Antipsychotics in pregnancy and lactation.

Research on psychotropic medications during pregnancy and lactation is limited as often involves complex ethical issues. Information on safety of psychotropic drugs during these critical phases is either inconclusive or undetermined. Many women with severe mental illness have unplanned pregnancies and require antipsychotic medication during pregnancy and lactation. Multiple issues have to be considered while choosing safe treatments for pregnant and lactating women and the best approach is to individualize the treatment. Medication should be guided primarily by its safety data and by the psychiatric history of the patient. Important issues to be kept in mind include pre-pregnancy counseling for all women, including planning pregnancies; folate supplementation, discussion with patient and family regarding options, and active liaison with obstetricians, ultrasonologists and pediatricians. Whenever possible, non-pharmacological approaches should be used in addition.

GENERAL PRINCIPLES

Research on psychotropic medications during pregnancy is complicated by numerous factors, often involving complex ethical issues.[1] Published literature on pharmacotherapy during pregnancy largely consists of case reports and observational studies with numerous confounding factors. Since many pregnancies are unplanned[8] and many women with mental illness do not experience symptom improvement during pregnancy, it is important to be aware about the approaches to and risks associated with medication treatment during pregnancy. The management of mental illness in pregnancy requires a sound knowledge of the psychiatric disease, clinical acumen and perhaps importantly, common sense.

Research-based knowledge on the fetal safety of psychotropic agents is limited since pregnant women have been excluded from drug trials understandably for ethical reasons.[1] Hence, we need to rely on animal studies, case reports, and observational studies for the safety of the medication. The effects on the fetus to psychotropic exposure can be classified as teratogenicity, neonatal toxicity, and behavioral teratogenicity. Several classifications have been proposed for classifying the teratogenic risks of medications. Among them are US Food and Drug Administration, the Australian Drug Evaluation Committee, and the Swedish Catalog of Approved Drugs. However, these classificatory systems have limitations in terms of not specifying the dose or duration of gestational exposure that may be associated with teratogenic risk.

ISSUES RELATED TO PREGNANCY

The first four embryonic weeks are described as the period of blastogenesis[2] it is the period of formation of the blastocyst, implantation and subsequently followed by the development of primitive streak. The next 4 weeks that is from 5th to 8th week of gestation is the period of organogenesis.[3] It is during this period that drug exposure in the mother has maximum effect on the outcome of pregnancy.

The pharmacokinetics and pharmacodynamics changes during pregnancy include delayed gastric emptying, decreased albumin levels (decreased drug-protein binding), increased vascular volume hence reduced serum levels of drugs, enhanced hepatic metabolism and increased renal clearance, all of which may can significantly affect drug levels in the body. The fetus has low levels of drug binding to plasma proteins, immature hepatic metabolism, a relatively permeable blood brain barrier and difficulties in transporting drug metabolites back to the maternal circulation combined with the reduced ability of the fetus to metabolize drugs to produce higher drug concentrations in fetal than maternal blood.[3] Hence at one end adequate levels of medication have to be maintained in the maternal serum, at the same level it has to be less in the fetal circulation.

