General information on drug use in pregnancy: psychotropic drugs

Prescribing psychotropic drugs in pregnancy: risk/benefit analysis

Box 11.1 can provide a framework for the practitioner to address the decision whether or not to prescribe a psychotropic drug during pregnancy. It can also guide discussion with the woman, preferably in conjunction with her partner.

A categorisation of harmful effects to the fetus has been developed utilising 5 classes as shown in Box 11.1. For classes 1 to 4 (death, congenital abnormality, growth retardation, neonatal toxicity), evidence (albeit of variable quality) is available for the more commonly used psychotropic medications. Class 5 (long-term neurodevelopmental effects) is largely unexplored, but should not deter prescribing where this is otherwise indicated. The relevance of the unknown risk in class 5 is to impress on the practitioner that no psychotropic can be considered 100% safe in pregnancy, nonpharmacological interventions always warrant consideration and unnecessarily high dose and duration of treatment should be avoided. There are, however, increases in total body water during pregnancy, as well as alterations in protein binding. Some pregnant women may require higher doses of some drugs (eg antidepressants) for an effective response.

Caution is warranted in prescribing only on the basis of preventing a condition (especially unipolar depression) which is not currently present (eg postnatal depression).

A number of findings have further clarified the risk to the fetus of untreated depression and anxiety during pregnancy. In addition to increased risk of smoking, alcohol and drug abuse, psychiatric disorders themselves appear to independently elevate risk in terms of spontaneous abortion, pre-eclampsia, premature birth, small-for-dates, low birthweight, smaller head circumference and longer-term neurodevelopmental problems. Such adverse effects also appear to be independent of the poor nutrition and antenatal care common in depressed women. Finally, poor neonatal adaptation (see below) has been demonstrated to be associated with untreated depression and anxiety during pregnancy. This latter association renders it very difficult to determine to what extent neonatal problems are attributable to maternal dysphoria during pregnancy as opposed to medication used to treat this. The adverse consequences for the fetus of not treating these disorders may have been insufficiently emphasised in the past.

Depression during pregnancy is as common as postnatal depression. Moreover, suicide is the leading cause of death in pregnant women, and also the leading cause of death in the perinatal/postnatal period, exceeding causes directly related to childbirth or its complications. Hence, while there is general agreement that effort should be made to minimise drug doses, it is equally important not to undertreat the psychiatric illness. The majority of women will relapse if antidepressant or mood stabiliser medication is ceased on confirmation of pregnancy. With judicious choice of medication type and dose, careful monitoring of mother and fetus/infant, and delivery in a hospital with neonatal facilities, most psychiatric illness can be safely and successfully treated during pregnancy with significant benefit for both mother and child.

Risk/benefit analysis for psychotropic drug prescribing in pregnancy (Box 11.1)

Antipsychotics

Second-generation antipsychotics

The safety of the second-generation antipsychotics (amisulpride, aripiprazole, clozapine, olanzapine, paliperidone, quetiapine, risperidone and ziprasidone) has yet to be established. However, on the basis of case reports and small series, there are no consistent reports of deleterious effects on the fetus. Isolated case reports of congenital abnormalities have been reported following clozapine use during pregnancy, but no definitive association has been established.

Olanzapine has been linked to an increased risk of maternal gestational diabetes, with associated risk to the fetus.

Of antipsychotic drugs with published data, olanzapine has the highest placental transfer, quetiapine the lowest, with risperidone between these.

Unlike first-generation antipsychotics, some second-generation antipsychotics (eg clozapine, quetiapine, aripiprazole) do not increase prolactin, and others (eg olanzapine) are less likely to increase prolactin, and hence to reduce women's fertility. When changing from a first- to a second-generation antipsychotic, warning women about this normalisation of their fertility is warranted.

First generation antipsychotics

On the basis of the limited data available, these drugs appear to present no major risk at usual doses. Opinion differs on the relative safety of individual drugs. More extensive data are available regarding the safety of haloperidol. Large doses of any of these drugs, especially when given continuously, may cause protracted withdrawal dyskinesias in the neonate.

Treatment of extrapyramidal adverse effects

Anticholinergic drugs have category B classifications and there is inconclusive evidence that they may have been associated with an increase in congenital abnormalities in some studies, as well as neonatal adverse effects. They should be avoided if possible in pregnancy. Beta blockers may relieve akathisia; however, possible cardiovascular adverse effects need to be taken into account.

