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Psychotropic medications in pregnant women: treatment dilemmas

Marie-Paule V Austin and Philip B Mitchell

MJA 1998; 169: 428-431  

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Abstract - Introduction - Methods - Outcome criteria - Results - Antidepressants - Benzodiazepines - Mood stabilisers - Antipsychotics - Conclusions - References - Authors' details
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Abstract Objectives: To review the evidence from all studies of adverse effects on infant outcome of psychotropic medications taken during pregnancy.
Data sources: MEDLINE January 1976 - February 1998, EMBASE 1976 - February 1998, and bibliographies of retrieved articles.
Study selection and data extraction: All studies focusing on adverse effects associated with psychotropic drug use during pregnancy, with a particular focus on prospective controlled studies.
Outcome criteria: Congenital anomalies, perinatal complications and neurobehavioural sequelae.
Data synthesis: 23 studies were identified, nine of which were prospective controlled studies: five involving antidepressants (tricyclic antidepressants [TCAs] and selective serotonin reuptake inhibitors [SSRIs]), one each involving lithium and carbamazepine, and two involving benzodiazepines. As statistical synthesis was not possible given the heterogeneity of outcome criteria, a qualitative review is provided. Neither the SSRIs nor the TCAs appear to cause major congenital anomalies, but both may be associated with a small increased risk of minor anomalies, prematurity and neonatal complications. Benzodiazepines, lithium, anticonvulsants and chlorpromazine do lead to an increased rate of congenital anomalies as well as neonatal problems. Studies of longer-term neurobehavioural sequelae of psychotropic medications are very limited, but at present do not indicate any adverse effects.
Conclusions: While some psychotropes are associated with congenital anomalies and perinatal complications, mental illness per se may also be associated with an adverse outcome in the infant. Clearly, the risks to both mother and infant need to be carefully weighed and discussed with the parents.
MJA 1998; 169: 428-431
Introduction Almost fifty per cent of pregnancies are unplanned,1 and up to 35% of pregnant women in western societies will be taking psychotropic medication.2 Most psychiatric disorders among women arise in the childbearing years, particularly in the Fperinatal period,3 and the effects of psychotropic medications on the fetus can present dilemmas in the treatment of pregnant women.

One solution may be to cease therapy with these medications when pregnancy is contemplated or confirmed. However, women who stop taking medications during pregnancy experience high relapse rates.4 Suicidal behaviour, poor self-care, inadequate nutrition and poor antenatal clinic attendance, with a consequent lack of fetal monitoring, can all present risk to the fetus. Another aspect of mental illness during pregnancy is the possible direct effect of maternal illness per se on the fetus. Some studies have found an association between antenatal anxiety in women and increased obstetric complications such as prematurity, low birth weight,5 smaller head circumference and poorer scores on neonatal neurological examination.6 Women of low socioeconomic status who have depression have higher rates of premature and low birth-weight infants,7 while women with bipolar disorder who are not medicated also have higher rates of neonatal deaths and structural anomalies.8,9 One meta-analysis reports a higher incidence of obstetric complications in women with schizophrenia, regardless of whether the illness (and medications) began before or after delivery.10

This review examines the available evidence on the effects on the fetus of psychotropic medication used during pregnancy and provides some recommendations for treatment.

Methods We searched MEDLINE (January 1976 - February 1998) using the following exploded medical subject headings (MeSH): "follow-up studies", "psychotropic drugs", "prenatal exposure", "adverse effects", "anticonvulsants", "pregnancy", "depressive disorder", "antidepressants", "infant" and "child development". A similar strategy was used in our EMBASE search (1976 - February 1998). Searches were limited to the English language.

Studies that provide the highest level of evidence -- randomised controlled trials -- are not ethically acceptable in pregnancy. Thus we reviewed abstracts of articles for studies that met the following selection criteria:

  • prospective controlled studies;

  • retrospective studies; and

  • case studies.

This review is qualitative as the heterogeneity of outcome indicators means that data could not be analysed statistically.  

Outcome criteria Psychotropic drug use in pregnancy may be associated with three types of adverse outcome for the infant.

Congenital anomalies: both major and minor physical anomalies (ie, those with and without cosmetic or functional importance) may occur with first-trimester exposure. The background incidence for each is 2%-4% and the cause is most often unknown.11

Perinatal complications: including poor obstetric outcome (eg, prematurity or low birth-weight) or syndromes related to drug use late in the third trimester, such as neonatal withdrawal or toxicity in the first few days after birth.

