Children born to mothers who took the antiepileptic drug sodium valproate during pregnancy may have a four to five-fold increased risk of developing neurodevelopmental disorders in early childhood, according to a study in Scientific Reports.
Fifty of the 991 French children (5%) who were exposed to sodium valproate were diagnosed with neurodevelopmental disorders in their first five years, compared to 15,270 of 1,710,441 children (0.89%) not exposed to any antiepileptic drugs.
Rosemary Dray-Spira and colleagues investigated the incidence of neurodevelopmental disorders in young children using anonymized medical records from 1,721,990 children born in France between January 2011 and December 2014.
11,549 of mothers had been treated with one of several common antiepileptic drugs during pregnancy and 15,458 (0.9%) children were identified as having neurodevelopmental disorders by the end of 2016.
Overall, children exposed to sodium valproate before birth had a higher risk of developing neurodevelopmental disorders in childhood than those not exposed to antiepileptic drugs, including a 5.1 times higher likelihood of intellectual disability, a 4.7 times higher likelihood of language, learning and motor disorders and a 4.6 times higher risk of autism spectrum disorders.
Increased risk was not observed in children exposed to sodium valproate during the first trimester only and the risk was lower among children exposed to lower doses of the drug, than among those exposed to higher doses.
Children born to mothers treated with the antiepileptic drugs lamotrigine, carbamazepine and pregabalin were 1.6 times, 1.9 times and 1.5 times more at risk of developing neurodevelopmental disorders, respectively.
No increased risk of neurodevelopmental disorders was observed in children born to mothers treated with the antiepileptic drugs clonazepam, gabapentin, levetiracetam or oxcarbazepine.
The findings indicate that exposure to sodium valproate, especially beyond the first trimester of pregnancy, may be associated with an increased risk of neurodevelopmental disorders in early childhood.
The risk of neurodevelopmental disorders associated with exposure to other antiepileptic drugs appears to be much lower, according to the authors.
In July 2017, almost 60 years after the thalidomide tragedy , the French National Agency for the Safety of Medicines and Health Products (ANSM) imposed a nationwide ban on the use of sodium valproate in pregnancy, on the grounds of teratogenicity .
Guidelines produced by the UK Royal College of Obstetricians and Gynaecologists in 2016 recommended avoiding this drug in any woman of child-bearing potential  (reflecting a previous NICE guideline published in 2014 ). More recently, regulatory bodies have tightened their stance significantly.
In February 2018, for example, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency recommended that valproate should not be used in pregnancy unless the woman has a form of epilepsy that is unresponsive to other anti-epileptic drugs, and also that the drug should not be prescribed for women of childbearing age who are not enrolled in a pregnancy prevention programme .
In April 2018, the UK Medicines and Healthcare Devices Regulatory Agency endorsed this recommendation .
Sodium valproate is a medication licensed for both epilepsy  and bipolar disorder , and is also used off label for a range of indications including migraine prophylaxis .
Whilst its use in epilepsy is falling in the UK as the use of third-generation anticonvulsants increases [9, 10], its use for bipolar disorder has been increasing, especially among women of childbearing age .
In Ireland, recent data corroborate these findings , which necessitate increased surveillance and an improved understanding of alternatives .
Bipolar disorder is a psychiatric condition characterised by alternating periods of elated mood and depression . The condition is a significant public health problem worldwide, and remains a challenge for patients and clinicians .
Systematic reviews examining the epidemiology of bipolar disorder show that it is associated with markedly increased suicide and self-harm rates , substance abuse  and other psychiatric morbidities [18–21]. Given the female preponderance and young age of onset of bipolar disorder (17.5 years) , women of childbearing age make up a significant proportion of patients. Management of bipolar disorder is difficult in this group, as many mood stabilisers have either been shown to be teratogenic or have unknown effects in pregnancy (see below) .
