Drug choice in pregnancy (from The Maudsley and Oxleas Prescribing Guidelines 11 th Edition, 2011)

Transcription

1 Drug choice in pregnancy (from The Maudsley and Oxleas Prescribing Guidelines 11 th Edition, 2011) A normal outcome to pregnancy can never be guaranteed. The spontaneous abortion rate in confirmed early pregnancy is 10 20% and the risk of spontaneous major malformation is 2 3% (approximately 1 in 40 pregnancies) 1. Lifestyle factors have an important influence on pregnancy outcome. It is well established that smoking cigarettes, eating a poor diet and drinking alcohol during pregnancy can have adverse consequences for the foetus. More recent data suggest that moderate maternal caffeine consumption is associated with low birth weight 2, and that pre-pregnancy obesity increases the risk of neural tube defects; (obese women seem to require higher doses of folate supplementation than women who have a BMI in the healthy range 3 ). In addition, psychiatric illness during pregnancy is an independent risk factor for congenital malformations and perinatal mortality 4. Affective illness increases the risk of pre-term delivery 5. Drugs account for a very small proportion of abnormalities (approximately 5% of the total). Potential risks of drugs include major malformation (first-trimester exposure), neonatal toxicity (third-trimester exposure), longer-term neurobehavioural effects.and increased risk of physical health problems in adult life. The safety of psychotropics in pregnancy cannot be clearly established because robust, prospective trials are obviously unethical. Individual decisions on psychotropic use in pregnancy are therefore based, at best on database studies that have many limitations including failure to control for the effects of illness and other medication, prospective data from teratology information centres and published case reports which are known to be biased towards adverse outcomes. At worst there may be no human data at all, only animal data from early preclinical studies. With new drugs early reports of adverse outcomes may or may not be replicated and a best guess assessment must be made of the risks and benefits associated with withdrawal or continuation of drug treatment. Even with established drugs, data related to long-term outcomes are rare. Pregnancy does not protect against mental illness and may even elevate overall risk. The patient s view of risks and benefits will have paramount importance. This section provides a brief summary of the relevant issues and evidence to date. General principles of prescribing in pregnancy In all women of child bearing potential Always discuss the possibility of pregnancy many pregnancies are unplanned Try to avoid using drugs that are contra-indicated during pregnancy in women of reproductive age, (especially valproate and carbamazepine). If these drugs are prescribed, women should be made fully aware of their teratogenic properties even if not planning pregnancy. Consider prescribing folate If mental illness is newly diagnosed in a pregnant woman Try to avoid all drugs in the first trimester (when major organs are being formed) unless benefits outweigh risks If non-drug treatments are not effective/appropriate, use an established drug at the lowest effective dose If a woman taking psychotopic drugs is planning a pregnancy Consideration should be given to discontinuing treatment if the woman is well and at low risk of relapse Discontinuation of treatment for women with SMI and at a high risk of relapse is unwise, but consideration should be given to switching to a low risk drug. Be aware that switching drugs may increase the risk of relapse If a woman taking psychotropic medication discovers that she is pregnant Abrupt discontinuation of treatment post-conception for women with SMI and at a high risk of relapse is unwise; relapse may ultimately be more harmful to the mother and child than continued, effective drug therapy Consider remaining with current (effective) medication rather than switching, to minimise the number of drugs to which the foetus is exposed If the patient smokes (smoking is more common in pregnant women with psychiatric illness) 6 Always encourage switching to nicotine replacement therapy smoking has numerous adverse outcomes, NRT does not 7 In all pregnant women Ensure that the parents are as involved as possible in all decisions Use the lowest effective dose Use the drug with the lowest known risk to mother and foetus Prescribe as few drugs as possible both simultaneously and in sequence Be prepared to adjust doses as pregnancy progresses and drug handling is altered. Dose increases are frequently required in the 3rd trimester 8 when blood volume expands by around 30%. Plasma level monitoring is helpful, where available. Note that hepatic enzyme activity changes markedly during pregnancy; CYP2D6 activity is increased by almost 50% by the end of pregnancy while the activity of CYP1A2 is reduced by up to 70% 9 Consider referral to specialist perinatal services Ensure adequate foetal screening Be aware of potential problems with individual drugs around the time of delivery Inform the obstetric team of psychotropic use and possible complications Monitor the neonate for withdrawal effects after birth Document all decisions

