Typical Antipsychotic Medication Exposure During Pregnancy (Table 1)
Few studies directly assess the long-term impact on child development of exposure to typical antipsychotic medication during pregnancy. A prospective study of 52 children exposed to 50 to 150 mg of chlorpromazine during pregnancy and postpartum reported no difference from their siblings or peers in birth, developmental history, tests of intelligence, observed behaviour, or mental disturbance (10). Unfortunately, only data from 2 of the 52 cases are presented in the paper, and methods for assessing the outcome measures are not reported. In 1990, Stika and others identified 68 infants exposed to 5 to 25 mg of chlorpromazine during pregnancy (11). At age 10 years, these children were compared with nonexposed control subjects, and no behavioural differences were detected. Both of these studies are methodologically flawed and therefore difficult to interpret clinically.
In contrast, Platt and others found that prenatal exposure to typical antipsychotic medication significantly affected the height and weight of children followed prospectively from pregnancy to age 7 years (12). Children born to parents with a psychiatric diagnosis and exposed to more than 2 months of typical antipsychotic medication during pregnancy were 3 cm taller at age 7 years than were nonexposed children of parents with a psychiatric diagnosis. This statistically significant increase in height was found regardless of whether these children were bottle- or breast-fed postpartum. Children born to psychiatrically well parents and exposed to typical antipsychotics during the treatment of maternal hyperemesis showed a statistically significant increase in height at 4 months and in weight at 1 year. However, the significance of these effects disappeared by age 7 years. That similar trends were seen in this group, likely exposed to a lesser dosage and shorter duration of medication, supports the argument that the differences observed are due to medication effects and are not simply artifacts of parental psychiatric diagnosis.
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Table 1 Typical antipsychotic medication exposure during pregnancy
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Congenital abnormalities
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Neonatal toxicity
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Neurobehavioural sequelae
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Phenothiazine for hyperemesis gravidarum during weeks 4–10 of gestation:
statistically signifigant increased incidence of nonspecific congenital
malformations, compared with the baseline rate in the general population
(42–44).
Haloperidol for hyperemesis gravidarum: 2 small retrospective studies (45,46)
demonstrated no increased risk of congenital abnormalities.
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After in utero exposure, case reports of motor restlessness, tremor, difficulty
feeding, hypertonicity, dystonic movements, withdrawal dyskinesias (47–49),
fever and cyanotic spells (50), megacystis (51), transient heart block
(52) jaundice (53), bowel obstruction (54), and necrotizing enterocolitis
(55).a
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Rats exposed in utero have demonstrated changes in spontaneous motor activity,
operant responses, neurotransmitter levels, and dopamine receptor sites,
as wells as decreased maze learning and increased susceptibility to induced
seizures (56–61). These findings have led to concern about the potential
long-term neurobehavioral effects on exposed infants.b
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aBecause these events have not been studied prospectively, one cannot conclude
that they are due to the antipsychotic medication exposure; however, some
of these events are similar to side effects reported by adults prescribed
these medications.
bSee text for human studies.
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Exposure to Typical Antipsychotic Medication During Lactation
There are case reports of infant exposure to flupenthixol, zuclopenthixol (13), perphenazine (14), haloperidol (15,16), and chlorpromazine (17,18) during breast-feeding. Levels of these typical antipsychotics in breast milk were less than 1% of the maternal daily dosage. The exposed infants were followed from 2 weeks to 1 year, and none were reported to display any abnormalities; however, there was no indication as to how the infants were assessed.
Yoshida and others conducted an open prospective controlled trial comparing the development of 2 groups of infants (19). Twelve infants were exposed postpartum through their mothers’ breast milk to haloperidol, chlorpromazine, trifluperazine, or a combination of these medications. Eighteen infants were bottle-fed by mothers taking similar medications for similar diagnoses. The mean duration of breast-feeding was 17 weeks, and on average, infants were exposed to less than 3% of the maternal daily dosage per kg of body weight. All infants were normal on the Amiel-Tison neurological examination. The infants were also assessed using the Bayley Scale of Infant Development (20).
Three of the breast-fed infants showed a significant decrease in their psychomotor index at age 12 to 18 months. Two of these infants also showed a significant decrease in their mental index at that time. The mothers of these infants were diagnosed with bipolar depression and mania; they were the only mothers simultaneously prescribed 2 antipsychotics: haloperidol (20 to 40 mg) and chlorpromazine (400 to 600 mg). The authors acknowledge that confounding factors in this study made the developmental outcome of these infants difficult to link directly to medication effects. These factors included severe maternal illness that required separation of infant and mother and lack of follow-up with the bottle-fed group after 11 months. Further, interpretation of Bayley scores obtained under age 12 months must be made with caution, because these scores have not been shown to significantly predict future cognitive and motor performance (21). Nevertheless, given the lack of information in this area, it may be wise to follow Yoshida and others’ advice and proceed with caution when considering breast-feeding for women taking typical antipsychotics in the upper end of their recommended ranges.
Atypical Antipsychotic Medication Exposure During Pregnancy (Table 2)
Olanzapine
Twenty-three prospectively identified pregnancies in which infants were exposed to olanzapine dosages ranging from 5 to 25 mg daily (22) showed rates of spontaneous abortion, stillbirth, and prematurity similar to the general population rates (23,24).
Two women with no family or personal history of diabetes developed gestational diabetes (22). Another woman, with a family history of diabetes, was reported to have developed gestational diabetes, hypertension, and preeclampsia while taking 15 to 20 mg of olanzapine daily throughout pregnancy. The baby was reported “viable at birth” (25).
