Psychotropic Treatment during Pregnancy: Perinatal Mental Health Considerations

The scope of the public health problem of perinatal mental disorders is discussed, followed by an examination of the specific research methods used to study birth and developmental outcomes associated with maternal mental illness and its treatment. The evidence on exposure to common psychotropics during pregnancy and lactation is reviewed.

> Antidepressants

Selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitor medications are not associated with higher rates of birth defects or long-term changes in mental development after adjustment for confounders associated with underlying psychiatric illnesses. .

> Neonatal adaptation syndrome

Neonatal adaptation syndrome (NAS) refers to the signs presented by a newborn exposed to SSRIs in utero. No consensus definition or measurement tool has been developed for SSRI-associated NAS.

Signs include neuromuscular, central nervous system, gastrointestinal, and respiratory difficulties. Malm et al. observed an increased risk of neonatal complications in infants exposed to SSRI medications, including risk of lower Apgar scores (OR = 1.68, 95% CI = 1.34-2.12) and admission to the unit neonatal intensive care (OR = 1.24, 95% CI = 1.14-1.35).

NAS occurs in 0%-30% of infants exposed to antidepressants in utero.27 This highly variable rate is indicative of the difficulty in measuring and describing the syndrome and the lack of understanding of the mechanism. It occurs more commonly in infants exposed to paroxetine, venlafaxine, and fluoxetine than in infants exposed to other serotonergic antidepressants.

Paroxetine is highly anticholinergic, venlafaxine has a well-described discontinuation syndrome, and fluoxetine and its active metabolite have long half-lives, affecting the metabolic capacity of the newborn.

The mechanism underlying SSRI-associated NAS has not been elucidated. It has been hypothesized to be secondary to rapid drug decline after birth (withdrawal), increased serotonergic tone as a side effect of the drug (serotonin toxicity/syndrome), and neurobehavioral teratological effects on the fetal central nervous system.

These mechanisms are not mutually exclusive and are associated with the pharmacological characteristics of the specific drug. Concomitant combined exposure to benzodiazepines and serotonergic antidepressants in utero results in an increased likelihood of signs of NAS, with some of these persisting 30 days postpartum.

> Premature birth

 Both depression and antidepressants have been associated with preterm birth, which is defined as birth before 37-0 weeks of gestation. Patients with major depressive disorder (MDD) who are medicated or unmedicated have higher rates of preterm birth (23% and 21%, respectively) than women without MDD or antidepressant treatment (6% preterm birth).

In a systematic review and meta-analysis of preterm birth and antidepressant medications, an adjusted pooled OR for the risk of preterm birth after exposure to antidepressants during pregnancy was 1.61 (95% CI = 1.26-2.05; p = 0.039) after adjusting for confounding variables and risk of maternal psychiatric illness.

The results suggest that determining the association between antidepressant exposure and preterm birth is challenging and depends on the direct contributions of medication versus disease exposure.

> Mood stabilizers

Lithium is the standard treatment for bipolar disorder, but its association with fetal heart malformations makes its use in pregnant women difficult. As a result, many psychiatrists, obstetricians, and patients avoid its use during pregnancy. However, women with bipolar disorder who stop lithium treatment are at high risk of relapse.

About 85% of women who stopped lithium near pregnancy experienced at least one mood episode during pregnancy. When women abruptly stopped lithium upon finding out they were pregnant, 50% had a recurrence within 2 weeks.

Lithium exposure is associated with an increased risk of fetal heart malformations, but this risk is lower than previously thought (absolute risk of Ebstein anomaly 6/1,000).

Serum lithium concentrations change during pregnancy. Stable concentrations before pregnancy and monthly concentration determinations during pregnancy are recommended. Dosing may be changed from once daily to two or three times daily to stabilize plasma concentrations due to rapid clearance and subsequent decreased half-life of the drug during pregnancy.

Infants exposed to higher lithium concentrations (>0.64 meq/L) at delivery are at risk for lower Apgar scores, longer hospital stays, and higher rates of neuromuscular and central nervous system complications. This risk can be mitigated by stopping lithium 24 to 48 hours before delivery.

> Antipsychotics

Antipsychotics are used during pregnancy for the FDA-approved indications of schizophrenia, bipolar disorder, psychosis, and depression and are commonly used off-label for sleep and anxiety disorders.

It is estimated that 1.3% of pregnancies are exposed to atypical antipsychotics and 0.1% of pregnancies are exposed to atypical antipsychotics. exposed to typical antipsychotics. In a population derived from a Medicaid database, antipsychotic use during the first trimester of pregnancy did not significantly increase the rate of malformations after adjusting for confounding variables.