2 What to include in discussions with pregnant women 10 Discussions should include: the woman s ability to cope with untreated illness/sub-threshold symptoms the potential impact of an untreated mental disorder on the fetus or infant the risks from stopping medication abruptly severity of previous episodes, response to treatment and the woman s preference the background risk of foetal malformations for pregnant women without a mental disorder the increased risk of harm associated with drug treatments during pregnancy and the postnatal period, including the risk in overdose (and acknowledge uncertainty surrounding risks) the possibility that stopping a drug with known teratogenic risk after pregnancy is confirmed may not remove the risk of malformations Where possible, written material should be provided to explain the risks (preferably individualised). Absolute and relative risks should be discussed. Risks should be described using natural frequencies rather than percentages (for example, 1 in 10 rather than 10%) and common denominators (for example, 1 in 100 and 25 in 100, rather than 1 in 100 and 1 in 4) Psychosis during pregnancy and postpartum Pregnancy does not protect against relapse Psychiatric illness during pregnancy predicts post-partum psychosis 11 The risk of perinatal psychosis is % in the general population, but is about 50% in women with a history of bipolar disorder During the month after childbirth there is a 20-fold increase (to 30-50%) in the relative risk of psychosis The risk of recurrent post-partum psychosis is 50 90% The mental health of the mother in the perinatal period influences foetal well-being, obstetric outcome and child development The risks of not treating psychosis include: harm to the mother through poor self-care or judgement, lack of obstetric care or impulsive acts harm to the foetus or neonate (ranging from neglect to infanticide) 12 It has long been established that people with schizophrenia are more likely to have minor physical anomalies than the general population 13. Some of these anomalies may be apparent at birth 4, while others are more subtle and may not be obvious until later in life. This background risk complicates assessment of the effects of antipsychotic drugs 14. (Psychiatric illness itself during pregnancy is an independent risk factor for congenital malformations and perinatal mortality 4 ). Treatment with antipsychotics Older, first generation antipsychotics are generally considered to have minimal risk of teratogenicity14,16, although data are less than convincing, as might be expected. Most data originate from studies that included primarily women with hyperemesis gravidarum (a condition associated with an increased risk of congenital malformations) treated with low doses of phenothiazines 14. The modest increase in risk identified in some of these studies, along with no clear clustering of congenital abnormalities suggest that the condition being treated may be responsible rather than drug treatment 17 There may be an association between haloperidol and limb defects, but if real, the risk is likely to be extremely low 14,16 Neonatal dyskinesia has been reported with FGAs 18 Neonatal jaundice has been reported with phenothiazines 14 It remains uncertain whether FGAs are entirely without risk to the foetus or to later development14, 19. However, this continued uncertainty and the wide use of these drugs over several decades suggest that any risk is small an assumption borne out by most studies 14. Data relating to second generation antipsychotics are growing. The extent of placental passage is highest for olanzapine followed by risperidone followed by quetiapine 20 There are most data for olanzapine which has been associated with both lower birth weight and increased risk of intensive care admission 17, and with macrosomia 21 ; the last of these is consistent with the reported increase in the risk of gestational diabetes 14,,23. Although olanzapine seems to be relatively safe with respect to congenital malformations, it has been associated with a range of problems including hip dysplasia 24, meningocele, ankyloblepharon 25, and neural tube defects 14 ; (an effect that could be related to prepregnancy obesity rather than drug exposure 2 ). Importantly there is no clustering of congenital malformations Limited data suggest that neither risperidone 14,23,26-28, nor quetiapine 23 are major teratogens in humans. There are virtually no published data relating to other SGAs 14 The use of clozapine appears to present no increased risk of malformation, although gestational diabetes and neonatal seizures may be more likely to occur 22. There is a single case report of maternal overdose resulting in foetal death 14 and there are theoretical concerns about the risk of agranulocytosis in the foetus/neonate 14. NICE recommends that pregnant women should be switched from clozapine to another antipsychotic 10. However, for almost all women who are prescribed clozapine, a switch to a different antipsychotic will result in relapse. On the balance of evidence available, clozapine should usually be continued. Overall, these data do not allow an assessment of relative risks associated with different agents and certainly do not confirm absolutely the safety of any particular drug. At least one study has suggested a small increased risk of malformation and caesarean section in people receiving antipsychotics 17. Older drugs may still be preferred in pregnancy, but, considering data available on some newer drugs, it may not now always be appropriate always to switch to these first generation drugs, should continued treatment be necessary. As with other drugs, decisions must be based on the latest available information and an individualised assessment of probable risks and benefits. If possible, specialist advice should be sought, and primary reference sources consulted.

