12 de noviembre de 2011

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


Deborah Yaeger; Healy G. Smith; Lori L. Altshuler

Am J Psychiatry 2006;163:2064-2070.

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.


Risk-Benefit Analysis

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.


Literature Review of Antipsychotics


Typical Antipsychotics

Much of the existing data on the use of typical antipsychotics during pregnancy comes from studies of the treatment of Hyperemesis gravidarum, which requires lower doses than those used for schizophrenia. A meta-analysis by Altshuler et al. (8) included 2,591 babies exposed in the first trimester to typical antipsychotics. That study found a small but statistically significant increase in the relative risk of congenital malformations from a background of 2.0% to 2.4% in offspring exposed during the first trimester to low-potency antipsychotics. No pattern of malformations emerged.

Data on high-potency antipsychotics are more limited. There have been three reports of limb malformations in offspring with first-trimester haloperidol exposure and one such report after first-trimester exposure to penfluridol, producing some concern of a possible association between high-potency antipsychotics (primarily haloperidol) and limb deformities (14, 15). Other studies did not confirm this association. A recent prospective controlled study involving 215 pregnant women exposed to either haloperidol or penfluridol had twice the risk of prematurity and had elevated rates of low birth weight among full-term infants (14).

A perinatal syndrome associated with typical antipsychotics includes symptoms of respiratory depression, difficulty feeding, floppy infant syndrome, hypertonicity, sluggish primitive reflexes, extrapyramidal symptoms, tremor, abnormal movements, irritability, and agitation (8, 15, 16). These symptoms are fairly rare and generally resolve within days (8).

Data on behavioral teratogenesis are sparse. Kris found normal social, emotional, and cognitive development in a cohort of 52 children born to mothers who took chlorpromazine during pregnancy (17). Stika et al. (18) also found no statistical differences in behavior or cognition in 66 9-and 10-year-olds with in utero exposure, only after the 20th week of gestation, to chlorpromazine or chlorprothixene.


Atypical Antipsychotics

To date, to our knowledge, there have been no blinded or randomized studies examining birth outcomes in women taking atypical antipsychotics, and these are unlikely given ethical considerations. There is one prospective study, and the remainder of the data come from case reports and two manufacturers’ data collections. Both case reports and manufacturers’ data may show a reporting bias that could overrepresent the rate of adverse outcomes. See data supplement 1 (available with the online version of the article at http://ajp.psychiatryonline.org) for information about these studies.

Of note, the prospective study done by McKenna et al. (19) grouped together subjects exposed to olanzapine, risperidone, quetiapine, and clozapine without any breakdown of results by medication, except for noting one malformation in a baby exposed to olanzapine. The exposed group showed no statistical differences in the rates of miscarriage, stillbirth, prematurity, congenital malformations, and perinatal syndromes in relation to healthy comparison subjects. There was an increased rate of babies with low birth weight and, in the mothers, greater body mass index and more elective abortions.



We found 129 cases reported in the literature of women taking olanzapine during their pregnancies, including 118 prospective (including case reports) and 11 retrospective cases. Sixty of these come from the study by McKenna et al (19). There was no recurrent pattern found in the four reported malformations. Two cases documented normal development; one reported delayed motor development at 7 months that resolved by 11 months.



We found 61 prospectively identified cases of fetal exposure to risperidone, including 49 from the study by McKenna et al. (19). There were no reported congenital malformations and two reports of normal development up to 1 year postpartum.



There were 39 prospectively identified cases of fetal exposure to quetiapine, including 36 in the study by McKenna et al. (19). We found no reports of congenital malformations. One case demonstrated normal development at 6 months.


Ziprasidone and Aripiprazole

To our knowledge, there are no reports of fetal exposure to ziprasidone or aripiprazole.



Nineteen prospective reports document fetal exposure to clozapine, including 13 case reports and six cases in the prospective study. There are two reports of perinatal/neonatal seizures and one child born prematurely with several anomalies and delayed development at 7 months. Normal development was reported in seven subjects evaluated up to 5 years of age. Gestational diabetes and/or pregnancy-induced hypertension complicated five pregnancies.

Retrospective data included 102 pregnancies with 59 deliveries resulting in 61 births. Data for 22 pregnancies were unavailable. Five had congenital malformations, and five had perinatal difficulties that were unspecified. There were no data on developmental outcomes.

Additional concerns include the known risks of agranulocytosis and orthostatic hypotension associated with clozapine. Although agranulocytosis has not been reported in a fetus, this possible risk warrants WBC monitoring in newborns, especially if the mothers are nursing. Additionally, maternal orthostatic hypotension could decrease placental blood flow, with potentially damaging effects to the fetus.


Medical Sequelae of Atypical Antipsychotics

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/m2). 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/m2) 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.


Risk for Postpartum Psychosis and Impact on Mother and Child

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).


Treatment of Schizophrenia Postpartum

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 (3537). 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

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