Summary

• Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including RISPERDAL CONSTA and RISPERDAL, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.^1,2
• Infertility in Females: Based on the pharmacologic action of risperidone (D₂ receptor antagonism), treatment with RISPERDAL CONSTA and RISPERDAL may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential.^1,2
• Placental Passage: A prospective observational study including 6 women treated with risperidone demonstrated placental passage of risperidone.^1-3
• Congenital Birth Defects/Cardiac Malformations: A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (relative risk [RR]=1.26, 95% confidence interval [CI] 1.02-1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88-1.81) in a subgroup of 1566 women exposed to risperidone during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates.^1,2,4
• Pregnancy Outcomes in Women Receiving Risperidone: A comprehensive review of the Benefit Risk Management Worldwide Safety database identified 713 pregnancies in women receiving oral risperidone or RISPERDAL CONSTA from 1993-2004. Overall, neonatal risperidone exposure did not appear to increase the risk of spontaneous abortions, structural malformations, and fetal teratogenic risk as compared to the general population.⁵
• Fetal/Neonatal Adverse Reactions: Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including RISPERDAL CONSTA and RISPERDAL during the third trimester of pregnancy. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recover within hours or days without specific treatment; others required prolonged hospitalization.^{1,2, 5,6}
• Lactation: The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for RISPERDAL CONSTA and RISPERDAL and any potential adverse effects on the breastfed child from RISPERDAL CONSTA and RISPERDAL or from the mother’s underlying condition.^1,2
  • Limited data from published literature reports the presence of risperidone and its metabolite, 9-hydroxyrisperidone, in human breast milk at relative infant dose ranging between 2.3% and 4.7% of the maternal weight-adjusted dosage.^1,7
  • Infants exposed to and RISPERDAL CONSTA  and RISPERDAL through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements).^1,2

Clinical Data – Use during PRegnancy

Observational, Retrospective & Prospective Studies

Huybrechts et al (2016)⁴ conducted an analysis of a US Medicaid database from 2000 to 2010 to examine the risk of overall congenital malformations and cardiac malformations associated with first-trimester exposure to antipsychotics (APs) in females aged 12 to 55 yrs. The study cohort included 1,341,715 women who met the inclusion criteria and whose pregnancies resulted in live births (mean age: 24 years). Pregnancies with a known exposure to teratogenic medications during the first trimester or pregnancies with chromosomal abnormalities were excluded. Women who filled at least 1 prescription for an AP during the first trimester were considered exposed to an AP. Potential confounder included the calendar year, age, race, smoking, multiple gestation, indications for APs, maternal morbidity, concomitant medication use and general markers of the burden of illness and were accounted for as part of the adjusted analyses.

The most frequently used atypical AP was quetiapine (n=4221) followed by aripiprazole (n=1756), risperidone (n=1566), olanzapine (n=1394) and ziprasidone (n=697). The unadjusted analysis implied a significantly increased risk for malformations for atypical APs. In the fully adjusted analysis, the RR shifted to the null for both typical (0.90; 95% CI, 0.62-1.31) and atypical APs (1.05; 95% CI, 0.96-1.16) but remained elevated for risperidone (1.26; 95% CI, 1.02-1.56) (Table: Maternal Exposure to Antipsychotics and Relative Risk for Malformations in Infants). The authors commented that the findings for risperidone will require confirmation in additional studies.

Kulkarni et al (2014⁸ and 2008⁹) prospectively followed 147 pregnancies and as part of the Australian National Register of Antipsychotic Medication in Pregnancy from 2005-2012. A total of 15 women (10%) received risperidone during the first trimester. Congenital anomalies were seen in 2 babies whose mothers received risperidone perinatally: abnormal renal collecting tubule and bilateral talipes in 1 case, and CHARGE syndrome (Coloboma, Heart defects, Choanal Atresia, Retarded growth, Genital anomalies, Ear anomalies) in another.