Antidepressants

Introduction

There has been concern about the safety of selective serotonin reuptake inhibitors (SSRIs) in pregnancy and data are lacking for the other newer antidepressants. As a result of this, tricyclic antidepressants (TCAs) are sometimes considered the drugs of choice in pregnancy.

Selective serotonin reuptake inhibitors

General information

Findings over the last four years from studies on the fetuses, neonates and children of women taking SSRIs during pregnancy have made the decision to prescribe these drugs significantly more complex in the face of increased awareness of apparent risk.

There are six areas of concern: teratogenicity, spontaneous abortion and premature labour, low birth weight/small-for-dates, poor neonatal adaptation, persistent pulmonary hypertension in the neonate, and neurodevelopmental difficulties in older children. Currently there is no clear evidence to recommend one SSRI over another. However, some potential problems have been reported with use of paroxetine and fluoxetine (see Teratogenicity, Spontaneous abortion and premature labour and Poor neonatal adaptation).

Teratogenicity

There is some inconsistency in published findings; however, with the exception of paroxetine, no conclusive evidence has emerged of teratogenicity of any other individual SSRI, nor from analyses that have considered the SSRI group as a whole. The risk of some rare malformations appears to be increased by SSRIs in some unreplicated studies; however, the absolute risk remains low, and there are a large number of potential confounding variables (including depression itself), which could account for such findings. Concerns regarding teratogenicity should not deter prescription of SSRIs (with the exception of paroxetine) for treatment of major depression in pregnancy.

Paroxetine use in the first trimester has been linked to cardiac defects (ventricular septal defects, which are often self-closing, and occasionally tetralogy of Fallot). Paroxetine has been associated with an increase in the relative risk of cardiac defects by 1.5 to 2.0.

Among SSRIs whose placental transfer has been measured, sertraline has been shown to have the lowest transfer.

Spontaneous abortion and premature labour

This association (reported mainly for fluoxetine) remains controversial due to dubious control for higher nicotine and alcohol usage, age and other risk factors in depressed women, as well as the influence of depression itself. In addition, several studies found no such association. Higher prescribing of fluoxetine may account for the larger number of reports.

Low birth weight/small-for-dates

Once again there are conflicting findings and the association is controversial (see above Spontaneous abortion and premature labour).

Poor neonatal adaptation

It is now well established that approximately 20% to 30% of neonates of mothers taking SSRIs in late pregnancy will experience a syndrome resembling serotonergic overstimulation, arising in the first one to two days postpartum. The base rate for serotonergic-like symptoms is 6% to 10%, so the relative risk is increased threefold. There is ongoing debate over whether this is a result of SSRI toxicity or withdrawal. It is characterised by:

In almost all cases the syndrome remits within two weeks with no apparent residual problems.

Tapering the dose of the SSRI two weeks before delivery reduces the likelihood of this problem; however, this increases the risk of maternal relapse and there is the uncertainty of delivery dates. Supportive care of the neonate may be preferable. The symptoms may be more likely with fluoxetine due to its long half-life.

Persistent pulmonary hypertension in the neonate

A single well-designed but retrospective study has found a statistically significant association between exposure to SSRIs in the second half of pregnancy (only) and persistent pulmonary hypertension in the neonate. This is a worrying finding as this condition carries 5% mortality and 50% severe morbidity rates; however, the absolute risk remains relatively small (6 to 10 in 1000). This finding awaits replication.

Neurodevelopmental difficulties in older children

Several prospective studies have assessed small cohorts of children, in both the shorter (age six months) and longer term (age six years), whose mothers were prescribed an SSRI in late pregnancy. One study found subtle impairments in motor development compared to matched controls. However, it was not blinded and the exposed group included mothers with higher alcohol and drug usage in pregnancy (and depression). The other studies, more numerous and more methodologically sound, failed to detect any impairment. A potential confounder would be the quality of parenting of women whose depression might be ongoing.

Aside from the potential problems with paroxetine and fluoxetine, there is no evidence to recommend any particular SSRI over another.

