Antipsychotic
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo–Fetal Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
PREGNANCY SUMMARY
Although no structural malformations attributable to risperidone have been reported, the number of exposures is too low to fully assess the embryo–fetal risk. In addition, there is a risk of extrapyramidal and/or withdrawal symptoms in the newborn if the drug is used in the 3rd trimester. Nevertheless, risperidone is indicated for severe debilitating mental disease and the benefits to the mother appear to outweigh the potential embryo–fetal risks. Folic acid 4 mg/day has been recommended for women taking atypical antipsychotics because they may have a higher risk of neural tube defects due to inadequate folate intake and obesity (1).
FETAL RISK SUMMARY
Risperidone, an atypical antipsychotic, is indicated for the management of the manifestations of psychotic disorders, such as schizophrenia. Risperidone is metabolized to an active metabolite, 9-hydroxyrisperidone (see Paliperidone), that has similar pharmacological activity as risperidone. Plasma protein binding is 90% and the mean elimination half-life of the parent drug and metabolite combined in extensive and poor metabolizers is about 20 hours (2). Risperidone is a benzisoxazole derivative in the same antipsychotic subclass as iloperidone, paliperidone, and ziprasidone. Although not approved for this indication by the FDA, it is also used for the management of bipolar disorder and in patients with dementia-related psychotic symptoms.
Reproduction studies have been conducted in pregnant rats and rabbits. No increase in the incidence of congenital malformations was observed in either species at doses 0.4–6 times the human dose based on BSA (HD). At 1.5 times the HD, however, an increase in stillbirths was noted in rats. In addition, increased pup mortality during the first 4 days of lactation occurred at 0.1–3 times the HD. There was no no-effect dose for this toxicity. It was not known if the deaths were due to a direct effect on the pups or toxicity in the dams. Risperidone caused a dose-related decrease in serum testosterone in Beagle dogs, as well as a decrease in sperm motility and concentration, at doses 0.6–10 times the HD (2).
Consistent with the molecular weight (about 410), risperidone crosses the human placenta.
In a 2007 study, six women taking a staple dose (mean 3 mg/day) of quetiapine for a mean 25.9 weeks before delivery had maternal and cord concentrations of the drug determined at birth (3). The cord blood concentration was 49.2% of the maternal concentration. The pregnancy outcomes included one growth-restricted infant (<2500 g). The mean Apgar scores were 8.7 and 9.2 at 1 and 5 minutes, respectively. There were no neonatal complications and no infants were admitted to the neonatal intensive care unit (3).
The outcomes of 10 pregnancies involving 9 women were described in a large postmarketing study involving 7684 patients treated with risperidone (4). The outcomes were three elective terminations and seven live births. No congenital malformations were reported among the live births (4). The manufacturer has also reported an unpublished case of agenesis of the corpus callosum in an infant exposed to risperidone during gestation (2). The relationship between the drug and the defect is unknown.
A 1997 review of antipsychotic use in pregnancy concluded that the safety of risperidone in human pregnancy had not been established (5). The reviewers commented that although no teratogenicity or direct toxicity had been shown in animal studies, some indirect, prolactin- and CNS-mediated effects had been observed.
A brief 2002 report described the pregnancy outcomes of two women with schizophrenia who were treated with risperidone throughout gestation (6). Both women delivered apparently healthy infants at term. The weight of the male infant was 8 pounds (about 3.63 kg), whereas the female infant weighed 5.81 pounds (about 2.64 kg). Risperidone was continued after birth and during nursing. No developmental abnormalities were noted in the infants at 9 months and over 1 year, respectively (6).
A 36-year-old pregnant woman was treated with multiple medications for schizophrenia and other conditions (7). Risperidone 4 mg/day was taken in gestational weeks 6–7. Other psychotropic agents were (daily dose and gestational weeks in parentheses): mirtazapine (30 mg; 1–5), thioridazine (300 mg; 1–5), diazepam (10 mg; 4–5), hydroxyzine (12.5 mg; 4–7), clomipramine (150 mg; 6–7), fluvoxamine (100 mg; 8–21), alprazolam (0.5 mg; 8–21), quetiapine (500–600 mg; 8–37), carbamazepine (600 mg; 8–21), and haloperidol (10 mg; 31–36). She gave birth at 37 weeks’ to a healthy 3000-g female infant with Apgar scores of 8 and 9, who was developing normally after 4 months (7).