During pregnancy, the placenta serves several critical physiological functions. Among these is an important barrier role to minimize fetal exposure to drugs taken by the mother and other chemicals in the maternal environment.[4] The fetal-placental circulation is established by 21 days’ gestation and is fully formed by the end of the 4th month of gestation.[4] The protective role of the placenta as a barrier and for removal of end products of metabolism is vital as the fetal hepatic and renal systems have immature and insufficient metabolic and excretory capacity.[5] In a study on placental passage ratio of antipsychotics medications, highest passage ration was for olanzapine (mean = 72.1%, standard deviation [SD] =42.0%), followed by haloperidol (mean = 65.5%, SD = 40.3%), risperidone (mean = 49.2%, SD = 33.9%), and lowest for quetiapine (mean = 23.8%, SD = 11.0%).[6] In a recent study among the atypical antipsychotics quetiapine and risperidone were relatively good P-glycoprotein (P-gp) substrates whereas, olanzapine showed intermediate affinity and clozapine showed the least affinity of the drugs studied.[7] Drugs that are avid substrates of a transporter responsible for drug efflux (e.g., P-gp) should have reduced passage across the placenta; while drugs that are poor substrates of the efflux transporter will not be affected by this physiological mechanism and may reach the fetus more easily dependent upon their lipid solubility, maternal dose, gestational age, and other disposition-related variables. Ideally, the drug should possess a high protein binding, a short elimination half-life and a small volume of distribution. Identification of drugs which interact with placental efflux transporters will allow the possibility of minimizing fetal exposure in the treatment of maternal conditions. For pregnancy, future drugs should be sought which can effectively treat the maternal condition, all the while minimizing fetal exposure. Ultimately, this may allow for drugs specifically designed for pregnancy to come into being.

A large number of pregnancies in mentally ill continue to be unplanned.[8] Hence, the chance of fetal exposure to psychotropic drugs, especially in the first trimester is high. With current pharmacological treatment being mostly symptom based, polytherapy is a rule rather than an exception.[789] This in turn increases the chance of women with unplanned pregnancies being on multiple drugs. There is ample evidence of an increase in teratogenicity with polypharmacy (Malm et al., 2003 and 2004; Headley et al., 2004; Peindl et al., 2007).[10111213] Hence planning pregnancy is of foremost importance in preventing the fetal exposure to multiple psychotropics.

There has been a decline in birth defects, mainly due to the introduction of ultrasound screening as part of routine prenatal care and followed by therapeutic termination of pregnancies. Primary prevention through folic acid supplementation during early pregnancy has been found by many epidemiological studies mostly in preventing neural tube defects.[14] During the second and third trimesters, many drugs may have deleterious effects on growth and/or functional development and toxic effects.[3] Hence, the clinician has to be vigilant during pregnancy and perinatal period.

ANTIPSYCHOTICS

Antipsychotics are routinely used in treating severe mental illnesses. Both first generation and second generation antipsychotics (FGAs and SGAs) are used in the treatment of serious and severe mental illness.[16]

Second generation antipsychotic agents

Evidence with regard to the safety of atypical antipsychotic agents is limited, although two recent cohort studies have revealed no evidence of any increased risk of major malformations in infants exposed to clozapine, olanzapine, risperidone and quetiapine.[15]

Many of these agents, however, induce maternal hyperglycemia, impaired glucose tolerance, weight gain and increase in birthweight (Newham et al., 2008)[16] all of which predispose to unfavorable obstetric outcomes and long-term maternal complications (Newham et al., 2001).[16] Studies have demonstrated increased risk of low birth weight,[17] while some have shown higher incidence of large for gestational age (Newham et al., 2008)[16] in infants exposed to atypical antipsychotics.

Olanzapine is often used in the treatment of severe mental illness both in schizophrenia and bipolar disorders. This drug has the increasing data of its use in pregnancy. Various congenital malformations have been reported after its use in pregnancy including four cases of neural tube defects.[18] However, there was the use of concomitant medication. Furthermore, recent reports of increased birth weight have been reported with the use of olanzapine during pregnancy (Newham et al., 2001).[16]

Risperidone is also one of the commonly used SGA. Reports of congenital anomalies of known typology have been observed, but there are no recurrent patterns of anomalies.[19] Perinatal complications have described with risperidone which range from transient withdrawal reactions to seizures. Paliperidone which it is chemically the active metabolite of risperidone, no data concerning the use of paliperidone in pregnancy is yet available.[18] One case of the use of long-acting injectable risperidone in pregnancy has been reported in the literature, in which the baby was born normal and healthy and continued to be so at 8 months of age when the report was done.[20]

