The Potential Risks of Commonly Prescribed Antipsychotics

Abstract

Chlorpromazine, haloperidol, fluphenazine, clozapine, risperidone, quetiapine, olanzapine, ziprasidone, and aripiprazole are antipsychotics commonly used in psychiatric medicine. Approximately one third of pregnant women with psychotic symptoms use antipsychotics at least once. This review will discuss the effects of antipsychotic use during pregnancy and lactation on the fetus and infant.

Although adequate and well-controlled studies have not been done in any one of these antipsychotic drugs, animal studies have revealed evidence of teratogenic or embryo/fetotoxic effects in all of them. Toxicities include skeletal malformations, central nervous system (CNS) defects, cleft palate, cardiac abnormalities, decreased fetal growth, and fetal death. For example, in pregnant women, congenital malformations and perinatal death have been reported with chlorpromazine use. Both chlorpromazine and fluphenazine in monotherapy have been shown to cause extrapyramidal symptoms and respiratory distress in infants born to mothers treated with these medications. Haloperidol use during pregnancy has been linked to severe limb reduction defects.

Effects of antipsychotic use in lactating mothers are mostly unknown. However, the use of chlorpromazine has been reported to result in drowsiness and lethargy in breastfed infants. Additionally, clozapine has been reported to cause sedation, decreased suckling, restlessness, irritability, seizures, and cardiovascular instability of infants were also reported with clozapine use in lactating mother. Use of antipsychotic drugs by pregnant and lactating mother may only be justified if the potential benefit outweighs the potential risk to the fetus.

Introduction

All psychotropic medications diffuse readily across the placenta to the fetus because of their relatively small molecular size and lipophilic or lipophobic properties.^1–3 The smaller the molecular size of a drug, the greater its placental transfer, with readily permeable compounds having a molecular weight of less than 600 Dalton.⁴ The high cardiac output in the fetal circulation hastens the availability of the drug to tissues. On the other hand, the immature fetal liver microsomal system results in slower biotransformation to less active compounds. An incomplete fetal blood-brain barrier increases the central nervous system (CNS) concentration of many drugs. Slower renal clearance delays excretion whereas decreased albumin leads to an increase in the unbound fraction of drug available to tissues.⁵ These factors increase the amount of drug available to tissues in the fetus increasing the probability of adverse effects on fetus.

Although almost all current neuroleptic drugs exert their antipsychotic effects through blockade of the dopaminergic D2 receptor, they differ in their actions on cholinergic, alpha-adrenergic, serotonin, and histamine receptors in varying degrees. The different modes of action, as well as differences in bioavailability to the fetal brain, result in differences in effects on fetuses and infants of pregnant and lactating mothers.^6,7 The fact that approximately one-third of all pregnant women take psychotropic drugs at least once during pregnancy⁸ makes it important that the effects of these drugs on fetus be evaluated. This review will highlight the effects of commonly used antipsychotics on fetus, neonates, and nursing infants.

The adverse effects of commonly used antipsychotics on fetuses and infants during pregnancy and lactations are described in detail in the following article and are listed in Table 1.

Table 1.

Possible adverse effects of use of common antipsychotics (typical and atypical) during pregnancy and lactation.

