Psychotropic drugs in pregnancy

C It r r e n t

OBSTETRICS & GYNAECOLOGY

Drugs

Psychotropic drugs in pregnancy

J.B. Loudon

On the other hand, the newer, cleaner agents cannot yet be recommended for use in pregnancy because of their unknown toxic potential. For the older antidepressant and antipsychotic drugs the dose required for successful treatment may show a 10-fold variation. Undoubtedly the benzodiazepines carry a quantifiable risk of producing physical dependence if taken chronically for over one month, and this has been well publicised in the last decade. However the opprobrium has tended to generalise to all psychotropics, quite unjustifiably, and it has become more difficult to persuade patients to start and stay on antidepressant treatment. Relatives and neighbours may consider themselves expert on psychotropies and offer advice on dosage and compliance; worse, they may act as additional sources of supply, unbeknown to the doctor. Groups of drugs encountered in practice include the anxiolytic hypnotics, which for all intents and purposes means the benzodiazepines. In the UK only a limited number of these can be prescribed on the NHS. The antidepressants fall into two main groups, the tricyclics or reuptake inhibitors, and the monoamine oxidase inhibitors. Lithium is used widely as an agent to prevent relapse of recurrent depressive and manic-depressive illness. In the last decade a variety of anticonvulsants, including carbamezepine and sodium valproate, have been used for the same purpose, and also to treat episodes of explosive behavioural disorders. Finally, the antipsychotics are used not only to treat acute episodes of schizophrenia or other similar psychoses, but also in the long term to prevent recurrence. In the management of psychiatric disorder drug therapy is but one component, and the patient's morale, the relationship with treating staffplus under-

Pregnancy is viewed as a relatively tranquil time from a psychiatric point of view. Indeed the occurrence of major mental disorders during pregnancy is less than at others during the female life span. However the psychiatrist sees but a tithe of the total psychological morbidity which presents from the community, and for over 10% of women pregnancy is a time which is associated with low-grade distress, z compared to that experienced in psychosis. This is especially in reaction to unfavourable life situations, or follows previous unrelated psychological disorder, sometimes termination of an earlier pregnancy. There will be some pressure from the patient for relief from her symptoms. Given the prevalence of significant psychological morbidity in the (non-pregnant) female population of about 15%, it is not an uncommon occurrence that a woman taking psychotropic drugs may become pregnant. Therefore, the question of psychotropic drug treatment in the pregannt woman will arise in these three different situations. The complications of the misuse and abuse of alcohol and stimulants will not be dealt with here. Psychotropic drugs differ from other medications in several respects. Their onset of action tends to be delayed, 2-3 weeks in the case of antidepressants, and for up to one month for the anti-psychotics. Similarly, a rebound of illness may not follow drug withdrawal for quite some time owing to the vagaries of tissue storage; it may be quite difficult for a patient to appreciate the connection. Many of the older psychotropics are excessively dirty with regard to side effects. J. B. Loudon, FRCPsych, Andrew Duncan Clinic, The Royal Edinburgh Hospital, Morningside Terrace, Edinburgh, EHI0 5ttF, UK Current Obstetrics and Gymlecolol.v (1992) 2, 115-120 199z t . o , ~ c~o~, t ~ L~

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116 CURRENTOBSTETRICSAND GYNAECOLOGY standing are as important. Support groups and community resources should not be forgotten. Tricyclic antidepressants, antipsychotics and benzodiazepines are all highly bound to plasma albumen, and with the fall in albumen consequent to the increase in plasma volume, the amount of free drug available can be expected to be greater for a given dose. However an increase in total body water, and fat, plus an increase in hepatic microsomal degradation and glomerular filtration rate all appear to underlie the slightly increased dosage of these drugs required for the same effect in pregnancy. All antidepressants and many antipsychotics tend to lower blood pressure by an alpha-adrenergic blocking effect, and may cause a tachycardia. Chlorpromazine has some diabetogenic potential through inhibition of insulin release. All psychotropic drugs must be assumed to pass through the placenta readily, assisted by their general high lipid solubility, and small molecular size. There will be some delay before a psychotropic drug reaches equilibrium in the fetus, which behaves pharmacologically as a deep compartment. However entry to the fetal brain is hindered less because of its immature blood-brain barrier. Owing to slower microsomal degradation and glomerular filtration, clearance of a drug is delayed in comparison to an adult, or to the maternal circulation. 2 With the exception of lithium and the anticonvulsants, there is little evidence in humans that psychotropic drugs cause organ dysgenesis. It is an underresearched area, but there is no confirmation for lasting functional or behavioural changes in the fetus exposed to psychotropic drugs in utero. This contrasts with an extensive literature showing such a relationship in animal studies and is surprising in the light of the involuntary sampling by the fetal brain of whatever psychotropic drug mother has chosen to take on a regular basis. In samples of 1513 and 524 children exposed to neuroleptics, no effect could be observed on intelligence or behaviour. It should be noted that the measures used did not permit the detection of subtle behavioural alterations, and the possibility of lasting change remains. Another potential for changed behaviour from the effect of a psychotropic indirectly administered to the fetus is the interaction between mother and child postpartum. An under-treated mother or a drug-influence infant may disturb the other with an influence on the child's subsequent emotional development. Again, the evidence is lacking.