Neurobehavioural sequelae: developmental delays, learning difficulties and neurological deficits resulting from drug exposure at any time in pregnancy.

Results Of 23 studies identified, nine were prospective, non-randomised controlled studies. Five of these involved antidepressants (tricyclic antidepressants [TCAs]12,13 and selective serotonin reuptake inhibitors [SSRIs]12-16), one involved lithium,17 one carbamazepine,18 and two, benzodiazepines.1,19 These studies all controlled for maternal age and past obstetric history; some controlled for alcohol and smoking,12,13,15 but none controlled for other drugs.

Summaries of the treatment of psychiatric disorders and use of psychotropic medications during pregnancy are shown in Boxes 1-4.  

Antidepressants Selective serotonin reuptake inhibitors (SSRIs): Fluoxetine was the first SSRI to be marketed and is the subject of most data currently available.

Two prospective, controlled, but non-randomised, studies, have examined infant outcome in terms of congenital anomalies and perinatal complications after exposure to fluoxetine during pregnancy.12,14 Pastuzsak et al,12 found that rates of major anomalies and obstetric complications were no greater for women with depression taking fluoxetine, than for two control groups (women with depression exposed to tricyclic antidepressants, and non-depressed women not exposed to antidepressants, or other potential teratogens). Both groups with depression had increased rates of miscarriage and neonatal complications, including jaundice, hypotonia, cyanosis, apnoea and a number of minor physical anomalies (club feet, hydrocele, congenital hip dislocation and lacrimal stenosis). Chambers et al,14 found no increase in the rate of miscarriage and major anomalies, but among 97 infants examined for minor physical anomalies there was a significant increase in the number of infants with three or more such anomalies in the fluoxetine-exposed group. Infants of women exposed to fluoxetine in the third trimester had higher rates of prematurity, admission to special-care nurseries and poor neonatal adaptation than those exposed only in the first- and second-trimesters.

In a prospective study of exposure to a variety of other SSRIs, Kulin et al found no increased rate of major congenital malformations, miscarriage, stillbirth or prematurity.15

Results from two non-controlled prospective studies of fluoxetine were conflicting. Goldstein, looking specifically at obstetric and neonatal complications with third-trimester exposure, reported a rate of neonatal complications comparable to that found in a general population survey, but almost double the normal rate of premature births,22 while McElhatton et al reported no increase in perinatal complications.23 Although the study of Chambers et al14 was far more methodologically sophisticated, its conclusions are still limited by its failure to control for use of other medication, smoking or alcohol. Given the lack of use of patients with depression as control subjects, none of these studies were able to separate any effect of depression per se from that of antidepressants on congenital anomalies or perinatal complications.

In terms of neurobehavioural sequelae, a well-controlled study of children exposed to fluoxetine in utero and followed-up to the age of four, showed no increase in neurobehavioural deficits or developmental delays compared with non-exposed children of depressed mothers.13

Tricyclic antidepressants (TCAs): In terms of congenital anomalies and perinatal complications, a recent review of pooled results of 338 mothers indicated no increased risk of major structural anomalies with first-trimester exposure.20 Only two prospective studies have examined the potential teratogenic risk of tricyclics.12,23 Their findings were identical to those reported for fluoxetine. There have been some case reports of neonatal TCA withdrawal syndromes (irritabilty, jitteriness and convulsions)24 and anticholinergic effects (constipation and urinary retention).17 For neurobehavioural sequelae, the study of Nulman et al reported no increase in neurobehavioural deficits or developmental delays compared with non-exposed children.13

Other antidepressants (moclobemide, venlafaxine, nefazodone, mianserin, MAOIs): Heinonen et al cite a study of the use of MAOIs during pregnancy,25 reporting a higher rate of congenital anomalies in exposed infants. A report of 48 infants exposed to mianserin found one case of congenital anomaly.23 The lack of data on the newer antidepressants (moclobemide, venlafaxine, nefazodone) probably reflects their more recent entries onto the market.  