3 Recommendations psychosis in pregnancy Patients with a history of psychosis who are maintained on antipsychotic medication should be advised to discuss a planned pregnancy as early as possible Be aware that drug-induced hyperprolactinaemia may prevent pregnancy. Consider switching to alternative drug Such patients, particularly if they have suffered repeated relapses, are best maintained on antipsychotics during and after pregnancy. This may minimise foetal exposure by avoiding the need for higher doses, and/or multiple drugs should relapse occur There is most experience with chlorpromazine (constipation and sedation can be a problem), trifluoperazine, haloperidol, olanzapine and clozapine (gestational diabetes may be a problem with both SGAs). If the patient is established on another antipsychotic, the most up-to-date advice should always be obtained. Experience with other drugs is growing and a change in treatment may not be necessary or wise NICE recommends avoiding depot preparations and anticholinergic drugs in pregnancy A few authorities recommend discontinuation of antipsychotics 5 10 days before anticipated delivery to minimise the chances of neonatal effects. This may, however, put mother and infant at risk and needs to be considered carefully. Antipsychotic discontinuation symptoms can occur in the neonate (e.g. crying, agitation, increased suckling). Some centres used mixed (breast/bottle) feeding to minimise withdrawal. With SGAs, discontinuation may not be necessary or desirable Depression during pregnancy and postpartum 29,30 (B,C) Approximately 10% of pregnant women develop a depressive illness and a further 16% a self-limiting depressive reaction. Much postpartum depression begins before birth Risk may be at least partially genetically determined There is a significant increase in new psychiatric episodes in the first 3 months after delivery. At least 80% are mood disorders, primarily depression Women who have had a previous episode of depressive illness (postpartum or not) are at higher risk of further episodes during pregnancy and post-partum. The risk is highest in women with bipolar illness It is unclear if depression increases the risk of spontaneous abortion, having a low birth weight or small for gestational age baby, or of pre-term delivery (D)The mental health of the mother influences foetal well-being, obstetric outcome and child development The risks of not treating depression include: harm to the mother through poor self-care, lack of obstetric care or self-harm harm to the foetus or neonate (ranging from neglect to infanticide) Treatment with antidepressants The use of antidepressants during pregnancy is common; in the Netherlands, up to 2% of women are prescribed antidepressants during the first trimester 32, and in the US around 10% of women are prescribed antidepressants at some point during their pregnancy 33 (D), and this rate is increasing (F). The majority of prescriptions are for SSRIs. Relapse rates are high in those with a history of depression who discontinue medication. One study found that 68% of women who were well on antidepressant treatment and stopped during pregnancy relapsed, compared with 26% who continued antidepressants 30. Some data suggest that antidepressants may increase the risk of spontaneous abortion (but note that confounding factors were not controlled for) (D,E). Antidepressants may also increase the risk of preterm delivery, respiratory distress in the neonate, a low APGAR score at birth and admission to a special care baby unit (D,G,H,I). Some antidepressants have been associated with specific congenital malformations, many of which are rare. Most of these potential associations remain unreplicated (D). There are conflicting data on the issue of the influence of duration of antidepressant use 34,35. The effects on neurodevelopment are poorly studied. Tricyclic antidepressants Foetal exposure to tricyclics (via umbilicus and amniotic fluid) is high 36,37 TCAs have been widely used throughout pregnancy without apparent detriment to the foetus 38,39 and have for many years been agents of choice in pregnancy Limited data suggest in utero exposure to tricyclics has no effects on later development 40,41 Some authorities recommend the use of nortriptyline and desipramine (not available in the UK) because these drugs are less anticholinergic and hypotensive than amitriptyline and imipramine (respectively, their tertiary amine parent molecules) TCA use during pregnancy increases the risk of pre-term delivery 38,39,42 Use of TCAs in the third trimester is well known to produce neonatal withdrawal effects; agitation, irritability, seizures, respiratory distress and endocrine and metabolic disturbances 38. These are usually mild and self-limiting Little is known of the developmental effects of prenatal exposure to tricyclics, although one small study detected no adverse consequences 40 SSRIs Sertraline appears to result in the least placental exposure 43 SSRIs appear not to be major teratogens 35,38, with most data supporting the safety of fluoxetine 40, Note though that one study revealed a slight overall increase in rate of malformation with SSRIs 48. Database and case control studies have reported an association between SSRIs and anencephaly, craniosynostosis, omphalocele, and persistent pulmonary hypertension of the newborn 49,50. These associations have not been replicated Paroxetine has been specifically associated with cardiac malformations 51 particularly after high dose (> 25mg/day), first trimester exposure 52. However some studies have failed to replicate this finding for paroxetine 38,53, and have implicated other SSRIs 54,55. Other studies have found no association between any SSRI and an increased risk of cardiac septal defects 50 SSRIs have also been associated with decreased gestational age (mean 1 week), spontaneous abortion 56 and decrease birth weight (mean 175 g) 44,45,57. The longer the duration of in-utero exposure, the greater the chance of low birth weight and respiratory distress 34 ; Three groups of symptoms are seen in neonates exposed to antidepressants in late pregnancy; those associated with serotonergic toxicity, those associated with antidepressant discontinuation symptoms and those related to early birth 59. Thirdtrimester exposure to sertraline has been associated with reduced early APGAR scores 44. Third-trimester use of paroxetine may give