The benzodiazepines Reports from Scandinavia in the early 1970s suggested greater use of benzodiazepines by the mothers of children born with defects of the palate, although other studies at the time failed to confirm the finding. More recently, a careful study which compared 611 infants with such deformities and 2498 controls found

no evidence of an excess of diazepam use by their mothers. 5 Again from Scandinavia, a highly significant relationship was found between benzodiazepine use as detected by the presence of drug in the serum of mothers and abnormalities of the CNS, palate and urogenital tract. 6 In two-thirds of the cases presenting with these abnormalities, (2.3 per 1000 of live births in Gothenburg in 1985 and 1986), serum samples were available for analysis, half of which were positive, compared to 3% for controls. The evidence of positively tested serum samples gives a power to the report denied to those based on histories. The conclusion must be that benzodiazepines should not be used in the first trimester as a matter of choice. It does not seem that the risk is sufficient to justify termination. In the light of the well-attested likelihood - 40 to 50% - of a withdrawal reaction, which may be quite incapacitating, including distorted sensory perceptions, in a person habituated to taking benzodiazepines regularly, what is to be done if she finds herself pregnant? The reaction may be worse if the patient is taking benzodiazepines with a short duration of action, metabolised to an inactive compound. She should be switched to chlordiazepoxide, whose active metabolite, desmethyldiazepam, has a long half life, which smooths out symptoms arising from fluctuations in the serum level. Personality factors affect the ease of withdrawal and tolerance of symptoms. 7 Support, education, of both patient and partner, relaxation training, and referral to a local support group for tranquilliser dependence will all help. By dint of a programme of drug reduction, more rapidly to start with and slowly latterly, written out in advance so the patient knows what is planned, it should be possible to complete withdrawal within 10 days, although circulating drug may not disappear for another 2 or 3 days. It is possible to screen urine for metabolites of psychotropic drugs, and to use this to detect non-compliance with the regime. There are no reports of ill-effects of benzodiazepines given during the second and third trimester on the fetus. As at any other time, habituation to and tolerance of their effects by the patient, as well as the development of dependence is avoided by the patient being instructed to use the drug only at times of particular discomfort, and in other, nonpharmacological, techniques of anxiety management. Quite apart from undesirable maternal effects, regular ingestion of a benzodiazepine such as diazepam will lead to accumulation in the fetus, and will take some time to clear from this deep compartment, a On the other hand a single bolus of up to 30 mg diazepam at the time of labour will have relatively little effect on the fetus, as measured by the Apgar score. A larger dose or sustained prenatal exposure can lead to the 'floppy infant' syndrome, which is characterised by hypotonia, respiratory embarrassment, difficulty in suckling and hypothermia.

PSYCHOTROPIC DRUGS IN PREGNANCY 117 A benzodiazepine withdrawal syndrome, with a hyperactive sucking reflex, irritability and tremor is also described. 9 Some manifestations may persist for months, (a phenomenon also found in adults). Benzodiazepines are excreted in breast milk, and although small amounts may be used without apparent harm, ~° there are reports of failure to thrive by infants exposed, al In summary, benzodiazepines should be avoided in the first trimester, and are better used on an 'as needed' basis during the second and third. Their use is not absolutely contraindicated in labour and the puerperium, but should be circumscribed.