One exception was risperidone , which was associated with a small increase in overall malformations (aRR = 1.26, 95% CI = 1.02-1.56) and a nonsignificant risk specifically for cardiac malformations (aRR = 1 .26, 95% CI = 0.88-1.81).

The study authors interpreted this as a possible safety signal for risperidone use during the first trimester. This relationship may also apply to paliperidone, which is the main active metabolite of risperidone.

Additionally, there is an increased risk of gestational diabetes with some atypical antipsychotics related to the adverse metabolic effects associated with these medications. Specifically, olanzapine and quetiapine have been associated with increased rates of gestational diabetes when continued during pregnancy.

Antipsychotics, other than risperidone and potentially paliperidone, have not been associated with an increase in birth defects; olanzapine and quetiapine have been associated with an increased risk of gestational diabetes.

> Stimulants

Adults with ADHD often develop coping strategies or work with therapists who specialize in non-pharmacological treatment of ADHD. However, severe ADHD and other conditions may require treatment with stimulants during pregnancy.

Researchers using the Medicaid database assessed the risk of birth defects with stimulant exposure during the first trimester.

They observed a non-significant aRR for heart defects after methylphenidate exposure [aRR = 1.28 (95% CI = 0.94–1.74)]. They combined their results with health information collected from the Nordic Health Registries (Denmark, Finland, Iceland, Norway and Sweden) that had similarly examined the risk of birth defects with in utero exposure to stimulants.

Combining data sets allowed the researcher to achieve enough statistical power to identify a small effect. The US data combined with the Nordic data resulted in an aRR of 1.28 (95% CI = 1.00-1.64).

This suggests a small increase in cardiac malformations associated with first trimester exposure to methylphenidate derivatives. No increased risk of malformations was observed with exposure during the first trimester to amphetamine-based derivatives.

> Benzodiazepines and hypnotics

Benzodiazepines are used by women when needed as scheduled medications primarily for anxiety. While initial studies reported an elevated risk of cleft lip/palate, 90 larger studies have not supported this association. A large European database review, which included nearly 2,000 pregnancies with first-trimester exposure to benzodiazepines or other hypnotics, found no increased risk of birth defects.

Benzodiazepines have been associated with signs of neonatal adaptation syndrome, including respiratory distress, infections, cardiac abnormalities, and neurobehavioral changes, and these symptoms may persist for up to a month after delivery. Lorazepam is the preferred benzodiazepine in lactation due to its relatively shorter half-life and lack of active metabolites.

Insomnia is a common complaint during pregnancy. While melatonin is a reasonable option outside of pregnancy, there is little data on its use during pregnancy.

Low-dose trazodone (50 to 150 mg at bedtime) is frequently used as a hypnotic. It does not increase the risk of congenital malformations and has acceptable safety data in breastfeeding.

Zolpidem has not been associated with an increased risk of congenital malformations and has minimal excretion in breast milk and can be used in breast-feeding.

Due to the dramatic physiological changes of pregnancy and increased hepatic metabolism, drug doses may need to be adjusted during pregnancy to maintain effectiveness. Untreated maternal psychiatric illness also carries substantial risks for the mother, fetus, infant, and family.

Psychiatric disorders during pregnancy and postpartum are common and 14% of women experience peripartum depression. Appropriate evaluation and treatment of psychiatric disorders optimizes women’s health, pregnancy, and infant outcomes.

Treatment involves a discussion with the patient about possible exposures of maternal mental health disorders, as well as the risks and benefits of pharmacotherapy and documentation of this decision making.

Large, well-designed studies that take confounding variables into account are most valuable for understanding risk and counseling patients regarding in utero exposure to psychiatric medications.

New conceptualizations of the impact of depression and drug exposure for maternal/infant pairs invoke a wide spectrum of potential outcomes. Some may have very favorable outcomes associated with drug exposure; For example, recent evidence suggests that exposure to citalopram in utero reverses the adverse effects of maternal gestational stress on fetal brain development.

The use of antidepressants during pregnancy may protect some fetuses from the adverse effects of maternal mental illness. Other pairs may have adverse effects from exposure to the drug. As the literature evolves, identifying the characteristics of mothers who are likely to benefit from pharmacotherapy (or, alternatively, experience adversity) will provide clinicians with critical information.

The goal of perinatal mental health is to treat women optimally to decrease the burden of maternal psychiatric disorders on the mother, fetus, infant, and family.