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In a recently updated practice bulletin from the American College of Obstetricians and Gynecologists (ACOG),1 lamotrigine(Drug information on lamotrigine) (Lamictal) has been deemed a relatively safe choice when a mood stabilizer is required for a pregnant patient with bipolar affective disorder. Paroxetine(Drug information on paroxetine) (Paxil) is considered to pose greater risk than other SSRIs in this setting.
The bulletin also weighs the possible adverse effects of psychiatric medications against the potential benefits of appropriate therapy to avoid substantial risks of untreated psychiatric illness to mother and child. The bulletin warns, “maternal psychiatric illness, if inadequately treated or untreated, may result in poor compliance with prenatal care, inadequate nutrition, exposure to additional medication or herbal remedies, increased alcohol(Drug information on alcohol) and tobacco use, deficits in mother-infant bonding, and disruption within the family environment.”1
Marlene Freeman, MD, director of the Women’s Mental Health Center, University of Texas Southwestern Medical Center, commented on the updated bulletin to Psychiatric Times. “The review of psychiatric disorders and their potential consequences for pregnant women and their babies is integral information for health care providers across disciplines, as well as for patients,” she indicated. “This provides an important context for a sophisticated review of the risks and benefits of medications during pregnancy and lactation.”
The bulletin notes that approximately 10% to 16% of pregnant women fulfill diagnostic criteria for depression and cautions that symptoms of depression may be overlooked or attributed to mood changes related to pregnancy. One of the studies cited in the bulletin found that depression recurred in 68% of women who discontinued antidepressant therapy; in contrast, the rate was 25% in women who continued to take their medications.2
In literature reviewed in the bulletin, the possible sequelae of untreated maternal depression, including premature birth, low birth weight, and postnatal complications, were most likely to occur in the late second or early third trimester.1 Rates of relapse of postpartum bipolar affective disorder ranged from 32% to 67%. In reviewing associations with anxiety disorders, the bulletin noted a heightened postpartum risk for exacerbations of panic disorder and obsessive-compulsive disorder.
The bulletin characterized the consequences of untreated symptoms of schizophrenia-spectrum disorders during pregnancy as potentially “devastating” for mother and child. Schizophrenia occurs in approximately 1% to 2% of women, most commonly during childbearing years. Consequences included maternal self-mutilation, denial of pregnancy with refusal of prenatal care, and infanticide.1
Weighing Medication Risk and Benefit
Because psychiatric medications cross the placenta and are present in amniotic fluid and in breast milk, all carry some risk during pregnancy and lactation. The bulletin makes a general recommendation for judicious use of a therapeutic agent that poses relatively low risk during periods of less vulnerability to adverse effect. Agents documented as teratogens are to be avoided—at least during the first trimester. The bulletin also suggests that a single agent (even if given at relatively high dosage) may be preferable to multiple medications. It also recommends maintaining a regimen that is reasonably effective rather than changing to another that may—or may not—improve response but that exposes the fetus to an additional compound.
The bulletin includes the FDA risk categories of psychiatric medications, while acknowledging that the ranking has “considerable limitations”3:
- Category A indicates that controlled studies show no risk.
- Category B reflects an absence of evidence for risk in humans.
- Category C indicates that risk cannot be ruled out.
- Category D corresponds to having evidence of risk.
- Category X drugs are contraindicated in pregnancy because of documented adverse effect.3
The bulletin also includes ratings of the safety of psychiatric drugs during breast-feeding.4
Freeman previously indicated that the FDA rating system, taken alone, does not provide a sufficient basis for psychiatric drug selection.5 She has noted that most psychiatric medications fall into category C or D, with none in A, and that there is no clear distinction among ratings regarding risk of untreated illness, or a sufficient prospective human database.
“The only psychotropic rated B is clozapine(Drug information on clozapine), based on almost no human data,” she observed. “This would suggest that it is a relatively safe choice, despite being one of the most risky and least studied drugs in pregnancy.”5
The ACOG guidelines also contain independent assessment of reports, case-control studies, and (where available), meta-analysis and prospective comparative studies of pregnancy outcomes between groups exposed and not exposed to particular psychotropic agents.
The assessment of lamotrigine as a potential maintenance therapy for bipolar disorder during pregnancy is based on its efficacy for bipolar depression and general tolerability, and a “growing reproductive safety profile relative to alternative mood stabilizers.” However, the bulletin notes the lack of studies on the effectiveness of lamotrigine as a mood stabilizer during pregnancy. While lamotrigine has not been associated with major fetal anomalies, the bulletin relates the finding in a pregnancy registry of a possible increased risk of midline facial clefts (0.89% of 564 exposures), which may be related to daily doses greater than 200 mg.1
The bulletin reports that lithium has a risk ratio of 1.2 to 7.7 for congenital cardiac malformations and 1.5 to 3 for overall congenital malformations. Valproate(Drug information on valproate) (Depakene, Depakote) exposure is associated with neural tube defects; long-term adverse neurocognitive effects; and a “fetal valproate syndrome,” with features of fetal growth restriction, facial dysmorphology, and limb and heart defects. A “fetal carbamazepine(Drug information on carbamazepine) syndrome” includes facial dysmorphism and fingernail hypoplasia.
The bulletin suggests tapering and discontinuing lithium(Drug information on lithium) before conception. The drug can be restarted after organogenesis if required for severe episodes or possibly used as maintenance therapy for especially severe and frequent episodes of illness. The bulletin recommends counseling the patient about reproductive risks, and obtaining fetal echocardiography when there is lithium exposure in the first trimester. Both valproate and carbamazepine (Tegretol) should be avoided in pregnancy if possible, especially during the first trimester.
The bulletin distinguishes paroxetine from other SSRIs based on several data sources. In a Swedish national registry and a US insurance claims database, there appeared to be a 1.5- to 2-fold increased risk of congenital cardiac malformations associated with paroxetine exposure in the first trimester. The FDA risk category for paroxetine was subsequently changed from C to D.
In 2 large, case-control studies, however, no significant associations were found between the SSRI category overall and congenital heart defects. In one study, a small potential risk was determined through multiple statistical testing between SSRI use in early pregnancy—particularly with paroxetine—and anencephaly, craniosynostosis, and omphalocele.6 In the other study, an association emerged between paroxetine and right ventricular outflow defects; and between sertraline(Drug information on sertraline) (Zoloft) and omphalocele and atrial and ventricular septum defects.7
The bulletin characterizes the absolute risk of cardiac defects with SSRI exposure during early pregnancy as small—no greater than 2 per 1000 births—and indicates that these agents are not major teratogens. It also notes reports of adverse effects on the neonate from SSRI exposure late in pregnancy, and also of an FDA public health advisory about risk of an unconfirmed association between SSRI exposure and persistent pulmonary hypertension in the newborn.4,8
Although the bulletin indicates that the decision to use SSRIs during pregnancy should be based on individual circumstance, it cautions against the use of paroxetine. “At this time, paroxetine use in pregnant women and women planning pregnancy should be avoided, if possible. Fetal echocardiography should be considered for women exposed to paroxetine in early pregnancy.”1
In her assessment of the ACOG bulletin, Freeman cautioned that any review of information on psychiatric medication treatment during pregnancy and postpartum is limited by the lack of adequately powered randomized controlled trials in this area. “As a field,” she said, “we need to problem solve around how to enrich the evidence base for treatments in psychiatric disorders that occur in the context of childbearing.”