Neuroleptic drugs Pregnant women are unlikely to start taking drugs of this group during pregnancy unless as an obsolete and inadvisable treatment for anxiety. A number of women who previously have suffered from episodes of a functional psychosis may be on long term neuroleptic treatment as prophylaxis. They may neglect contraceptive measures as a result of the aftereffects of the illness, or of continuing symptoms. Some may present seeking advice as to the wisdom of conceiving. A study of schizophrenic mothers showed that neonatal mortality is twice that of normal controls, ~z which makes assessment of the dangers of neuroleptics more difficult. As most neuroleptics are highly lipid soluble, the original drug and active metabolites may continue to be excreted for some months after ingestion ceased. This is particularly true of the depot preparations, where the drug is esterified and injected in an oily vehicle to delay adsorption. Therefore stopping treatment in such circumstances for someone already pregnant is going to make little difference to the environmen[ of the fetus. Ideally, someone on medication and thinking of becoming pregnant should come off it well before conception. This will show how fragile their well-being is in the drug-free state, as well as minimising exposure of the fetus. As opinion is shifting towards patients being maintained on lower doses of neuroleptic than hitherto, ~3 a careful reduction in dose could be negotiated with the patient and her general practitioner or psychiatrist, but a subsequent need to treat the relapse resulting from an over enthusiastic pursuit of this goal benefits no-one. The puerperium is a time of increased risk of relapse for those who have had a previous schizophrenic or schizoaffective illness, and remaining on medication has some protective effect. Several studies have failed to show a teratogenic effect of neuroleptic drugs, especially with a piperafine substituted phenothiazine, trifluoperazine ('Stelafine'). The innocence of aliphatic phenothiazines such as chlorpromazine ('Largactil') is less certain, with a trend to cardio-vascular malformations. This parallels evidence from the rat, showing neuronal and cerebrovascular malformations, and postpartum behavioural

changes. One study has found that a compound used more for the treatment of hyperemesis, prochlorperazine, ('Stemetil'), is associated with congenital abnormalities, including limb deformities, if taken between the sixth and tenth week of gestation, 14 but this observation requires confirmation since other studies have suggested that prochlorperazine is not teratogenic. Other neuroleptics, such as the butyrophenones, ('Haloperidor) have not been associated with deformities. 15 This may be a function of less intense use, compared to the phenothiazines. There are reports of what appears to be a pseudoparkinsonian reaction in neonates born to mothers taking oral or depot neuroleptic drugs. 16 This includes restlessness, tremor, excessive activity and abnormal movements, and may persist for some weeks. To avoid this, the last dose of depot medication should be given at least one inter-injection interval before the estimated date of delivery (EDD), as the patients clinical state allows; similarly, the dose of oral neuroleptic should be reduced to the minimum one week or 10 days before the EDD. Neuroleptics enter breast milk in clinically insignificant amounts) 7 To summarise, the first trimester should be neuroleptic free for the fetus, but this may be difficult to realise in practice. Prochlorperazine should be absolutely avoided, and chlorpromazine if possible. During the rest of pregnancy, neuroleptics can be given with apparent safety, in as low as possible a dose. By means of a dip in dosage just before delivery, the fetus can be born with as low a burden of neuroleptic as possible. Continued neuroleptic treatment is consistent with breast-feeding. Antidepressants There is a close structural relationship between the tricyclic antidepressants and phenothiazines, and much overlap in their pharmacological effects. Not surprisingly, the information available about safety of use in pregnancy indicates a similar lack of major toxicity. The newer non-tricyclics are a different matter in that their safety in this area is not yet proved. Given that two such drugs have had to be withdrawn because of unexpected toxicity once they came into widespread use, the newer drugs are best avoided in pregnancy. A number of large scale surveillance studies have failed to show any consistent trend for tricyclics to be associated with teratogenic effects. 1s'19 A number of isolated case reports exist, especially of limb deformities. This family of drugs undoubtedly are teratogenic in rodents. There are no grounds on which to exempt antidepressants from the general rule that the first trimester should be drug free. If possible, a patient taking antidepressants longterm to prevent a relapse would withdraw gradually from them before becoming pregnant, which has the additional effect of showing her and her partner how robust is her apparent well-being. If depressive symp-