More data is available now regarding the use of quetiapine. Of the 227 reports of pregnancies, there were eight reports of major malformations of unknown typology have been observed.[18] In a retrospective chart review, 16 women who were treated with atypical antipsychotics were analyzed.[21] Among them, quetiapine was the most frequently prescribed atypical antipsychotic (58.82% of all exposures) with risperidone, aripiprazole, and ziprasidone in declining order. Average birth weight was appropriate for gestational age with one major malformation was noted which was with the use of aripiprazole.[21]

Little published evidence exists with regard to the safety profiles of newer agents such as aripiprazole and ziprasidone, though animal studies have shown teratogenic effects, delays in skeletal ossification, reduced fetal weight and increased mortality.[18]

The data on the safety of aripiprazole is limited to case reports. In one case report, transient unwanted side effects on the neonatal cardiac rhythm were observed.[18] There is a lack of human data on the safety of amisulpride, ziprasidone, and sertindole.

Among SGA, gestational metabolic complications like gestational diabetes have been observed with use of olanzapine and clozapine.[18] There is a report of risperidone induced gestational diabetes. There are reports increased birth weights in infants with the use of SGA mainly olanzapine and clozapine.[22]

It is important to monitor the women for gestational diabetes who are on typical antipsychotics. There is a lack of information on the long-term cognitive and behavioral outcome in the infants exposed to atypical antipsychotics.

First generation antipsychotic agents

With the advent of SGAs, the use of FGA has been limited. Phenothiazines and butyrophenones have historically been used to treat hyperemesis gravidarum, nausea, and less commonly, psychotic disorders in pregnant women. FGA agents are often prescribed with anticholinergic agents such as benztropine mesylate or trihexyphenidyl despite the lack of studies on the safety of anticholinergics in pregnancy.[18]

High-potency conventional antipsychotic agents such as haloperidol do not appear to increase the risk of teratogenicity, whilst low-potency antipsychotic agents such as chlorpromazine have a small, but statistically significant increased risk of nonspecific teratogenic effects with first trimester exposure.[22232425] There have been reports of limb anomalies associated with haloperidol in the first trimester[26] though larger case series have not supported this.[18] However, in a survey of more than 50,000 mother-child pairs that identified 142 first trimester exposures and 284 total exposures to chlorpromazine, there was no elevation in the rate of physical malformations with chlorpromazine.[22] The same study also suggests that related compounds, including trifluoperazine, perphenazine, and prochlorperazine, are similarly not associated with higher than expected rates of malformations.[22] A meta-analytic study of first trimester exposure to low-potency neuroleptics found an increase of one case of malformation for every 250 pregnancies in which exposure occurred.[18]

Transient complications have been documented in the neonate, including withdrawal symptoms, extrapyramidal signs (abnormalities of tone and underdeveloped reflexes), neonatal jaundice and intestinal obstruction.[18] Extrapyramidal symptoms, including hypertonicity, tremors, motor restlessness, spasticity, and difficulty with feeding, have been found in infants exposed to chlorpromazine.[22] Such symptoms have been reported to last up to 10 months, but most resolve within days. On the other hand, hypotonicity can occur in the neonate if the mother's dose of chlorpromazine is high.[22] Perinatal complications associated with the use of haloperidol in late pregnancy have also been documented.[26] Children with and without histories of neuroleptic exposure showed no differences in behavioral functioning or Intelligence Quotient (IQ) when followed up to 5 years of age.[23]

First generation antipsychotic agents continue to have a role in the treatment of mania or psychosis during pregnancy to control acute agitation.[27] There have been sparse studies looking at drugs and safety of medication for acute control of agitation and violence. The only attempt to address this issue was done with the Clinical Consensus Guidelines published in 2001,[28] who recommend the use of haloperidol for agitation in pregnant women. A high-potency conventional antipsychotic was rated as the first-line response by 76% of the consensus panel. The other second line recommendations were benzodiazepine alone; risperidone alone; and a combination of a benzodiazepine and a high-potency conventional antipsychotic. In a retrospective study by Ladavac et al.[27] on 80 pregnant women, lorazepam was the only benzodiazepine, while various antipsychotics including haloperidol, risperidone, ziprasidone, and quetiapine were used for acute control of agitation. Intramuscular (IM) haloperidol was the most frequently administered, followed by oral risperidone. The fetal risk of using several doses of psychotropic medication to treat agitated pregnant women in the emergency setting remains unknown. Hence in the above clinical situation haloperidol IM or oral risperidone can be used to treat agitation.

