A large number of women develop psychiatric disorders during the reproductive years. Therefore, many female patients will require management of their psychiatric disorders during pregnancy and breast-feeding periods. Unlike many neurologic disorders that improve temporarily during pregnancy, many psychiatric disorders relapse during pregnancy, and their treatment poses a formidable challenge to the treating physician. Clinicians are often uncomfortable with treatment of pregnant and breast-feeding psychiatric patients as the effects of psychiatric medications on pregnant women and unborn children are largely unknown. The authors of this chapter present a balanced review of the latest information about this significant issue so readers will be able to make informed and reasonable therapeutic decisions about this vulnerable group of psychiatric patients.

Introduction

During the past two decades the complex interactions among psychiatric disorders and reproductive processes such as menarche, pregnancy, delivery, lactation, and menopause have been elucidated, making more accurate information available for treating physicians and other health care providers who are involved in management of pregnant and breast-feeding psychiatric patients. In general, women are at great risk of developing psychiatric disorders during their reproductive years of life (between ages 18 and 45 years). Therefore, a large number of women may develop a new psychiatric illness or experience worsening of their existing psychiatric disorder during pregnancy or lactation. The two most common psychiatric disorders among women are depression and anxiety disorders. Other less prevalent psychiatric illnesses include schizophrenia, eating disorders, and bipolar disorders (BPD). In general, management of these psychiatric disorders during pregnancy poses a significant challenge to treating psychiatrists and successful treatment outcomes require familiarity with the course of these disorders during pregnancy and thorough knowledge of the potential effects of psychiatric medications on the fetus.

Schizophrenia and Pregnancy

Schizophrenia is a severe and complex mental disorder which includes chronic or relapsing psychotic episodes and long-term compromise of the individual’s functional capacity. Schizophrenia affects 1% of individuals worldwide and primarily is characterized by abnormalities in perception or expression of reality. Many female patients with schizophrenia are in their childbearing years. This chronic psychiatric disorder, with typical onset in young adulthood, manifests clinically with severe social withdrawal, auditory hallucinations, disorganized thought process, paranoid and bizarre delusions, and misinterpretation of reality. Diagnostic criteria for schizophrenia are presented in Table 8.1 . Psychiatric symptoms of schizophrenia are classified as positive (such as perceiving things which other individuals cannot see or hear) and negative (such as loss of motivation and apathy). Schizophrenic patients also suffer from cognitive decline with impairment of abstract thinking, lack of focus and attention, memory loss, and difficulty with carrying on a meaningful conversation. Other symptoms consist of mood instability, impaired executive function, and impaired language processing. Magnetic resonance imaging of patients with schizophrenia reveals reduction of the volumes of the hippocampus–amygdala complex and parahippocampal gyrus.

Schizophrenia differs in women versus men in various aspects. The risk of schizophrenia may be lower in women and its peak age of onset is later in women with a second smaller peak between 45 and 49 years of age. In addition, women are more likely than men to finish school, start an occupation, and be married with children by the time of clinical diagnosis of schizophrenia. Family histories of schizophrenia and affective disorders are more common among schizophrenic females compared to males . The doses of antipsychotics needed to treat schizophrenic women may be smaller because of the higher females’ body fat which accumulates lipophilic antipsychotics and higher blood levels of antipsychotics in women .

A significant number of pregnancies in females with schizophrenia are unplanned and unwanted ; therefore, these fetuses may already be exposed to mother’s poor nutritional status, nicotine, drug abuse, and high concentrations of antipsychotics during the first trimester of pregnancy. In addition, many of these pregnant schizophrenic women are not married and have restricted social support . Studies of the outcome of pregnancy in schizophrenic patients reveal significantly elevated risks of stillbirth, infant death, premature labor, low birth weight, newborns who are small for gestational age, and lower APGAR scores . A significant issue about the pregnancy outcome in schizophrenia is that psychosis is harmful to the fetus. Nilsson et al. assessed the pregnancy and birth outcomes in 1438 mothers with schizophrenia and reported higher adverse pregnancy outcomes (which included stillbirth, prematurity, small size for gestation, and death) in women who developed a psychotic attack during pregnancy. Apart from psychosis and its adverse impact on pregnancy and its outcomes, the mother’s stress and agitation, particularly during the third trimester, is associated with long-term effect on the baby’s hypothalamic–pituitary–adrenal axis and may increase the possibility of congenital malformations and low birth weight . Therefore, when one considers treating pregnant schizophrenic patients, the risks to the fetus in untreated psychosis should be compared to the risks and benefits of using antipsychotics and exposing the fetus to these medications.

