Sodium valproate in pregnancy: what are the risks and should we use a shared decision-making approach?

Sodium valproate in pregnancy: what are the risks and should we use a shared decision-making... Background: Despite significant teratogenic risks, sodium valproate is still widely prescribed in many countries to women of childbearing age, as a mood stabiliser in bipolar disorder and also in epilepsy. The UK has recently banned valproate use in women who are not in a pregnancy prevention programme. Whilst this ruling reflects prevailing clinical practice, it also highlights an ongoing debate about when (if ever) a woman who is or could become pregnant should be allowed to choose to take valproate. Main body: We review the benefits and harms of drugs available for bipolar disorder and epilepsy in women of childbearing age, with a particular focus on teratogenic risk. We speculate on hypothetical rare situations in which potential benefits of valproate may outweigh potential harms in such women. We also review the literature on shared decision-making – on which there is now a NICE guideline and numerous evidence-based decision tools. Drawing on previous work by experts in shared decision-making, we offer a list of ‘frequently asked questions’ and a matrix of options to support conversations with women about continuing or discontinuing the drug in (or in anticipation of) pregnancy. We also consider whether shared decision-making is an appropriate paradigm when considering whether to continue a teratogenic drug. Conclusion: We conclude that because valproate in pregnancy remains the subject of such debate, there is scope for further research – not only into the relative efficacy and safety of alternatives to it – but also into the dynamics of communication and shared decision-making in this situation. Keywords: Sodium valproate, Pregnancy, Teratogenicity, Epilepsy, Bipolar disorder, Shared decision-making Background Medicines Agency recommended that valproate should In July 2017, almost 60 years after the thalidomide tra- not be used in pregnancy unless the woman has a form gedy [1], the French National Agency for the Safety of of epilepsy that is unresponsive to other anti-epileptic Medicines and Health Products (ANSM) imposed a na- drugs, and also that the drug should not be prescribed tionwide ban on the use of sodium valproate in preg- for women of childbearing age who are not enrolled in a nancy, on the grounds of teratogenicity [2]. Guidelines pregnancy prevention programme [5]. In April 2018, the produced by the UK Royal College of Obstetricians and UK Medicines and Healthcare Devices Regulatory Gynaecologists in 2016 recommended avoiding this drug Agency endorsed this recommendation [6]. in any woman of child-bearing potential [3] (reflecting a Sodium valproate is a medication licensed for both previous NICE guideline published in 2014 [4]). More epilepsy [7] and bipolar disorder [8], and is also used off recently, regulatory bodies have tightened their stance label for a range of indications including migraine significantly. In February 2018, for example, the Pharma- prophylaxis [5]. Whilst its use in epilepsy is falling in the covigilance Risk Assessment Committee of the European UK as the use of third-generation anticonvulsants in- creases [9, 10], its use for bipolar disorder has been in- * Correspondence: alastair.macfarlane@nhs.net creasing, especially among women of childbearing age Academic Foundation Year 1 Doctor, Barnet Hospital, Wellhouse Lane, [11]. In Ireland, recent data corroborate these findings Barnet EN5 3DJ, UK Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Macfarlane and Greenhalgh BMC Pregnancy and Childbirth (2018) 18:200 Page 2 of 11 [12], which necessitate increased surveillance and an im- the UK showed that valproate made up 25% of proved understanding of alternatives [13]. anti-epileptic drug prescriptions in pregnancy [28]. Bipolar disorder is a psychiatric condition charac- This article will explore the benefits and harms of so- terised by alternating periods of elated mood and de- dium valproate and its alternatives in current or planned pression [14]. The condition is a significant public pregnancy in the context of a tightening regulatory sys- health problem worldwide, and remains a challenge for tem for this drug. We will suggest questions that should patients and clinicians [15]. Systematic reviews examin- guide decision-making for these patients, and address ing the epidemiology of bipolar disorder show that it is the crucial issue of whether and how patients can be in- associated with markedly increased suicide and volved as democratic partners in such decisions. self-harm rates [16], substance abuse [17] and other psy- chiatric morbidities [18–21]. Given the female prepon- Main text derance and young age of onset of bipolar disorder Mood stabilisers in bipolar disorder (17.5 years) [22], women of childbearing age make up a Mood stabilisers are the mainstay of pharmacological significant proportion of patients. Management of bipo- management in patients with bipolar disorder. Although lar disorder is difficult in this group, as many mood sta- there is some contention about what exactly constitutes bilisers have either been shown to be teratogenic or have a mood stabiliser [29], the defining feature is that these unknown effects in pregnancy (see below) [23]. drugs improve both manic and depressive symptoms Epilepsy is a condition characterised by abnormal exces- without significantly worsening either polarity [8]. Some sive synchronous neuronal activity in the brain causing drugs may be of benefit in patients with bipolar disorder seizures [24], and is associated with a variety of neurobio- but are not classed as mood stabilisers because of their logical, psychological, social and cognitive consequences. ability to precipitate mania (e.g. some antidepressants) The prevalence of active epilepsy in adults is 5–10 per or worsen depression (e.g. some antipsychotics). 1000, and is influenced by many factors, both genetic and Table 1 shows the main classes of mood stabiliser used environmental [25]. One risk factor for seizure activity is in the treatment of bipolar disorder. Sodium valproate, a oestrogen [26], hence pregnancy can increase the seizure mood stabiliser of the anticonvulsant class, is commonly rate [27]. Information from EURAP, the International prescribed for the treatment of mania and the prophy- Registry of Anti-Epileptic Drugs and Pregnancy, suggests laxis of bipolar disorder [30]. A systematic review asses- that 20% of pregnant patients with epilepsy were sing valproate efficacy in acute mania showed that it has treated with valproate from 1999 to 2004, despite know- a has a number needed to treat (NNT) of between 2.3 ledge of its teratogenic risks [27]. A more recent study in and 4.3 [31], and may be used in patients who have Table 1 Main classes of mood stabiliser (and alternatives to valproate in the treatment of bipolar disorder), mechanisms of action and side effects (not including foetal or maternal risks). Compiled from various sources [10, 33, 34, 91–100] Class Medication Proposed mechanism(s) of action Side effects name Mineral Lithium Enhances serotonergic neuron activity, inhibits Common: GI upset, fine tremor, polyuria, polydipsia, metallic pAp-phosphatase enzyme, interacts with nitric taste in mouth, ankle oedema, weight gain. Chronic: renal oxide signalling activity toxicity, hypothyroidism. Anti- Sodium GABA potentiation, blocks voltage gated sodium Common: GI upset, hyperammonaemia (causing nausea), epileptics valproate channels, epigenetically inhibits histone weight gain, tremor, hair loss with curly regrowth. deacetylase In women: polycystic ovarian syndrome, hyperandrogenism. Rare: fulminant liver failure. Lamotrigine GABA potentiation, suppresses glutamate release, Common: tremors, dizziness, tiredness, loss of co-ordination, inhibits serotonin reuptake menstrual disturbance, dry mouth, sleep problems. Carbamazepine Blocks voltage gated sodium channels Common: dizziness, diplopia, drowsiness, ataxia, nausea, headaches, dry mouth, oedema, hyponatraemia, erythematous rash, sexual dysfunction. Rare: agranulocytosis. Atypical Risperidone Dopaminergic (D ) receptor antagonist, Common: sexual dysfunction (hyperprolactinaemia). 1–5 antipsychotics serotonergic (5-HT ) receptor antagonist Long term: movement disorders (e.g. tardive dyskinesia, 2A/C Olanzapine akathisia, parkinsonism), increased risk of cardiovascular disease. Quetiapine Rare: neuroleptic malignant syndrome Aripiprazole Dopaminergic (D ) and serotonergic (5-HT ) Common: weight gain, headache, agitation, insomnia, 2 1A receptor partial agonist gastrointestinal effects, disinhibition. Macfarlane and Greenhalgh BMC Pregnancy and Childbirth (2018) 18:200 Page 3 of 11 either failed to respond to lithium [32], or those who do summarises the main foetal and maternal risks associ- not tolerate it [33]. Prophylactically, the NNT to prevent ated with mood stabilisers. manic and depressive episodes respectively is 21.3 and 10.5 [34]. Anti-epileptic drugs Valproate has a number of side effects other than risks In epilepsy as in bipolar disorder, valproate is not the to the mother and foetus, which are summarised in only available drug for women of childbearing age. And Table 1. In any patient, these side effects must be again, there is a somewhat complex picture of efficacy weighed against the significant risks associated with un- and safety in the different alternatives. Schmidt and treated mania or bipolar disorder, including suicide [16]. Schachter recently reviewed drug treatment for epilepsy A high proportion of patients with bipolar disorder [10], and highlighted that epilepsy is not a single condi- will face the scenario of needing to manage their illness tion but an umbrella term encompassing different during an anticipated or current pregnancy [22]. This underlying pathologies and clinical manifestations. Dif- raises a very difficult clinical issue: managing the mental ferent kinds of epilepsy respond to different drugs and health needs of the mother whilst minimising the terato- in the 20–30% of cases that are