Limited case literature is available to psychiatrists to guide the management of pregnancy among women who are treated with clozapine. The case literature has reported that stabilized patients who receive clozapine may express the desire for a child (1,2,3) and that accumulation of clozapine in fetal serum (2) may increase the risk of perinatal morbidity, in particular, "floppy infant syndrome" (3) and neonatal seizures (4). These reports have also highlighted the need to optimize the dose of clozapine for pregnant women, either by reducing the dose (2) or increasing it (3,4). There have also been reports that the resolution during clozapine treatment of hyperprolactinemia that had been induced by neuroleptics may increase the risk of pregnancy, both desired (1) and unwanted (5). Breastfeeding is not recommended because of the high concentration of clozapine found in breast milk (2).
The case described below adds to the reported experience in this area and suggests clinical issues for psychiatrists to consider in managing the treatment of women who receive clozapine.
Ms. T is a 28-year-old woman who resides with her husband; both have a diagnosis of schizophrenia. Ms. T had an 11-year history of persistent and severe symptoms, which included a marked thought form disorder, delusions, inappropriate affect, and disorganized behavior. She had been referred for day hospital treatment under the first author's care because outpatient appointments did not provide the intensity of treatment she required.
Because Ms. T had persistent severe psychotic symptoms and mild tardive dyskinesia while taking typical neuroleptics and because she had failed to improve on risperidone, the decision was made to initiate clozapine. Before clozapine initiation, Ms. T was receiving 62.5 mg of fluphenazine decanoate every two weeks. Her prolactin levels at two evaluations were elevated to 46.1 and 73.4 micrograms per liter (reference range, 1 to 15 micrograms per liter).
Ms. T was briefly hospitalized to initiate clozapine treatment, as was required by drug labeling law at that time. After her discharge, the medication was titrated to 450 mg daily, and she began to improve clinically. After four months of clozapine treatment, she complained of vomiting. Although she denied the possibility of pregnancy, a urine test for the beta subunit of human chorionic gonadotropin was positive. Ultrasound indicated that the fetus's gestational age was seven weeks. The couple said that they had been trying to conceive but had not previously been successful, and they were delighted by this outcome. Ms. T had previously been prescribed birth control pills but had not taken them.
During her pregnancy, Ms. T required intermittent hospitalizations for symptom exacerbations, inability to care for herself, and significant fatigue and hypersomnolence. Clozapine was progressively reduced to 200 to 250 mg daily during her second trimester and to 150 mg daily during the last two months of her pregnancy.
Before her referral to the author's care, Ms. T had been informed that she had "high sugars," but her hyperglycemia was not treated until she was hospitalized for initiation of clozapine. While she was in the hospital, she was referred to an endocrinologist for management of diabetes, and metformin was prescribed.
After Ms. T had been started on clozapine but before her pregnancy had been detected, she became increasingly hyperglycemic and required an increase in metformin. This oral hypoglycemic, a potential teratogen, was discontinued when her pregnancy was confirmed. Insulin injections were initiated to manage her diabetes. However, her psychiatric illness interfered with her ability to monitor her blood glucose, comply with a diabetic diet, and self-administer insulin. The erratic control of her blood glucose complicated assessment of her mental state. A nurse provided Ms. T with outpatient diabetic care during her pregnancy. However, the nurse reported that Ms. T showed limited motivation to participate in her own care.
An obstetrician managed Ms. T's prenatal care and delivery. Labor was induced at 38 weeks' gestation. Delivery was complicated by shoulder dystocia and was assisted by low mid forceps; the baby was healthy. Ms. T did not experience exacerbation of her psychosis during delivery or the postpartum period. She did not breastfeed. While she was still in the hospital, child welfare workers, who had been contacted well in advance of delivery, became actively involved. Initially, 24-hour in-home care was required to support the parents and to ensure a safe environment for the baby.
At three years after the baby's birth, intensive community support and psychiatric care are still required to support this couple's desire to parent. Although Ms. T is functionally improved on clozapine and has not needed inpatient treatment, her negative symptoms, behavioral disorganization, and cognitive impairment hamper her ability to function as an autonomous mother. Her tardive dyskinesia and hyperprolactinemia have resolved on clozapine.