Clozapine
In a 1997 paper, Stoner and others comment on the possible association between seizure and clozapine exposure, although the infant described was also exposed to typical antipsychotics, lithium, and benzodiazepines (62). Baker and Chengappa speculate that the gastroesophageal reflux in this infant may also be linked to clozapine exposure (26).
Of the 2 reported cases of gestational diabetes, one woman had a history of diabetes prior to pregnancy or treatment with clozapine.
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Table 2 Atypical antipsychotic medication exposure during pregnancy
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Congenital abnormalities
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Neonatal toxicity
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Neurobehavioural sequelae
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Medication complications of pregnancy:
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Olanzapine
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n = 23: no increase in major malformations vs general population (22).
n = 1: healthy baby born to a mother treated from 18 weeks gestation with
olanzapine 10 mg daily (27).
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n = 7: unilateral dysplastic kidney, Down syndrome, jaundice, sedation,
cardiomegally, cardiac murmur, tachycardia, convulsions, sudden infant
death syndrome at two months (22).a
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No published studies.
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n = 3: gestational diabetes. (22,25)
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Clozapine
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n = 5: no congential abnormalities (50-650 mg daily; 1 dose not reported)
(28,62–64).
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n = 1: low-grade fever (62)a.
n = 1: reported seizure and gastroesophageal reflux (62)a.
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No published studies.
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n = 2: gestational diabetes in mothers and shoulder dystocia in infants
(63,64).
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Risperidone
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No published case reports.
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No published case reports.
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No published case reports.
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No published case reports.
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Quetiapine
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No published case reports.
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No published case reports.
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No published case reports.
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No published case reports.
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aThe association between these events and exposure to medication(refer
to both olanzapine and clozapine data) is difficult to comment on because
these events have not been studied prospectively, and certainly, some are
not generally considered to be secondary to medication exposure (for example,
Down syndrome).
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Atypical Antipsychotic Medication Exposure During Lactation
Olanzapine
We reviewed 3 case reports of breast-fed infants whose mothers were taking olanzapine (22,27). However, it is premature to interpret the infant outcomes from these case reports. In all 3, breast-milk levels of the drug were not reported. In 1 infant, exposed to clozapine 10 mg/d, the drug serum levels were taken and were undetectable. This infant could not roll from back to front at age 7 months but had a “normal” developmental exam by age 11 months (27). A second infant exposed at birth developed jaundice, sedation, heart murmur, and cardiomegally. Jaundice and sedation continued despite the mother being switched to a typical antipsychotic (22). The third infant was reported to have no adverse symptoms (22).
Clozapine, Risperidone, and Quetiapine
The literature has no case reports of infant exposure to clozapine, risperidone, or quetiapine during breast-feeding. There are 2 case reports on transmission of clozapine and risperidone into breast milk of women taking these medications and bottle-feeding their infants. Barnas and others measured levels of clozapine in the breast milk of a mother prescribed 50 to 100 mg of clozapine daily and found that levels of clozapine in the foremilk were 2.8 to 4.3 times the levels of clozapine in the maternal plasma (28). Hill and others calculated risperidone and the active metabolite 9-hydroxyrisperidone to have respective milk-to-plasma ratios of 0.42 and 0.24 in 24 hours, with an estimated exposure of 4.3% of weight-adjusted maternal daily dosage (29).
Course of Schizophrenia During Pregnancy and Postpartum
The literature has limited and contradictory information on the course of schizophrenia in pregnancy and postpartum. In 1984, McNeil and others observed that patients with schizophrenia were more likely to report their mental health to be “a little worse” or “much worse” during pregnancy, compared with healthy control subjects (30). However, chart reviews showed that patients who reported worsening of mental health were just as likely to be described as “improved” or “unchanged” by their clinician. Despite the discrepancy, the authors concluded that during pregnancy women were much more likely to experience a worsening of psychosis than an improvement. In 1989, Krener and others reported on 14 women who had a DSM-III-R diagnosis of psychosis either during pregnancy or within the 2 years preceding pregnancy (31). Only 48% of these women were initially treated with antipsychotic medications, and all of them were able to decrease the dosage or discontinue their medication during pregnancy. The authors suggested that this reflected a relative amelioration of psychotic symptoms during pregnancy, because less antipsychotic medication was prescribed.
In 1987, McNeil reported that women with schizophrenia had the lowest risk for psychosis in the first 6 months postpartum, compared with women diagnosed with other functional psychoses (32)
The contradictory results of the above studies likely reflect not only the subject’s complexity but also the methodological difficulties present in all these studies—difficulties that limit our ability to draw conclusions from their results. These studies are limited by poorly defined diagnostic criteria, poorly defined symptom measures, and lack of information regarding medication dosage or duration.
Terp and Mortensen undertook a 20-year retrospective review of the course of postpartum psychosis, comparing the Danish psychiatric registry with the central birth registry (33). They looked at several ICD-8 diagnoses with psychotic symptomatology, including schizophrenia. For schizophrenia, they found that the relative risk of first admission is not increased during the postpartum period, readmission is reduced in the postpartum period, and admission is not increased before delivery. They acknowledge that these results are difficult to interpret because, while they may reflect ameliorated symptoms, they may only reflect the decreased fertility rates (30% to 80% of the general population rate) recorded in patients with schizophrenia between the years 1893 and 1979 (34).
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