ANTIPSYCHOTICS/PREGNANCY CATEGORY	DOSAGE RANGE (mg/day) PO/IM	EFFECTS OF USE OF COMMON ANTIPSYCHOTICS
		In Pregnancy		During Lactation
Typical Antipsychotics		In Animals	In Humans
Chlorpromazine Pregnancy Category C	50–2000mg/day PO Half life 8–35 hrs	Teratogenic effects: skeletal defect, CNS, eye, and cleft palate Fetotoxic effects: fetal death, decreased fertility, viability, and fetal weight gain Visual disturbances, behavioral abnormalities and decreased performances in the offspring	Congenital malformations and fetotoxic effects, e.g., perinatal deaths, neurological dysfunction with extrapyramidal signs (neonatal withdrawal) such as hypertonia, tremulousness, dyskinesias, akathisia, weakness, poor sucking and motor maturity during late pregnancy Also, respiratory distress, cyanosis, lethargy, hypotonia, depressed reflex responses, fall in blood pressure and increase in height	Effect unknown
Fluphenazine Pregnancy Category C	2–40mg/day PO Half life 10–20 hrs 12.5–75mg/day IM (deconoate) Half life 2 wks	Congenital malformations: skeletal defects, dilated ventricles, and cleft palate Fetotoxic effects: decreased fetal weight and length	Delayed extrapyramidal manifestation or neonatal withdrawal, severe rhinorrhea, and respiratory distress	Effects unknown
Haloperidol Pregnancy Category C	2–40mg/day PO Half life 10–20 hrs 50-300mg/day IM (deconoate) Half life 4 wks	Teratogenic effects: cleft palate, micromelia, CNS, and skeletal malformation Embryonic death Fetotoxic effects: fetal death, decreased fetal and postnatal growth, long lasting alteration of behavior in the offspring of pregnant rats	Increased risk of severe limb reduction defects during first trimester.	No adverse effects reported
Atypical Antipsychotics
Clozapine Pregnancy Category C	75–900mg/day PO Half life 14 hrs	No evidence of impaired fertility or harm to the fetus with 2–4 times the recommended human dose	No clinical reports linking the use of clozapine to congenital defects	Sedation, decreased suckling, restlessness, irritability, seizures, and cardiovascular instability
Risperidone Pregnancy Category C	4–6mg/day PO Half life 20 hrs	No teratogenic effects in the offspring of rats and rabbits Increase in pup death and stillborn pups in the offspring of rats at doses higher than the recommended human dose.	No clinical reports of any adverse effects	Effects unknown
Quetiapine Pregnancy Category C	150–750mg/day PO Half life 7 hrs	Embryotoxic effects and fetotoxic effects-delays in skeletal ossification, increase in minor soft tissue anomaly, and in fetal and pup death; decrease in mean litter weight and in fetal body weight No evidence of teratogenic effects in the offspring of rats and rabbits at doses higher than the recommended human dose	No clinical reports of any adverse effects	Effects unknown
Olanzapine Pregnancy Category C	5–20mg/day PO Half life 30 hrs	Fetotoxic effects-early resorptions, increased nonviable fetuses and decreased fetal weight. But no evidence of teratogenic effects at doses higher than the recommended human dose	No clinical reports of any adverse effects	Effects unknown
Ziprasidone Pregnancy Category C	60–180mg/day PO Half life 5-10 hrs	Increased time to copulation in rats in two fertility and early embryonic development studies at doses higher than the recommended human dose	No clinical reports of any adverse effects	Ziprasidone's excretion and that of its metabolites in human milk is not known at present.
Aripiprazole Pregnancy Category C	10–30mg/day PO Half life 75 hrs	Developmental toxicity including teratogenic effects in rats and rabbits In pregnant rats: Slightly prolonged gestation, stillbirths, decreased fetal weight, undescended testes, delayed skeletal ossification and increased incidences of hepato- diaphragmatic nodules and diaphragmatic hernia along with postnatal effects of delayed vaginal opening and impaired reproductive performance Pregnant rabbits: Decreased maternal food consumption and fetal weight gain. Increased abortions, fetal mortality, and skeletal abnormality	No clinical reports of any adverse effects	Aripiprazole excreted in milk of lactating rats, but its excretion in human milk not known.

Table 2.

Food and Drug Administration Pregnancy Categories

Category A	Controlled studies show no significant risk. Human studies have failed to demonstrate a risk in the first or later trimesters of pregnancy. The possibility of fetal harm is remote.
Category B	No available evidence of significant risk in humans. Animal studies have not demonstrated a fetal risk, and human studies are lacking. Alternatively, animal studies have demonstrated adverse effects, but these effects have not been confirmed by first trimester human studies, and there is no evidence of adverse effects in later trimesters.
Category C	Risk cannot be adequately ruled out. Animal and human studies shown an adverse effect (i.e., teratogenic or embryo-lethal), but there are no adequate human studies.
Category D	Positive evidence of risk exists. There is evidence of a risk of harm to the human fetus, but benefits from use might outweigh the risk.
Category X	Contraindication in pregnancy. Animal or human studies have demonstrated a significant risk of teratogenesis and that the risk is clearly greater than the benefits.

Chlorpromazine

Exposure during pregnancy. In animals. Chlorpromazine readily crosses the placenta.^3,9 The adverse effects in the newborn rodents whose mothers were treated with chlorpromazine many times higher than the human recommended dose during pregnancy include congenital malformations involving skeletal system, central nervous system, eye, and cleft palate as well as fetal death, and reduced fetal weight gain.^10–12 In several studies, visual disturbances,^13,14 and behavioral abnormalities^15–17 were observed in the offspring of treated rodents and monkeys.