4 rise to neonatal complications, presumably related to abrupt withdrawal 60,61. Other SSRIs have similar, possibly less severe effects 61,62 Data relating to neurodevelopmental outcome of foetal exposure to SSRIs suggest that these drugs are safe, although data are less 40,41,63,64. Depression itself may have more obvious adverse effects on development40 than conclusive Although associated with an increased risk of bleeding overall, SSRIs do not seem to confer a disproportionate risk of postpartum haemorrhage 65 Other antidepressants Rather more scarce data suggest the absence of teratogenic potential with mocobemide 66, reboxetine 67 and venlafaxine (although neonatal withdrawal may occur) 45,68,69, Second trimester exposure to venlafaxine has been associated with babies being born small for gestational age (I). None of these drugs can be specifically recommended. Similarly, trazodone, bupropion (amfebutamone) and mirtazapine cannot be recommended because there are few data supporting their safety 45,70,71. Recent data suggest that both bupropion and mirtazapine are not associated with malformations but, like SSRIs, may be linked to an increased rate of spontaneous abortion 72,73 Bupropion exposure in-utero has been associated with an increased risk of ADHD in young children (J). MAOIs should be avoided in pregnancy because of a suspected increased risk of congenital malformation and because of the risk of hypertensive crisis 74 There is no evidence to suggest that ECT causes harm to either the mother or foetus during pregnancy 75 although general anaesthesia is of course not without risks. In resistant depression, NICE recommend that ECT is used before/instead of drug combinations Omega-3 fatty acids may also be a treatment option 76 although efficacy and safety data are scant Recommendations depression in pregnancy Patients who are already receiving antidepressants and are at high risk of relapse are best maintained on antidepressants during and after pregnancy Those who develop a moderate or severe depressive illness during pregnancy should be treated with antidepressant drugs There is most experience with amitriptyline, imipramine (constipation and sedation can be a problem with both; withdrawal symptoms may occur) and fluoxetine (increased chance of earlier delivery and reduced birth weight). If the patient is established on another antidepressant, always obtain the most up-to-date advice. Experience with other drugs is growing and a change in treatment may not be necessary or wise. Paroxetine may be less safe than other SSRIs The neonate may experience discontinuation symptoms such as agitation and irritability, or even convulsions (with SSRIs). The risk is assumed to be particularly high with short half-life drugs such as paroxetine and venlafaxine. Continuing to breast feed and then weaning by switching to mixed (breast/bottle) feeding may help reduce the severity of reactions When taken in late pregnancy, SSRIs may increase the risk of persistent pulmonary hypertension of the new-born Bipolar illness during pregnancy and postpartum The risk of relapse during pregnancy if mood stabilising medication is discontinued is high; one study found that bipolar women who were euthymic at conception and discontinued mood stabilisers were twice as likely to relapse and spent 5 times as long in relapse ill than women who continued mood stabilisers 77 The risk of relapse after delivery is hugely increased: up to eight-fold in the first month post-partum The mental health of the mother influences foetal well-being, obstetric outcome and child development The risks of not stabilising mood include: harm to the mother through poor self-care, lack of obstetric care or self-harm harm to the foetus or neonate (ranging from neglect to infanticide) Treatment with mood-stabilisers Lithium completely equilibrates across the placenta 78 Although the overall risk of major malformations in infants exposed in-utero has probably been overestimated, lithium should be avoided in pregnancy if possible. Slow discontinuation before conception is the preferred course of action 22,79 because abrupt discontinuation is suspected of worsening the risk of relapse. The relapse rate post-partum may be as high as 70% in women who discontinued lithium before conception 80. If discontinuation is unsuccessful during pregnancy restart and continue Lithium use during pregnancy has a well-known association with the cardiac malformation Ebstein s anomoly (relative risk is times more than control, but the absolute risk is low at 1:1000) 81. The period of maximum risk to the foetus is 2 6 weeks after conception 82, before many women know that they are pregnant. The risk of atrial and ventricular septal defects may also be increased 17 If lithium is continued during pregnancy, high-resolution ultrasound and echocardiography should be performed at 6 and 18 weeks of gestation In the third trimester, the use of lithium may be problematic because of changing pharmacokinetics: an increasing dose of lithium is required to maintain the lithium level during pregnancy as total body water increases, but the requirements return abruptly to prepregnancy levels immediately after delivery 83. Lithium plasma levels should be monitored every month during pregnancy and immediately after birth. Women taking lithium should deliver in hospital where fluid balance can be monitored and maintained Neonatal goitre, hypotonia, lethargy and cardiac arrhythmia can occur Most data relating to carbamazepine and valproate come from studies in epilepsy, a condition associated with increased neonatal malformation. These data may not be precisely relevant to use in mental illness. Both carbamazepine and valproate have a clear causal link with increased risk of a variety of foetal abnormalities, particularly spina bifida 84. Both drugs should be avoided, if possible, and an antipsychotic prescribed instead. Valproate confers a higher risk than carbamazapine 85,86. Although 1 in 20 women of child bearing age who are in long term contact with mental health services are prescribed mood stabilising drugs, awareness of the teratogenic potential of these drugs amongst psychiatrists is low 84