refractory, multiple genic risk to the developing foetus. Bipolar disorder per drugs need to be used in combination. Getting the right se does not increase the risk of malformation or foetal drug for a person with epilepsy involves balancing bene- death [35], but several mood stabilisers are associated fits and side effects as well as taking account of lifestyle with major teratogenicity. issues and personal preferences [37]. All psychotropic medications cross the placenta [36]. Table 3 summarises the main anti-epileptic drugs that As well as the recognised risk of teratogenicity – which could be offered to a woman of childbearing age. Whilst occurs in the first trimester during organogenesis – valproate (first licensed in 1967) is no longer the common- there are further ways in which these medications may est anti-epileptic drug prescribed, it remains one of the adversely affect a pregnancy. Viguera et al. categorise most effective. It is still used in emergency settings to con- the effects of psychotropic medication use in pregnancy trol focal and generalised seizures; it may be effective when into: [1] obstetric complications (such as low birth newer anticonvulsants have not worked; and it is the rec- weight), [2] perinatal complications (occurring shortly ommended first-line therapy for complex partial seizures. after birth) and [3] long-term neurological and behav- Schmidt and Schachter point out that whilst two in ioural sequelae (such as autism) [23]. Table 2 every three women with epilepsy who become pregnant Table 2 Foetal and maternal risks associated with selected mood stabilisers. Compiled from various sources [50, 53, 78, 79, 101–106] Medication Risks to offspring associated with use in pregnancy Maternal risks associated with use in pregnancy Lithium Severe toxicity in newborn. There are limited and conflicting data Renal lithium clearance rises during pregnancy, so levels need to regarding the risk of cardiovascular malformations (including be monitored regularly to maintain therapeutic levels. Ebstein’s anomaly) following lithium exposure in utero. A large cohort study in 2017 showed that the relative risk was still elevated (1.7), and also dose dependent, but lower than previously thought. Absolute risk remains low (< 1/1500). Non-teratogenic associations include low birth weight, cyanosis, bradycardia, GI bleeding, polyhydramnios, seizures. Valproate Significantly elevates the risk of major defects (7 times higher). Increased hepatic clearance of valproate and increased apparent These include spina bifida, atrial septal defect, cleft palate, volume of distribution cause lower maternal levels of the drug. hypospadias, polydactyly and craniosynostosis. See Table 4 and main text for further details. Non-teratogenic associations include case reports of intra-uterine growth restriction, infant hepatic toxicity and foetal distress dur- ing labour. Neurodevelopmental associations – foetal exposure to valproate in utero is associated with 1.7 times risk of autism spectrum disorder. Carbamazepine Risk of major congenital abnormalities increased 1.8 times, Crosses placenta and lowers maternal serum levels, so doses including malformations of neural tube, urinary tract and may need to be increased. cardiovascular system, and cleft palate. Lamotrigine Conflicting evidence on the risk of malformations, especially Crosses placenta and lowers maternal serum levels, so dose may regarding dose response. need to be increased. Dizziness, diplopia and ataxia have been Evidence emerging that it appears to be a relatively safe drug in reported following these dose increases in pregnant women. pregnancy. Atypical Most do not appear to significantly increase malformation rate. Crosses placenta and lowers maternal serum levels, so doses antipsychotics Risperidone requires additional study. may need to be increased. Macfarlane and Greenhalgh BMC Pregnancy and Childbirth (2018) 18:200 Page 4 of 11 Table 3 Selected anti-epileptic drugs (and alternatives to valproate in the treatment of epilepsy), adapted from Schmidt and Schachter [10] Class of Name of drug Proposed mechanism Side effects Additional information drug 1st Phenytoin Sodium channel blocker Enzyme inducer (hence interaction First line for focal and generalised seizures generation with other medications), skin with focal onset hypersensitivity Ethosuxamide T-type calcium channel blocker Gastrointestinal side effects, First line for absence seizures insomnia, psychosis 2nd Carbamazepine Sodium channel blocker Enzyme inducer, skin First line for focal and generalised seizures generation hypersensitivity with focal onset Valproate GABA potentiation, blocks voltage GI upset, weight gain, tremor, hair First line for focal and generalised seizures, gated sodium channels, loss with curly regrowth, no skin hypersensitivity, no newer drugs epigenetically inhibits histone teratogenicity (see Table 4) have been shown to have higher efficacy deacetylase In women: polycystic ovarian syndrome, hyperandrogenism Rare: fulminant liver failure 3rd Vigabatrin GABA potentiation Visual defects, weight gain, seizure Use in infantile spasms, adjunct in complex generation aggravation, encephalopathy partial seizures Lamotrigine GABA potentiation, suppresses Tremor, dizziness, tiredness, loss of First line for focal and generalised seizures, glutamate release, inhibits co-ordination, menstrual disturb- lower efficacy than valproate for absence serotonin reuptake ance, dry mouth, sleep problems seizures Oxcarbazepine Sodium channel blocker Enzyme inducer, hyponatraemia, First line for focal and generalised seizures skin hypersensitivity with focal onset Gabapentin Calcium channel blocker Weight gain, psychosis, seizure Adjunctive use only, used in focal and aggravation, tiredness, dizziness generalised seizures with focal onset Levetiracetam SV2A modulation Tiredness, dizziness, behavioural First line in focal and generalised seizures problems with focal onset and myoclonic seizures. Topiramate GABA potentiation, glutamate Tiredness, dizziness, skin First line for focal and generalised seizures inhibition, sodium/calcium channel hypersensitivity, weight loss, blocker teratogenicity remain seizure free throughout their pregnancy, antiepi- various reasons, including sexual disinhibition associated leptic drug dosages may need to be adjusted as the preg- with mania [30]. nancy progresses, particularly when seizures occur in the Within these two scenarios, several factors might affect first trimester. Women taking lamotrigine, levetiracetam, the clinical outcome for both mother and child: the severity topiramate, and oxcarbazepine may need an increase in of the condition (including frequency and duration of re- dose to compensate for pregnancy-related increase in lapses), co-existing medication (including the need for com- clearance of these drugs so as to reduce the risk of bination therapy to control the bipolar disorder or breakthrough seizures. These authors also highlight the epilepsy), drug and alcohol use, co-morbidity, sociocultural small increased risk that the children of women who factors, level of social support; and also (in the second sce- take an antiepileptic drug during pregnancy will be small nario) the stage at which the pregnancy was confirmed. for gestational age and have a lower Apgar score. Deciding whether or not to continue valproate in these situations requires a complex risk assessment. Many studies over the years have assessed the sequelae of con- A woman of childbearing age taking valproate… tinuation and discontinuation of valproate – both to There are two conceivable scenarios when a woman tak- mother and child. We review these below. ing valproate would have the dilemma of continuing it during pregnancy: [1] she is planning to become preg- Risks of continuation nant whilst taking valproate; or [2] she has already be- Prospective controlled trials on the effects of valproate come pregnant whilst taking valproate. Both these during pregnancy are limited for obvious reasons, but scenarios are currently fairly common in both primary cohort studies have shown that women who reported and secondary care [38]. In addition to the fact that both using the medication during the first trimester of preg- bipolar disorder and epilepsy are common in women of nancy had a seven-fold higher risk of congenital malfor- childbearing age [15], patients suffering from bipolar dis- mations compared to the baseline rate of 1.62% [39]. order are at increased risk of unintended pregnancy for Indeed, the relative risk of valproate on major defects is Macfarlane and Greenhalgh BMC Pregnancy and Childbirth (2018) 18:200 Page 5 of 11 so high, and these defects are so characteristic, that the relapse than those who continued mood stabilisers, and term ‘foetal valproate syndrome’ has been described the median time until first recurrence was four times [40]. Reasons for the teratogenic effects are not fully shorter [57]. If the mood stabiliser was discontinued understood, but possibly involve epigenetic effects, in- abruptly, recurrence latency was eleven times shorter. cluding the inhibition of histone deactylase with associ- Most studies of mood stabiliser discontinuation during ated changes in gene expression [41], increases in foetal pregnancy have been on lithium withdrawal [58–60]; oxidative stress, or the antagonism of folate required for specific evidence on discontinuing valproate in preg- DNA synthesis [42]. nancy is sparse. However, evidence for valproate with- As well as its teratogenic effects, valproate may lead drawal outside of pregnancy illustrates similar trends: to problems after birth, including immediate withdrawal relapse rates are high, especially during abrupt with- effects such as jitteriness [40]. Valproate therapy during drawal [61–63], and there is even a case report of one pregnancy has been shown to correlate with longer-term patient being treated for epilepsy developing new-onset neurodevelopmental problems leading to repetitive be- mania following valproate withdrawal [64]. haviours, impaired communication and social isolation Discontinuation can also be problematic in epilepsy. [43, 44], as well as