In humans. There have no adequate and well controlled studies have not been done to determine the fetal risk of chlorpromazine during pregnancy.

Sobel¹⁸ and Reider, et al.,¹⁹ reported an increased incidence of perinatal deaths and malformations in infants born to schizophrenic mothers on chlorpromazine as compared to the general population, but found no significant correlation between chlorpromazine exposure and fetal mortality. No increased frequency of congenital anomalies was found among the children of 142 pregnant women²⁰ and of 284 pregnant women²¹ treated with chlorpromazine during last trimester in two separate studies. In contrast, another study found a higher rate of birth defects in newborns from 189 women receiving chlorpromazine during the last trimester as compared to exposure to other medications including fluphenazine or mesoridazine.²² Similarly, Altshuler and colleague, after conducting a meta-analysis of outcome studies with first-trimester exposure to low-potency antipsychotics, found an increased relative risk of approximately 0.4 percent, though no specific pattern or cluster of malformations has been consistently identified.²³

Kris²⁴ found no congenital anomalies or behavioral or emotional problems at four-year follow-up of 14 children exposed to 50 to 150mg chlorpromazine daily throughout gestation.^24,25 Sobel²⁵ studied 52 pregnant women with chlorpromazine and found the incidence of fetal damage to be similar to the control group.

Neurological dysfunction with extrapyramidal signs has been reported in several infants born to women given chlorpromazine during late pregnancy.^4,26,27 The muscle rigidity, hypertonia, and tremor seen in these children appear to be transient.²⁸ Most commonly, the infants of women treated with chlorpromazine late in pregnancy exhibit hypertonia, tremulousness, dyskinesias, akathisia, weakness, poor sucking, and poor motor maturity suggestive of withdrawal, though it is low in frequency.²⁹

Another study evaluating the effects of prenatal chlorpromazine exposure (total daily dose 150–900mg) in infants found no differences in early years of physical and mental development of the child when compared with their siblings or peers of the same social and cultural background.³⁰ There have also been similar reports on child development in other studies.^31,32 Another study showed that the children of mothers who had taken chlorpromazine or other neuroleptic for more than two months during gestation, whether or not they were breast-fed, were significantly taller than nonexposed controls at four months, one year, and seven years of age.³³

There have been few reports to treat nausea and vomiting by chlorpromazine during all stages of gestation, including labor and hyperemesis gravidarum.^34,35 Furthermore, its use has been found to be safe during labor to produce analgesia, amnesia and sedation in two studies.^36,37 However, some other studies have reported an unpredictable marked fall in blood pressure without any other observed adverse effects in the mother and fetus.^35,38

In summary, most studies show that chlorpromazine is not teratogenic.^39,40 The bulk of the clinical evidence with chlorpromazine treatment during gestation indicates no adverse effects on fetus, although there have been occasional reports of congenital anomalies during first trimester of pregnancy. Thus, it should be used with caution during pregnancy when its benefits outweigh the potential risks involved.

Risks related to breast-feeding. Chlorpromazine is excreted in the breast milk in low concentrations, depending on maternal dosage.^41–43 Based on data obtained from five lactating women, the amount of chlorpromazine that the breastfed infant is expected to ingest is between 0.03 to 1.3 percent of the lowest pediatric dose (less than 10% of the normal dose is considered to likely be safe) and thus no adverse effects were reported with it.^44,45 Another study found no adverse effects on infants whose nursing mothers were on chlorpromazine.³⁰ More studies are needed to determine the effects of chlorpromazine on nursing infants. Thus, Chlorpromazine should be used in lactating mother only if risk benefit assessment justifies the potential risk to the infant.

