Increasingly, women with psychiatric illness are undergoing pharmacologic treatment during pregnancy. In the United States, an estimated 8% of pregnant women are prescribed antidepressants, and the number of such cases has risen over the past 15 years.1 Women with a psychiatric diagnosis were once instructed either to discontinue all medication immediately on learning they were pregnant, or to forgo motherhood because their illness might have a negative effect on a child or because avoiding medication during pregnancy might lead to a relapse.
Fortunately, women with depression, anxiety, bipolar disorder, or schizophrenia no longer are being told that they cannot become mothers. For many women, however, stopping medication is not an option. Furthermore, psychiatric illness sometimes is diagnosed initially during pregnancy and requires treatment.
Pregnant women and their physicians need accurate information about when to taper off medication, when to start or continue, and which medications are safest. Even for clinicians with a solid knowledge base, counseling a woman who needs or may need psychotropic medication during pregnancy and breastfeeding is a daunting task. Some clinicians still recommend no drug treatment as the safest and best option, given the potential risks to the fetus.
In this review we offer a methodologic approach for decision making about pharmacologic treatment during pregnancy. As the scientific literature is constantly being updated, it is imperative to have the most current information on psychotropics and to know how to individualize that information when counseling a pregnant woman and her family. Using this framework for analyzing the risks and benefits for both mother and fetus, clinicians can avoid the unanswerable question of which medication is the “safest.”
A patient’s mental health care provider is a useful resource for information about a woman’s mental health history and current stability, but he or she may not be expert or comfortable in recommending treatment for a pregnant patient. During pregnancy, a woman’s obstetrician often becomes the “expert” for all treatment decisions.
Antidepressants. Previous studies may have overestimated the association between prenatal use of antidepressants and attention deficit/hyperactivity disorder (ADHD) in children because they did not control for shared family factors, according to investigators who say that their recent study findings raise the possibility that "confounding by indication" might partially explain the observed association.1
In a population-based cohort study in Hong Kong, Man and colleagues analyzed the records of 190,618 maternal-child pairs.1 A total of 1,252 children were exposed to maternal antidepressant use during pregnancy. Medications included selective serotonin reuptake inhibitors (SSRIs), non-SSRIs, and antipsychotics as monotherapy or in various combination regimens. Overall, 5,659 of the cohort children (3%) were diagnosed with or received treatment for ADHD.
When gestational medication users were compared with nongestational users, the crude hazard ratio (HR) of antidepressant use during pregnancy and ADHD was 2.26 (P<.01). After adjusting for potential confounding factors (such as maternal psychiatric disorders and use of other psychotropic drugs), this reduced to 1.39 (95% confidence interval [CI], 1.07-1.82; P = .01). Children of mothers with psychiatric disorders had a higher risk of ADHD than did children of mothers without psychiatric disorders (HR, 1.84; 95% CI, 1.54-2.18; P<.01), even if the mothers had never used antidepressants.
While acknowledging the potential for type 2 error in the study analysis, the investigators proposed that the results "further strengthen our hypothesis that confounding by indication may play a major role in the observed positive association between gestational use of antidepressants and ADHD in offspring."
Lithium. Similarly, investigators of another recently published study found that the magnitude of the association between prenatal lithium use and increased risk of cardiac malformations in infants was smaller than previously shown.2 This finding may be important clinically because lithium is a first-line treatment for many US women of reproductive age with bipolar disorder.
Most earlier data were derived from a database registry, case reports, and small studies that often had conflicting results. However, Patorno and colleagues conducted a large retrospective cohort study that involved data on 1,325,563 pregnancies in women enrolled in Medicaid.2 Exposure to lithium was defined as at least 1 filled prescription during the first trimester, and the primary reference group included women with no lithium or lamotrigine (another mood stabilizer not associated with congenital malformations) dispensing during the 3 months before the start of pregnancy or during the first trimester.
A total of 663 pregnancies (0.05%) were exposed to lithium and 1,945 (0.15%) were exposed to lamotrigine during the first trimester. The adjusted risk ratios for cardiac malformations among infants exposed to lithium were 1.65 (95% CI, 1.02-2.68) as compared with nonexposed infants and 2.25 (95% CI, 1.17-4.34) as compared with lamotrigine-exposed infants. Notably, all right ventricular outflow tract obstruction defects identified in the infants exposed to lithium occurred with a daily dose of more than 600 mg.
Although the study results suggest an increased risk of cardiac malformations--of approximately 1 additional case per 100 live births--associated with lithium use in early pregnancy, the magnitude of risk is much lower than originally proposed based on early lithium registry data.
-- Kathy Christie, Senior Editor
- Man KC, Chan EW, Ip P, et al. Prenatal antidepressant use and risk of attention-deficit/hyperactivity disorder in offspring: population based cohort study. BMJ. 2017;357:j2350.
- Patorno E, Huybrechts KR, Bateman BT, et al. Lithium use in pregnancy and risk of cardiac malformations. N Engl J Med. 2017;376(23):2245-2254.
Analyze risks and benefits of medication versus no medication
The US Food and Drug Administration (FDA) has not approved any psychotropic medication for use during pregnancy. While a clinical study would provide more scientifically rigorous safety data, conducting a double-blinded, placebo-controlled trial in pregnant women with a psychiatric disorder is unethical. Thus, the literature consists mostly of reports on case series, retrospective chart reviews, prospective naturalistic studies, and analyses of large registry databases. Each has benefits and limitations. It is important to understand the limitations when making treatment decisions.
In 1979, the FDA developed a 5-lettersystem (A, B, C, D, X) for classifying the relative safety of medications used during pregnancy.2 Many clinicians and pregnant women relied on this system to decide which medications were safe. Unfortunately, the information in the system was inadequate for making informed decisions. For example, although a class B medication might have appeared safer than one in class C, the studies of risk in humans might not have been adequate to permit comparisons. Drug safety classifications were seldom changed, despite the availability of additional data.
In June 2015, the FDA changed the requirements for the Pregnancy and Lactation subsections of the labeling for human prescription drugs and biologic products. Drug manufacturers must now include in each subsection a risk summary, clinical considerations supporting patient care decisions and counseling, and detailed data. These subsections provide information on available human and animal studies, known or potential maternal or fetal adverse reactions, and dose adjustments needed during pregnancy and the postpartum period. In addition, the FDA added a subsection: Females and Males of Reproductive Potential.3
These changes acknowledge there is no list of “safe” medications. The safest medication generally is the one that works for a particular patient at the lowest effective dose. As each woman’s history of illness and effective treatment is different, the best medication may differ as well, even among women with the same illness. Therefore, medication should be individualized to the patient. A risk–benefit analysis comparing psychotropic medication treatment with no medication treatment must be performed for each patient according to her personal history and the best available data.