5 Valproate monotherapy has also been associated with an increased relative risk of atrial septal defects, cleft palate, hypospadias, polydactyly and craniosynostosis, although absolute risks are low (K). Where continued use of valproate or carbamazepine is deemed essential, low-dose monotherapy is strongly recommended, as the teratogenic effect is probably dose-related 87,88. NICE recommends that the dose of valproate should be limited to 1000mg a day Vulnerability to valproate-induced neural tube defects may be genetically determined via genes that code for folate metabolism/handling 89 Ideally, all patients should take folic acid (5 mg daily) for at least a month before conception (this may reduce the risk of neonatal neural tube defects). Note, however, that some authorities recommend a lower dose 90, presumably because of a risk of twin births 91 Use of carbamazepine in the third trimester may necessitate maternal vitamin K Data for lamotrigine suggest a low risk of foetal malformations when used as monotherapy 90,92,93 although a substantially increased risk of cleft palate has been reported 94. Clearance of lamotrigine seems to increase radically during pregnancy 95. NICE suggest that lamotrigine should not be routinely prescribed in pregnancy Recommendations bipolar disorder in pregnancy For women who have had a long period without relapse, the possibility of switching to a safer drug (antipsychotic) or withdrawing treatment completely before conception and for at least the first trimester should be considered The risk of relapse both pre- and post-partum is very high if medication is discontinued abruptly. Women with severe illness or who are known to relapse quickly after discontinuation of a mood-stabiliser should be advised to continue their medication following discussion of the risks No mood-stabiliser is clearly safe. Women prescribed lithium should undergo level 2 ultrasound of the foetus at 6 and 18 weeks gestation to screen for Ebstein s anomaly. Those prescribed valproate or carbamazepine (both teratogenic) should receive prophylactic folic acid to reduce the incidence of neural tube defects, and receive appropriate antenatal screening tests If carbamazepine is used, prophylactic vitamin K should be administered to the mother and neonate after delivery Valproate (the most teratogenic) and combinations of mood-stabilisers should be avoided Lamotrigine may be associated with cleft palate NICE recommends the use of mood-stabilising antipsychotics as a preferable alternative to continuation with a mood-stabiliser In acute mania in pregnancy use an antipsychotic and if ineffective consider ECT In bipolar depression during pregnancy use CBT for moderate depression and an SSRI for more severe depression Epilepsy during pregnancy and post-partum In pregnant women with epilepsy, there is an increased risk of maternal complications such as severe morning sickness, eclampsia, vaginal bleeding and premature labour. Women should get as much sleep and rest as possible and comply with medication (if prescribed) in order to minimise the risk of seizures The risk of having a child with minor malformations may be increased regardless of treatment with antiepileptic drugs (AEDs) The risks of not treating epilepsy are as follows: If seizures are inadequately controlled, there is an increased risk of accidents resulting in foetal injury. Post-partum the mother may be less able to look after herself and her child The risk of seizures during delivery is 1 2%, potentially worsening maternal and neonatal mortality Treatment with anticonvulsant drugs It is established that treatment with anticonvulsant drugs increases the risk of having a child with major congenital malformation to two- to three-fold that seen in the general population. Congenital heart defects (1.8%) and facial clefts (1.7%) are the most common congenital malformations. Both carbamazepine and valproate are associated with a hugely increased incidence of spina bifida at 0.5 1% and 1 2%, respectively. The risk of other neural tube defects is also increased. In women with epilepsy, the risk of foetal malformations with carbamazepine is 2.3%; with lamotrigine, 3%; and with valproate, 7.2% 96, possibly even higher 86,88. Higher doses (particularly doses of valproate exceeding 1000 mg/day) and anticonvulsant polypharmacy are particularly problematic 88,97. Cognitive deficits have been reported in older children who have been exposed to valproate in utero (L). Those exposed to carbamazepine may not be similarly disadvantaged 98. Early data with lamotrigine 92,99 and oxcarbazepine 100 suggest a relatively lower risk of malformation, but confirmation is required (and note risk of cleft palate with lamotrigine 94 ). Pharmacokinetics change during pregnancy, and there is marked inter-individual variation 101. Dosage adjustment may be required to keep the patient seizure-free 102. Serum levels usually return to pre-pregnancy levels within a month of delivery often much more rapidly. Doses may need to be reduced at this point. Best practice guidelines recommend that a woman should receive the lowest possible dose of a single anticonvulsant. Recommendations epilepsy in pregnancy For women who have been seizure free for a long period, the possibility of withdrawing treatment before conception and for at least the first trimester should be considered No anticonvulsant is clearly safer. Valproate should be avoided if possible. Women prescribed valproate or carbamazepine should receive prophylactic folic acid to reduce the risk of neural tube defects. Prophylactic vitamin K should be administered to the mother and neonate after delivery Valproate and combinations of anticonvulsants should be avoided if possible All women with epilepsy should have a full discussion with their neurologist to quantify the risks and benefits of continuing anticonvulsant drugs during pregnancy

