USE OF CLOZAPINE IN PREGNANCY

Clozapine is an atypical antipsychotic (AAP) used in the treatment of schizophrenia and for psychosis associated with Parkinson’s disease, where other antipsychotic (AP) drugs are not tolerated or are ineffective.

A single cohort study found no increased risk of overall malformation among ~100 pregnancies exposed to clozapine in the first trimester. Data on risks of other adverse pregnancy outcomes following maternal clozapine use in pregnancy are extremely limited or absent. Potential users should be made aware of this lack of data, and the decision to prescribe in pregnancy made on a case-by-case basis, based an assessment of the benefits of controlling the maternal condition versus the possible risks to the fetus.

Studies of antipsychotics (APs)/AAPs as therapeutic classes that include a collective total of ~50,000 exposures are largely reassuring for most outcomes. However, data relating to stillbirth risks are conflicting, and similarly, associations have been described for first generation AP exposure with preterm delivery and small for gestational age, and preterm delivery and AAP exposure, though these data are also conflicting and likely confounded. These data do not provide compelling evidence of causal associations, and further research is required to confirm or refute these findings.

In the non-pregnant population, use of AAPs (particularly olanzapine, clozapine and quetiapine) is a risk factor for impaired glucose homeostasis and type 2 diabetes. Concerns therefore exist regarding an increased risk of maternal gestational diabetes mellitus (GDM) and its sequelae following gestational clozapine use. A single study has identified increased risks of GDM and large for gestational age (LGA) among olanzapine-, clozapine- or quetiapine-exposed pregnancies, which were analysed together as a ‘high-metabolic risk’ group. Data investigating AAPs generally have also identified increased risks of infant birth weight >97th centile. Enhanced diabetes screening for all women prescribed APs (with oral glucose tolerance test) is advised.

Use of clozapine and other APs throughout pregnancy or near delivery has been associated with withdrawal symptoms in the neonate and/or poor neonatal adaptation syndrome (PNAS). These symptoms are likely to be more severe in infants exposed in utero to more than one CNS acting drug. Delivery should therefore be planned in a unit with neonatal intensive care facilities.

It is important to ensure that maternal mental health conditions are treated appropriately. Where a woman’s illness is well-controlled on clozapine, either prior to conception or during pregnancy, the perceived advantages of discontinuing or changing medication, or reducing the dose, should be carefully weighed against the risk of relapse. Where clinically appropriate, discussion of the advantages and disadvantages of continued clozapine during pregnancy with the patient is encouraged. Where the benefit of continued treatment is considered to outweigh any potential or known risks, clozapine may be prescribed for use in pregnancy.