reduced IQ [45]. These autistic-like Observations from the EURAP study showed that with- traits have been demonstrated in both animal models drawal of valproate in the first trimester (when it is most [46, 47] and human studies, affecting around 40% of teratogenic) was associated with a significantly higher children exposed to valproate [48, 49]. Actual diagnoses rate of generalised tonic clonic seizures (33%) compared of autism spectrum disorder are lower, however, at to when it was continued (16%) [65]. More striking, around 4% [50]. Although the mechanisms underlying however, is that the rate of seizures was also elevated these are yet to be elucidated, there is a possible link (29%) when valproate was switched to another with lower cell density in the cerebellum [51], associated anti-epileptic medication. with mutations in the PTEN gene [52]. Another consideration for bipolar disorder patients The risk of valproate use in pregnancy on specific mal- should include the risks of puerperal psychosis. Preva- formations has been quantified. Table 4 shows the odds lence of this condition in the general population is about ratio of different malformations based on an extensive 0.1–0.25%, but may be up to 50% in women with bipolar review of the research literature [53]. Risk of malforma- disorder [66]. Hospitalisation for psychiatric morbidity tion increases with drug dose and with combination predicts the risk of puerperal psychosis [67], so un- therapy [54–56]. treated bipolar disorder may not just affect the mother Considerations about continuation should also address during pregnancy, but also in the weeks afterwards. drug-related risks to the mother. Full blood count and liver Psychosis during the perinatal period must be viewed in function tests, for example, should be measured regularly a broader context: leaving it untreated can cause harm to to rule out blood dyscrasias or liver pathology [30]. the mother through poor self-care, increased drug and al- cohol use, non-attendance for obstetric care and impulsive Risks of discontinuation acts [30]. In severe cases, there may be direct harm to the There are risks associated with discontinuing valproate child through untreated maternal psychomorbidity, in- in a patient whose bipolar disorder or epilepsy is well cluding neglect or even infanticide [68, 69]. A 20-year controlled. Viguera et al. found that pregnant women study on puerperal psychosis in Austria found that out of with bipolar disorder who were euthymic at conception 96 patients, six died from suicide, with three ‘extended but stopped mood stabilisers were twice as likely to suicide attempts’ leading to two cases of infanticide [70]. Furthermore, severe mental health issues during and soon after pregnancy can adversely impact the child’semo- Table 4 Odds ratios and absolute risk of congenital tional, cognitive and physical health later in life [71]. The malformation with sodium valproate (adapted from Jentink) [53] child may be removed from the care of the mother for Condition Odds ratio Absolute risk safeguarding reasons, leading to problems with bonding. (median and range) in offspring of mothers In sum, whilst there are good reasons to minimise the who took valproate in pregnancy use of sodium valproate in pregnancy, it is theoretically Spina bifida 12.7 (7.7–20.7) 0.6% possible that in some individual cases, the risks of dis- Atrial septal defect 2.5 (1.4–4.4) 0.5% continuing the drug could outweigh the benefits. Cleft palate 5.2 (2.8–9.9) 0.3% Pregnancy prevention programmes and valproate Hypospadias 4.8 (2.9–8.1) 0.7% A ‘pregnancy prevention programme’ is defined by the Polydactyly 2.2 (1.0–4.5) 0.2% new UK regulations on valproate prescribing as fol- Craniosynostosis 6.8 (1.8–18.8) 0.1% lows [5]: Macfarlane and Greenhalgh BMC Pregnancy and Childbirth (2018) 18:200 Page 6 of 11 1. There must be an assessment of the woman’s Patients with bipolar disorder who are already taking potential to become pregnant and pregnancy tests valproate and are planning pregnancy have two options: before and during treatment. (1) withdraw valproate slowly prior to conception, with 2. The woman must be offered counselling about the close monitoring of their mental health status, or (2) risk of valproate to her unborn child and the switch to a lower-risk mood stabiliser. The first option importance of using effective contraception while needs to be carried out cautiously to minimise risk of re- taking the drug. lapse, and the decision to do this should take into ac- 3. Review by a specialist is now mandatory, and count past history of relapse, co-existing medications women taking valproate will be required to have and any protective or predisposing risk factors. annual specialist reviews including completing a The second option reduces the risk of maternal psy- risk acknowledgement form. chomorbidity during pregnancy, but with a higher risk 4. The packaging for valproate will carry a visual to the foetus. Although the most commonly prescribed warning of the risks associated with pregnancy. mood stabilisers (lithium, carbamazepine and valproate) Pharmacists will be required to discuss the risks are associated with foetal abnormalities – albeit to differ- and issue a warning card every time they dispense ing extents – current evidence on lamotrigine and atyp- valproate to women of childbearing age. ical antipsychotics is more favourable [36]. Various studies have looked at the safety of lamotrigine Many of these steps reflect what has become accepted use in pregnancy, particularly regarding its dose. Tomson good practice in several countries over the past few years et al..., using the EURAP data, found differences in the [4, 72], but they are now becoming mandatory in the malformation rates in patients given < 300 mg/day and UK. Clinicians generally avoid starting women of child- ≥300mg/day (2 and 4.5% respectively) [76]. Campbell et bearing age on valproate, but when this is viewed as clin- al, using data from the UK Epilepsy and Pregnancy Regis- ically unavoidable, information and a discussion about ter, found no significant relationship between dose and risks, along with an offer of contraception, are a core malformation rate, and concluded that whilst ‘lamotrigine component of care. has a favourable profile compared with valproate for ad- Whilst the new requirements are therefore in line with verse pregnancy outcomes, the requirements for seizure current recommended best practice, there is also evi- control should not be overlooked’. dence suggesting an evidence-practice gap. For example, Atypical antipsychotic drugs may be used in the man- a recent study in the UK showed that around half the agement of bipolar disorder and are typically recom- women taking sodium valproate were unaware of its po- mended for short-term use [77]. In a review of tential to damage the foetus [73]. A literature review on treatment of bipolar disorder in pregnancy, Grover and management of women with substance-use disorders Avasthi cite numerous studies with differing findings on found that unplanned pregnancy was common but the safety profiles of olanzapine, risperidone, quetiapine, also that access to long-acting reversible contraception amisupiride, ziprasidone, aripiprazole and clozapine, but through integrated contraception services was an ef- conclude that these drugs are nonetheless safer than fective approach to targeting this problem [74]. We lithium or valproate in pregnancy [36]. A recent large could learn from approaches taken in low-income cohort study in the United States showed that anti- countries, such as the implementation of post-abortion psychotic use early in pregnancy does not ‘meaningfully contraception in Zimbabwe, which has significantly de- increase the risk for congenital malformations overall or creased unplanned pregnancy rates in women with cardiac malformations in general’ [78]. Risperidone car- mental health conditions [75]. ries a small increased risk, and requires additional study. The above measures will only be relevant, of course, if A recent letter in the BMJ highlighted that as the the woman finds it acceptable to prevent pregnancy. In warnings regarding valproate use in pregnancy are justi- many women, there comes a time when pregnancy is de- fiably being strengthened, it is very important to search sired. The clinician should explain to the women that for safer alternatives [79]. Nevertheless, we should not whilst it is never possible to promise a healthy baby, the underestimate the difficulty of interpreting observational chances of this happening will be best if the pregnancy data on medication effects during pregnancy. is carefully planned, including adjusting medication in the pre-conception period – which in the UK must (with How to minimise valproate use during pregnancy rare exceptions) involve discontinuation of valproate. The most difficult clinical decisions may arise when a pa- Women should be encouraged to report a pregnancy as tient using valproate presents when already pregnant. Pre- soon as the test is positive – and reassured that the doc- sentations later in pregnancy and those in women on tor will not be judgemental even if the pregnancy was higher doses of valproate are associated with an increased “unplanned”. risk of foetal abnormalities [56]. Current recommendations Macfarlane and Greenhalgh BMC Pregnancy and Childbirth (2018) 18:200 Page 7 of 11 are to withdraw the drug if possible, and especially during treatment concordance and decision quality in epilepsy the first trimester [49]. However, in a systematic review management, specifically for situations like pregnancy examining the risk of bipolar disorder recurrence fol- and medication withdrawal [84]. The model involves lowing discontinuation of mood stabilisers, the au- three kinds of talk: (1) team talk, where the patient is thors concluded that in women with unstable forms encouraged to consider different management strategies of the disease, the high risk of relapse associated with (e.g. valproate vs. levetiracetam for epilepsy); (2) option rapid withdrawal of mood stabilisers more than bal- talk, where more detailed information about the options anced the