Wichman et al (2009) identified 16 women (mean age: 29.3 years) receiving atypical antipsychotics during pregnancy in a retrospective chart review of 30,092 deliveries from 1993-2007 (Mayo Clinic). Four of the 16 patients were identified as continuing risperidone throughout the pregnancy, with 1 of the 4 patients also taking ziprasidone concomitantly.

Reis et al (2008)¹⁰ identified 2908 women from the Swedish Medical Birth Register who received an antipsychotic or lithium during early pregnancy. The authors studied malformation rates and reported relative severe malformations with the exclusion of known chromosome anomalies. The use of risperidone during pregnancy was specifically identified in 51 patients. Of the 51 exposed infants, 2 (3.9%) patients had malformations, 1 had Turner syndrome (not believed to be due to drug use during pregnancy) and 1 had anal atresia and lung malformation.

Coppola et al (2007)⁵ identified 713 pregnancies in women receiving oral risperidone or RISPERDAL CONSTA from June 1993 through December 2004 via a search of the Benefit Risk Management Worldwide Safety database. Of the 713 pregnancies, 188 were categorized as live births, 77 as interrupted pregnancies, and 448 with an unknown outcome.

Prospectively Reported Cases: Of the 25 interrupted pregnancies prospectively reported with a known outcome, 18 patients received oral risperidone, 3 patients received RISPERDAL CONSTA, and 3 received oral plus RISPERDAL CONSTA. Twenty-one of 25 interrupted pregnancies with information, all confirmed first-trimester exposure to risperidone (with 11 cases reporting a median duration of 11.3 weeks). Of the 15 induced abortions, 1 case reported a fetal abnormality (tricuspid atresia) with the remaining majority of abortions for nonmedical reasons or with no information regarding the interruption of pregnancy. No fetal abnormalities were reported for the 9 reported cases of spontaneous abortions (occurring between 8 and 14 weeks in 4 cases reporting gestational age). One pregnancy resulted in a stillbirth at 27 weeks due to placental abruption.

Major organ malformations were prospectively reported in 2 uninterrupted pregnancies. At 40 weeks gestation, a 2.9 kg boy with grade III esophageal atresia, hypoplasia of the pinna of the ear, and slight facial dysmorphia was born to a 35-year-old woman with gestational diabetes who took risperidone daily throughout her pregnancy. She also took several other medications including dipotassium clorazepate which is known to be teratogenic. A 2.8 kg girl with multiple congenital abnormalities consistent with Ivemark's Syndrome (pulmonary artery stenosis, abdominal heterotaxy and splenic agenesis) was born to a 39-year-old woman who took risperidone daily for 1 month during her first trimester.

Four cases of perinatal syndromes were reported prospectively: possible withdrawal syndrome (n=1), birth trauma (n=1; nuchal cord), and prematurity (n=2). Each case included alcohol or illicit drug use without congenital anomalies or long-term complications.

Retrospectively Reported Cases: Of the 52 interrupted pregnancies retrospectively reported with a known outcome, 44 patients received oral risperidone, 2 patients received long-acting risperidone, and 1 patient received oral plus long-acting risperidone. Of the 16 induced abortions, 2 cases reported a fetal abnormality (both were considered unrelated to risperidone exposure) with the remaining abortions for nonmedical reasons or with no information regarding the interruption of pregnancy. Two fetal abnormalities (unspecified chromosomal abnormalities resulting in fetal loss at 10- and 12-weeks’ gestation) were reported for the 33 cases of spontaneous abortions. Three pregnancies resulted in stillbirth (1 report had no information, 1 report due to placental abruption, and 1 report due to maternal-fetal toxoplasmosis (in addition to rubella, cytomegalovirus and herpes simplex syndrome).

Major organ malformations were retrospectively reported in 12 uninterrupted pregnancies, including the face: lip/palate (n=2); auricle (n=1), brain (n=3), heart (n=3), skeleton (n=1), mid-gut (n=1), and a multi-organ syndrome (Pierre Robing) (n=1). Risperidone use varied between trimesters and 10 of the 12 cases included a concomitant or cosuspect medication.

