Over the past two decades, the use of antipsychotic medications to treat psychiatric disorders has greatly expanded in the United States (
1). Schizophrenia and other psychotic disorders have long been treated with both first-generation and second-generation antipsychotics. However, since 2000, a number of second-generation antipsychotics have received approval for broader indications, including irritability in autism, mood stabilization in bipolar disorder, and adjunct therapy for major depressive disorder. Increased off-label use of antipsychotics to treat attention-deficit hyperactivity disorder (ADHD) or behavioral disorders has also been reported in recent years (
2–
4).
For women, psychiatric disorders that are treated with antipsychotics often present during the childbearing years (
5), and managing the risk-benefit trade-off of providing treatment during pregnancy is challenging. Although continuous treatment may be important to prevent symptomatic episodes or relapse (
6), concerns exist about the effects of antipsychotic treatment on maternal and fetal safety. Case reports and studies with small samples have reported conflicting findings on the association between use of first-generation antipsychotics and the risk of congenital anomalies (
7–
9). There are few large, well-controlled studies examining the teratogenicity of second-generation antipsychotics (
10,
11), but the results from a recent large study with 9,258 women exposed to second-generation antipsychotics did not find increased risk of congenital malformation (
12). Second-generation antipsychotics are known to cause weight gain and increase the risk of type 2 diabetes mellitus in the general population (
13). Among pregnant women, these risks may translate into higher risks for diabetes-associated adverse pregnancy outcomes, such as fetal macrosomia or gestational diabetes and its attendant effects.
It is important to understand the extent and patterns of use of antipsychotics among pregnant women, in light of the changes that have occurred in antipsychotic prescribing in the past decade (
1–
3). During that time, there has been rising use of antipsychotics in the general population and broadening of the indications for antipsychotic treatment. At the same time, there is limited information on the safety profile of this drug class during pregnancy. Describing antipsychotic utilization trends in a publicly insured population is especially important because Medicaid covers the costs for approximately 80% of all antipsychotic prescriptions (
14) and for close to 50% of all deliveries of babies in the United States (
15). We used nationwide Medicaid data to investigate the patterns of antipsychotic use among publicly insured women in the United States.
Discussion
In a nationwide sample of publicly insured pregnant women in the United States, the use of second-generation antipsychotics rose from .4% in 2001 to 1.3% in 2010, a threefold increase. The trend was largely driven by an increase in the use of two second-generation antipsychotics, aripiprazole and quetiapine. The characteristics of women who use antipsychotics during pregnancy have changed over time, with a notable increase in diagnosis of bipolar disorders. Use of antipsychotics for treatment of bipolar disorder among pregnant women has also increased significantly. Among the women who used antipsychotics during pregnancy, a large proportion were treated concomitantly with other psychotropic medications. More than 50% of women who used second-generation antipsychotics during the three months before LMP discontinued the medications in the first trimester. Among women who switched medications during the first trimester, the majority switched to quetiapine.
The prevalence of women on antipsychotic treatment during pregnancy was higher in our study compared with findings from other populations during partly overlapping periods (
18–
22). In European cohorts, the prevalence of women on antipsychotic treatment during pregnancy ranged from .1% to .3% (
19–
22). Among privately insured women in the United States, .7% used second-generation antipsychotics (
18). That is not surprising because the prevalence of mental illness is known to be higher for the Medicaid-insured population compared with a privately insured population, due partly to the Medicaid population’s lower socioeconomic status and higher proportion of persons from racial-ethnic minority groups (
23).
The increase in bipolar disorder diagnoses in our study population is consistent with the increase observed for the general population, including children and adolescents (
24,
25). It is not entirely clear why there has been such a rapid increase in bipolar disorder diagnoses, but plausible explanations include improved classification of persons who were previously misdiagnosed as having unipolar depression and overdiagnosis of this condition (
25,
26). We also observed a small increase in the use of antipsychotics for women with anxiety or ADHD, consistent with previous studies reporting frequent off-label use among nonpregnant populations with either disorder (
1,
4). Given that both anxiety and ADHD often co-occur with other psychiatric disorders, it is also possible that we did not capture the diagnoses in the claims for which the antipsychotics were truly used (
27).