potential risk to the foetus [80]. This sug- is provided (typically using an ‘option grid’– a matrix gests that gradual withdrawal through down-titration structured around questions the patient might ask and of dose is preferable to abrupt discontinuation. covering all potential options for a particular set of cir- It is possible to conceptualise hypothetical scenarios in cumstances), and (3) decision talk, where the clinician which continuation of sodium valproate during preg- assists the patient with decisions by providing facts, fig- nancy could be clinically justifiable. For example, if a pa- ures and risks [87]. tient on valproate presents in her final trimester with a The talk model maps well to questions around val- history of severe and unstable bipolar disorder, has re- proate use in which women who are pregnant (or lapsed during a previous pregnancy and caused signifi- planning on becoming pregnant). The clinician should cant harm to herself and/or her baby, the risks of firstly present the different management options. discontinuation may outweigh the risks of continuation, These would include: (1) continuing the drug at the though even in such an extreme case, careful dose re- current dose, (2) titrating down to a lower dose, (3) duction may also be an option. discontinuing the drug, or (4) changing to a different In rare situations where sodium valproate prescription medication. To support more detailed conversations, continues during pregnancy, use should be restricted to amatrixof options couldbeoffered(seeexample in monotherapy [81] and at the lowest dose possible [56, 76]. Table 5). Thethird step in thetalk model wouldbefor the A role for shared decision-making? patient to discuss their preferred option with the clin- In view of the new regulations requiring a woman of ician in detail, which would involve getting a more childbearing age to sign a risk acceptance form if she accurate picture of the risks involved. For example, if chooses to continue valproate, informed decision-making the woman chooses to discontinue valproate (column is more important than ever. 4inTable 3) the clinician should outline that this Shared decision-making is a process whereby health still presents risks to the baby, with the potential for professionals and patients work together to make health- the mother to become mentally unwell and hence care choices [82]. When deciding which treatments are perhaps neglect herself and her baby, leading in ex- appropriate, a discussion should involve the patient, with treme cases to separation via social services. As noted the clinician guiding them through the benefits and risks above, the precise risks of this eventuality will depend in order to make an informed decision [83]. Policy- on the medical and sociodemographic details of the makers have called for increased collaboration between individual case. It is hoped that in most cases clin- patients and clinicians [84], and patients are more likely ician and patient will be able to collaboratively weigh to adhere to a healthcare decision if they have been in- up the pros and cons and achieve a decision that volved in the process [85]. takes account of both mother and baby’s health. Legare et al. have carried out a narrative review of the The question of shared decision-making for a terato- literature on shared decision-making, and systematically genic drug in pregnancy raises an ethical conundrum. debunked various myths regarding it. These include the Whilst the mother may choose to continue valproate assumptions that it takes longer to carry out in consulta- (e.g. if her bipolar disorder or epilepsy is tions, costs more money, or that it is incompatible with well-controlled on it), the foetus has no chance to ex- following clinical practice guidelines [82]. The authors press a view. Arguably, a ‘paternalistic’ decision by the also show that contrary to many clinicians’ expectations, clinician to discontinue (or not commence) valproate in vulnerable patients who appear passive tend to gain a pregnant woman is actually a form of advocacy for a more clinical benefit than those whose decision is made second patient (the foetus). Others might argue that for them. this line of reasoning presupposes that a) the foetus will There is a wide variety of evidence-based tools to sup- necessarily come to less harm overall if valproate is not port shared decision-making during the clinical encoun- given (in reality the balance of benefits versus harms ter [86], and some of these have been trialled may be more complex); and b) the mother will be moti- successfully in specific diseases. For example, the talk vated by self-interest rather than taking her unborn model, developed by Elwyn et al. [87], improves child’s needs into account. Macfarlane and Greenhalgh BMC Pregnancy and Childbirth (2018) 18:200 Page 8 of 11 Table 5 List of frequently asked questions and management options to support shared decision-making regarding valproate use for bipolar disorder before or during pregnancy Frequently Continuing the current dose of Lowering the dose of valproate Discontinuing valproate Changing to another medication asked valproate questions What does No change to medication or Over a period of weeks to Over a period of weeks to Switching to a different medication it involve? dose months, decreasing the months, gradually stopping (e.g. lamotrigine or an amount of valproate valproate antipsychotic) What are Usual side effects of valproate Usual side effects of valproate, Higher risk of relapse Risk of relapse if the other the risks to potential for relapse (depends on a variety of medication is not as effective as me? factors – discuss with your valproate; risk of new side effects clinician), increased risk of puerperal psychosis What are Congenital malformations (see Reduced risk of congenital Indirect risks, e.g. disinhibition Some medications are much safer the risks to Table 4) long-term developmen- malformations and from poorly controlled for your unborn baby (specifically my baby? tal disorders (estimated one in 3) developmental disorders (risk bipolar disorder (discuss with lamotrigine, some antipsychotics) depends on the dose, discuss your clinician) with your clinician) What are You are less likely to relapse or Your unborn baby will have a Your unborn baby will have If you can tolerate the new drug, the suffer from puerperal psychosis lower risk of malformations the same risk of you are less likely to relapse or benefits? than if you continue the full malformations as the general suffer from puerperal psychosis; the dose population other medication could have adverse effects Who People with unstable bipolar People with bipolar disorder People who have been stable People who are stable on would disorder and frequent relapses who are not controlled on off valproate and do not wish alternatives to valproate benefit who are not controlled on other other medication to take other medications most from medication or lower doses of during pregnancy this? valproate The future Although the teratogenic and long-term neurodevelop- Given the limited evidence base on the precise benefits mental effects of valproate are now well established, the and harms associated with alternatives to sodium valpro- current evidence suggests that the recent strengthening ate during pregnancy, randomised controlled trials to as- of regulatory restrictions on its use are justified. How- sess their relative efficacies and safety profiles are ever, it would be premature to ban the use of this drug justified. Various such trials are ongoing. in women of childbearing age in the UK (since in rare Personalised (that is, stratified) medicine offers some cases the benefits of its use may outweigh potential potential avenues for further research. One study has harms). In the light of the new regulatory framework, we demonstrated that specific maternal and foetal genotypes believe that informed, democratic conversations are in mice confer a greater susceptibility to the teratogenic needed and we have provided an evidence-based frame- effects of valproate [88], and may mean that in the future, work to support shared decision-making. More research some human genotypes could be preselected for continu- should be undertaken on how shared decision-making ing (or not continuing) the drug during pregnancy. More plays out in this group of patients, as well as on the effi- speculatively, environmental factors may predict suscepti- cacy and safety of the various alternatives to sodium val- bility to valproate-induced teratogenicity. Ogawa et al. proate in bipolar disorder and epilepsy. showed that geographical stressors, in particular the loca- tion of conception, significantly affected pregnant rats’ Abbreviations sensitivity to teratogenicity during valproate use [89]. ANSM: French National Agency for the Safety of Medicines and Health Products; EURAP: International Registry of Anti-Epileptic Drugs and Preg- However, in general the hope for stratified solutions has nancy; MHRA: Medicines and Healthcare Devices Regulatory Agency; greatly exceeded the clinical benefit of such solutions, so NNT: Number Needed to Treat we should remain cautious about such options [90]. Acknowledgements Conclusion We thank the two reviewers for exceptionally helpful and detailed The management of bipolar disorder and epilepsy during comments on a previous version of this paper, including suggestions for pregnancy continues to carry complex challenges. So- additional books and papers to include. dium valproate use is a growing issue in women of child- bearing age, and patients and clinicians may well be Funding faced with a situation in which they must weigh up the TG’s contribution was part funded by the National Institute for Health benefits and harms of continuation. Research Biomedical Research Centre, Oxford, grant BRC-1215-20008. Macfarlane and Greenhalgh BMC Pregnancy and Childbirth (2018) 18:200 Page 9 of 11 Authors’ contributions 17. Hunt GE, Malhi GS, Cleary M, Lai HMX, Sitharthan T. 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Sodium valproate in pregnancy: what are the risks and should we use a shared decision-making approach?