Fluphenazine

Exposure during pregnancy. In animals. Fluphenazine, a piperazine derivative readily crosses the placenta and accumulates in the fetal tissue.^4,9 Two studies in which rats were treated with oral fluphenazine used many times the maximum recommended human daily dose (MRHD), during pregnancy found no adverse effects in the offspring.⁴⁶ However, a third study demonstrated a significant increase in the incidence of dilated ventricles of the CNS, skeletal defects, reduction in fetal weight and length.⁴⁷ In addition, multiple abnormalities in embryo chicks and cleft palate in fetal mice have been reported elsewhere.⁴⁸

In humans. Although there have been no well controlled studies to determine the risk to the fetus during pregnancy with fluphenazine use, few cases of severe rhinorrhea, respiratory distress⁴⁹ and delayed extrapyramidal symptoms^27,50 have been reported. On the other hand, a retrospective study found the incidence of spontaneous abortion, perinatal mortality, premature birth and twinning to be similar in 244 patients who received fluphenazine during pregnancy and in 150 patients in the control group.⁵¹

Although there have been some reports of congenital anomalies associated with using fluphenazine during pregnancy, the majority of the clinical experience with it indicates that pregnant women can be treated with fluphenazine with no ill effects to them or their infants.^52,53 However, the potential benefits should always be weighed against the possible hazards when prescribing this drug to pregnant women.

Risk to the infant during breast-feeding. As seen with other phenothiazines, fluphenazine should be expected to pass into breast milk. Although its effects on the nursing infant are unknown, the possible potential for the risk of adverse effects from exposure to fluphenazine in the breastfed infants should be weighed against its potential benefits to the breast feeding mother.

Haloperidol

Exposure during pregnancy. Haloperidol, a butyrophenone-derivative, readily crosses the placenta. It is used in the treatment of psychosis, mania, Tourette syndrome, nausea and anxiety. Haloperidol is approximately 100 times as potent as chlorpromazine in blocking dopamine receptors.⁵⁴

In animals. Congenital malformations associated with Haloperidol use in animal reproduction studies at doses higher than the recommended human dose include cleft palate, micromelia, fetal death in rats,^48,55 increased rates of central nervous system and skeletal malformations and reduced fetal and postnatal growth in mice,^48,56,57 as well as increased rates of embryonic death, brain and skull malformation in hamsters.⁵⁸ Long lasting behavioral changes have also been noted among the offspring of pregnant rats treated with haloperidol in doses similar or greater than those used in humans.^59,60 Even though delay in implantation in mice and rats at the time of conception was noted, normal-weight newborns were delivered at term.⁶¹

In humans. Lack of adequate and well-controlled studies preclude determination of the fetal risk during pregnancy. Two isolated cases of infants with severe limb reduction defects were born to women who used haloperidol (concomitantly with other drugs) for hyperemesis gravidarum during the 1st trimester, though causal relationship could not be established.^62–64 Kopelman and colleagues⁶⁵ reported multiple upper and lower limb defects, an aortic valve defect, and subsequent death in one infant; whereas, phocomelia was reported in another infant with use of haloperidol in the first trimester,⁶⁶ no teratogenic effects have been reported with the use of haloperidol in the second and third trimester. However, a retrospective study by Hanson and Oakley⁶⁷ found no association between limb deformities and exposure to haloperidol.

The first report of fetal cardiac toxicity secondary to the combination of haloperidol and chlorpromazine was reported as transient fetal heart block. Within two days after delivery, the heart rate was within normal limits, and ECG showed normal sinus rhythm.⁶⁸

There is also a report of haloperidol overdose in a 34-week pregnant female. After ingesting 300mg of haloperidol, she was found aphasic and unable to follow commands (69). Her brain CT scan and EEG were normal and the fetus had a biophysical profile (BPP) score of 2 (out of 10) with minimal long and short-term heart variability and no evidence of fetal movement, breathing, or flexion-extension. Within 16 hours, the mother had full recovered, however the fetuses BPP score remained persistently low. At 48 hours, the BPP score was only 6, but by day 5 post-ingestion, the BPP score reached 10 and the baby was subsequently delivered at 39 weeks with no cardiac sequelae. This case illustrates delayed fetal recovery compared with that of the mother after intentional overdose of haloperidol possibly due to increased fetal CNS sensitivity and impaired fetal hepatic metabolic capacity.

In a large retrospective study of 100 pregnant women with hyperemesis gravidarum, 6 mg of haloperidol was administered orally twice daily. Ninety-two women received haloperidol during the first trimester, eight during the second trimester. Less than 10 percent of the women also received meclizine, pyridoxine, prochlorperazine, and dexchlorpheniramine.⁷⁰ Haloperidol was found to have no effect upon duration of gestation, perinatal or neonatal survival, birth weight, or congenital malformations.⁷⁰ Similarly, Van Waes and Van de Velde found no association between haloperidol use for hyperemesis during the first trimester and fetal anomalies.⁷¹

Pregnant women should thus be treated with haloperidol with caution because of some reports of teratogenicity with it.

