Postpartum Depression

Etiology

The exact cause of PPD is not fully understood, but potential underlying etiologies contributing to the development of this condition include hormonal changes, genetic predisposition, and psychosocial stressors. The rapid drop in estrogen and progesterone levels after delivery, coupled with the stress and sleep deprivation that often accompany caring for a newborn, can trigger depressive episodes in susceptible people.

In a meta-analysis of 33 studies, gestational diabetes, having boy infants, a history of depression, and epidural anesthesia use were noted as risk factors. However, further research is needed to assess the true significance of these reported risk factors, especially the sex of the infant and the use of epidural anesthesia.[3] Besides hormonal, other changes in many metabolic pathways may be associated with the development of postpartum depression, including alterations in energy metabolism, the purine and amino acid cycles, steroid and neurotransmitter metabolism, and exposure to xenobiotics.[6]

Postpartum Depression Risk Factors

Factors associated with a high risk of developing postpartum depression include:

• Psychological: A personal history of depression and anxiety, premenstrual syndrome, a negative attitude towards the baby, the reluctance of the baby's sex, and a history of sexual abuse 

• Obstetric risk factors: A high-risk pregnancy, hospitalization during pregnancy, and traumatic events during childbirth that include emergency Cesarean section, in-utero meconium passage, umbilical cord prolapse, preterm or low birth weight infant, and low hemoglobin 

• Social factors: Lack of social support, domestic violence in the form of spousal abuse (eg, sexual, physical, or verbal), smoking, and young maternal age during pregnancy [6]

• Lifestyle: Poor eating habits, decreased physical activity and exercise, vitamin B6 deficiency (via its conversion to tryptophan and, later on, serotonin, which, in turn, affects mood), and lack of sleep; exercise decreases low self-esteem caused by depression and increases endogenous endorphins and opioids, which brings positive effects on mental health and improves self-confidence and problem-solving capacity.[7]

• Family history of psychiatric disorders: Recent studies have shown that a family history of psychiatric disorders is a risk factor for developing postpartum depression. This increased risk is likely due to genetic and environmental factors during childhood and later life associated with a lack of social support, which is a risk for PPD.[8]

Epidemiology

Depression is the most common psychiatric condition of the peripartum period. Moreover, PPD is associated with an increased risk of parental suicide, which is the second most common cause of mortality postpartum.[9] PPD affects 6.5% to 20% of postpartum individuals globally.[10] The incidence varies based on contributing factors, including the country's cultural environment and economic conditions. Different studies have found varying risk factors for postpartum depression, resulting in little consistency between studies.[3] According to studies, depression occurs more commonly in adolescents, patients who deliver premature infants, and those living in urban areas. In a meta-analysis, the prevalence of postpartum depression was the highest in China, at 21.4%. In comparison, the prevalence in Japan was 14%, and the prevalence in the United States was 8.6%. The average time of onset of postpartum depression is 14 weeks postpartum.[3] Overall, Black and Hispanic patients tend to report the onset of symptoms within 2 weeks of delivery, unlike White patients, who more frequently report the onset of symptoms later.

Pathophysiology

The pathogenesis of PPD is currently unknown but is likely multifactorial.[10] Genetic, hormonal, psychological, and social life stressors have been suggested to play a role in PPD development.[11][12][13] The role of reproductive hormones in depressive behavior suggests neuroendocrine pathophysiology for PPD. Ample data advocating that changes in the reproductive hormones stimulate the dysregulation of these hormones in sensitive individuals has been documented. The pathophysiology of PPD can be caused by alterations of multiple biological and endocrine systems, for example, the immunological system, the hypothalamic-pituitary-adrenal axis (HPA), and lactogenic hormones.

The HPA is known to be involved in the disease process of postpartum depression. The HPA axis causes the release of cortisol in trauma and stress; with HPA axis dysfunction, the release of catecholamines is decreased, leading to a poor stress response. HPA-releasing hormones increase during pregnancy and remain elevated up to 12 weeks postpartum. Recent evidence suggests that PPD is linked to the gamma-aminobutyric acid (GABA) neurotransmission system. The imbalance in GABA, the chief inhibitory neurotransmitter in the brain, likely plays a role in causing PPD.[10]

The rapid drop in reproductive hormones like estradiol and progesterone following delivery can be a potential stressor in patients who are susceptible, and these changes can lead to the onset of depressive symptoms. Elevated cortisol levels and low tryptophan levels may be noted.[6] Oxytocin and prolactin also play an essential role in the pathogenesis of PPD. These hormones regulate the milk let-down reflex and the synthesis of breast milk. Failure to lactate and the onset of PPD are often observed to coincide. Low levels of oxytocin are particularly observed in PPD and unwanted early weaning. During the third trimester, lower levels of oxytocin are associated with increased depressive symptoms during pregnancy and following delivery.[14]