118 CURRENTOBSTETRICSAND GYNAECOLOGY toms return, all concerned will be in a dilemma. For a patient who has suffered a previous major depressive episode, the risk of a recurrence after a subsequent pregnancy is at least one in ten. 2° If she enters the pregnancy with symptoms or on medication to suppress them, the postpartum period is likely to be difficult, but not so difficult as to prohibit pregnancy. Both patient and partner should receive enough information and counselling to allow them to make a choice. There is a good chance that being on an adequate dose of antidepressant will prevent recurrence postpartum. The availability of other, nonpharmacological, treatments, such as cognitive behaviour therapy should be borne in mind. An episode of depressive illness occurring during pregnancy can be treated quite safely with a tricyclic antidepressant, preferably at the minimum dose consistent with clinical effectiveness. However, it must be remembered that the dose required may range from 25-150 mg of amitriptyline or equivalent, and if there is no response at a lower dose, a larger one has to be tried, if it was worth embarking on antidepressant treatment in the first place. The tertiary compounds, such as amitriptyline or imipramine often cause side-effects such as constipation or postural hypotension. One of the secondary amines, such as nortriptyline or desipramine may be preferable. It is possible for electroconvulsive therapy (ECT) to be given during pregnancy for treatment-resistant cases without undue hazard to the fetus. The important role of support, counselling and more specialised psychotherapy should not be forgotten. Adults accustomed to taking tricycles for some time may show a withdrawal reaction, consisting of malaise, headache and nausea, if they are withdrawn abruptly. For that reason, withdrawal generally takes 2 or 3 weeks. There are reports of neonates born to mothers taking tricyclics until labour suffering withdrawal symptoms, including irritability, apparent abdominal cramps, restlessness, insomnia and fever. One solution is for the tricyclic to be withdrawn over the month prior to the EDD, in order for the drug to clear the fetus gradually.21 The opposing view is that supportive and perhaps resuscitative measures can only be applied postpartumfl z If withdrawal antipartum can be gradual, that is the better option. Sudden withdrawal in the week prior to EDD should be avoided. With regard to the monoamine oxidase inhibitors (MAOI) there is little published evidence of their use in pregnancy. This reflects the ambiguous position they have held in the antidepressant armoury over the past two decades. One study shows an increased risk of malformations.23 More recently, there has been something of a reawakening of interest in their use. New selective MAOI are near to release onto the market. New compounds should not be used in pregnancy. The older MAOI are best avoided, not because of demonstrable toxicity, but because their interaction - with sympathomimetics, beta blockers,

opiates such as pethidine, and with foodstuffs such as cheese - cause a potentially fatal hypertension, and make the anaesthetist's task unenviable, especially if not all goes well. The risk of interaction persists for 10 days after the MAOI is withdrawn, as the enzyme inhibition is irreversible. Another side-effect, hypotension, poses a risk to fetal well-being. Two-thirds of women will experience transiently a self-limiting period of lability of mood postpartum; this is a normal reaction perhaps related to the major hormonal changes taking place. 10-15% will suffer from a depressive disorder, which may be quite difficult to distinguish from the normal adjustment, tiredness, and concerns of the time. 24 A screening questionnaire is sensitive enough to pick up the disorder, which often is amenable to support and counselling. However, antidepressant drugs may be necessary. Tricyclics enter breast milk in detectable amounts, 25 and, although no long term ill-effects have been shown, sometimes behavioural changes can be observed in the infant. If a mother who needs treatment with tricyclics is determined to breast-feed, then compromise may be necessary. Ideally she could be brought to an understanding that it is more important that she is well enough emotionally to give of her best to her child, in terms of overall care, rather than just by lactating. Given the partial loss of insight and heightened emotionality of the time, it may be reasonable for her to continue feeding, with the child under close observation. It may be safe for monoamine oxidase inhibitors to be used at this time, but specialist advice should be sought. To summarise, the continuing ingestion of tricyclic antidepressants and pregnancy are not incompatible, but parturition and lactation are likely to prove problematic. Drugs used in mood disorder

prophylaxis

Those who previously have suffered a major affeetive psychosis or 2 less severe episodes are at sufficiently high risk of relapse to justify being placed on longterm treatment with lithium carbonate or an anticonvulsant, most commonly carbamezepine. Women of child-bearing age should have received advice about contraception. Before conception is attempted it is best that the immediate risk of relapse is assessed by gradual withdrawal of the drug, as both carry an appreciable risk of teratogenesis if consumed in the first trimester. The practitioner has to beware of the patient who bounces into the consulting room full of enthusiasm for an early conception, as the eagerness may be a manifestation of relapse just held in check by the medication. The partner should be involved in the counselling process, as the risk of relapse in the puerperium for a mother with such a past psychiatric history reaches 1 in 5, on no medication. There is an appreciable risk of a rebound illness if lithium is withdrawn abruptlyfl 6 However, in a woman on lithium, suddenly disco-