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Medicine & Public Health; Reproductive Medicine; Maternal and Child Health; Gynecology
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Abstract

Background: Despite significant teratogenic risks, sodium valproate is still widely prescribed in many countries to women of childbearing age, as a mood stabiliser in bipolar disorder and also in epilepsy. The UK has recently banned valproate use in women who are not in a pregnancy prevention programme. Whilst this ruling reflects prevailing clinical practice, it also highlights an ongoing debate about when (if ever) a woman who is or could become pregnant should be allowed to choose to take valproate. Main body: We review the benefits and harms of drugs available for bipolar disorder and epilepsy in women of childbearing age, with a particular focus on teratogenic risk. We speculate on hypothetical rare situations in which potential benefits of valproate may outweigh potential harms in such women. We also review the literature on shared decision-making – on which there is now a NICE guideline and numerous evidence-based decision tools. Drawing on previous work by experts in shared decision-making, we offer a list of ‘frequently asked questions’ and a matrix of options to support conversations with women about continuing or discontinuing the drug in (or in anticipation of) pregnancy. We also consider whether shared decision-making is an appropriate paradigm when considering whether to continue a teratogenic drug. Conclusion: We conclude that because valproate in pregnancy remains the subject of such debate, there is scope for further research – not only into the relative efficacy and safety of alternatives to it – but also into the dynamics of communication and shared decision-making in this situation. Keywords: Sodium valproate, Pregnancy, Teratogenicity, Epilepsy, Bipolar disorder, Shared decision-making Background Medicines Agency recommended that valproate should In July 2017, almost 60 years after the thalidomide tra- not be used in pregnancy unless the woman has a form gedy [1], the French National Agency for the Safety of of epilepsy that is unresponsive to other anti-epileptic Medicines and Health Products (ANSM) imposed a na- drugs, and also that the drug should not be prescribed tionwide ban on the use of sodium valproate in preg- for women of childbearing age who are not enrolled in a nancy, on the grounds of teratogenicity [2]. Guidelines pregnancy prevention programme [5]. In April 2018, the produced by the UK Royal College of Obstetricians and UK Medicines and Healthcare Devices Regulatory Gynaecologists in 2016 recommended avoiding this drug Agency endorsed this recommendation [6]. in any woman of child-bearing potential [3] (reflecting a Sodium valproate is a medication licensed for both previous NICE guideline published in 2014 [4]). More epilepsy [7] and bipolar disorder [8], and is also used off recently, regulatory bodies have tightened their stance label for a range of indications including migraine significantly. In February 2018, for example, the Pharma- prophylaxis [5]. Whilst its use in epilepsy is falling in the covigilance Risk Assessment Committee of the European UK as the use of third-generation anticonvulsants in- creases [9, 10], its use for bipolar disorder has been in- * Correspondence: alastair.macfarlane@nhs.net creasing, especially among women of childbearing age Academic Foundation Year 1 Doctor, Barnet Hospital, Wellhouse Lane, [11]. In Ireland, recent data corroborate these findings Barnet EN5 3DJ, UK Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Macfarlane and Greenhalgh BMC Pregnancy and Childbirth (2018) 18:200 Page 2 of 11 [12], which necessitate increased surveillance and an im- the UK showed that valproate made up 25% of proved understanding of alternatives [13]. anti-epileptic drug prescriptions in pregnancy [28]. Bipolar disorder is a psychiatric condition charac- This article will explore the benefits and harms of so- terised by alternating periods of elated mood and de- dium valproate and its alternatives in current or planned pression [14]. The condition is a significant public pregnancy in the context of a tightening regulatory sys- health problem worldwide, and remains a challenge for tem for this drug. We will suggest questions that should patients and clinicians [15]. Systematic reviews examin- guide decision-making for these patients, and address ing the epidemiology of bipolar disorder show that it is the crucial issue of whether and how patients can be in- associated with markedly increased suicide and volved as democratic partners in such decisions. self-harm rates [16], substance abuse [17] and other psy- chiatric morbidities [18–21]. Given the female prepon- Main text derance and young age of onset of bipolar disorder Mood stabilisers in bipolar disorder (17.5 years) [22], women of childbearing age make up a Mood stabilisers are the mainstay of pharmacological significant proportion of patients. Management of bipo- management in patients with bipolar disorder. Although lar disorder is difficult in this group, as many mood sta- there is some contention about what exactly constitutes bilisers have either been shown to be teratogenic or have a mood stabiliser [29], the defining feature is that these unknown effects in pregnancy (see below) [23]. drugs improve both manic and depressive symptoms Epilepsy is a condition characterised by abnormal exces- without significantly worsening either polarity [8]. Some sive synchronous neuronal activity in the brain causing drugs may be of benefit in patients with bipolar disorder seizures [24], and is associated with a variety of neurobio- but are not classed as mood stabilisers because of their logical, psychological, social and cognitive consequences. ability to precipitate mania (e.g. some antidepressants) The prevalence of active epilepsy in adults is 5–10 per or worsen depression (e.g. some antipsychotics). 1000, and is influenced by many factors, both genetic and Table 1 shows the main classes of mood stabiliser used environmental [25]. One risk factor for seizure activity is in the treatment of bipolar disorder. Sodium valproate, a oestrogen [26], hence pregnancy can increase the seizure mood stabiliser of the anticonvulsant class, is commonly rate [27]. Information from EURAP, the International prescribed for the treatment of mania and the prophy- Registry of Anti-Epileptic Drugs and Pregnancy, suggests laxis of bipolar disorder [30]. A systematic review asses- that 20% of pregnant patients with epilepsy were sing valproate efficacy in acute mania showed that it has treated with valproate from 1999 to 2004, despite know- a has a number needed to treat (NNT) of between 2.3 ledge of its teratogenic risks [27]. A more recent study in and 4.3 [31], and may be used in patients who have Table 1 Main classes of mood stabiliser (and alternatives to valproate in the treatment of bipolar disorder), mechanisms of action and side effects (not including foetal or maternal risks). Compiled from various sources [10, 33, 34, 91–100] Class Medication Proposed mechanism(s) of action Side effects name Mineral Lithium Enhances serotonergic neuron activity, inhibits Common: GI upset, fine tremor, polyuria, polydipsia, metallic pAp-phosphatase enzyme, interacts with nitric taste in mouth, ankle oedema, weight gain. Chronic: renal oxide signalling activity toxicity, hypothyroidism. Anti- Sodium GABA potentiation, blocks voltage gated sodium Common: GI upset, hyperammonaemia (causing nausea), epileptics valproate channels, epigenetically inhibits histone weight gain, tremor, hair loss with curly regrowth. deacetylase In women: polycystic ovarian syndrome, hyperandrogenism. Rare: fulminant liver failure. Lamotrigine GABA potentiation, suppresses glutamate release, Common: tremors, dizziness, tiredness, loss of co-ordination, inhibits serotonin reuptake menstrual disturbance, dry mouth, sleep problems. Carbamazepine Blocks voltage gated sodium channels Common: dizziness, diplopia, drowsiness, ataxia, nausea, headaches, dry mouth, oedema, hyponatraemia, erythematous rash, sexual dysfunction. Rare: agranulocytosis. Atypical Risperidone Dopaminergic (D ) receptor antagonist, Common: sexual dysfunction (hyperprolactinaemia). 1–5 antipsychotics serotonergic (5-HT ) receptor antagonist Long term: movement disorders (e.g. tardive dyskinesia, 2A/C Olanzapine akathisia, parkinsonism), increased risk of cardiovascular disease. Quetiapine Rare: neuroleptic malignant syndrome Aripiprazole Dopaminergic (D ) and serotonergic (5-HT ) Common: weight gain, headache, agitation, insomnia, 2 1A receptor partial agonist gastrointestinal effects, disinhibition. Macfarlane and Greenhalgh BMC Pregnancy and Childbirth (2018) 18:200 Page 3 of 11 either failed to respond to lithium [32], or those who do summarises the main foetal and maternal risks associ- not tolerate it [33]. Prophylactically, the NNT to prevent ated with mood stabilisers. manic and depressive episodes respectively is 21.3 and 10.5 [34]. Anti-epileptic drugs Valproate has a number of side effects other than risks In epilepsy as in bipolar disorder, valproate is not the to the mother and foetus, which are summarised in only available drug for women of childbearing age. And Table 1. In any patient, these side effects must be again, there is a somewhat complex picture of efficacy weighed against the significant risks associated with un- and safety in the different alternatives. Schmidt and treated mania or bipolar disorder, including suicide [16]. Schachter recently reviewed drug treatment for epilepsy A high proportion of patients with bipolar disorder [10], and highlighted that epilepsy is not a single condi- will face the scenario of needing to manage their illness tion but an umbrella term encompassing different during an anticipated or current pregnancy [22]. This underlying pathologies and clinical manifestations. Dif- raises a very difficult clinical issue: managing the mental ferent kinds of epilepsy respond to different drugs and health needs of the mother whilst minimising the terato- in the 20–30% of cases that are refractory, multiple genic risk to the developing foetus. Bipolar disorder per drugs need to be used in combination. Getting the right se does not increase the risk of malformation or foetal drug for a person with epilepsy involves balancing bene- death [35], but several mood stabilisers are associated fits and side effects as well as taking account of lifestyle with major teratogenicity. issues and personal preferences [37]. All psychotropic