Minor organ malformation was retrospectively reported in 3 pregnancies: capillary hemangioma in the leg, undescended testis and hydrocele, and an unspecified skeletal malformation requiring a 'Craig splint' to prevent hip displacement. Thirty-seven cases of perinatal syndromes were reported retrospectively. Of these, 21 cases of perinatal syndromes either referred explicitly to drug withdrawal or represented a possible withdrawal-emergent syndrome from birth to 13 days. More than half of the infants were exposed to risperidone during the third trimester and 18 of the 21 cases were confounded by concomitant medication. All but 2 cases did not provide information about whether the infant was breast-fed, making it difficult to determine if or when risperidone was completely withdrawn. Poorly defined long-term developmental syndromes were reported in 4 pregnancies (most with concomitant medication) and included seizures with a degree of developmental delay, significant neurodevelopmental problems (mother had illicit drug use throughout the pregnancy), motor problems, and myotonia.

Newport et al (2007)³ conducted a prospective observational study assessing the placental passage of antipsychotic medications in 54 pregnant females. Placental passage was defined as the ratio of plasma umbilical cord concentration (ng/mL) to maternal plasma concentration (ng/mL) for both parent and, in the case of risperidone, metabolite. Patients included those receiving risperidone (n=6; 3.0 mg/day mean dose) for at least 2 weeks. Mean placental passage ratio was 49.2% for risperidone (n=6). Mean umbilical cord plasma concentrations for risperidone and 9-hydroxyrisperidone were 0.36 ng/mL and 1.31 ng/mL, respectively, while mean maternal plasma concentrations were 0.32 ng/mL and 3.57 ng/mL, respectively. The resulting mean risperidone to 9-hydroxyrisperidone concentration ratio was 0.58 in umbilical cord plasma and 0.12 in maternal plasma. Obstetrical outcome data for risperidone included low (<2500 g; n=1) birth weight neonates. Mean APGAR scores at 1 and 5 minutes, in the 6 neonates exposed to risperidone, were 8.7 and 9.2, respectively.

Paulus et al (2005)¹¹ conducted a prospective follow-up study to determine the effect of atypical antipsychotic agents in early pregnancy. Pregnancy outcomes data were collected from 95 women who were on atypical antipsychotic agents over the past 15 years. Antipsychotic agents used by the women included risperidone (n=18). Exposure to risperidone resulted in 1 case of cryptorchidism.

Yaris et al (2005)¹² conducted a prospective case-control study to evaluate the potential difference between fetal outcomes of pregnant women (n=124) exposed to psychotropic drugs (antipsychotics, antidepressants, anxiolytics) compared to an age-matched control group (n=248) without any drug exposure. The 2 risperidone cases delivered healthy babies.

Mackay et al (1998)¹³ conducted a noninterventional, observational, postmarketing, cohort study for the purpose of examining the safety of risperidone in a large patient population treated in a general practice setting (N=7684). Nine of the patients were taking risperidone during 10 pregnancies (1 patient had 2 pregnancies while taking the drug). Of these 10 pregnancies, there were 7 live births and 3 early therapeutic terminations of the pregnancy. Further review determined that there were no abnormalities reported among the live births.

Case Reports

Review

Reinstein et al (2020)²⁹ published a review and guidance for the use of long-acting injectable antipsychotics (LAIs) during pregnancy.

Women with a history of psychotic and affective illness are at a higher risk for psychiatric symptoms during pregnancy. The continuation of LAIs may be appropriate in women with a history of significant psychiatric illness who either wish to become pregnant or recently have become pregnant, unless there is a compelling reason for discontinuation. Clinical risk factors to be considered are nonadherence with oral antipsychotic medication, history of frequent and extended psychiatric hospitalization associated with schizophrenia, previous psychiatric decompensation during pregnancies, and illicit substance abuse.