Risk to the infant during breast-feeding. Haloperidol has been detected in unquantifiable amounts in breast milk, though some animal studies have found haloperidol in sufficient quantity in milk to cause drowsiness and motor function impairment in breastfeeding offspring.^72–74 There are also reports of quantifiable amounts in breast milk with haloperidol.^75,76 Whalley and colleagues⁷⁵ found upto 23.5 micrograms/L of haloperidol in breast milk when the breastfeeding mother was on 5mg twice daily oral dose of haloperidol for puerperal psychosis with no adverse effects observed in infant. Thus, the possible benefits of haloperidol administration to breastfeeding mother should be weighed against the potential hazards to the infant.

Clozapine

Exposure during pregnancy. In animals. Clozapine, a dibenzodiazepine derivative, is an atypical antipsychotic agent that readily crosses the placenta.⁷² No evidence of impaired fertility or harm to the fetus due to clozapine has been noticed in rats and rabbits at two to four times the human dose.⁷⁷

In humans. Presently, there are no epidemiologic studies demonstrating an association between congenital anomalies and gestational clozapine therapy. There are three clinical case reports demonstrating no apparent fetal adverse effects associated with the use of clozapine before and during gestation.^78–80 One of the three reports described 14 women who were exposed to clozapine during gestation with no known adverse sequelae in their newborn.⁸⁰

Dickson and Hogg⁸¹ reported on a healthy infant born at 38 weeks to a schizophrenic mother treated with clozapine along with metformin and later insulin for her history of “high sugars.” In a report by Stoner and colleagues⁸² two full-term pregnant females with continuous clozapine therapy delivered normal, healthy infants. In this report, specifically, the first patient who received clozapine (300mg/day) for 17 months total along with lithium till her first trimester, delivered an infant by vacuum extraction with cephalohematoma, hyperpigmented folds and coccygeal dimple all of which resolved by Day 2. The infant had a seizure episode on Day 8 but was healthy at two years of age. In the second case, a healthy infant weighing 2.5kg was born to a patient who had been taking clozapine (600–625mg/day) for 35 months in combination with lithium before becoming pregnant and subsequently stopped taking it during her pregnancy.

In a case illustration of fetal accumulation, Barnas and colleagues reported that a mother was treated with clozapine (100mg/day), throughout most of her pregnancy. The dose was reduced to 50mg/day during the last nine weeks with a level of 15.4ng/mL.⁸³ On the day of delivery, maternal level was 14.1ng/mL, fetal concentration was 27ng/mL and amniotic fluid level was 11.6ng/mL. Two possible explanations for this fetal accumulation given were increased fetal albumin causing increased clozapine-albumin binding or ion trapping producing a pH gradient in the fetus. Thus, doses of clozapine should be kept to minimum possible doses and further reduction in dose just prior to delivery should be attempted in order to avoid adverse effects such as withdrawal seizures and CNS depression.

While available data suggests that clozapine does not cause major fetal malformations, Pinkofsky and colleagues have raised the issue of potential clozapine-induced fetal agranulocytosis.⁸⁴ Thus, white blood cell counts of all newborn infants whose mothers are receiving clozapine during pregnancy or while breastfeeding, should be monitored weekly for first six months to detect agranulocytosis that may result in fatal infection. Clozapine can be used during pregnancy if the clinical benefit justifies the conceivable risk to the fetus. Clozapine should only be used during pregnancy for the treatment of severely ill schizophrenic patients who fail to respond to other neuroleptic agents or who cannot tolerate the adverse effects from those other agents.

Risk to the infant during breast-feeding. Clozapine is concentrated in the breast milk^72,77 and has been known to cause sedation, decreased suckling, restlessness or irritability, seizures, and cardiovascular instability in the breastfeeding infant.⁷² Given the potential for serious adverse consequences to infants who are exposed to clozapine, breast-feeding should be avoided when maternal clozapine therapy is indicated.