medications cross the placenta [36]. Table 3 summarises the main anti-epileptic drugs that As well as the recognised risk of teratogenicity – which could be offered to a woman of childbearing age. Whilst occurs in the first trimester during organogenesis – valproate (first licensed in 1967) is no longer the common- there are further ways in which these medications may est anti-epileptic drug prescribed, it remains one of the adversely affect a pregnancy. Viguera et al. categorise most effective. It is still used in emergency settings to con- the effects of psychotropic medication use in pregnancy trol focal and generalised seizures; it may be effective when into: [1] obstetric complications (such as low birth newer anticonvulsants have not worked; and it is the rec- weight), [2] perinatal complications (occurring shortly ommended first-line therapy for complex partial seizures. after birth) and [3] long-term neurological and behav- Schmidt and Schachter point out that whilst two in ioural sequelae (such as autism) [23]. Table 2 every three women with epilepsy who become pregnant Table 2 Foetal and maternal risks associated with selected mood stabilisers. Compiled from various sources [50, 53, 78, 79, 101–106] Medication Risks to offspring associated with use in pregnancy Maternal risks associated with use in pregnancy Lithium Severe toxicity in newborn. There are limited and conflicting data Renal lithium clearance rises during pregnancy, so levels need to regarding the risk of cardiovascular malformations (including be monitored regularly to maintain therapeutic levels. Ebstein’s anomaly) following lithium exposure in utero. A large cohort study in 2017 showed that the relative risk was still elevated (1.7), and also dose dependent, but lower than previously thought. Absolute risk remains low (< 1/1500). Non-teratogenic associations include low birth weight, cyanosis, bradycardia, GI bleeding, polyhydramnios, seizures. Valproate Significantly elevates the risk of major defects (7 times higher). Increased hepatic clearance of valproate and increased apparent These include spina bifida, atrial septal defect, cleft palate, volume of distribution cause lower maternal levels of the drug. hypospadias, polydactyly and craniosynostosis. See Table 4 and main text for further details. Non-teratogenic associations include case reports of intra-uterine growth restriction, infant hepatic toxicity and foetal distress dur- ing labour. Neurodevelopmental associations – foetal exposure to valproate in utero is associated with 1.7 times risk of autism spectrum disorder. Carbamazepine Risk of major congenital abnormalities increased 1.8 times, Crosses placenta and lowers maternal serum levels, so doses including malformations of neural tube, urinary tract and may need to be increased. cardiovascular system, and cleft palate. Lamotrigine Conflicting evidence on the risk of malformations, especially Crosses placenta and lowers maternal serum levels, so dose may regarding dose response. need to be increased. Dizziness, diplopia and ataxia have been Evidence emerging that it appears to be a relatively safe drug in reported following these dose increases in pregnant women. pregnancy. Atypical Most do not appear to significantly increase malformation rate. Crosses placenta and lowers maternal serum levels, so doses antipsychotics Risperidone requires additional study. may need to be increased. Macfarlane and Greenhalgh BMC Pregnancy and Childbirth (2018) 18:200 Page 4 of 11 Table 3 Selected anti-epileptic drugs (and alternatives to valproate in the treatment of epilepsy), adapted from Schmidt and Schachter [10] Class of Name of drug Proposed mechanism Side effects Additional information drug 1st Phenytoin Sodium channel blocker Enzyme inducer (hence interaction First line for focal and generalised seizures generation with other medications), skin with focal onset hypersensitivity Ethosuxamide T-type calcium channel blocker Gastrointestinal side effects, First line for absence seizures insomnia, psychosis 2nd Carbamazepine Sodium channel blocker Enzyme inducer, skin First line for focal and generalised seizures generation hypersensitivity with focal onset Valproate GABA potentiation, blocks voltage GI upset, weight gain, tremor, hair First line for focal and generalised seizures, gated sodium channels, loss with curly regrowth, no skin hypersensitivity, no newer drugs epigenetically inhibits histone teratogenicity (see Table 4) have been shown to have higher efficacy deacetylase In women: polycystic ovarian syndrome, hyperandrogenism Rare: fulminant liver failure 3rd Vigabatrin GABA potentiation Visual defects, weight gain, seizure Use in infantile spasms, adjunct in complex generation aggravation, encephalopathy partial seizures Lamotrigine GABA potentiation, suppresses Tremor, dizziness, tiredness, loss of First line for focal and generalised seizures, glutamate release, inhibits co-ordination, menstrual disturb- lower efficacy than valproate for absence serotonin reuptake ance, dry mouth, sleep problems seizures Oxcarbazepine Sodium channel blocker Enzyme inducer, hyponatraemia, First line for focal and generalised seizures skin hypersensitivity with focal onset Gabapentin Calcium channel blocker Weight gain, psychosis, seizure Adjunctive use only, used in focal and aggravation, tiredness, dizziness generalised seizures with focal onset Levetiracetam SV2A modulation Tiredness, dizziness, behavioural First line in focal and generalised seizures problems with focal onset and myoclonic seizures. Topiramate GABA potentiation, glutamate Tiredness, dizziness, skin First line for focal and generalised seizures inhibition, sodium/calcium channel hypersensitivity, weight loss, blocker teratogenicity remain seizure free throughout their pregnancy, antiepi- various reasons, including sexual disinhibition associated leptic drug dosages may need to be adjusted as the preg- with mania [30]. nancy progresses, particularly when seizures occur in the Within these two scenarios, several factors might affect first trimester. Women taking lamotrigine, levetiracetam, the clinical outcome for both mother and child: the severity topiramate, and oxcarbazepine may need an increase in of the condition (including frequency and duration of re- dose to compensate for pregnancy-related increase in lapses), co-existing medication (including the need for com- clearance of these drugs so as to reduce the risk of bination therapy to control the bipolar disorder or breakthrough seizures. These authors also highlight the epilepsy), drug and alcohol use, co-morbidity, sociocultural small increased risk that the children of women who factors, level of social support; and also (in the second sce- take an antiepileptic drug during pregnancy will be small nario) the stage at which the pregnancy was confirmed. for gestational age and have a lower Apgar score. Deciding whether or not to continue valproate in these situations requires a complex risk assessment. Many studies over the years have assessed the sequelae of con- A woman of childbearing age taking valproate… tinuation and discontinuation of valproate – both to There are two conceivable scenarios when a woman tak- mother and child. We review these below. ing valproate would have the dilemma of continuing it during pregnancy: [1] she is planning to become preg- Risks of continuation nant whilst taking valproate; or [2] she has already be- Prospective controlled trials on the effects of valproate come pregnant whilst taking valproate. Both these during pregnancy are limited for obvious reasons, but scenarios are currently fairly common in both primary cohort studies have shown that women who reported and secondary care [38]. In addition to the fact that both using the medication during the first trimester of preg- bipolar disorder and epilepsy are common in women of nancy had a seven-fold higher risk of congenital malfor- childbearing age [15], patients suffering from bipolar dis- mations compared to the baseline rate of 1.62% [39]. order are at increased risk of unintended pregnancy for Indeed, the relative risk of valproate on major defects is Macfarlane and Greenhalgh BMC Pregnancy and Childbirth (2018) 18:200 Page 5 of 11 so high, and these defects are so characteristic, that the relapse than those who continued mood stabilisers, and term ‘foetal valproate syndrome’ has been described the median time until first recurrence was four times [40]. Reasons for the teratogenic effects are not fully shorter [57]. If the mood stabiliser was discontinued understood, but possibly involve epigenetic effects, in- abruptly, recurrence latency was eleven times shorter. cluding the inhibition of histone deactylase with associ- Most studies of mood stabiliser discontinuation during ated changes in gene expression [41], increases in foetal pregnancy have been on lithium withdrawal [58–60]; oxidative stress, or the antagonism of folate required for specific evidence on discontinuing valproate in preg- DNA synthesis [42]. nancy is sparse. However, evidence for valproate with- As well as its teratogenic effects, valproate may lead drawal outside of pregnancy illustrates similar trends: to problems after birth, including immediate withdrawal relapse rates are high, especially during abrupt with- effects such as jitteriness [40]. Valproate therapy during drawal [61–63], and there is even a case report of one pregnancy has been shown to correlate with longer-term patient being treated for epilepsy developing new-onset neurodevelopmental problems leading to repetitive be- mania following valproate withdrawal [64]. haviours, impaired communication and social isolation Discontinuation can also be problematic in epilepsy. [43, 44], as well as reduced IQ [45]. These autistic-like Observations from the EURAP study showed that with- traits have been demonstrated in both animal models drawal of valproate in the first trimester (when it is most [46, 47] and human studies, affecting around 40% of teratogenic) was associated with a significantly higher children exposed to valproate [48, 49]. Actual diagnoses rate of generalised tonic clonic seizures (33%) compared of autism spectrum disorder are lower, however, at to when it was continued (16%) [65]. More striking, around 4% [50]. Although the mechanisms underlying however, is that the rate of seizures was also elevated these are yet to be elucidated, there is a possible link (29%) when valproate was switched to another with lower cell density in the cerebellum [51], associated anti-epileptic medication. with mutations in the PTEN gene [52]. Another consideration for