Course of Schizophrenia During Pregnancy and Postpartum

The course of schizophrenia during pregnancy varies, and it remains unknown whether physiologic changes associated with pregnancy and lactation alter the course and symptomatology of this chronic psychiatric illness. Therefore, these pregnancies should be regarded as high risk . Women with schizophrenia usually have less contact with psychiatric hospitals and their admission rates during pregnancy are lower compared to periods pre- and postdelivery . Although some patients may experience improvement of their symptoms, others may experience more delusions and psychotically deny the pregnancy and attempt to harm the unborn child . In addition, pregnant women with schizophrenia do not demonstrate a need for smaller doses of maintenance medications . Many schizophrenic women who wish to have children may discontinue their medication(s) abruptly in order to avoid any potential harmful effect of these medications on the fetus. Such a poorly planned disruption in treatment may result in further deterioration of the disease.

While the prevalence of postpartum psychosis in the general population is 1–2 per 1000 childbirths, this rate is 100 times higher in women who suffer from BPD or have a past history of postpartum psychosis . Patients with schizophrenia demonstrate a higher prevalence of postpartum psychosis . Within a 6-month period following delivery, 16% of schizophrenic patients are admitted to the hospital due to postpartum psychosis. The etiology of such elevated rates of postpartum psychosis in schizophrenic patients remains unknown; however, an abrupt drop in serum levels of female hormones and increased dopaminergic activity following postpartum estrogen drop may play a pathogenic role . Postpartum psychosis in schizophrenic patients is a psychiatric emergency and hospital admission is necessary to secure the safety of both mother and child. In cases of medication-resistant psychosis or psychosis in a breast-feeding patient electroconvulsive therapy should be considered.

Antipsychotic Medications and Pregnancy

Pregnant women with psychiatric disorders are frequently treated with antipsychotics . Psychotropic medications diffuse across the placenta during pregnancy; therefore, use of antipsychotics during pregnancy is associated with potential teratogenic complications as well as obstetric complications and neurobehavioral and neonatal toxicity . Currently, the data on the efficacy and safety of use of antipsychotics during pregnancy is limited. After the launching of the atypical antipsychotics, pregnancy rates in schizophrenic women have increased and despite the paucity of safety data, these medications are being used commonly for treatment of pregnant women with psychosis . Practically, the fundamental task for both the treating psychiatrist and psychotic pregnant patient is to weigh the risks versus benefits of treating these patients and protecting the unborn fetus against complications including developmental problems that may arise during infancy. A summary of mechanisms of actions of the atypical and typical antipsychotics are presented in Tables 8.2 and 8.3 .

Most of the existing data on the impact of typical antipsychotics on pregnant women stems from their application for treatment of hyperemesis gravidarum. Of course, the required doses for treating this condition are smaller than doses used for treatment of schizophrenia. Altshuler et al. reviewed the literature regarding the effects of prenatal exposure to psychotropic agents on fetal outcome and performed a meta-analysis on published literature between 1966 and 1995. The results of this study revealed that three primary effects were associated with medication use during pregnancy: teratogenicity, perinatal syndromes, and postnatal behavioral sequelae. The authors concluded that there was a small but statistically important increase in the risk of congenital anomalies on babies exposed to the low-potency antipsychotics during the first trimester. Based on their study, there was no specific pattern of anomalies. Information on the behavioral sequelae in children who were exposed to antipsychotics during pregnancy is scarce. Two different studies by Kris and Stika et al. did not establish any significant behavioral or cognitive abnormalities in children who were exposed to chlorpromazine or chlorprothixene in utero.

The typical older antipsychotics possess many side effects, including parkinsonian syndrome and tardive dyskinesia (TD). Other adverse effects consist of weight gain, cardiac conduction disorders, postural hypotension, and cognitive decline. The atypical antipsychotics used in schizophrenia include risperidone, olanzepine, quetiapine, ziprasidone, aripiprazole, and clozapine. The benefits of the atypical antipsychotics over the older-generation medications include better responses of some patients who are resistant to the first-generation antipsychotics, improvement of negative symptoms and cognitive decline, and decreased potential for development of short-term acute or long-term parkinsonism, dystonia, or akathesia. Significant side effects of atypical antipsychotics consist of weight gain, their impact on the insulin and leptin effects, which increases the chance of obesity and diabetes, sedation, and hypertension. The obesity which is associated with treatment with atypical antipsychotics in turn may be associated with higher rates of obstetric complications such as gestational diabetes, preeclampsia, and cesarean delivery .

So far, there are no randomized or blinded evaluations to assess and determine the birth outcome measures following treatment of pregnant psychotic patients with atypical antipsychotics. One prospective study by McKenna et al. assessed the rates of major malformations, spontaneous and therapeutic abortions, rates of stillbirth, birth weight, and gestational age in patients treated with olanzepine, risperidone, quetiapine, and clozapine and reported that only one malformation in one baby exposed to olanzepine was detected. While the group exposed to the atypical antipsychotics did not show any statistically significant differences in the rates of miscarriage, stillbirth, prematurity, congenital malformation, and perinatal syndromes compared to the healthy controls, their results indicated an increased rate of low birth weight babies.