit widespread clinical adoption to exceptionally severe cases.

Ketamine is an NMDA receptor antagonist, commonly used anesthetic agent with known antidepressant effects. Ketamine has rapid anti-suicidal effects(39**, 40) and is frequently used in treatment of major depressive disorder in non-pregnant populations. Its therapeutic mechanism is thought to be related to reversal of synaptic chronic stress pathophysiology by activating postsynaptic glutamate activation, although other mechanisms are also being investigated(41, 42). The duration of these effects and ideal dose administration is not known. Due to side effects of salivation, increased heart rate, increases on systemic arterial pressure and intracranial pressure, and psychomimetic properties, its use must be under strict monitoring(39). Esketamine, the active S(+) enantiomer form of ketamine, is well-tolerated with fewer side effects than racemic ketamine; it is available as both intravenous formulation and a nasal spray(37, 39). In 2019 esketamine was FDA-approved for use in treatment-resistant depression, and in 2020 was approved for expanded use for treatment of major depressive disorder with acute suicidal ideation or behavior in adults(43*). Clinically, it is given for acute suicidal ideation symptom relief while longer-term, comprehensive depression treatments are undertaken. For pregnant and postpartum persons, ketamine agents for depression treatment are not often used because data is lacking on safety in pregnancy and lactation, an important knowledge gap due to co-existing concerns about the effects of NMDA receptor antagonists on synaptogenesis and neuronal development in animals(44–46). The clinical translation and significance of these neuronal effects with low-dose ketamine administration in humans is controversial. Ongoing research efforts in these areas will shed light on relative safety of ketamine as a therapeutic option in this special population.

Non-pharmacologic modalities including cognitive behavioral therapy (CBT), interpersonal therapy (IPT), biofeedback, light therapy, social support, natural products, and complementary and alternative or integrative medicine, are used or are being investigated for PPD treatment(47). Therapies such as CBT and IPT are known to be effective alone or in combination with medications for people with mild or moderate depression; lack of availability of mental health professionals can pose a barrier to treatment engagement in some settings. However, telemedicine is increasing the availability of mental health services in previously underserved communities. The advantages of non-pharmacologic therapy, mind-body, and integrative health options include accessibility and acceptability for disadvantaged individuals who may not be able to receive mental health treatments for any reason. Research on mind-body practices and natural products is needed to identify mechanisms, biological effects, interactions/safety, responders and non-responders, effects on healthy behaviors, pain, and anxiety.

CONCLUSION

PPD monitoring and timely treatment is important to postpartum recovery and function. Identifying and addressing acute care factors, such as pain, suffering, and stress, around childbirth, can improve maternal mental health. Ongoing research on these factors and new treatment modalities will improve maternal and societal health.

KEY POINTS.

• General anesthesia and post-dural puncture headaches are associated with, but probably do not cause, PPD.

• Labor and perinatal pain and depression have bi-directional relationships; for certain individuals, addressing suffering and stress around childbirth may promote a healthy transition to new parenthood.

• Studies on labor pain and PPD risk should focus on multifaceted dimensions of pain, stress, and other complex factors, rather than use or non-use of analgesia, since the latter can be influenced by many confounding factors.

• Ongoing research on acute event factors such as pain and stress, novel treatments, complementary and alternative medicine, and/or drug repurposing in this special population will improve postpartum mental health in the “fourth trimester.”