Other newer antidepressants

Preliminary data suggest venlafaxine is not associated with congenital abnormality, but neonatal withdrawal has been reported. The safety during pregnancy of desvenlafaxine, duloxetine, mirtazapine, moclobemide and reboxetine has not been adequately studied.

Tricyclic antidepressants

There is no evidence that exposure to TCAs, even in the first trimester, carries any significantly increased risk of malformation. These antidepressants are often considered the drugs of choice in severe depression during pregnancy, on the grounds of the more extensive available evidence. Isolated case reports have suggested a possible increased risk with the use of doxepin, but this evidence is inconclusive. However, the prescriber needs to be aware of the much higher lethality in overdose of these antidepressants, compared to SSRIs. Doses may need to be increased in late pregnancy to maintain efficacy.

Nortriptyline is sometimes regarded as the TCA of choice during pregnancy due to its lower likelihood of anticholinergic adverse effects and orthostatic hypotension. In addition, maternal serum concentration of this drug can be measured.

In the neonate, anticholinergic adverse effects have occasionally been observed, as has a rebound reaction (irritability, insomnia, fever and colic). Abrupt discontinuation of clomipramine in pregnancy has been associated with premature delivery, and subsequent seizures in the newborn.

Other antidepressants

The safety during pregnancy of mianserin and irreversible nonselective monoamine oxidase inhibitors (MAOIs) has not been adequately studied. Most guidelines recommend these drugs be avoided.

Drugs used in bipolar disorder

General information

Drugs used in the treatment of bipolar disorder include lithium, sodium valproate, carbamazepine and lamotrigine, as well as second-generation antipsychotics. For the majority of patients with bipolar disorder, discontinuation of their treatment during pregnancy will result in relapse. The risks versus benefits must be carefully weighed, taking into account the following, and mindful that polypharmacy should be avoided wherever possible due to substantial increases in teratogenic risk.

These drugs should usually be avoided in the first trimester. Thereafter, it would appear that lithium is preferable to valproate or carbamazepine. The use of lamotrigine is discussed further below.

Lithium

The use of lithium within the first trimester has, in many studies, been linked to fetal abnormalities. In particular, the risk of serious cardiac malformations (Ebstein's anomaly) was thought to be very significantly increased. Animal experiments have demonstrated marked teratogenic effects of lithium. Reviews have confirmed that earlier estimates of risk in humans had been overestimated. Although the risk of Ebstein's anomaly is significantly increased, the absolute risk (approximately 1 in 1000 to 2000) remains low. The benefits of lithium prophylaxis during pregnancy may, in some cases of severe bipolar disorder, outweigh the risks, and lithium has been considered as a first-line treatment during pregnancy for some such women. Nevertheless, lithium is not normally recommended during pregnancy. Some experts have suggested that lithium be avoided until cardiogenesis is complete, ie about 50 days postconception, and then resumed if necessary. Any woman who has been exposed to lithium during pregnancy should have a high-resolution fetal echocardiogram and level 2 ultrasound around 18 to 20 weeks. The potential risks of illness recurrence after withdrawal of this medication must be balanced against the teratogenic risk to the fetus from lithium.

Lithium has also been associated with premature delivery, stillbirth and neonatal goitre in some case reports.

In general, patients who are on lithium and who wish to become pregnant should be informed of the risk, and have their lithium gradually withdrawn before conception occurs. If the pregnant patient develops symptoms and is in need of pharmacological treatment, then antidepressants and antipsychotic drugs can be prescribed for depressive or manic symptoms, especially during the first trimester.

Renal clearance increases during pregnancy and falls abruptly after delivery. Careful monitoring of serum lithium concentration is indicated and dose adjustments of the order of 25% are often required. At delivery, lithium has been associated with the neonate being 'floppy' and less responsive.

The puerperium is a time of high risk of relapse of mania or depression. Prophylactic treatment with lithium immediately after delivery is sometimes appropriate for patients with bipolar disorder who have been well-controlled on lithium. However, the implications for breastfeeding must also be considered.

Antiepileptics

Antiepileptics should only be used during pregnancy under exceptional circumstances, because of their risk of teratogenicity (see below). If a woman with severe bipolar disorder becomes pregnant while stabilised on these drugs, the clinician faces a dilemma as cessation of the drug carries a 60% to 70% risk of relapse. Nevertheless, in many cases a decision will be made, in consultation with the woman and her partner, to discontinue antiepileptics at least during the first 15 to 20 weeks. Attempt to manage any relapse symptomatically using safer drugs such as antipsychotics or antidepressants (or electroconvulsive therapy [ECT], since this is not contraindicated in pregnancy). However, in some cases, it may be judged more appropriate to continue antiepileptics, in which case regular monitoring with high-resolution ultrasound would be indicated.