A 2005 study, involving women from Canada, Israeli, and England, described 151 pregnancy outcomes in women using atypical antipsychotic drugs (8). The exposed group was matched with a comparison group (N = 151) who had not been exposed to these agents. The drugs and number of pregnancies were olanzapine (N = 60), risperidone (N = 49), quetiapine (N = 36), and clozapine (N = 6). In those exposed, there were 110 live births (72.8%), 22 spontaneous abortions (14.6%), 15 elective abortions (9.9%), and 4 stillbirths (2.6%). Among the live births, one infant exposed in utero to olanzapine had multiple anomalies including midline defects (cleft lip, encephalocele, and aqueductal stenosis). The mean birth weight was 3341 g. There were no statistically significant differences, including rates of neonatal complications, between the cases and controls, with the exceptions of low birth weight (10% vs. 2%, p = 0.05) and elective abortions (9.9% vs. 1.3%, p = 0.003). The low birth weight may have been caused by the increased rate of cigarette smoking (38% vs. 13%, p ≤0.001) and heavy/binge alcohol use (5 vs. 1) in the exposed group (8).
In a comparison of drugs used in the treatment of schizophrenia during pregnancy, the American Academy of Pediatrics (AAP) classified risperidone as high potency (9). The classification was based on the potential for extrapyramidal reactions (e.g., acute dystonia, akathisia, parkinsonism, and tardive dyskinesia). The AAP cautioned that large maternal doses of high-potency drugs could produce these effects in newborns. However, it did note that high-potency antipsychotics were preferred to minimize maternal anticholinergic, hypotensive, and antihistamine effects. No recommendation concerning the use of risperidone during pregnancy was made because of the lack of data (9).
The manufacturer reported a case of agenesis of the corpus callosum in an infant exposed to risperidone during pregnancy (2). No further details were provided.
A 2006 case report described a woman with a long history of paranoid schizophrenia who was treated with oral risperidone (10). Early in an unknown pregnancy she was started on IM risperidone 25 mg every 2 weeks; the therapy was stopped when she was found pregnant in the 20th week. At 38 weeks, she was hospitalized because of psychotic decompensation with malnutrition (weight 59 kg). She gave birth spontaneously about 2 weeks later to a healthy but small-for-date 2900-g female infant without malformations. At 2.5 years of age, no major health problems had occurred. A minor retardation in her motor development was described but still within the normal range (10).
A 35-year-old woman with a 7-year history of schizophrenia was treated before and throughout pregnancy with long-acting IM risperidone 25 mg every 2 weeks (11). At 37 weeks, her membranes ruptured and she delivered vaginally a 2230-g female infant with Apgar scores of 9 at 1 and 5 minutes. No congenital anomalies were found and the infant was developing normally at 8 months of age (11).
In an extensive literature search, representatives of a manufacturer identified 713 pregnancies in which the mothers were treated with risperidone (12). The reported data were prospective in 516 cases and retrospective in the remaining 197 cases. Adverse pregnancy outcomes were more frequently reported in the retrospective cases. In the 68 prospectively reported pregnancies with a known outcome and after exclusion of 13 elective abortions, structural anomalies and spontaneous abortions occurred in 3.8% and 16.9%, respectively. These results were thought to be consistent with the background rates in the general population. In the retrospective cases, major structural anomalies were observed in 12 pregnancies. The defects most frequently reported involved the heart, brain, and lip and/or palate. In addition, there were 37 outcomes involving perinatal syndromes, of which 21 involved behavioral or motor disorders. The authors concluded that the results do not appear to show an increased risk of congenital anomalies or SABs, but limited extrapyramidal effects in the neonate did occur when risperidone was used in the 3rd trimester (12).