bipolar disorder patients The risk of valproate use in pregnancy on specific mal- should include the risks of puerperal psychosis. Preva- formations has been quantified. Table 4 shows the odds lence of this condition in the general population is about ratio of different malformations based on an extensive 0.1–0.25%, but may be up to 50% in women with bipolar review of the research literature [53]. Risk of malforma- disorder [66]. Hospitalisation for psychiatric morbidity tion increases with drug dose and with combination predicts the risk of puerperal psychosis [67], so un- therapy [54–56]. treated bipolar disorder may not just affect the mother Considerations about continuation should also address during pregnancy, but also in the weeks afterwards. drug-related risks to the mother. Full blood count and liver Psychosis during the perinatal period must be viewed in function tests, for example, should be measured regularly a broader context: leaving it untreated can cause harm to to rule out blood dyscrasias or liver pathology [30]. the mother through poor self-care, increased drug and al- cohol use, non-attendance for obstetric care and impulsive Risks of discontinuation acts [30]. In severe cases, there may be direct harm to the There are risks associated with discontinuing valproate child through untreated maternal psychomorbidity, in- in a patient whose bipolar disorder or epilepsy is well cluding neglect or even infanticide [68, 69]. A 20-year controlled. Viguera et al. found that pregnant women study on puerperal psychosis in Austria found that out of with bipolar disorder who were euthymic at conception 96 patients, six died from suicide, with three ‘extended but stopped mood stabilisers were twice as likely to suicide attempts’ leading to two cases of infanticide [70]. Furthermore, severe mental health issues during and soon after pregnancy can adversely impact the child’semo- Table 4 Odds ratios and absolute risk of congenital tional, cognitive and physical health later in life [71]. The malformation with sodium valproate (adapted from Jentink) [53] child may be removed from the care of the mother for Condition Odds ratio Absolute risk safeguarding reasons, leading to problems with bonding. (median and range) in offspring of mothers In sum, whilst there are good reasons to minimise the who took valproate in pregnancy use of sodium valproate in pregnancy, it is theoretically Spina bifida 12.7 (7.7–20.7) 0.6% possible that in some individual cases, the risks of dis- Atrial septal defect 2.5 (1.4–4.4) 0.5% continuing the drug could outweigh the benefits. Cleft palate 5.2 (2.8–9.9) 0.3% Pregnancy prevention programmes and valproate Hypospadias 4.8 (2.9–8.1) 0.7% A ‘pregnancy prevention programme’ is defined by the Polydactyly 2.2 (1.0–4.5) 0.2% new UK regulations on valproate prescribing as fol- Craniosynostosis 6.8 (1.8–18.8) 0.1% lows [5]: Macfarlane and Greenhalgh BMC Pregnancy and Childbirth (2018) 18:200 Page 6 of 11 1. There must be an assessment of the woman’s Patients with bipolar disorder who are already taking potential to become pregnant and pregnancy tests valproate and are planning pregnancy have two options: before and during treatment. (1) withdraw valproate slowly prior to conception, with 2. The woman must be offered counselling about the close monitoring of their mental health status, or (2) risk of valproate to her unborn child and the switch to a lower-risk mood stabiliser. The first option importance of using effective contraception while needs to be carried out cautiously to minimise risk of re- taking the drug. lapse, and the decision to do this should take into ac- 3. Review by a specialist is now mandatory, and count past history of relapse, co-existing medications women taking valproate will be required to have and any protective or predisposing risk factors. annual specialist reviews including completing a The second option reduces the risk of maternal psy- risk acknowledgement form. chomorbidity during pregnancy, but with a higher risk 4. The packaging for valproate will carry a visual to the foetus. Although the most commonly prescribed warning of the risks associated with pregnancy. mood stabilisers (lithium, carbamazepine and valproate) Pharmacists will be required to discuss the risks are associated with foetal abnormalities – albeit to differ- and issue a warning card every time they dispense ing extents – current evidence on lamotrigine and atyp- valproate to women of childbearing age. ical antipsychotics is more favourable [36]. Various studies have looked at the safety of lamotrigine Many of these steps reflect what has become accepted use in pregnancy, particularly regarding its dose. Tomson good practice in several countries over the past few years et al..., using the EURAP data, found differences in the [4, 72], but they are now becoming mandatory in the malformation rates in patients given < 300 mg/day and UK. Clinicians generally avoid starting women of child- ≥300mg/day (2 and 4.5% respectively) [76]. Campbell et bearing age on valproate, but when this is viewed as clin- al, using data from the UK Epilepsy and Pregnancy Regis- ically unavoidable, information and a discussion about ter, found no significant relationship between dose and risks, along with an offer of contraception, are a core malformation rate, and concluded that whilst ‘lamotrigine component of care. has a favourable profile compared with valproate for ad- Whilst the new requirements are therefore in line with verse pregnancy outcomes, the requirements for seizure current recommended best practice, there is also evi- control should not be overlooked’. dence suggesting an evidence-practice gap. For example, Atypical antipsychotic drugs may be used in the man- a recent study in the UK showed that around half the agement of bipolar disorder and are typically recom- women taking sodium valproate were unaware of its po- mended for short-term use [77]. In a review of tential to damage the foetus [73]. A literature review on treatment of bipolar disorder in pregnancy, Grover and management of women with substance-use disorders Avasthi cite numerous studies with differing findings on found that unplanned pregnancy was common but the safety profiles of olanzapine, risperidone, quetiapine, also that access to long-acting reversible contraception amisupiride, ziprasidone, aripiprazole and clozapine, but through integrated contraception services was an ef- conclude that these drugs are nonetheless safer than fective approach to targeting this problem [74]. We lithium or valproate in pregnancy [36]. A recent large could learn from approaches taken in low-income cohort study in the United States showed that anti- countries, such as the implementation of post-abortion psychotic use early in pregnancy does not ‘meaningfully contraception in Zimbabwe, which has significantly de- increase the risk for congenital malformations overall or creased unplanned pregnancy rates in women with cardiac malformations in general’ [78]. Risperidone car- mental health conditions [75]. ries a small increased risk, and requires additional study. The above measures will only be relevant, of course, if A recent letter in the BMJ highlighted that as the the woman finds it acceptable to prevent pregnancy. In warnings regarding valproate use in pregnancy are justi- many women, there comes a time when pregnancy is de- fiably being strengthened, it is very important to search sired. The clinician should explain to the women that for safer alternatives [79]. Nevertheless, we should not whilst it is never possible to promise a healthy baby, the underestimate the difficulty of interpreting observational chances of this happening will be best if the pregnancy data on medication effects during pregnancy. is carefully planned, including adjusting medication in the pre-conception period – which in the UK must (with How to minimise valproate use during pregnancy rare exceptions) involve discontinuation of valproate. The most difficult clinical decisions may arise when a pa- Women should be encouraged to report a pregnancy as tient using valproate presents when already pregnant. Pre- soon as the test is positive – and reassured that the doc- sentations later in pregnancy and those in women on tor will not be judgemental even if the pregnancy was higher doses of valproate are associated with an increased “unplanned”. risk of foetal abnormalities [56]. Current recommendations Macfarlane and Greenhalgh BMC Pregnancy and Childbirth (2018) 18:200 Page 7 of 11 are to withdraw the drug if possible, and especially during treatment concordance and decision quality in epilepsy the first trimester [49]. However, in a systematic review management, specifically for situations like pregnancy examining the risk of bipolar disorder recurrence fol- and medication withdrawal [84]. The model involves lowing discontinuation of mood stabilisers, the au- three kinds of talk: (1) team talk, where the patient is thors concluded that in women with unstable forms encouraged to consider different management strategies of the disease, the high risk of relapse associated with (e.g. valproate vs. levetiracetam for epilepsy); (2) option rapid withdrawal of mood stabilisers more than bal- talk, where more detailed information about the options anced the potential risk to the foetus [80]. This sug- is provided (typically using an ‘option grid’– a matrix gests that gradual withdrawal through down-titration structured around questions the patient might ask and of dose is preferable to abrupt discontinuation. covering all potential options for a particular set of cir- It is possible to conceptualise hypothetical scenarios in cumstances), and (3) decision talk, where the clinician which continuation of sodium valproate during preg- assists the patient with decisions by providing facts, fig- nancy could be clinically justifiable. For example, if a pa- ures and risks [87]. tient on valproate presents in her final trimester with a The talk model maps well to questions around val- history of severe and unstable bipolar disorder, has re- proate use in which women who are pregnant (or lapsed during a previous pregnancy and caused signifi- planning on becoming pregnant). The clinician should cant harm to herself and/or her baby, the risks of firstly present the different management options. discontinuation may outweigh the risks of continuation, These would include: (1) continuing the drug at the though even in such an extreme case, careful dose re- current dose, (2) titrating down to a lower dose, (3) duction may also be an option. discontinuing the drug, or (4) changing