History and Physical

PPD is diagnosed when at least 5 depressive symptoms are present for at least 2 weeks. Most experts include the onset of symptoms that occur up to 12 months postpartum.[15] The following 9 symptoms in affected people may be present almost daily and represent a change from the previous routine; however, a PPD diagnosis should include either depression or anhedonia:

• Depressed mood (subjective or observed) is present most of the day
• Loss of interest or pleasure (anhedonia), most of the day
• Sleep disturbances (insomnia or hypersomnia)
• Psychomotor retardation or agitation
• Worthlessness or guilt
• Loss of energy or fatigue
• Suicidal ideation or attempt and recurrent thoughts of death
• Impaired concentration or indecisiveness
• Change in weight or appetite (eg, a weight change of 5% over 1 month)

The symptoms can lead to significant distress and impairment. Furthermore, these symptoms are not attributable to substance use or a medical condition. A psychotic disorder does not cause the episode, nor has there been a prior manic or hypomanic episode.[9] The International Classification of Diseases-10 describes a depressive episode as follows:

• In typical mild, moderate, or severe depressive episodes, the patient has a depressed mood with a decrease in activity and energy.
• Capacity for enjoyment, interest, and concentration is reduced. The patient feels tired after minimum effort, with sleep disturbance and a decreased appetite. Guilt, worthlessness, lowered self-esteem, and lowered self-confidence are commonly present.
• Somatic symptoms, including anhedonia, unusual waking in the very early morning, agitation, weight loss, loss of libido, decreased appetite, and marked psychomotor retardation are noted. These symptoms may vary daily and are not responsive to a change in circumstances.
• A depressive episode may be classified as mild, moderate, or severe, depending on the severity and number of the symptoms.

The signs and symptoms of PPD are identical to nonpuerperal depression with an additional history of childbirth. Symptoms include depressed mood, loss of interest, changes in sleep patterns, change in appetite, feelings of worthlessness, inability to concentrate, and suicidal ideation. Women may also experience anxiety. Patients with PPD may also have psychotic symptoms, which include delusions and hallucinations, such as voices saying to harm infants. PPD may lead to poor maternal-infant bonds, failure of breastfeeding, harmful parenting practices, marital discord, as well as worse outcomes concerning the child's physical and psychological development. The remission of symptoms reduces the risk of behavioral and psychiatric problems in the offspring. A prior episode of PPD increases the future risk of major depression, bipolar disorder, and PPD. Past personal and family histories of PPD and postpartum psychosis should also be noted.

Evaluation

The American College of Obstetricians and Gynecologists (ACOG), the American Academy of Pediatrics (AAP), and the American Academy of Family Medicine (AAFP) all recommend screening every patient for postpartum depression using the EPDS.[3] During the evaluation, the inclusion of drug and alcohol history, smoking habits, and all prescription and over-the-counter drug medications is essential. PPD screening should be performed during pregnancy and postpartum.[16]

Several screening tools are available, though the most frequently used is the EPDS, a 10-item questionnaire completed by patients within a few minutes. A score ≥13 is associated with an increased risk of developing PPD and provides the basis for additional clinical assessment. The objectives of the clinical evaluation are to constitute the diagnosis, assess suicidal and homicidal risks, and rule out other psychiatric illnesses.[17]

Treatment / Management

Prevention of postpartum depression in high-risk patients using counseling and cognitive behavioral therapy, as well as interpersonal therapy, has been effective. Clinicians should identify and implement these interventions as preventative measures for high-risk patients.[15] (A1)

Antidepressant Medications

The first-line treatment for peripartum depression is psychotherapy and antidepressant medications. Psychotherapy is the first-line treatment option for patients with mild to moderate peripartum depression. A combination of therapy and antidepressant medications is recommended for moderate to severe depression. Referral to a behavioral health resource may also be recommended.[15] ACOG recommends using selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants for PPD medical therapy.[9](A1)

Selective serotonin reuptake inhibitors are the first choice medications for PPD. Consideration should be given to switching to serotonin-norepinephrine reuptake inhibitors or mirtazapine if selective serotonin reuptake inhibitors are ineffective. Sertraline or escitalopram are good first-line choices for medical therapy. Sertraline has extensive and reassuring safety research. Fluoxetine and paroxetine, if previously used effectively for a specific individual, may be considered despite an increased risk of neonatal adaptation syndrome. As such, the treatment for patients who have had successful medical therapy with an antidepressant in the past should be allowed to resume that effective medication during or after pregnancy.[15](A1)