PSYCHOTROPIC DRUGS IN PREGNANCY vered to be pregnant, the risk o f relapse, (and the likelihood that safer neuroleptics can be used in that eventuality), should be outweighed by the need to protect the fetus, as quickly as possible. Lithium easily crosses the placenta, and serum lithium levels are found to be similar in b o t h m o t h e r and fetus. P o l y h y d r a m n i o s , t h o u g h t to be due to lithium induced diabetes insipidus has been reported. 27 It appears to be teratogenic in l a b o r a t o r y animals. There is g o o d evidence that the use o f lithium in pregnancy is associated ~vith an increased incidence o f perinatal death. 2s Its use in the first trimester is associated particularly ~vith cardiovascular malformations, including Ebstein's a n o m aly. z9 R e c o r d e d in a register o f pregnancies occurring in 225 w o m e n w h o t o o k lithium during pregnancy there were 7 stillbirths and 25 serious congenital malformations, o f which 18 were o f the heart and great vessels. 3° In infants born to m o t h e r s who had been taking lithium, neurological a n d cardiovascular problems predominate; floppiness, less activity and loss o f n o r m a l m o t o r reflexes are seen, and cyanosis, congestive failure, plus irregular action are found. Lithium enters breast milk at a concentration which is half that o f the m o t h e r ' s serum level, a n d lithium can be f o u n d in the infants serum in detectable amounts, up to 50% o f mother's. 3t Given the infant's immature renal function and its vulnerability to dehydration, it is not surprising that toxicity is reported. There is general agreement that lithium ingestion by the m o t h e r is an absolute contraindication to breastfeeding. 23 Maternal relapse with a manic illness in the second and third trimesters is best dealt with by neuroleptic treatment first. I f s y m p t o m s c a n n o t be controlled by the addition o f carbamezepine (see below) to the neuroleptic, and if there is a history o f a previous response to lithium, it m a y be tried as an adjunct. The role o f E C T in manic illness should not be forgotten. In lithium treatment the serum level should be kept to the low end o f the therapeutic w i n d o w (0.5-1.00 mmol/1). It should be checked (12 h after the last dose) not less than m o n t h l y because lithium clearance increases in pregnancy. T h e patient should be well informed a b o u t action to be taken in the event o f vomiting or other fluid losses - stop lithium immediately a n d p h o n e in to report. The dose should be cut one week or two before E D D ; if this seems to have an adverse effect on the m o t h e r ' s mental state then there is the option o f inducing labour earlier. As soon as labour is over there is a pressing need to restart lithium to a therapeutic serum level to forestall any p o s t p a r t u m relapse into psychosis. Because o f the m a j o r changes in maternal fluid balance occurring at this time daily lithium levels are indicated. 3z Carbamezepine offers itself as an alternative to lithium, being almost as effective in manic depressive illness for acute treatment and prevention, for use during pregnancy, and m a y be less h a r m f u l overall. Perhaps because carbamazepine induces its o w n

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catabolism, the fetus can handle it almost as well as the adult. There is no clear therapeutic window for the serum level, but 30meg is an acceptable upper limit, gained usually on a dose o f 4 0 0 - 6 0 0 m g per day. Side effects are minimised by starting on a low dose and building up. C a r b a m a z e p i n e has a role in the m o t h e r at high risk o f relapse and determined to breast-feed.