Epilepsy is a condition characterised by abnormal excessive synchronous neuronal activity in the brain causing seizures , and is associated with a variety of neurobiological, psychological, social and cognitive consequences. The prevalence of active epilepsy in adults is 5–10 per 1000, and is influenced by many factors, both genetic and environmental .
One risk factor for seizure activity is oestrogen , hence pregnancy can increase the seizure rate . Information from EURAP, the International Registry of Anti-Epileptic Drugs and Pregnancy, suggests that 20% of pregnant patients with epilepsy were treated with valproate from 1999 to 2004, despite knowledge of its teratogenic risks . A more recent study in the UK showed that valproate made up 25% of anti-epileptic drug prescriptions in pregnancy .
This article will explore the benefits and harms of sodium valproate and its alternatives in current or planned pregnancy in the context of a tightening regulatory system for this drug. We will suggest questions that should guide decision-making for these patients, and address the crucial issue of whether and how patients can be involved as democratic partners in such decisions.
Mood stabilisers in bipolar disorder
Mood stabilisers are the mainstay of pharmacological management in patients with bipolar disorder. Although there is some contention about what exactly constitutes a mood stabiliser , the defining feature is that these drugs improve both manic and depressive symptoms without significantly worsening either polarity .
Some drugs may be of benefit in patients with bipolar disorder but are not classed as mood stabilisers because of their ability to precipitate mania (e.g. some antidepressants) or worsen depression (e.g. some antipsychotics).
Table 1 shows the main classes of mood stabiliser used in the treatment of bipolar disorder. Sodium valproate, a mood stabiliser of the anticonvulsant class, is commonly prescribed for the treatment of mania and the prophylaxis of bipolar disorder . A systematic review assessing valproate efficacy in acute mania showed that it has a has a number needed to treat (NNT) of between 2.3 and 4.3 , and may be used in patients who have either failed to respond to lithium , or those who do not tolerate it . Prophylactically, the NNT to prevent manic and depressive episodes respectively is 21.3 and 10.5 .
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 name||Proposed mechanism(s) of action||Side effects|
|Mineral||Lithium||Enhances serotonergic neuron activity, inhibits pAp-phosphatase enzyme, interacts with nitric oxide signalling activity||Common: GI upset, fine tremor, polyuria, polydipsia, metallic taste in mouth, ankle oedema, weight gain. Chronic: renal toxicity, hypothyroidism.|
|Anti-epileptics||Sodium valproate||GABA potentiation, blocks voltage gated sodium channels, epigenetically inhibits histone deacetylase||Common: GI upset, hyperammonaemia (causing nausea), weight gain, tremor, hair loss with curly regrowth.|
In women: polycystic ovarian syndrome, hyperandrogenism.
Rare: fulminant liver failure.
|Lamotrigine||GABA potentiation, suppresses glutamate release, inhibits serotonin reuptake||Common: tremors, dizziness, tiredness, loss of co-ordination, 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.|
|Atypical antipsychotics||Risperidone||Dopaminergic (D1–5) receptor antagonist, serotonergic (5-HT2A/C) receptor antagonist||Common: sexual dysfunction (hyperprolactinaemia).|
Long term: movement disorders (e.g. tardive dyskinesia, akathisia, parkinsonism), increased risk of cardiovascular disease.
Rare: neuroleptic malignant syndrome
|Aripiprazole||Dopaminergic (D2) and serotonergic (5-HT1A) receptor partial agonist||Common: weight gain, headache, agitation, insomnia, gastrointestinal effects, disinhibition.|
Valproate has a number of side effects other than risks to the mother and foetus, which are summarised in Table Table1.1. In any patient, these side effects must be weighed against the significant risks associated with untreated mania or bipolar disorder, including suicide .
A high proportion of patients with bipolar disorder will face the scenario of needing to manage their illness during an anticipated or current pregnancy . This raises a very difficult clinical issue: managing the mental health needs of the mother whilst minimising the teratogenic risk to the developing foetus. Bipolar disorder per se does not increase the risk of malformation or foetal death , but several mood stabilisers are associated with major teratogenicity.