The goal of treatment for PPD is remission or resolution of symptoms of depression. The same screening tool should be used to track symptoms. An improvement of 50% or more defines a treatment response. Algorithms may be used to help in adjusting dosages of medications with continued use of the Patient Health Questionairre-9 or EPDS. Inadequately or untreated mental health conditions are associated with perinatal risks, as are any pharmacologic agents; the risks of both need to be recognized. The lowest effective dose of medication should be used to achieve illness remission. However, avoiding undertreatment, which is common in obstetrics, is critical. Polypharmacy and switching medications should be avoided if remission is possible with the use of a single agent.[15] Although benefits may be reported within 1 week of the start of oral therapy, symptom improvement may take 4 to 8 weeks.[9](A1)

Once an effective dose is reached, continued treatment for at least 6 to 12 months is recommended to prevent relapse of symptoms.[18] Discontinuation of medical therapy during pregnancy or in the postpartum period results in a high risk of recurrence and is not recommended; also, discontinuing medication in the third trimester to mitigate the risk of neonatal adaptation syndrome is not recommended. Additionally, abrupt discontinuation of both selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors is associated with complications unless a progressive taper over 2 to 4 weeks is used. Discontinuation symptoms may include gastrointestinal upset, agitation, anxiety, headache, dizziness, fatigue, sleep disruption, tremors, myalgias, and electric-like shocks.[15](A1)

Pharmacologic recommendations for people who are lactating should include discussing the benefits of breastfeeding, the risks of antidepressant use during lactation, and the risks of untreated illness. Repetitive transcranial magnetic stimulation is a treatment that may provide an alternative option for people who breastfeed and are concerned about their babies being exposed to medication. The risk of breastfeeding while taking a serotonin reuptake inhibitor is relatively low, and patients can be encouraged to breastfeed while on antidepressants. After 12 weeks, cognitive behavioral therapy, sertraline monotherapy, and combination therapy were helpful. The cognitive behavioral therapy monotherapy group found the most accelerated initial gains after treatment startup. 

Neurosteroid Therapy

Brexanolone, an intravenous neurosteroid that positively acts at the GABA-A receptors, was approved by the Food and Drug Administration (FDA) in March 2019, specifically for PPD. Brexanolone may be considered for use with moderate to severe depression in the third trimester or postpartum. Patients must be enrolled in the Risk Evaluation and Mitigation Strategy Program.[19] Brexanolone has a rapid onset of action but is hard to access and may be cost-prohibitive. No data supports its safety with breastfeeding or efficacy beyond 30 days of use. Inpatient monitoring for increased sedative effects, sudden loss of consciousness, and hypoxia during infusion is required.[9][15](A1)

Brexanolone, an analog of allopregnanolone, a metabolite of progesterone, was the first medication approved by the FDA for the treatment of moderate to severe postpartum depression.[19] Brexanolone is administered intravenously as a continuous 60-hour infusion lasting approximately 2.5 days. Multiple clinical trials demonstrate that brexanolone is usually well-tolerated in women with moderate to severe PPD and can provide a rapid beneficial response.[20][21] Breastfeeding is not recommended during and for 4 days after brexanolone infusion therapy. More clinical trials are needed to assess further the long-term safety and efficacy of brexanolone in treating PPD.[15](A1)

Zuranolone, a neuroactive steroid like brexanolone, is also a GABA-A receptor modulator that was FDA-approved on August 4, 2023, for PPD management. A 50-mg oral dose every night is given with a fat-containing (700 cal; 30% fat) meal for 14 days. Zuranolone may be used alone or in combination with oral antidepressants. The onset of action is rapid, from hours to days, which helps give more immediate relief. Because of the central nervous system depression seen with zuranolone, patients should be counseled that their driving ability may be reduced. Also, zuranolone has been suggested to produce harmful effects on the fetus during pregnancy and lactation. Overall, zuranolone is well tolerated and has minimal side effects.[10] The most common adverse event reported by over 26% of patients was somnolence.[22] Because safety and effectiveness have not yet been studied, zuranolone is not recommended to be continued for longer than 14 days.