Like the patient described by Kaplan and colleagues (5), Ms. T did not conceive while on traditional neuroleptics despite being sexually active. Both women conceived approximately two months after initiation of clozapine. Clozapine does not elevate prolactin levels; with resolution of neuroleptic-induced hyperprolactinemia, menstrual cycles and more consistent ovulation may resume, and the chance of pregnancy increases. Thus physicians must be aware of drug-induced changes in fertility and educate women about potential change in reproductive fitness. The introduction of prolactin-sparing atypical neuroleptic medications makes the implementation of effective contraceptive counseling for seriously mentally ill patients even more urgent.
It is of interest that Ms. T at age 28 was the youngest patient described in case reports of women who became pregnant while taking clozapine. The average age at the time of pregnancy of the women in other reports was 32.8 years, with a range from 30 to 37 years (1,2,3,4,5). Whether even more pregnancies will occur as clozapine is prescribed to younger women earlier in the course of their illness, and presumably at a time of relatively higher fertility in their life cycle, seems possible but is currently unknown.
Although clozapine is not known to have teratogenic effects, only limited data are available (6). One author has warned that clozapine may pose extra risks in pregnancy, given the lack of knowledge about neonatal risks for clozapine-induced agranulocytosis and the inability to monitor fetal hematology (7). However, the risks and benefits of continuing clozapine during pregnancy must be carefully analyzed on a case-by-case basis. In the treatment of Ms. T, for example, reverting to ineffective traditional antipsychotic therapy would have increased the risk of exacerbation of psychosis, an outcome that may ultimately have been more dangerous to the mother and child than continuation of clozapine. Clozapine treatment combined with intensive psychosocial support allowed Ms. T to remain competent, to cooperate with prenatal care, and to manage labor and delivery.
Ms. T's hyperglycemia predated clozapine treatment and pregnancy, but it worsened during initial clozapine treatment and pregnancy. Popli and colleagues (8) reported four cases of increasing glucose intolerance after initiation of clozapine. Both Ms. T and the patient described by Waldman and Safferman (1) developed gestational diabetes and experienced shoulder dystocia. Whether use of clozapine during pregnancy increases the risk of difficult delivery through increased risk of maternal hyperglycemia and resulting fetal macrosomia is unknown, but physicians should be alert to this possibility.
At last follow-up three years after the birth of their baby, Ms. T and her husband were succeeding in their goal to be parents. Although intensive community support and psychiatric rehabilitation have contributed to this positive outcome, without clozapine's efficacy in treating Ms. T's psychotic symptoms, it is doubtful that she would have been able to participate in psychosocial treatment. Given the desire of many women with serious mental illnesses to bear and raise children, clozapine treatment may have a role in optimizing outcomes. Timing of pregnancy may also be important. Had Ms. T delayed conception until maximally stabilized, she would have been more capable of active participation in her prenatal care and the initial care of her infant.
The psychiatrist plays an important role in coordinating comprehensive care and educating other medical specialists and community workers about treatment-resistant schizophrenia and the benefits and limitations of new drug treatments. As more men and women with severe mental disorders are treated in community settings, achieve better control of their psychiatric symptoms, and receive drugs that cause fewer sexual and reproductive side effects, more pregnancies are likely to occur (9).
Women may experience an increase in fertility and subsequent pregnancies when switched from traditional prolactin-elevating neuroleptic medications to clozapine. When pregnancy occurs, management may require the collaboration of multiple medical specialists and community organizations to achieve an optimal outcome. In treating women who have become pregnant, the minimal effective dose of clozapine should be used; both increased and decreased dose requirements during pregnancy have been described. Clozapine may also increase the risk of developing gestational diabetes. The psychiatrist plays a crucial role in advocating for and coordinating comprehensive continuous care for pregnant women with schizophrenia.
The authors thank endocrinologist A. Edwards, M.B., F.R.C.P.C., and obstetrician-gynecologist S. Iwanicki, M.D., F.R.C.O.G., for assistance with this report.
Dr. Dickson is associate professor in the department of psychiatry at the University of Calgary and chief of the specialized programs division of the department of psychiatry of the Calgary Regional Health Authority, 3500 26th Avenue, N.E., Calgary, Alberta, Canada T1Y 6J4. Dr. Hogg is clinical lecturer in the department of psychiatry at the University of Calgary Foothills Hospital in Calgary.