All psychotropic medications cross the placenta . As well as the recognised risk of teratogenicity – which occurs in the first trimester during organogenesis – there are further ways in which these medications may adversely affect a pregnancy. Viguera et al. categorise the effects of psychotropic medication use in pregnancy into:  obstetric complications (such as low birth weight),  perinatal complications (occurring shortly after birth) and  long-term neurological and behavioural sequelae (such as autism) . Table 2 summarises the main foetal and maternal risks associated with mood stabilisers.
|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 regarding the risk of cardiovascular malformations (including 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.
|Renal lithium clearance rises during pregnancy, so levels need to be monitored regularly to maintain therapeutic levels.|
|Valproate||Significantly elevates the risk of major defects (7 times higher). These include spina bifida, atrial septal defect, cleft palate, hypospadias, polydactyly and craniosynostosis. See Table Table44 and main text for further details.|
Non-teratogenic associations include case reports of intra-uterine growth restriction, infant hepatic toxicity and foetal distress during labour.
Neurodevelopmental associations – foetal exposure to valproate in utero is associated with 1.7 times risk of autism spectrum disorder.
|Increased hepatic clearance of valproate and increased apparent volume of distribution cause lower maternal levels of the drug.|
|Carbamazepine||Risk of major congenital abnormalities increased 1.8 times, including malformations of neural tube, urinary tract and cardiovascular system, and cleft palate.||Crosses placenta and lowers maternal serum levels, so doses may need to be increased.|
|Lamotrigine||Conflicting evidence on the risk of malformations, especially regarding dose response.|
Evidence emerging that it appears to be a relatively safe drug in pregnancy.
|Crosses placenta and lowers maternal serum levels, so dose may need to be increased. Dizziness, diplopia and ataxia have been reported following these dose increases in pregnant women.|
|Atypical antipsychotics||Most do not appear to significantly increase malformation rate. Risperidone requires additional study.||Crosses placenta and lowers maternal serum levels, so doses may need to be increased.|
Pregnancy prevention programmes and valproate
A ‘pregnancy prevention programme’ is defined by the new UK regulations on valproate prescribing as follows :
There must be an assessment of the woman’s potential to become pregnant and pregnancy tests before and during treatment.
The woman must be offered counselling about the risk of valproate to her unborn child and the importance of using effective contraception while taking the drug.
Review by a specialist is now mandatory, and women taking valproate will be required to have annual specialist reviews including completing a risk acknowledgement form.
The packaging for valproate will carry a visual warning of the risks associated with pregnancy. Pharmacists will be required to discuss the risks and issue a warning card every time they dispense valproate to women of childbearing age.
Many of these steps reflect what has become accepted good practice in several countries over the past few years [4, 72], but they are now becoming mandatory in the UK. Clinicians generally avoid starting women of childbearing age on valproate, but when this is viewed as clinically unavoidable, information and a discussion about risks, along with an offer of contraception, are a core component of care.
Whilst the new requirements are therefore in line with current recommended best practice, there is also evidence suggesting an evidence-practice gap. For example, a recent study in the UK showed that around half the women taking sodium valproate were unaware of its potential to damage the foetus .
A literature review on management of women with substance-use disorders found that unplanned pregnancy was common but also that access to long-acting reversible contraception through integrated contraception services was an effective approach to targeting this problem .
We could learn from approaches taken in low-income countries, such as the implementation of post-abortion contraception in Zimbabwe, which has significantly decreased unplanned pregnancy rates in women with mental health conditions .
The above measures will only be relevant, of course, if the woman finds it acceptable to prevent pregnancy. In many women, there comes a time when pregnancy is desired.