References

I. Kumar R, Robson IC. Neurotic disturbance during pregnancy and the puerperium. In: Sandier M, ed Mental Illness in pregnancy and the puerperium. Oxford: Oxford University Press, 1979 2. Krauer B, Krauer F, Hytten F. Drug prescribing in pregnancy. Edinburgh Churchill Livingstone, 1984 3. Slone D, Siskind V, Heinomen OP et al. Antenatal exposure to the phenothiazines. A M J Obstet Gynecol 1977; 128: 486-488 4. Kris EB, Children of mothers maintained on pharmacotherapy during pregnancy and post partum. Curt Ther Res 1965; 7:785-799 5. Rosenberg L, Mitchell AA, Parsella JL et al. Lack of relation of oral clefts to diazepam use during pregnancy. N Engl J Med 1983; 309:1282-1285 6. Laegreid L, Olegard R, Conrad Net al. Congenital malformations and maternal consumption of benzodiazepines. Dev Med Cluld Neurol 1990; 32:432-441 7. Tyrer P, Ower R, Dawling S. Gradual withdrawal of diazepam after long term therapy. Lancet 1983 i 1402-1406 8. Kanto JH. The use of benzodiazepines during pregnancy labour and lactation with particular reference to pharmacokinefic considerations. Drugs 1982; 23:354-380 9. Rementeria JL, Bhatt K. Withdrawal symptoms in neonates from intrauterine exposure of diazepam. Pediatr Pharmacol 1977; 90:123-126 I0. Wesson DR, Camber S, Harkey M et al. Diazepam and desmethyldiazepam in breast milk. J Psychoactive Drugs 1985; 17:55-56 I 1. Patrick MJ, Tilstone WJ, Reavey P. Diazepam and breast feeding. Lancet 1972; I: 542-543 12. Rieder RD. The offspring of schizophrenic mothers - fetal and neonatal deaths. Archives of General Psychiatry 1975; 32:200-211 13. Rifkin A, Doddi S, Karajgi Bet al. Dosage ofhaloperidol for schizophrenia. Archives of General Psychiatry 1991; 48: 166-170 14. Edlund MJ, Craig TJ. Antipsychotic drug use and birth defects. Comp Psychiatry 1984; 25:32-37 15. Van Waes A, Van de Velde E. Safety evaluation of haloperidol in the treatment of hyperemesis gravidarum. J Clin Pharmacol 1969; 9:224-227 16. Hill RM, Desmond MM, Kay JI. Extrapyramidal dysfunction in an infant of a schizophrenic mother. J Pediatr 1966; 69:589-595 17. Whalley LJ, Blain PG, Prime JK. Haloperidol secreted in breast milk. Brit Med J 1981; 282:1746-1747 18. Kuenssberg EV, Knox JDE. lmipramine in pregnancy. Brit Med J 1972; 2:292 19. Sanlon FJ. Use of antidepressant drugs during the first trimester. Med J Aust. 1969; 2:1077 20. Kendell RE, Chalmers JC, Platz C. Epidemiology of puerperal psychoses. Brit J Psychiatry 1987; 50:662-673 21. Calabrese JR, Gulledge AD. Psychotropics during pregnancy and lactation. Pscyhosomatics 1985; 413-16, 424-426 22. Mortola JF. The use of psychotropic agents in pregnancy and lactation. Psychiatric Clinics of North America 1989; 1: 69-87 23. Heinoneu OP, Slone D, Shapiro S. Birth defects and drugs in pregnancy. Littleton: Publishing Sciences Group 1977; 336 24 Fox JL, Connor Y, Kendell RE. Prospective study of the psychiatric disorders ofchiMbirth. Brit J Psyciatry 1982; 140: 111-117 25. Brixen-Rasmussen L, Halgrener J, Jorgenson A.

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Amitriptyline and nortriptyline excretion in human breast milk. Psychopharmacology (Berlin) 1982; 76:94-95 26. Mander A, Loudon JB. Rapid recurrence of mania following abrupt discontinuation of lithium. Lancet 1988; ii: 15-17 27. Krause S, Ebbesen F, Lange AP. Polyhdramnios with maternal lithium treatment. Obstet Gynecol 1990; 75:

30. Schou M, Goldfield MD, Weinstein MR et al. Lithium and pregnancy. Brit Med J 1973; 2:1356-1360 31. Tunnessen WW jr, Hertz CG. Toxic effects of lithium in newborn infants. J Pediatr 1972; 81:804-807 32. Mackay AVP, Loose R, Glen AIM. Labour on lithium. Bfit Med J 1976; h 878

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Further reading Briggs GG, Freeman RK, Yaffer SJ. Drugs in pregnancy and lactation (3rd ed). Baltimore, Williams and Wilkins 1990