Data regarding the safety of fluphenazine, thioridazone, and promethazine is limited.

ANTIPSYCHOTIC USE DURING THE PUERPERIUM AND WHILE BREAST-FEEDING

Breast-feeding carries many health advantages and is described as the only nutrition source necessary during the first 4 months of life.[29] Apart from improved mother-child bonding, breastfed babies benefit from lower prevalence rates of infection and mortality rates.

Women with severe mental illness who relapse during the immediate postpartum period (or the third trimester) may require antipsychotic medications. Medication prophylaxis during the immediate postpartum period should be considered, although data to support this practice are available only for treatment with lithium.[18]

The passage of a drug into breast milk is influenced by many factors including its volume of distribution, molecular weight, lipid/water solubility, relative affinity for plasma and milk proteins, the pH of blood and milk (the degree of ionization of a drug) and blood flow to the breast.[30] An infant plasma concentration of 10% (or less) of that established as therapeutic in the mother is considered acceptable and safe.[31] Safe maternal psychotropic drug dosage limits, however, remain to be established and in this context, it is recommended that preterm immature infants should not be exposed to psychotropic agents. It is also prudent to monitor breast-feeding babies for signs of drug-related toxicity and adverse effects mainly extrapyramidal symptoms, sedation and weight monitoring (Yoshida et al., 1998).[32]

These drugs appear safe, evidenced by lactation studies that have consistently reported milk/plasma ratios of <1, without evidence of toxic or other adverse effects. Ten reports have addressed a total of 28 infants’ exposure to antipsychotic agents through nursing. In the majority of cases, no adverse events were observed (Yoshida et al., 1997).[32]

The safety of these drugs remains to be established. Hill et al.[31] calculated the estimated infant dose exposure during breast-feeding and found that both olanzapine and risperidone were well below the “attention critical” concentration. Olanzapine[33] and risperidone[34] achieve very low levels in infant plasma, with no evident adverse effects, suggesting that these agents may be safe. The level of infant exposure appears to be similarly small with quetiapine.[35] Clozapine, however, achieves relatively high concentrations in breast milk and infant serum and agranulocytosis and somnolence have been reported in breast-fed infants.[36] This agent is therefore contraindicated during breast-feeding. Little published evidence exists with regard to amisulpride, aripiprazole, and ziprasidone.

GUIDELINES AND CONCLUSIONS

Psychiatric disorders during pregnancy and the postpartum period are common. Many women are likely to require treatment for the same during pregnancy. Clinicians are often apprehensive about treating pregnant women, as the information on the safety of psychotropics is either inconclusive or undetermined. With the advent of newer psychotropics, often minimal data is available, and one has to keep continuously pace with newer information on drug safety. Multiple issues have to be considered while choosing safe treatments for pregnant women, and the best approach is to individualize treatment. Treatment of these conditions is important as they can affect the health of the mother and the fetus/infant. Issues become even more complex with multiple drugs and if there are associated medical problems or the infant is premature. Important issues to be kept in mind include folate supplementation in all women in the reproductive age group; planning pregnancies to minimize fetal exposure, discussion with patient and family regarding options and documentation of all discussions and decisions. Active liaison with obstetricians, ultrasonologists and pediatricians need to be stressed, as also the need for local registries. Whenever possible, use nonpharmacological approaches in addition. If a psychotropic is necessary, the choice of medication should be guided primarily by its safety data during pregnancy and by the psychiatric history of the patient.