6 Sedatives Anxiety disorders and insomnia are commonly seen in pregnancy 103. Preferred treatments are CBT and sleep-hygiene measures respectively. First-trimester exposure to benzodiazepines has been associated with an increased risk of oral clefts in new-borns 104, although two recent studies have failed to confirm this association 105 (M ref to follow hopefully in press). Benzodiazepines have been associated with pylorostenosis and alimentary tract atresia 105 ; replication of these findings is required There is an association between benzodiazepine use in pregnancy, low birth weight and pre-term delivery 105 (G) Third-trimester use is commonly associated with neonatal difficulties (floppy baby syndrome) 106 Promethazine has been used in hyperemesis gravidarum and appears not to be teratogenic, although data are limited NICE recommends the use of low dose chlorpromazine or amitriptyline Rapid tranquillisation There is almost no published information on the use of rapid tranquillisation in pregnant women. The acute use of short-acting benzodiazepines such as lorazepam and of the sedative antihistamine promethazine is unlikely to be harmful. Presumably, the use of either drug will be problematic immediately before birth. NICE also recommends the use of an antipsychotic but do not specify a particular drug 10. Note that antipsychotics are not generally recommended as a first line treatment for managing acute behavioural disturbance (see section on acute behavioural disturbance) Recommendations psychotropics in pregnancy Psychotropic group Antidepressants Antipsychotics Mood-stabilisers Sedatives Recommendations Nortriptyline Amitriptyline Imipramine Fluoxetine FGAs have been widely used, although safety is not fully established. Most experience with chlorpromazine, haloperidol and trifluoperazine. No clear evidence that any antipsychotic is a major teratogen, although data for SGAs other than olanzapine and clozapine are scarce Screen for adverse metabolic effects. Consider using an antipsychotic as a mood stabiliser rather than an anticonvulsant drug Avoid anticonvulsants unless risks and consequences of relapse outweigh the known risk of teratogenesis. Women of childbearing potential taking carbamazepine or valproate should receive prophylactic folic acid. Avoid valproate and combinations where possible Non drug measures are preferred. Benzodiazepines are probably not teratogenic but are best avoided in late pregnancy. Promethazine is widely used but supporting safety data are scarce

7 References 1. McElhatton PR. Pregnancy: (2) General principles of drug use in pregnancy. Pharm J 2003; 270: CARE Study Group. Maternal caffeine intake during pregnancy and risk of fetal growth restriction: a large prospective observational study. BMJ 2008; 337:a Rasmussen SA et al. Maternal obesity and risk of neural tube defects: a metaanalysis. Am J Obstet Gynecol 2008; 198: Schneid-Kofman N et al. Psychiatric illness and adverse pregnancy outcome. Int J Gynaecol Obstet 2008; 101: MacCabe JH et al. Adverse pregnancy outcomes in mothers with affective psychosis. Bipolar Disord 2007; 9: Goodwin RD et al. Mental disorders and nicotine dependence among pregnant women in the United States. Obstet Gynecol 2007; 109: Tobacco Advisory group of the Royal College of Physicians. Harm reduction in nicotine addiction. Helping people who can't quit Sit DK et al. Changes in antidepressant metabolism and dosing across pregnancy and early postpartum. J Clin Psychiatry 2008; 69: Ter Horst PG et al. Pharmacological aspects of neonatal antidepressant withdrawal. Obstet Gynecol Surv 2008; 63: National Institute for Clinical Excellence. Antenatal and postnatal mental health. Clinical management and service guidance (reissued April 2007) Harlow BL et al. Incidence of hospitalization for postpartum psychotic and bipolar episodes in women with and without prior prepregnancy or prenatal psychiatric hospitalizations. Arch Gen Psychiatry 2007; 64: Spinelli MG. A systematic investigation of 16 cases of neonaticide. Am J Psychiatry 2001; 158: Ismail B et al. Minor physical anomalies in schizophrenic patients and their siblings. Am J Psychiatry 1998; 155: Gentile S. Antipsychotic therapy during early and late pregnancy. A systematic review. Schizophr Bull 2008;2010,36; <delete> 16. Diav-Citrin O et al. Safety of haloperidol and penfluridol in pregnancy: a multicenter, prospective, controlled study. J Clin Psychiatry 2005; 66: Reis M et al. Maternal use of antipsychotics in early pregnancy and delivery outcome. J Clin Psychopharmacol 2008; 28: Collins KO et al. Maternal haloperidol therapy associated with dyskinesia in a newborn. Am J Health Syst Pharm 2003; 60: <delete> 20. Newport DJ et al. Atypical antipsychotic administration during late pregnancy: placental passage and obstetrical outcomes. Am J Psychiatry 2007; 164: Newham JJ et al. Birth weight of infants after maternal exposure to typical and atypical antipsychotics: prospective comparison study. Br J Psychiatry 2008; 192: <delete> 23. McKenna K et al. Pregnancy outcome of women using atypical antipsychotic drugs: a prospective comparative study. J Clin Psychiatry 2005; 66: Spyropoulou AC et al. Hip dysplasia following a case of olanzapine exposed pregnancy: a questionable association. Arch Womens Ment Health 2006; 9: Arora M et al. Meningocele and ankyloblepharon following in utero exposure to olanzapine. Eur Psychiatry 2006; 21: Ratnayake T et al. No complications with risperidone treatment before and throughout pregnancy and during the nursing period. J Clin Psychiatry 2002; 63: Dabbert D et al. Follow-up of a pregnancy with risperidone microspheres. Pharmacopsychiatry 2006; 39: Kim SW et al. Use of long-acting injectable risperidone before and throughout pregnancy in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: <delete> 30. Cohen LS et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA 2006; 295: <delete> 32. Ververs T et al. Prevalence and patterns of antidepressant drug use during pregnancy. Eur J Clin Pharmacol 2006; 62: Andrade SE et al. Use of antidepressant medications during pregnancy: a multisite study. Am J Obstet Gynecol 2008; 198: Oberlander TF et al. Effects of timing and duration of gestational exposure to serotonin reuptake inhibitor antidepressants: population-based study. Br J Psychiatry 2008; 192: Ramos E et al. Duration of antidepressant use during pregnancy and risk of major congenital malformations. Br J Psychiatry 2008; 192: Loughhead AM et al. Placental passage of tricyclic antidepressants. Biol Psychiatry 2006; 59: Loughhead AM et al. Antidepressants in amniotic fluid: another route of fetal exposure. Am J Psychiatry 2006; 163: Davis RL et al. Risks of congenital malformations and perinatal events among infants exposed to antidepressant medications during pregnancy. Pharmacoepidemiol Drug Saf 2007; 16: Kallen B. Neonate characteristics after maternal use of antidepressants in late pregnancy. Arch Pediatr Adolesc Med 2004; 158: Nulman I et al. Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: a prospective, controlled study. Am J Psychiatry 2002; 159: Nulman I et al. Neurodevelopment of children exposed in utero to antidepressant drugs. N Engl J Med 1997; 336: Maschi S et al. Neonatal outcome following pregnancy exposure to antidepressants: a prospective controlled cohort study. BJOG 2008; 115: Hendrick V et al. Placental passage of antidepressant medications. Am J Psychiatry 2003; 160: Hallberg P et al. The use of selective serotonin reuptake inhibitors during pregnancy and breast-feeding: a review and clinical aspects. J Clin Psychopharmacol 2005; 25: Gentile S. The safety of newer antidepressants in pregnancy and breastfeeding. Drug Saf 2005; 28: Kallen BA et al. Maternal use of selective serotonin re-uptake inhibitors in early pregnancy and infant congenital malformations. Birth Defects Res A Clin Mol Teratol Einarson TR et al. Newer antidepressants in pregnancy and rates of major malformations: a meta-analysis of prospective comparative studies. Pharmacoepidemiol Drug Saf 2005; 14: Wogelius P et al. Maternal use of selective serotonin reuptake inhibitors and risk of congenital malformations. Epidemiology 2006; 17: Chambers CD et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med 2006; 354: Alwan S et al. Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med 2007; 356: Thormahlen GM. Paroxetine use during pregnancy: is it safe? Ann Pharmacother 2006; 40:

8 52. Berard A et al. First trimester exposure to paroxetine and risk of cardiac malformations in infants: the importance of dosage. Birth Defects Res B Dev Reprod Toxicol Einarson A et al. Evaluation of the risk of congenital cardiovascular defects associated with use of paroxetine during pregnancy. Am J Psychiatry 2008; 165: Diav-Citrin O et al. Paroxetine and fluoxetine in pregnancy: a prospective, multicentre, controlled, observational study. Br J Clin Pharmacol 2008; 66: Louik C et al. First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med 2007; 356: Hemels ME et al. Antidepressant use during pregnancy and the rates of spontaneous abortions: a meta-analysis. Ann Pharmacother 2005; 39: Oberlander TF et al. Neonatal outcomes after prenatal exposure to selective serotonin reuptake inhibitor antidepressants and maternal depression using population-based linked health data. Arch Gen Psychiatry 2006; 63: Suri R et al. Effects of antenatal depression and antidepressant treatment on gestational age at birth and risk of preterm birth. Am J Psychiatry 2007; 164: Boucher N et al. A new look at the neonate's clinical presentation after in utero exposure to antidepressants in late pregnancy. J Clin Psychopharmacol 2008; 28: Haddad PM et al. Neonatal symptoms following maternal paroxetine treatment: serotonin toxicity or paroxetine discontinuation syndrome? J Psychopharmacol 2005; 19: Sanz EJ et al. Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome: a database analysis. Lancet 2005; 365: Koren G. Discontinuation syndrome following late pregnancy exposure to antidepressants. Arch Pediatr Adolesc Med 2004; 158: Gentile S. SSRIs in pregnancy and lactation: emphasis on neurodevelopmental outcome. CNS Drugs 2005; 19: Casper RC et al. Follow-up of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy. J Pediatr 2003; 142: Salkeld E et al. The risk of postpartum hemorrhage with selective serotonin reuptake inhibitors and other antidepressants. J Clin Psychopharmacol 2008; 28: Rybakowski JK. Moclobemide in pregnancy. Pharmacopsychiatry 2001; 34: Pharmacia Ltd. Erdronax: Use on pregnancy, renally and hepatically impaired patients. Personal Communication Einarson A et al. Pregnancy outcome following gestational exposure to venlafaxine: a multicenter prospective controlled study. Am J Psychiatry 2001; 158: Ferreira E et al. Effects of selective serotonin reuptake inhibitors and venlafaxine during pregnancy in term and preterm neonates. Pediatrics 2007; 119: Einarson A et al. A multicentre prospective controlled study to determine the safety of trazodone and nefazodone use during pregnancy. Can J Psychiatry 2003; 48: Rohde A et al. Mirtazapine (Remergil) for treatment resistant hyperemesis gravidarum: rescue of a twin pregnancy. Arch Gynecol Obstet 2003; 268: Djulus J et al. Exposure to mirtazapine during pregnancy: a prospective, comparative study of birth outcomes. J Clin Psychiatry 2006; 67: Cole JA et al. Bupropion in pregnancy and the prevalence of congenital malformations. Pharmacoepidemiol Drug Saf 2007; 16: Hendrick V et al. Management of major depression during pregnancy. Am J Psychiatry 2002; 159: Miller LJ. Use of electroconvulsive therapy during pregnancy. Hosp Community Psychiatry 1994; 45: Freeman MP et al. An open trial of Omega-3 fatty