The utilization trends over time were different for the various antipsychotic agents. The greater increase in the use of aripiprazole and quetiapine may be due in part to the expansion of the drugs’ indications in 2007 (aripiprazole) and 2009 (quetiapine) for treatment of major depressive disorder. However, an increase in use of these drugs was observed during the years preceding the expansion of indications. Quetiapine has a wide range of off-label uses, which may partly explain why its use increased during the years preceding the expansion of indications. It is also perceived as relatively safe because of prior evidence showing a lower rate of placental passage for quetiapine compared with the other antipsychotics (
28,
29). The decrease in the use of olanzapine may be explained by the known risk of metabolic side effects, including weight gain (
30). Risperidone was the first second-generation antipsychotic to be approved, but its potential to cause hyperprolactinemia may explain why it is used less commonly among pregnant women compared with the general population (
31).
The discontinuation patterns observed in this study were similar to the results from previous studies in the United Kingdom. Close to 50% of women in those studies had discontinued second-generation antipsychotics by six weeks of pregnancy, and 62% to 72.3% had discontinued second-generation antipsychotics by the third trimester (
19,
22). Interestingly, a greater number of women filled a prescription for a first-generation antipsychotic after LMP compared with the baseline period; a similar trend was not seen for second-generation antipsychotics. This might be due to the fact that physicians have more experience prescribing first-generation antipsychotics during pregnancy and therefore feel more comfortable doing so. In particular, concerns about the risk of metabolic side effects may deter physicians from prescribing second-generation antipsychotics during pregnancy. A small number of women appeared to initiate treatment during pregnancy. Although some might be true initiators, it should be acknowledged that for some of these women it might be a continuation of treatment from the prepregnancy period prior to our three-month baseline period.
Polytherapy with other psychotropic medications was very common, given that antipsychotics are often indicated as an adjunct agent (
32). Potential drug interactions between antipsychotics and other psychotropics are largely unknown, particularly in pregnancy; given the high frequency of such use, this is an important priority for future research. It is also notable that opioid use during pregnancy was remarkably high among pregnant women taking antipsychotics, which may be due to a higher prevalence of mental illness among Medicaid recipients compared with a privately insured population and a strong link between mental illness and physical pain (
33). There are potential harms associated with opioid use in pregnancy, such as neonatal abstinence syndrome (
34), and the risk of other negative maternal and fetal outcomes is largely unknown. More attention to appropriate use of opioids in this population is needed.
This study had strengths and limitations. We used a nationwide sample of more than 1.5 million pregnancies covered by Medicaid. Because Medicaid pays for close to 50% of all deliveries of babies in the United States, the results reflect the real-world utilization of antipsychotics in a large proportion of pregnant women in the U.S. population. In addition, our study population was racially diverse—58% of the population was from nonwhite racial-ethnic minority groups compared with 39% in the general nonelderly U.S. population. The population was also young—the mean age was 24.1 compared with 25.4 in the general U.S. population (
35,
36). We were able to study trends by racial groups, which can be a proxy for differential access to mental health care (
37).
Our study also had some limitations. The study findings about prevalence of use are not applicable to women with private insurance, given that the use of psychotropic medication is higher in Medicaid (
14), but other trends in use may still be generalizable. Antipsychotic exposure was defined based on filling a prescription, which does not guarantee the actual intake. But claims from automated dispensing records are considered to be more accurate for defining drug exposures compared with other methods, such as patient recall or medical records (
38,
39). The date of LMP was estimated, so some misclassification of exposure timing is possible. But the algorithm we used estimated 75% of preterm and 99% of term deliveries within two weeks of the clinical gestational age at birth (
17).
We defined psychiatric morbidity by using
ICD-9 diagnostic codes that have imperfect sensitivity (
40), and as a result we could have underestimated the prevalence of each psychiatric diagnosis in the study. However, because pregnant women have frequent contact with health services and because we required continuous coverage over the pregnancy period, concerns about incomplete capture of diagnoses are reduced. Also a number of women had more than one psychiatric diagnosis recorded, which implies that different diagnoses were recorded over time. We were not able to ascertain the specific diagnosis for which antipsychotics may have been prescribed. The lower than expected prevalence of smoking and alcohol problems in this cohort of women with psychiatric disorders (
22,
41) is attributed to the underrecording of lifestyle variables in claims data. Last, some of the trends in use might have been affected by changes in each state’s Medicaid program at various points in time, such as implementation of prior authorization or coverage expansion (
42). We were not able to disentangle the impact of changes in policies versus changes in clinician preference. Nevertheless, this study provides insight into the observed patterns of antipsychotic medication use over time at a national level.