Risperidone

Exposure during pregnancy. In animals. Risperidone, a benzisoxazole-derivative, is chemically unrelated to other atypical antipsychotic agents. In three teratogenicity studies in rats and rabbits, the incidence of malformations was not increased as compared with controls after being given 0.4 to 6 times the maximum recommended human dose (MRHD) of risperidone. Nevertheless, one other study found a significant increase in the number of stillborn pups of rats receiving risperidone at doses of 1.5 times the MRHD.⁷²

In humans. Ratnayake and Libretto⁸⁵ report two cases of risperidone use during pregnancy. Both infants were delivered without complications by cesarian section and no postnatal developmental abnormalities were noted. In the first case, the 36 year-old mother had been taking risperidone (4mg/day) for two years and was continued on it during pregnancy for risk of relapse. In the second case, a 30-year-old mother had been taking risperidone (6mg/day) throughout pregnancy. Additionally, Mackay and colleagues⁸⁶ reported on nine women receiving risperidone during 10 pregnancies. Three pregnancies ended with therapeutic abortions, but of the seven live births, no malformations were reported.

Since no adequate and well-controlled studies of fetal effects using risperidone in pregnant women have been done, risperidone should be used during pregnancy only if the benefit to the mother justifies the potential risk to the fetus.

Risk to the infant during breast-feeding. Caution should be exercised when risperidone is administered to breastfeeding women, since it has been found to be distributed in breast milk in greater than or equal to plasma concentrations in animal studies.⁷² It may thus also pass into human milk causing unwanted behavioral changes in breastfed babies.⁸⁷

Quetiapine

Exposure during pregnancy. In animals. Quetiapine, a dibenzothiazepine derivative, is an atypical antipsychotic. Embryo/fetal toxicity in the form of skeletal ossification delays, reduced fetal body weight, and increased incidence of carpal/tarsal flexure in rat fetuses and in rabbits at 1.2 and 2.4 times the maximum human dose was observed. An increase in fetal and pup death, and decrease in mean litter weight at three times the maximum human dose were also found.⁷⁷

In humans. There are two reports of quetiapine use during pregnancy. In one case, the 24-year old woman was treated with lithium (1500mg/day) for bipolar disorder, (which was discontinued on her getting pregnant) and with quetiapine, which was maintained at 25mg/day throughout pregnancy. She delivered a healthy infant with no malformations. In the second case, 38-year-old woman with schizophrenia who received unknown dose of quetiapine delivered a healthy infant at 38 weeks with APGAR scores of 9 and 10 at 1 minute and 5 minutes, respectively.⁸⁸

Since no adequate and well-controlled studies in pregnant women have been done, quetiapine should be used during pregnancy only if the benefit justifies the potential risk to the fetus.

Risk to the infant during breast-feeding. Quetiapine has been found to be excreted in milk of lactating animals.⁷⁷ However excretion in human milk may be possible. Therefore, caution should be exercised in prescribing quetiapine during lactation.

Olanzapine

Exposure during pregnancy. Olanzapine, a thienobenzodiazepine-derivative, is chemically and pharmacologically similar to clozapine, but differs pharmacologically from other currently available antipsychotic agents (e.g., phenothiazine, butyrophenones) and is thus, considered an atypical antipsychotic.

In animals. Olanzapine crosses the placenta in rat pups.⁷⁷ In reproduction studies in rats, no evidence of teratogenicity was reported, though early resorptions and nonviable fetuses were observed at doses of 9 times the maximum recommended human daily dose (MRHD), while gestation was prolonged at five times the MRHD. In rabbits, no teratogenic effect was noted, though increased resorption and reduced fetal weight occurred at 30 times the MRHD.⁷⁷

In humans. Prospective and retrospective cases of in-utero olanzapine exposure through October 1, 1998, have been provided by The Lilly Worldwide Pharmacovigilance Safety Data Base, which reports 37 prospectively identified cases during this period. Fourteen of the 37 pregnancies were electively terminated without fetal abnormalities. Of the 23 remaining pregnancies, 16 healthy infants without complications were born, where exposure was limited to first trimester in eight infants, first and second trimesters in one infant and all trimesters in seven infants. Here, one infant was delivered by cesarian at 30 weeks of gestation whose mother was treated for gestational diabetes, hypothyroidism, preeclampsia, and elevated liver enzymes along with schizophrenia throughout her pregnancy. A second infant weighing 3.66kg, whose mother received olanzapine throughout pregnancy (10mg/day), with fetal distress was delivered by labor induction 10 days after term and had a normal postnatal development. The third infant whose mother received unknown dose of olanzapine during first trimester of pregnancy had meconium aspiration during a cesarian section for postmaturity. Whereas, three pregnant women of these 23 pregnancies had spontaneous abortions (13%), at a rate consistent with historical data (15%) but no malformations were noted in any of these abortuses.⁸⁹