Benzodiazepines Pooled results from retrospective studies based on birth defect registry data on several hundred women indicate that the relative risk of cleft palate and lip is approximately 2-3-fold with first-trimester exposure to diazepam and 7-fold with alprazolam.20 While this increase in risk is statistically significant, the absolute risk remains small (having increased from 0.06% to 0.7%). The risk associated with other benzodiazepines has not been evaluated. Pastuszak et al prospectively examined 137 cases of benzodiazepine exposure in the first trimester and found no increase in congenital anomalies in the exposed group, but almost double the rate of miscarriages.1

Third-trimester exposure to benzodiazepines, especially to those with a long half-life, may lead to neonatal hypotonicity, failure to feed, apnoea and low Apgar scores.20 A small prospective study of 17 infants reported delays in developmental milestones at 18 months.19 However, a review of the literature on 550 infants followed-up to a maximum of four years of age, found no increase in neurobehavioural sequelae.26  

Mood stabilisers Lithium: Initial reports from the Danish Register of Lithium Babies indicated significantly increased rates of cardiovascular malformations.27 A recent review of pooled data suggests a more modest risk of Ebstein's anomaly of the tricuspid valve (10-20 times that in the general population where it occurs in 1/20 000 cases).28 A prospective controlled study of 148 women, found a relative risk of 1.2 for all congenital anomalies and of 3.5 for cardiac anomalies in the babies exposed to lithium.29

The "floppy baby" syndrome, in which the infant is hypotonic, cyanosed and suckles poorly is thought to be the result of lithium toxicity.30 Lithium has also been reported to affect neonatal thyroid function. A five-year follow-up of 60 children exposed to lithium in the second- and third-trimesters found no significant differences in developmental anomalies compared with non-exposed siblings.31 This was further supported by follow-up of 21 prospectively recruited infants, which found no difference in attainment of developmental milestones with the matched control group.32

Anticonvulsants: Carbamazepine and sodium valproate are effective mood stabilisers often used as alternatives to lithium for bipolar disorder.33 Data on the safety of using anticonvulsants during pregnancy derives from studies of women with epilepsy. Spina bifida occurs in 0.5%-1% of babies exposed to carbamazepine in the first trimester34 and in 1%-5% of those exposed to sodium valproate (compared with 0.03% in the general population).35 The risk may increase with higher serum levels and use of more than one anticonvulsant. Orofacial clefts and a number of minor malformations may also be associated with the use of these drugs. Withdrawal seizures in the infant have been reported with sodium valproate in a small case series.36 A recent small prospective controlled study of 36 infants indicates no developmental delays or cognitive impairment associated with carbamazepine use throughout pregnancy.18  

Antipsychotics Among the typical (older) antipsychotics, pooled results of large retrospective and small prospective controlled studies of low dose chlorpromazine in weeks 4-10 indicate that its use in the first trimester may increase congenital anomalies by 0.4%.20 However, this increase in congenital anomalies was not seen with trifluoperazine.37 Two small retrospective studies of haloperidol exposure in utero also failed to show an increased rate of congenital malformations.38,39 Case reports, and one case series of chlorpromazine and other typical antipsychotics used in the third trimester, report neonatal restlessness, tremor, poor suckling, abnormal movements, jaundice and functional bowel obstruction.40 A five-year follow-up study showed no abnormalities in infants exposed to chlorpromazine in utero.41

For the atypical (newer) antipsychotics (eg, clozapine, risperidone, olanzapine, zuclopenthixol) the only data currently available are from case reports, and so far there is no evidence of teratogenicity. There are no data available on neonatal complications or neurobehavioural sequelae.

Conclusions The TCAs and SSRIs appear to be relatively safe in pregnancy, although they are possibly associated with increased rates of minor physical anomalies, prematurity, and neonatal complications. Chlorpromazine, long-acting benzodiazepines, lithium, and carbamazepine appear to be associated with major physical anomalies and poor neonatal adaptation. There is, however, some evidence to suggest that mental illness per se may be associated with an adverse outcome in the infant, while the risks to both mother and infant of a prolonged untreated episode of mental illness bear a considerable cost. The chain of causal events linking maternal illness and the use of medication to adverse outcomes in the offspring remains a complex issue. Before a decision concerning the use of psychotropic medication in pregnant women can be made, the risk-benefit ratio must be determined and discussed with the parents.
References
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(Received 16 Feb, accepted 8 Jul 1998)
Authors' details Prince of Wales Hospital, Sydney, NSW.

