Atypical Antipsychotics in the Treatment of Schizophrenia During Pregnancy and the Postpartum

Significant gender differences exist in the course, characteristics, and treatment response of schizophrenia. Although schizophrenia has classically been thought to have equal incidence in men and women, the risk may be lower in women (1) . The peak onset of schizophrenia is later in women, occurring mainly in the mid to late 20s, with a second, much smaller peak between 45 and 49 years of age. One hypothesis for the differences in the age of onset is the protective antidopaminergic effect of estrogen on psychosis, leading to later onset in women in the earlier years and increased onset in the perimenopausal and menopausal years. It is also possible that these different ages of onset represent different subtypes of the disease (1, 2) .

These differences in age of onset have implications for the course of illness. In contrast to men, women are more likely to have finished school, started working, and be married with children by the time of  diagnosis (3) . Women show greater functionality in all domains in the first 15 years of illness; this trend appears to reverse by the third decade of illness, perhaps related to the decrease in estrogen levels with menopause. Women also tend to demonstrate milder symptoms than men, fewer and shorter hospitalizations, greater posthospitalization employment, more intimate relationships, fewer legal problems, and a lower risk for suicide (4) .

Women with schizophrenia are more likely than men to have positive family histories of schizophrenia and affective disorders (2) . The diagnosis is often missed initially because of women’s “atypical” form of the disease that is characterized by more mood and fewer negative symptoms and faster resolution of both, with lower doses of antipsychotics (3, 4) . Lower doses may be necessary because of several factors, including women’s higher percentage of body fat in which to store lipophilic antipsychotics, the protective effects of estrogen, and higher blood levels of antipsychotics. Women, however, experience more side effects, particularly akathisia, tardive dyskinesia, extrapyramidal symptoms, blood dyscrasias, and gastrointestinal and dermatological conditions.

Although it appears that women with schizophrenia may have lower fertility rates than women in the general population, the majority of women with psychotic disorders do have children (5) . They have a higher risk of unplanned and unwanted pregnancies and are more likely to be unmarried and to have limited social support (6) .

The majority of women with schizophrenia experience loss of custody, with their children most often going into intermittent foster care (7) . Such inconsistency in their upbringing can confer additional risk to the offspring, who already have increased genetic and in utero vulnerability to the disease.

Although the course of schizophrenia during pregnancy is not well defined, these pregnancies should be considered high risk (6) . Women with schizophrenia tend to receive less prenatal care, have poorer nutrition, and use more tobacco, alcohol, and illicit drugs compared to women without schizophrenia. The offspring of women with schizophrenia appear to face an increased risk of lower APGAR scores, low birth weight, intrauterine growth retardation, preterm delivery, stillbirth, malformation, and infant death (6, 8) . Of note, many of the studies examining the effects of schizophrenia on pregnancy did not control for maternal medication use. Studies evaluating the effects of medication on the fetus generally did not control for the impact of maternal illness.

Psychosis itself appears to be particularly harmful to the fetus: Nilsson et al. (9) found a doubling of adverse pregnancy outcomes in women who experienced a psychotic episode during pregnancy. These adverse outcomes, including stillbirth, death, prematurity, and small size for gestational age, were found despite control for other variables, including single motherhood, smoking, parity, age, education, and pregnancy-induced hypertensive disorders.

Additionally, a woman with psychosis is often agitated and anxious. Prenatal stress, particularly in the third trimester, is associated with a long-term impact on the hypothalamic-pituitary-adrenal axis in offspring (10) and may increase the risk of congenital malformations (11) and low birth weight (12) . Further, research suggests that prenatal anxiety can negatively affect behavior, emotionality, and cognition in the growing child (13) . Thus, although fetal medication exposure is more obviously identified as a risk to pregnancy outcome, maternal mental illness and its risks to the fetus must also be clearly evaluated when one considers treatment during pregnancy.

Given the risks of psychosis during pregnancy, the risks of fetal medication exposure must be weighed against the risks of no treatment; for example, stopping medication often leads to relapse. The classic triad of medication exposure risks includes the following: 1) congenital malformations associated with medication use during the first trimester, the major time of organogenesis; 2) perinatal complications reflecting medication exposure or withdrawal late in the third trimester; and 3) behavioral teratogenesis, which describes disturbances in behavior and cognition observed in a developing child exposed to medication in utero.

Increasingly, atypical antipsychotics are being prescribed as first-line agents for new-onset schizophrenia, and many women with existing schizophrenia are switching to them as well. Therefore, the group of reproductively aged women taking atypical antipsychotics may well be expanding. But the issue of whether to use typical versus atypical medication during pregnancy is a difficult one. There is more data on low-potency typical antipsychotics, which carry a slightly higher risk of congenital malformations. There is less safety data on high-potency agents, and they may require additional potentially teratogenic medications to manage side effects. On the other hand, data on atypicals during pregnancy are quite limited. Furthermore, these agents are associated with medical conditions that can themselves pose risks to both the mother and the fetus.