Kirchheiner's report of a schizophrenic women treated with olanzapine from the 18th week of gestation through delivery showed no complications, as the infant was found to be healthy at birth. The plasma levels in the infant was approximately one-third of that of the mother and the female infant weighed 3.19kg with APGAR scores of 9, 10, and 10 at 1 minute, 5 minutes, and 10 minutes respectively.⁹⁰ More studies are needed to determine the effects of olanzapine on pregnant women. Thus, olanzapine should be used in pregnant women only if risk benefit assessment justifies the potential risk to the infant.

Risk to the infant during breast feeding. Olanzapine is excreted in the milk of treated rats during lactation but similar effect in humans is not known.⁷⁷ Therefore, caution should be exercised when olanzapine is administered to breastfeeding women.

Ziprasidone

Exposure during pregnancy. In animals. Ziprasidone is an atypical antipsychotic drug. Increased time to copulation in rats in two fertility and early embryonic development studies at doses of 10 to 160mg/kg/day (0.5 to 8 times the MRHD). Fertility rate was reduced at eight times the MRHD, though no effect was found at two times the MRHD.^72,77 Studies in rabbits suggest that ziprasidone is associated with anomalies such as ventricular septal defects, other cardiovascular malformations, and kidney alterations. However, there is no evidence that these resulted from maternal toxicities.⁹¹

In humans. There are no adequate and well-controlled studies in pregnant women. Ziprasidone should be used during pregnancy only if the benefit justifies the potential risk to the fetus.^72,77

Risk to the infant during breast-feeding. Ziprasidone's excretion and that of its metabolites in human milk is not known at present. Therefore, it is recommended that women receiving ziprasidone should not breast feed.

Aripiprazole

Exposure during pregnancy. This drug is different from other antipsychotics since Aripiprazole is a partial agonist at D2 and 5-HT1A receptors and antagonist at 5-HT2A receptors.

In animals. Aripiprazole showed developmental toxicity including teratogenic effects in rats and rabbits. When pregnant rats were treated with 10 times the MRHD, slightly prolonged gestation, stillbirths, decreased fetal weight, undescended testes, delayed skeletal ossification and increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia along with postnatal effects of delayed vaginal opening and impaired reproductive performance have been observed. Similarly, pregnant rabbits treated with 11 times the MRHD of aripiprazole during period of organogenesis were found to have decreased maternal food consumption and increased abortions along with increased fetal mortality, skeletal abnormality and decreased fetal weight.⁹²

In humans. There are no adequate and well-controlled studies in pregnant women. It is not known whether aripiprazole can cause fetal malformations when administered to pregnant women or can affect their reproductive capacity. Thus, it should be prescribed during pregnancy only if the benefit outweighs the potential risk to the fetus.⁹²

Risk to the infant during breast-feeding. Aripiprazole is excreted in milk of lactating rats, but its excretion in human milk is not known. Thus, it is recommended that women receiving aripiprazole should not breast feed.

Conclusion

Currently available information indicates that there are no antipsychotic preparations on the market that can be considered entirely appropriate or completely safe for expectant and nursing mothers. On the other hand, there have been some studies and case reports of fetal malformations, such as congenital heart disease, perinatal deaths, neurological dysfunction with extrapyramidal manifestations, respiratory distress, rhinorrhea, jaundice, hypotension, and neonatal withdrawal associated with the use of antipsychotics. However, the extensive review of congenital malformations in the infants of women who received antipsychotics during pregnancy reveal the occurrence of only very few cases of congenital defects, the incidence of which are neither higher nor lower than the control groups. Furthermore, some of these antipsychotic drugs (e.g., olanzapine, ziprasidone, aripiprazole) are newer agents and there may not be much experience with them during pregnancy and breastfeeding, unlike that with older agents such as haloperidol or chlorpromazine, where there appears to be an increased risk of congenital malformations on exposure to phenothiazines between Weeks 4 to 10 of gestation.⁹³ Therefore, while conclusive elucidation await well controlled studies, the use of antipsychotic drugs during pregnancy and lactation can be justified only if its benefit outweighs such potential risks.