Marie-Paule V Austin, MB BS, FRANZCP, Staff Specialist in Liaison Psychiatry, and Conjoint Lecturer, School of Psychiatry, University of New South Wales;

Philip B Mitchell, MD, FRANZCP, Administrative Director, Mood Disorders Unit, and Associate Professor, School of Psychiatry, University of New South Wales.
Reprints will not be available from the authors. Correspondence: Dr M-P V Austin, Department of Liaison Psychiatry, Prince of Wales Hospital, Randwick, NSW 2031.
E-mail: m.austinATunsw.edu.au

©MJA 1998
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→  Anne E Buist, Bryanne E W Barnett, Jeannette Milgrom, Sherryl Pope, John T Condon, David A Ellwood, Phillip M Boyce, Marie-Paule V Austin and Barbara A Hayes. To screen or not to screen — that is the question in perinatal depression Med J Aust 2002; 177 (7 Suppl): S101-S105. [Preventing Depression] <http://www.mja.com.au/public/issues/177_07_071002/bui10367_fm.html>

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1: Treatment of depression in pregnancy

If a pregnant woman is currently well, but has a history of relapse on withdrawal of medications, or if her current depressive episode is severe, the benefits of medications (direct for the mother and indirect for the infant) will usually outweigh the potential risks to the infant. It is good practice to use the minimum effective dosage and, if the mother does not plan to breast-feed, to halve the dose in the week before delivery to minimise any potential withdrawal in the infant. The infant should then be observed for withdrawal symptoms. The importance of general issues such as ceasing cigarette and alcohol intake, taking folate supplements and regular antenatal clinic attendance should be stressed to all expectant mothers.

2: Treatment of anxiety disorders in pregnancy

Mothers taking a benzodiazepine regularly should be advised to taper the dose and to stop taking it before they become pregnant, and to use cognitive-behavioural management techniques and/or a small dose of a sedating tricyclic antidepressant (such as dothiepen) instead. Intermittent use of short-acting benzodiazepines is probably safe, and the long-acting diazepam used infrequently after the first trimester is probably not harmful. However, long-acting benzodiazepines (diazepam, clonazepam) should be avoided in the days before labour as they may compromise the infant's respiratory function during delivery. In mothers taking benzodiazepines on a long-term basis during pregnancy, and who do not plan to breast-feed, the medication should be slowly reduced before delivery to minimise neonatal withdrawal, and the infant will need to be observed for withdrawal symptoms.

3: Treatment of bipolar disorder in pregnancy

First trimester Where possible, plan a drug-free first trimester by slowly tapering both lithium and anticonvulsants (to avoid acute relapse and withdrawal seizures, respectively) before conception. If the use of a mood stabiliser is unavoidable, lithium is a safer option. If first-trimester exposure has occured, an ultrasound scan and echocardiogram should be performed at 16-20 weeks to exclude cardiovascular, midline and other defects, and alpha-fetoprotein levels should be measured, as high levels are associated with congenital abnormalities. With inadvertent exposure to anticonvulsants, folate (which may reduce the risk of neural tube defects) should be given until the end of the first trimester.20 Antipsychotic medications may have to be used to achieve control of any disturbed behaviour in cases of manic relapse.

Second- and third-trimesters When necessary, mood stabilisers may be recommenced in the second trimester. Lithium requirements will increase in the third trimester, but it is wise to reduce the dose by 25% just before delivery to avoid possible neonatal toxicity, and babies should be monitored for lithium toxicity for up to 10 days after birth. If the mother does not intend to breast-feed, it is best to reduce anticonvulsants before birth to minimise the risk of neonatal withdrawal symptoms. As women with bipolar disorder are at p articular risk of relapse postpartum (50%),21 therapy with mood stabilisers must be recommenced after the birth of the child.

4: Treatment of psychosis in pregnancy

Chronic psychosis: depot antipsychotics are probably best avoided, given the potential for accumulation and toxicity in the neonate. For women with chronic psychosis, it is preferable to switch as early as possible to minimum effective doses of oral trifluoperazine or haloperidol and perform an ultrasound at 16-18 weeks to exclude the development of congenital abnormalities. Intensive case management and liaison with obstetric services is essential during this period as these women are at increased risk of relapse and poor antenatal care once they cease depot medication.

Acute recurrent psychosis: should be managed as for bipolar disorder.

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