acids for depression in pregnancy. Acta Neuropsychiatr 2006; 18: Viguera AC et al. Risk of recurrence in women with bipolar disorder during pregnancy: prospective study of mood stabilizer discontinuation. Am J Psychiatry 2007; 164: Newport DJ et al. Lithium placental passage and obstetrical outcome: implications for clinical management during late pregnancy. Am J Psychiatry 2005; 162: Dodd S et al. The pharmacology of bipolar disorder during pregnancy and breastfeeding. Expert Opin Drug Saf 2004; 3: Viguera AC et al. Risk of recurrence of bipolar disorder in pregnant and nonpregnant women after discontinuing lithium maintenance. Am J Psychiatry 2000; 157: Cohen LS et al. A reevaluation of risk of in utero exposure to lithium. JAMA 1994; 271: Yonkers KA et al. Lithium during pregnancy: drug effects and therapeutic implications. CNS Drugs 1998; 4: Blake LD et al. Lithium toxicity and the parturient: case report and literature review. Int J Obstet Anesth 2008; 17: James L et al. Informing patients of the teratogenic potential of mood stabilising drugs; a case notes review of the practice of psychiatrists. J Psychopharmacol 2007; 21: Wide K et al. Major malformations in infants exposed to antiepileptic drugs in utero, with emphasis on carbamazepine and valproic acid: a nation-wide, population-based register study. Acta Paediatr 2004; 93: Wyszynski DF et al. Increased rate of major malformations in offspring exposed to valproate during pregnancy. Neurology 2005; 64: Vajda FJ et al. Critical relationship between sodium valproate dose and human teratogenicity: results of the Australian register of anti-epileptic drugs in pregnancy. J Clin Neurosci 2004; 11: Vajda FJ et al. Maternal valproate dosage and foetal malformations. Acta Neurol Scand 2005; 112: Duncan S. Teratogenesis of sodium valproate. Curr Opin Neurol 2007; 20: Yonkers KA et al. Management of bipolar disorder during pregnancy and the postpartum period. Am J Psychiatry 2004; 161: Czeizel AE. Folic acid and the prevention of neural-tube defects. N Engl J Med 2004; 350: Sabers A et al. Epilepsy and pregnancy: lamotrigine as main drug used. Acta Neurol Scand 2004; 109: Cunnington M et al. Lamotrigine and the risk of malformations in pregnancy. Neurology 2005; 64: Holmes LB et al. Increased risk for non-syndromic cleft palate among infants exposed to lamotrigine during pregnancy. Birth Defects Research 2006; 76: de Haan GJ et al. Gestation-induced changes in lamotrigine pharmacokinetics: a monotherapy study. Neurology 2004; 63: National Institute of Clinical Excellence. The clinical effectiveness and cost effectiveness of newer drugs for epilepsy in adults. Technology Appraisal Vajda FJ et al. The Australian Register of Antiepileptic Drugs in Pregnancy: the first 1002 pregnancies. Aust N Z J Obstet Gynaecol 2007; 47: Gaily E et al. Normal intelligence in children with prenatal exposure to carbamazepine. Neurology 2004; 62: Vajda FJ et al. The Australian registry of anti-epileptic drugs in pregnancy: experience after 30 months. J Clin Neurosci 2003; 10: Meischenguiser R et al. Oxcarbazepine in pregnancy: clinical experience in Argentina. Epilepsy Behav 2004; 5:

9 101. Brodtkorb E et al. Seizure control and pharmacokinetics of antiepileptic drugs in pregnant women with epilepsy. Seizure 2008; 17: Adab N. Therapeutic monitoring of antiepileptic drugs during pregnancy and in the postpartum period: is it useful? CNS Drugs 2006; 20: Ross LE et al. Anxiety disorders during pregnancy and the postpartum period: A systematic review. J Clin Psychiatry 2006; 67: Dolovich LR et al. Benzodiazepine use in pregnancy and major malformations or oral cleft: meta-analysis of cohort and case-control studies. BMJ 1998; 317: Wikner BN et al. Use of benzodiazepines and benzodiazepine receptor agonists during pregnancy: neonatal outcome and congenital malformations. Pharmacoepidemiol Drug Saf 2007; 16: McElhatton PR. The effects of benzodiazepine use during pregnancy and lactation. Reprod Toxicol 1994; 8: Further reading NICE guidance (reissued April 2007) Paton C. Prescribing in pregnancy. Br J Psychiatry 2008; 192: Sanz EJ et al. Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome: a database analysis. Lancet 2005; 365: Ruchkin V et al. SSRIs and the developing brain. Lancet 2005; 365: Other sources of information National Teratology Information Service. New References (B) Munk-Olson T et al. New parents and mental disorders: a population based register study. JAMA 2006,296; (C) Mahon PB et al. Genome-wide linkage and follow-up association study of postpartum mood symptoms. Am J Psychiatry 2009,166; (D) Yonkers KA et al. The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. General Hospital Psychiatry 2009,31; (E) Nakhai-Pour HR et al. Use of antidepressants during pregnancy and the risk of spontaneous abortion. CMAJ 2010, doi10:1503/cmaj (F) Alwan S et al. Patterns of antidepressant medication use among pregnant women in a United States population. Journal of Clinical Pharmacology 2010, doi: / (G) Calderon-Margalit R et al. Risk of preterm delivery and other adverse perinatal outcomes in relation to maternal use of psychotropic medications during pregnancy. Am J Obstetrics and Gynecology 2009,201;579.e1-8 (H) Lund N et al. Selective serotonin reuptake inhibitor exposure in utero and pregnancy outcomes. Arch Paediatr Adolesc Med 2009,163; (I) Ramos E et al. Association between antidepressant use during pregnancy and infants born small for gestational age. Canadian Journal of Psychiatry 2010,55; (J) Figueroa R. Use of antidepressants during pregnancy and risk of attention-deficit/hyperactivity disorder in the offspring. J Dev Behav Pediatr 2010,31; (K) Jentink J et al. Valproic acid monotherapy in pregnancy and major congenital malformations. NEJM ; (L) Forsberg L et al. School performance at age 16 in children exposed to antiepileptic drugs in utero a population-based study. Epilepsia 2010, doi: /j x