Sodium valproate has been associated with up to a 10-fold (from 0.2% to 2%) increased risk of spina bifida, as well as other serious malformations (11% risk in total) and coagulopathies. These effects are thought to be dose-related.

Carbamazepine is sometimes used as a substitute for lithium in patients with recurring mood disorder where mania is the prominent feature. However, it has also been associated with a significant increased risk of spina bifida in addition to developmental delay and craniofacial defects. The overall risk of major malformations is approximately 6%.

Women taking sodium valproate or carbamazepine who become pregnant should be counselled and offered antenatal screening. The latter can involve biochemical (alpha-feto protein), radiological and ultrasound investigations, and expert opinion should be sought.

If a decision is taken to continue these antiepileptics, animal data suggest that the risk of neural tube defects may be reduced if larger than the standard dose of folic acid is taken before pregnancy (ie 5 mg/day instead of 0.5 mg/day). This has not been demonstrated in humans. A number of studies suggest that Vitamin K (10 to 20 mg/day) taken from 36 weeks of pregnancy reduces the risk of coagulopathies in the neonates of women who have been taking antiepileptic drugs during pregnancy.

Early data suggested that lamotrigine (if taken alone) may not be associated with increased risk of congenital abnormality, even if used in early pregnancy; however, this should not be regarded as definitive in the light of other data. The overall risk of major malformations with lamotrigine has been reported as 2.9%, but other data suggest this may be an underestimate. Risk increases to 10% to 15% if lamotrigine is combined with other antiepileptics, and monotherapy is highly desirable for all antiepileptics. Lamotrigine clearance may be increased by up to 50% in late pregnancy requiring a substantially increased dose, with corresponding dose reduction after delivery.

Early data raise the possibility that all antiepileptic drug use in pregnancy may be associated with later developmental delay; however, epilepsy itself is a potential confounder.

Anxiolytics and hypnotics

The issue of whether first trimester exposure to benzodiazepines is associated with increased risk of cleft lip and/or palate remains controversial. Pooled data from prospective cohort studies have shown no increase in malformations. However, poorer quality, case-control studies have shown an association between exposure to benzodiazepines and major malformations or oral cleft alone. The first eight weeks appears to be the period of highest risk. Level 2 ultrasound examination should be considered for such women.

After the first trimester, anxious patients who do not respond to counselling or sleep hygiene measures may benefit from the intermittent use of low-dose benzodiazepines as hypnotics. There is some evidence that oxazepam or temazepam, being shorter-acting drugs, are preferable to longer-acting benzodiazepines such as diazepam.

If benzodiazepines (especially those with long half-life) are taken in late pregnancy, they can cause neonatal drowsiness, respiratory depression, poor temperature regulation, poor feeding and hypotonicity (the 'floppy infant syndrome'). Neonatal withdrawal symptoms have also been reported.

There are no available data to enable a definitive judgment to be made about the safety of zopiclone and zolpidem during pregnancy. However, evidence from small series suggests that zopiclone is not a major human teratogen.

Drugs for opioid dependence

There is consensus that the risks associated with opioid substitution therapy during pregnancy are far less than continued use of 'street drugs' or medical detoxification. Methadone substitution is the therapy of choice for opioid-dependent women, but its safety and efficacy in pregnant women has not been fully established. However, most guidelines currently recommend methadone on the grounds that almost 30 years of experience has accumulated. Neonatal withdrawal syndrome, respiratory depression and low birthweight are potential problems in infants born to women receiving methadone for the management of opioid addiction. Increased stillbirth rates have also been noted.

Buprenorphine is currently gaining acceptance as an alternative to methadone, and placental transfer appears less than with methadone. To date, no teratogenic effects or other serious increase in adverse effects have been reported during pregnancy. The incidence and severity of neonatal withdrawal are probably lower compared to methadone.

Revised October 2008 ©Therapeutic Guidelines Limited (etg31demo, July 2010)