BREASTFEEDING SUMMARY
Risperidone and its active metabolite, 9-hydroxyrisperidone, are excreted into breast milk (13–15). A 21-year-old mother with a 2-year history of bipolar disorder stopped all medication when her pregnancy was diagnosed (13). She did well during pregnancy and delivered a healthy infant at 38 weeks’ gestation. When her disease relapsed, she was admitted to the hospital 2.5 months after birth of her infant, stopped breastfeeding, and started on risperidone, eventually reaching a steady-state dose of 6 mg/day. Concentrations of risperidone and the active metabolite were determined in the plasma and milk. The milk:plasma ratios for the parent drug and metabolite, based on AUC, were 0.42 and 0.24, respectively. Based on a daily milk intake of 150 mL/kg, the nursing infant would have received 0.84% of the mother’s risperidone dose (mg/kg/day) and an additional 3.46% from the metabolite (as risperidone equivalents), or about 4.3% of the weight-adjusted maternal dose. Although the combined amounts of risperidone and metabolite in breast milk appear to be too low to cause extrapyramidal effects, concern was expressed for other effects, such as neuroleptic malignant syndrome, and effects on cognitive development (13).
A 2004 study measured the steady-state plasma and milk concentrations of risperidone and 9-hydroxyrisperidone in two breastfeeding women and one woman with risperidone-induced galactorrhea (14). The 29-year-old woman with galactorrhea was taking risperidone 3 mg at night (37.5 mcg/kg/day) for schizophrenia. The galactorrhea was attributed to elevated prolactin concentrations due to the D2 antagonist effects of risperidone. Milk and plasma samples were collected 20 hours postdose, and then milk only on days 2 and 3, each at 21 hours postdose. The plasma concentrations of risperidone and the metabolite were <1 and 14 mcg/L, respectively. All milk risperidone concentrations were <1 mcg/L, whereas the mean concentration of the metabolite was 5.1 mcg/L (range 4.4–5.6 mcg/L). Although the woman was not nursing, the absolute and relative infant doses were 0.88 mcg/kg/day or 2.3% (as risperidone equivalents) (14).
The two women who were breastfeeding were treated for psychosis with risperidone doses of 42.1 mcg/kg/day (2 mg every 12 hours) and 23.1 mcg/kg/day (0.5 mg in the morning and 1 mg at night), respectively (14). The nursing infants were a 3.3-month-old female and a 6-week-old male, respectively. In the first woman, milk concentrations of the parent drug and metabolite were 49 and 142 mcg•hr/L (AUC), respectively, whereas the average concentrations were 2.1 and 6 mcg/L, respectively. The absolute infant doses were 0.32 and 0.9 mcg/kg/day, respectively. In the second woman, milk concentrations were 3.1 and 56.5 mcg•hr/L (AUC), respectively, whereas the average concentrations over 24 hours were 0.39 and 7.06 mcg/L, respectively. The absolute infant doses were 0.06 and 1.06 mcg/kg/day, respectively. The milk:plasma ratios were 0.1 and 0.5, respectively. Neither risperidone nor the metabolite was detected in the plasma of the infants and both were developing normally at 9 and 12 months, respectively (14).
No developmental abnormalities were observed in two infants of mothers treated with risperidone throughout gestation and during breastfeeding (6) (see Fetal Risk Summary).
A 23-year-old woman, nursing a 4.2-kg male infant, was diagnosed with paranoid schizophrenia 1 week after birth (15). She was hospitalized and started on risperidone 1 mg twice daily. The dose was changed to 2 mg every evening on day 7, and then to 3 mg every evening on day 10. Milk (fore and hind) and maternal plasma concentrations of risperidone and paliperidone were determined on days 6, 10, and 20. No drug accumulation was observed and the concentrations of paliperidone always exceeded those of risperidone. The ranges of risperidone and paliperidone milk concentrations were 0–3 and 1.2–11 ng/mL, respectively, whereas the plasma concentrations were 0.4–10 and 4–43 ng/mL, respectively. Moreover, the concentrations in fore- and hind-milk were comparable. On day 10, 15 hours after a 2 mg dose, the concentrations of risperidone and paliperidone in infant plasma were 0 and 0.1 ng/mL, respectively. The mother was discharged home on risperidone after 5 weeks. The psychomotor development of the infant during the mother’s hospitalization was normal and no adverse effects or sedation in the infant were observed. The mother and infant were doing well 2 months after discharge (15).
The AAP classifies other antipsychotic drugs as agents for which the effect on nursing infants is unknown but may be of concern, especially when given for long periods (16). Although risperidone was not mentioned, the AAP noted that antipsychotics are excreted into breast milk and could conceivably alter both short-term and long-term central nervous system function. Although no adverse effects from exposure to risperidone have been observed, studies have not been conducted to determine if there are long-term effects.
References
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