Nonpharmacologic Therapies

Transcranial magnetic stimulation is a noninvasive procedure that uses magnetic waves to stimulate and activate nerve cells in a targeted area of the brain.[23] These cells are underactive in people with major depression. Transcranial magnetic stimulation is usually done once a day for 4 to 6 weeks to be effective. This therapy may be used in patients who are not responding to antidepressants and psychotherapy. Generally, transcranial magnetic stimulation is safe and well-tolerated, but some side effects can include headaches, lightheadedness, scalp discomfort, and facial muscle twitching. Some serious side effects are rare, including seizures, hearing loss if ear protection is not adequate, and mania in people with bipolar disorder.[24] Although early results are promising, future studies are needed to address the benefits of transcranial magnetic stimulation for PPD.[23](A1)

Patients with severe PPD may not respond to psychotherapy and pharmacotherapy. For patients refractory to 4 consecutive medication trials, electroconvulsive therapy (ECT) may be recommended. ECT is beneficial in patients with psychotic depression, with intent or plans on committing suicide or infanticide, and refusal to eat, leading to malnutrition and dehydration.[25][26] Several observational studies have suggested ECT as a safer option for lactating patients as there are fewer adverse events for the mother and the infant.[27][28] Other authors are not as supportive of ECT use for PPD. (B2)

Differential Diagnosis

Differential diagnoses that should also be considered when evaluating postpartum depression include:

• Baby blues: Baby blues most commonly occur within a week after delivery and resolve within a few days, around day 10 to 14 postpartum. Approximately 50% to 75% of patients experience baby blues, which are temporary and require no treatment. Symptoms may include crying bouts, sadness, anxiety, irritability, sleep disturbance, appetite changes, confusion, and fatigue. The baby blues does not affect daily functioning or the ability to care for the baby. However, severe postpartum baby blues is associated with a risk for PPD.[29]
• Hyperthyroidism and hypothyroidism: These conditions can also lead to mood disorders. Thyroid disorders can be assessed by testing thyroid-stimulating hormone levels.
• Postpartum anxiety, adjustment disorder, or posttraumatic stress disorder: Postpartum anxiety focuses on excessive worry. Adjustment disorder includes emotional and behavioral responses to the stress of childbirth, which are less severe and shorter in duration than PPD. Posttraumatic stress disorder involves trauma-related symptoms due to a traumatic birth experience.
• Postpartum psychosis: Postpartum psychosis is defined as the onset of psychosis during the first 4 weeks postpartum. Most women do not have a known history of psychiatric disorders, but some have had bipolar disorder in the past. Usually, onset is within 3 to 10 days postpartum but may occur over 4 weeks postpartum. Postpartum psychosis is a psychiatric emergency with potential suicide and infanticidal risk. A patient can experience hallucinations, agitation, unusual behavior, disorganized thoughts, and delusions. This is a rare disorder, occurring in only 1 to 2 per 1000 pregnancies, and presents with an acute onset of manic or depressive psychosis within the first few days or weeks after delivery.[15]

Prognosis

Dose adjustments may be needed based on monitoring symptoms through clinical assessment, validated screening tools, or both. Due to increased renal clearance, increased distribution volume, and changes in enzyme activity with advancing gestation, an increase in medication dose during pregnancy may be required. Empiric down-titration of psychiatric medications in the third trimester is not recommended as neonatal outcomes were not improved, and the associated risk of worsening mental health conditions was noted.[15] 

A pivotal factor in the duration of PPD is delayed treatment. Approximately 25% of patients with perinatal depression will have symptoms for 3 years after giving birth.[15] PPD has repercussions beyond possible physical harm to the child. Data reveal that the condition also affects parent-infant bonding. Often, the child is treated inappropriately with a negative attitude that can significantly impact the child's growth and development. Children born to patients with PPD have been found to exhibit marked changes in behavior, altered cognitive development, and early onset of depressive illness. More importantly, these children may struggle with obesity and dysfunction in social interactions.

Complications

PPD affects the parents and the infant and can lead to a chronic depressive disorder if untreated. Even if treated, PPD can be a risk for future episodes of major depression. Moreover, PPD is a stressful event for the entire family, as children may be affected also. Children of parents who have untreated depression can develop behavioral and emotional problems, including language development delays, which are commonly seen, sleeping problems, eating difficulties, excessive crying, and attention-deficit/hyperactivity disorder.

When untreated, PPD is associated with negative consequences for those who are postpartum, including disrupted health behaviors, relationships, physiology, and parenting. This results in a risk for the fetus, the partner, and the whole family.[15] Therefore, ACOG does not recommend withholding or stopping psychiatric medications due to pregnancy status alone.[15]