Prior to prescribing an LAI for a patient who is pregnant or wishes to become pregnant, it is important to engage in an informed consent discussion with the patient and to fully discuss the potential risks and benefits of LAI treatment during pregnancy.

When selecting LAIs for pregnant women, clinicians should consider the metabolic profiles of medications, the potential for an increase in dose during pregnancy, length of dosing intervals, consistent plasma drug levels, approved indications, and plans for breast feeding.

clinical data – Use During Lactation

Weggelaar et al (2011)³⁰ published a case report of a 40-year-old woman with bipolar disorder, treated with risperidone 1 mg/day daily during 8 months of pregnancy and 2 mg/day during the final month. The infant was fed breast milk only and the mother volunteered to measurements of risperidone levels both in the serum and breast milk. Samples were taken over the 24-hour post dose period. The resulting serum level in the infant was also to be measured.

Risperidone and the metabolite, 9-hydroxyrisperidone could be detected in the serum of the mother. The highest level of risperidone detected in the serum was approximately 4 μg/L, 1-hour post-dose; at 2 hours post-dose the level was approximately 1 μg/L. Only the active metabolite 9-hydroxyrisperidone could be detected in the breast milk; concentrations recorded between the 3 and 20 hour post-dose period were approximately 4 μg/L. No risperidone could be detected in the serum of the infant. The product of the average drug concentration in the breast milk and the milk intake of the infant (150 mL/kg per day) was used to calculate the exposure of the infant to the drug and the metabolite. The authors calculated that the total intake of 9-hydroxyrisperidone by the infant was 4.7% of the weight-adjusted oral intake of the mother.

Aichhorn et al (2005)³¹ published a case report of a 23-year-old female diagnosed with paranoid schizophrenia, second episode, 1 week after the delivery of her son. The patient was initiated on 2 mg/day of risperidone. The dose was increased to 3 mg/day on day 10, secondary to poor clinical response associated with low maternal drug plasma levels. The mother fed her infant 6 times a day. Risperidone levels in the mother’s and infant’s serum, and in the breast milk are presented in Table: Risperidone (R) and 9-hydroxyrisperidone (OH) Concentrations (ng/mL). Fore and hind milk were determined separately, based on the presumption that higher lipid content in hind milk would lead to higher concentrations.

The infant’s psychomotor development while in the hospital was normal, and no sedation or adverse events related to risperidone were detected. Two months after discharge, and 5 months after risperidone initiation, mother and baby were well.

Ilett et al (2004)⁷ assessed the safety of breast-feeding during maternal risperidone administration by studying the transfer of risperidone and 9-hydroxyrisperidone into the breast milk of 3 women (2 breast feeding and 1 risperidone-induced galactorrhea). Infant plasma concentrations were measured. Estimates were made with regards to the amount of drug the infant received. The results are listed in Table: Breast Milk Study Results.

The authors concluded that an infant’s short-term exposure to risperidone via breast milk is unlikely to be a significant hazard, but due to limited data, an individual risk-benefit assessment should be made prior to making the decision on whether to breast-feed during risperidone therapy.

Hill et al (2000)³² discussed a case report of a 21-year-old female with a 2-year history of bipolar disorder. After delivering her baby, she became increasingly withdrawn and depressed, suffering from paranoid delusions and passivity phenomena. She stopped breast-feeding and started on risperidone. Her risperidone dose gradually titrated to 6 mg per day. After 1 week on risperidone 6 mg per day, 7 serial samples of plasma and 6 serial samples of breast milk were drawn over a 24-hour period and tested for risperidone and 9-hydroxyrisperidone levels. The researchers concluded that the nursing infant would receive 0.84% of the maternal dose of risperidone and an additional 3.46% from 9-hydroxyrisperidone. The authors concluded that their recommendation to the patient to discontinue nursing was conservative but appropriate.

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 28 November 2024.