Major side effects posed by atypical antipsychotics include weight gain, diabetes, sedation, and hypertension. These all confer significant risks for pregnancy. The rate of obesity has increased significantly in recent years. It is associated with high rates of obstetrical complications, including gestational diabetes mellitus, preeclampsia, and cesarean delivery (20) . The rise in obesity may well account for increased perinatal adversity rates (21), as well as increased rates of gestational diabetes mellitus. For the mother, gestational diabetes is a strong risk factor for diabetes mellitus in a later nonpregnant state. Immediate risks to the fetus include macrosomia, hypoglycemia, shoulder dystocia, and associated birth injuries, such as fractures and nerve palsies.

Boney et al. (22) found that a neonate who is both large for gestational age and exposed to maternal obesity—with or without gestational diabetes mellitis—is at increased risk for metabolic syndrome during its childhood. Previously, abnormal birth weight (large or small for gestational age) and in utero exposure to maternal diabetes were found to be significant risk factors for the onset of type II diabetes mellitus in Pima Indian children. These findings suggest that fetal hyperinsulinemia may develop as a result of maternal hyperglycemia in an obese mother, potentially causing both the short-term problem of being either large or small for gestational age and the more insidious risk of glucose intolerance later in the offspring’s childhood.

Other studies have found that prepregnancy body mass index is also a major risk factor for stillbirth and neonatal death. Kristensen (23), in a prospective study, found a doubling of the risk of these outcomes in children born to obese mothers compared with those born to normal weight women. Of interest, adjustment for maternal cigarette smoking, caffeine and alcohol intake, maternal age, parity, education, and cohabitation with partner did not change the effect, nor did the exclusion of women with hypertension or diabetes. Diabetes was 10-fold more common in obese women compared with those of normal weight (5.5% versus 0.4%, respectively), whereas the proportion of women with hypertension rose from 3.7% in women of normal weight to 16.6% in those with obesity.

Maternal diabetes mellitus before pregnancy is an established risk factor for congenital malformations including CNS defects. Anderson et al. (24) found a substantially increased risk of anencephaly, spina bifida, or isolated hydrocephaly in the offspring of obese mothers (body mass index ≥30.0 kg/m ² ). In an earlier study, Moore et al. (25) found that the offspring of pregnant women with both obesity and diabetes were three times as likely to have a major, nonchromosomal congenital defect, suggesting that there may be a synergistic teratological effect between these disorders.

Another complication of rising body mass index is hypertension. Ricart et al. (26) prospectively collected information on body mass index and glucose tolerance on more than 9,000 women. He found that prepregnancy body mass index surpassed abnormal blood glucose tolerance as a risk factor for macrosomia, cesarean section, pregnancy-induced hypertension, and small-for-gestational-age babies. In fact, the upper quartile of prepregnancy body mass index (>26.1 kg/m ² ) accounted for 50% of the pregnancy-induced hypertension compared with only 9% caused by abnormal blood glucose levels. Hypertension is itself a major risk factor for small size for gestational age, preterm delivery, and resultant long-term developmental issues. In a prospective study of nearly 2,000 women with hypertension during pregnancy, Ray et al. (27) found that the greatest risk for obstetrical adversity was in mothers who developed preeclampsia, with or without underlying chronic hypertension. After adding control for maternal obesity and prior history of preterm delivery, Ray et al. found that preeclampsia doubled the risk of prematurity, prolonged ventilation, and perinatal death.

In the postpartum period, the risk for relapse of schizophrenia is worst during the first 3 months after parturition (28) . McNeil (29) found a rate of postpartum relapse of nearly 24% in patients with schizophrenia, and their relapse occurred somewhat later than in women with predominately affective illness. Women with schizoaffective disorder are particularly susceptible (30) .

Within the first few days after delivery, levels of estrogen and progesterone fall from as much as hundreds of times normal to their lowest levels during the follicular phase. These rapid shifts have been implicated in postpartum depression and psychosis by other authors. The loss of estrogen’s antidopaminergic activity may increase the schizophrenic mother’s risk for decompensation.

A mother’s worsening mental state is clearly dangerous for her neonate. Thought disorganization, attention to psychotic symptoms, blunted emotional awareness, anergy, and unresponsiveness can cause disruptions in mother-infant interactions (31) and may well have a lasting impact on a child’s cognitive and behavioral development (32) . Furthermore, loss of a responsive, empathic mother may harm the child’s ability to attach or to develop object constancy. This is worsened when a mother must be hospitalized.

The worst outcome of a mother’s psychotic decompensation is infanticide. Although most postpartum psychoses are due to affective illness, infants with schizophrenic mothers still may be at great risk if the infant becomes part of the mother’s delusions. A woman with schizophrenia is more likely to kill her infant when her psychosis worsens as a result of medication discontinuation or stressors associated with the postpartum (33) .

Fourteen case reports have shown that nurslings receive a small fraction of the maternal dose of olanzapine, risperidone, and quetiapine. Nurslings generally did well with mothers taking olanzapine, although sedation has been reported (34) . We found three documented infant exposures to risperidone through lactation with no report of adversity (35 – 37) . To our knowledge, there is only one case report of breast-feeding with quetiapine with normal findings in an infant at 4.5 months (38) . Breast-feeding should not be encouraged in mothers taking clozapine because agranulocytosis and excess sedation have been reported in nurslings (39), and seizures are potential side effects. We found no reports of babies exposed to ziprasidone or aripiprazole.