to a different In rare situations where sodium valproate prescription medication. To support more detailed conversations, continues during pregnancy, use should be restricted to amatrixof options couldbeoffered(seeexample in monotherapy [81] and at the lowest dose possible [56, 76]. Table 5). Thethird step in thetalk model wouldbefor the A role for shared decision-making? patient to discuss their preferred option with the clin- In view of the new regulations requiring a woman of ician in detail, which would involve getting a more childbearing age to sign a risk acceptance form if she accurate picture of the risks involved. For example, if chooses to continue valproate, informed decision-making the woman chooses to discontinue valproate (column is more important than ever. 4inTable 3) the clinician should outline that this Shared decision-making is a process whereby health still presents risks to the baby, with the potential for professionals and patients work together to make health- the mother to become mentally unwell and hence care choices [82]. When deciding which treatments are perhaps neglect herself and her baby, leading in ex- appropriate, a discussion should involve the patient, with treme cases to separation via social services. As noted the clinician guiding them through the benefits and risks above, the precise risks of this eventuality will depend in order to make an informed decision [83]. Policy- on the medical and sociodemographic details of the makers have called for increased collaboration between individual case. It is hoped that in most cases clin- patients and clinicians [84], and patients are more likely ician and patient will be able to collaboratively weigh to adhere to a healthcare decision if they have been in- up the pros and cons and achieve a decision that volved in the process [85]. takes account of both mother and baby’s health. Legare et al. have carried out a narrative review of the The question of shared decision-making for a terato- literature on shared decision-making, and systematically genic drug in pregnancy raises an ethical conundrum. debunked various myths regarding it. These include the Whilst the mother may choose to continue valproate assumptions that it takes longer to carry out in consulta- (e.g. if her bipolar disorder or epilepsy is tions, costs more money, or that it is incompatible with well-controlled on it), the foetus has no chance to ex- following clinical practice guidelines [82]. The authors press a view. Arguably, a ‘paternalistic’ decision by the also show that contrary to many clinicians’ expectations, clinician to discontinue (or not commence) valproate in vulnerable patients who appear passive tend to gain a pregnant woman is actually a form of advocacy for a more clinical benefit than those whose decision is made second patient (the foetus). Others might argue that for them. this line of reasoning presupposes that a) the foetus will There is a wide variety of evidence-based tools to sup- necessarily come to less harm overall if valproate is not port shared decision-making during the clinical encoun- given (in reality the balance of benefits versus harms ter [86], and some of these have been trialled may be more complex); and b) the mother will be moti- successfully in specific diseases. For example, the talk vated by self-interest rather than taking her unborn model, developed by Elwyn et al. [87], improves child’s needs into account. Macfarlane and Greenhalgh BMC Pregnancy and Childbirth (2018) 18:200 Page 8 of 11 Table 5 List of frequently asked questions and management options to support shared decision-making regarding valproate use for bipolar disorder before or during pregnancy Frequently Continuing the current dose of Lowering the dose of valproate Discontinuing valproate Changing to another medication asked valproate questions What does No change to medication or Over a period of weeks to Over a period of weeks to Switching to a different medication it involve? dose months, decreasing the months, gradually stopping (e.g. lamotrigine or an amount of valproate valproate antipsychotic) What are Usual side effects of valproate Usual side effects of valproate, Higher risk of relapse Risk of relapse if the other the risks to potential for relapse (depends on a variety of medication is not as effective as me? factors – discuss with your valproate; risk of new side effects clinician), increased risk of puerperal psychosis What are Congenital malformations (see Reduced risk of congenital Indirect risks, e.g. disinhibition Some medications are much safer the risks to Table 4) long-term developmen- malformations and from poorly controlled for your unborn baby (specifically my baby? tal disorders (estimated one in 3) developmental disorders (risk bipolar disorder (discuss with lamotrigine, some antipsychotics) depends on the dose, discuss your clinician) with your clinician) What are You are less likely to relapse or Your unborn baby will have a Your unborn baby will have If you can tolerate the new drug, the suffer from puerperal psychosis lower risk of malformations the same risk of you are less likely to relapse or benefits? than if you continue the full malformations as the general suffer from puerperal psychosis; the dose population other medication could have adverse effects Who People with unstable bipolar People with bipolar disorder People who have been stable People who are stable on would disorder and frequent relapses who are not controlled on off valproate and do not wish alternatives to valproate benefit who are not controlled on other other medication to take other medications most from medication or lower doses of during pregnancy this? valproate The future Although the teratogenic and long-term neurodevelop- Given the limited evidence base on the precise benefits mental effects of valproate are now well established, the and harms associated with alternatives to sodium valpro- current evidence suggests that the recent strengthening ate during pregnancy, randomised controlled trials to as- of regulatory restrictions on its use are justified. How- sess their relative efficacies and safety profiles are ever, it would be premature to ban the use of this drug justified. Various such trials are ongoing. in women of childbearing age in the UK (since in rare Personalised (that is, stratified) medicine offers some cases the benefits of its use may outweigh potential potential avenues for further research. One study has harms). In the light of the new regulatory framework, we demonstrated that specific maternal and foetal genotypes believe that informed, democratic conversations are in mice confer a greater susceptibility to the teratogenic needed and we have provided an evidence-based frame- effects of valproate [88], and may mean that in the future, work to support shared decision-making. More research some human genotypes could be preselected for continu- should be undertaken on how shared decision-making ing (or not continuing) the drug during pregnancy. More plays out in this group of patients, as well as on the effi- speculatively, environmental factors may predict suscepti- cacy and safety of the various alternatives to sodium val- bility to valproate-induced teratogenicity. Ogawa et al. proate in bipolar disorder and epilepsy. showed that geographical stressors, in particular the loca- tion of conception, significantly affected pregnant rats’ Abbreviations sensitivity to teratogenicity during valproate use [89]. ANSM: French National Agency for the Safety of Medicines and Health Products; EURAP: International Registry of Anti-Epileptic Drugs and Preg- However, in general the hope for stratified solutions has nancy; MHRA: Medicines and Healthcare Devices Regulatory Agency; greatly exceeded the clinical benefit of such solutions, so NNT: Number Needed to Treat we should remain cautious about such options [90]. Acknowledgements Conclusion We thank the two reviewers for exceptionally helpful and detailed The management of bipolar disorder and epilepsy during comments on a previous version of this paper, including suggestions for pregnancy continues to carry complex challenges. So- additional books and papers to include. dium valproate use is a growing issue in women of child- bearing age, and patients and clinicians may well be Funding faced with a situation in which they must weigh up the TG’s contribution was part funded by the National Institute for Health benefits and harms of continuation. Research Biomedical Research Centre, Oxford, grant BRC-1215-20008. Macfarlane and Greenhalgh BMC Pregnancy and Childbirth (2018) 18:200 Page 9 of 11 Authors’ contributions 17. Hunt GE, Malhi GS, Cleary M, Lai HMX, Sitharthan T. Prevalence of comorbid AM carried out a narrative review of the literature to formulate the debate bipolar and substance use disorders in clinical settings, 1990-2015: article and drafted the manuscript. TG checked the first draft, redrafted some systematic review and meta-analysis. J Affect Disord. 2016;206:331–49. paragraphs and suggested additional references. Both authors contributed to 18. Di Florio A, Craddock N, van den Bree M. Alcohol misuse in bipolar disorder: revising the paper. Both authors have given approval for the work to be a systematic review and meta-analysis of comorbidity rates. Eur Psychiat. published, and agree to be jointly accountable for all aspects of the work. 2014;29(3):117–24. 19. Amerio A, Odone A, Liapis CC, Ghaemi SN. Diagnostic validity of comorbid bipolar disorder and obsessive compulsive disorder: a systematic review. Authors’ information Acta Psychiatr Scand. 2014;129(5):343–58. Alastair Macfarlane MA, MBBS is an Academic Foundation Year 1 doctor 20. Wingo AP, Ghaemi SN. A systematic review of rates and diagnostic validity working at the Royal Free Foundation Trust. He is currently working in of comorbid adult attention deficit hyperactivity disorder and bipolar psychiatry at the Springwell Centre, Barnet Hospital. Trisha Greenhalgh disorder. J Clin Psychiatry. 2007;68(11):1776–84. FMedSci is a GP and Professor of Primary Care Health Sciences at the 21. Simon NM, Otto MW, Wisniewski SR, Fossey M, Sagduyu K, Frank E, Sachs University of Oxford. GS, Nierenberg AA, Thase ME, Pollack MH, et al. Anxiety disorder comorbidity in bipolar disorder patients: data from the first 500 participants Ethics approval and consent to participate in the systematic treatment enhancement program for bipolar disorder N/A (STEP-BD). Am J Psychiat. 2004;161(12):2222–9. 22. Kupfer DJ, Frank E, Grochocinski VJ, Cluss PA, Houck PR, Stapf DA. 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