The clinician should explain to the women that whilst it is never possible to promise a healthy baby, the chances of this happening will be best if the pregnancy is carefully planned, including adjusting medication in the pre-conception period – which in the UK must (with rare exceptions) involve discontinuation of valproate. Women should be encouraged to report a pregnancy as soon as the test is positive – and reassured that the doctor will not be judgemental even if the pregnancy was “unplanned”.
Patients with bipolar disorder who are already taking valproate and are planning pregnancy have two options: (1) withdraw valproate slowly prior to conception, with close monitoring of their mental health status, or (2) switch to a lower-risk mood stabiliser. The first option needs to be carried out cautiously to minimise risk of relapse, and the decision to do this should take into account past history of relapse, co-existing medications and any protective or predisposing risk factors.
The second option reduces the risk of maternal psychomorbidity during pregnancy, but with a higher risk to the foetus. Although the most commonly prescribed mood stabilisers (lithium, carbamazepine and valproate) are associated with foetal abnormalities – albeit to differing extents – current evidence on lamotrigine and atypical antipsychotics is more favourable .
Various studies have looked at the safety of lamotrigine use in pregnancy, particularly regarding its dose. Tomson et al…, using the EURAP data, found differences in the malformation rates in patients given < 300 mg/day and ≥300mg/day (2 and 4.5% respectively) .
Campbell et al, using data from the UK Epilepsy and Pregnancy Register, found no significant relationship between dose and malformation rate, and concluded that whilst ‘lamotrigine has a favourable profile compared with valproate for adverse pregnancy outcomes, the requirements for seizure control should not be overlooked’.
Atypical antipsychotic drugs may be used in the management of bipolar disorder and are typically recommended for short-term use . In a review of treatment of bipolar disorder in pregnancy, Grover and Avasthi cite numerous studies with differing findings on the safety profiles of olanzapine, risperidone, quetiapine, amisupiride, ziprasidone, aripiprazole and clozapine, but conclude that these drugs are nonetheless safer than lithium or valproate in pregnancy .
A recent large cohort study in the United States showed that antipsychotic use early in pregnancy does not ‘meaningfully increase the risk for congenital malformations overall or cardiac malformations in general’ . Risperidone carries a small increased risk, and requires additional study.
A recent letter in the BMJ highlighted that as the warnings regarding valproate use in pregnancy are justifiably being strengthened, it is very important to search for safer alternatives . Nevertheless, we should not underestimate the difficulty of interpreting observational data on medication effects during pregnancy.
How to minimise valproate use during pregnancy
The most difficult clinical decisions may arise when a patient using valproate presents when already pregnant. Presentations later in pregnancy and those in women on higher doses of valproate are associated with an increased risk of foetal abnormalities . Current recommendations are to withdraw the drug if possible, and especially during the first trimester .
However, in a systematic review examining the risk of bipolar disorder recurrence following discontinuation of mood stabilisers, the authors concluded that in women with unstable forms of the disease, the high risk of relapse associated with rapid withdrawal of mood stabilisers more than balanced the potential risk to the foetus . This suggests that gradual withdrawal through down-titration of dose is preferable to abrupt discontinuation.
It is possible to conceptualise hypothetical scenarios in which continuation of sodium valproate during pregnancy could be clinically justifiable. For example, if a patient on valproate presents in her final trimester with a history of severe and unstable bipolar disorder, has relapsed during a previous pregnancy and caused significant harm to herself and/or her baby, the risks of discontinuation may outweigh the risks of continuation, though even in such an extreme case, careful dose reduction may also be an option.
In rare situations where sodium valproate prescription continues during pregnancy, use should be restricted to monotherapy  and at the lowest dose possible [56, 76].
reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984824/
More information: Risk of early neurodevelopmental disorders associated with in utero exposure to valproate and other antiepileptic drugs: a nationwide cohort study in France , Scientific Reports (2020). DOI: 10.1038/s41598-020-74409-x , www.nature.com/articles/s41598-020-74409-x