[Clozapine and pregnancy]

This article reviews the relations between clozapine and pregnancy. Six case reports are identified in the literature of pregnant patients who received clozapine. Novartis at Basle, Switzerland, through its pharmacovigilance and epidemiology, service, has data on nearly 200 cases summarized in this article. We also describe the case of a patient with paranoid schizophrenia who was hospitalized 10 times between the age of 22 to 32. She received clozapine when she was 29 years old and, with a daily dosage of 350 mg, she became asymptomatic. At the age of 33 and 37, she became pregnant and continued clozapine during her 2 pregnancies. During her first pregnancy, she received insulin due to gestational diabetes associated with a body weight mass (BWM) of 30.4 (N = 20 to 25). During her second pregnancy, the BWM was 23.7 and she did not develop diabetes. She delivered at term 2 daughters who are at the time of this report 5 and 3 years old. The two girls are doing well and have no developmental delay. Psychotic symptoms exacerbation: the plasma concentration of clozapine diminishes during pregnancy due to a higher hepatic metabolism and distribution volume. Monitoring plasma concentration of clozapine can help to adjust its dosage. In case of psychotic symptoms exacerbation, the following can be recommended: 1) Increase the clozapine dosage; 2) Add a classic antipsychotic like perphenazine, trifluoperazine or haloperidol. Diabetes: obesity, glucose intolerance or a family history of diabetes are risk factors to develop gestational diabetes. The follow-up of patients, who take an atypical antipsychotic, should include constant monitoring of the blood glucose or Hb1A and lipid dosages. Complications at labor: Clozapine increases the secretion of oxytocine and the contraction of the uterine muscle. But, no studies can explain how clozapine affects the labor exactly. Some case studies report use of forceps, vacuum or cesarean.

Stoner (1997) described neonatal convulsions 8 days after birth. The mother was receiving 350 mg of clozapine, but also lorazepam and haloperidol during her pregnancy. The newborn withdrawal of lorazepam can increase the risk of convulsions and also haloperidol can diminish the convulsion threshold. Floppy infant syndrome: in the case described by Dimichele (1996), the mother received a daily dosage of 300 mg of clozapine and 2.5 mg of lorazepam 3 to 5 times a day. This can explain hypotonia. Stoner (1997) reports a second case where a mother, who received 600 mg of clozapine during pregnancy, gave birth to a child who had no convulsions neither hypotonia.

The cases described concerning studies of children until age 2 to 3 years by Stoner (1997) and Dickson (1998) and until 6 years old by Barnas (1994), do not mention any developmental problem, similar to the two daughters of our patient. The pharmacovigilance service of Novarits reports 6% of malformations. But these reports must be considered with caution since they represent only the pregnancies reported spontaneously to the pharmaceutical company. This is only a portion of all pregnancies associated with clozapine.

No specific risks for the mother and children can be attributed to the use of clozapine during pregnancy. However, the plasma concentration of clozapine is higher in the fetus compared to the mother (Barnas, 1994); therefore, a minimal dosage should be used. Since clozapine is present in the maternal milk, breast feeding should be avoided. The advantages to use clozapine during pregnancy must exceed the risks. It is justified to continue the use of this medication even if data on classic antipsychotics (e.g.: haloperidol) are more extensive. Because the risk of psychotic exacerbation is higher, the substitution of clozapine is not recommended. The psychosocial support and the obstetrical follow-up must be intensive too. An institutional pharmacovigilance service should complement the one provided by the industry. Also, further case-control and cohort studies are essential to better estimate the long-term risks.