Taking valproate during pregnancy is a serious risk: An update on practice implications

The risks of inadequate warnings about damage done by valproate exposure in utero have become a focus of national and international attention by policymakers (Hunt, 2018; European Medicines Agency [EMA], 2017).

There is a pressing need now for a ‘new valproate prevention programme’ in the UK and in Europe. This includes assessing pregnancy potential/intentions, pregnancy tests before and during treatment with valproate, individualised counselling, informed consent using a new ‘risk acknowledgement form’, regular reviews of treatment, and effective contraception while taking valproate. Crucially, there is now equal emphasis on all women of childbearing potential, replacing the previous focus on already pregnant women. Strengthening preconception education about valproate is a welcome preventative development.


Jonathan Sher Independent Consultant and Visiting Expert at Edinburgh University’s Scottish Collaboration for Public Health Research and Policy (SCPHRP)

Two years ago, when I cited the prescription medication ‘valproate’ as an example of the need for preconception education, counselling and care, there was little reaction (Sher, 2016). Now, a tipping point has finally been reached. Why? Not because of a recent scientific breakthrough or dramatic new research findings. 

Valproate is a powerful teratogen (i.e. something capable of harming normal fetal development). This was established by decades of rigorous undisputed evidence (Meador & Loring, 2016; EMA, 2014; Meador et al, 2013). Among live births, up to 40% of babies exposed to valproate in utero experience long-term neurodevelopmental problems, while 10% are born with significant physical abnormalities (Meador, 2016; Medicines & Healthcare products Regulatory Agency [MHRA}, 2016). Valproate exposure can also cause miscarriages and stillbirths.

Valproate is not a rare medication. In England alone, approximately 23,000 prescriptions are given to girls and women of childbearing age every three months (NHS England, 2017; NHS Digital, 2015).

The impetus for current attention and action did not come from health professionals. Instead, it is primarily the families whose children (now often teens or adults) suffered lasting impairment who prompted this ‘discovery’ of valproate. They are angered by inadequate warnings, as well as the lack of preconception advice and consent. They are also very discontent about the paucity of follow-up treatment and the absence of compensation from manufacturers, prescribers or government (EMA, 2017a; Martin, 2017).  Historical, and ongoing, shortcomings led valproate victims to band together to enlist both policy and legal advocates. As is often the case, it has taken campaigners years of perseverance to become an ‘overnight success’. By means of legal action and protests, the families pressured national agencies to pay attention. There has been direct action in the UK to gain support from the families’ Westminster representatives. Major lawsuits have been filed in France and France’s parliament has established an initial compensation fund for valproate victims (Health News, 2016, www.reuters.com/). The French medicines regulator (ANSM) had already taken independent action and then pressed the EMA to consider more robust regulations and warnings about the avoidable negative outcomes of this teratogen (ANSM, 2017).

The formidable European Medicines Agency never held a Public Hearing during its 22-year history – until last year. EMA’s first-ever Public Hearing occurred in September 2017. The single subject was valproate (EMA, 2017b). The Hearing was fascinating, occasionally heart-rending and remarkable for more than being a first. Many individuals (mostly women) shared their lived experiences and specialist organisations provided supporting evidence. A remarkable feature was the oft-expressed desire for EMA not only to create more effective warnings but also to go well beyond this and recommend broader actions. This reflected the concern that stronger warnings - and even quality informational materials, e.g. the UK’s ‘Valproate Toolkit’ - might not be adequate in preventing continuing harm (MHRA, 2016a). Making informational materials available does not guarantee they will be read, understood and change behaviour among patients, prescribers, dispensers and distributors. The final noteworthy aspect of this Public Hearing was its heavy emphasis on epilepsy. Valproate was originally created as, and remains, an effective epilepsy medication. A small proportion of women will still require it to prevent severe seizures, even during pregnancy. It was agreed, however, that valproate should only be used during pregnancy when no effective alternative exists. 

Valproate’s high teratogenicity is why women with epilepsy have historically been most likely to receive preconception counselling, monitoring and care. ‘Most likely’ does not mean universally, as repeatedly pointed out to the EMA. Crucially, however, the reality is that valproate has been prescribed, dispensed and taken by many women of childbearing potential for numerous reasons other than epilepsy – such as migraine prevention, personality disorders and mood swings, pain relief, aggression and bipolar disorder (Murphy et al., 2016; Adedinsewo et al., 2013).

Pre-prescribing counselling of women and girls about the dangers of valproate appears inadequate

The EMA’s Public Hearing focussed heavily on epilepsy, but only lightly on these other uses, including the ‘off label’ ones. No explicit attention was paid to the efficacy of ‘off label’ prescribing of valproate to girls and women of reproductive potential. This is particularly worrisome, given that there are alternative medications - possibly equally effective and less teratogenic - available for all the conditions for which valproate is currently prescribed (Wen et al., 2015). There was a corresponding lack of information at the Public Hearing about any efforts made to warn about, or prevent, prescribing valproate to girls and women of childbearing potential who do not have epilepsy. No evidence was offered that these women routinely receive adequate preconception care, monitoring and counselling. In fact, one alarming, small-scale survey in England reported that: ‘The use of valproate [2005-2012] was increased overall by 64% and there was an 18% increase in off-label valproate use. The rate of clinical discussion carried out during commencement declined from 70% to 35% and at annual review from 50% to 22%’ (Atturu & Odelola, 2015). 

In the absence of a serious informed consent process, no competent physician would prescribe valproate to a woman known to be pregnant. However, in the UK and some other Organisation for Economic Co-operation and Development (OECD) nations, roughly half of all pregnancies are still unplanned, unintended or mistimed. Thus, women sometimes continue taking valproate before knowing they are pregnant and so, inadvertently risk avoidable harm. Preconception action is especially important since, as was pointed out during the EMA’s Public Hearing, it is not safe to discontinue or replace valproate immediately. At least one month’s weaning is recommended.

Early this year, the EMA, which will move its headquarters from London, post-Brexit, issued its findings (EMA, 2018) and recommendations based upon the Public Hearing and other submissions to its Pharmacovigilance Risk Assessment Committee (PRAC). This brief document is well worth reading. The EMA’s encouragement of new restrictions is a major step forward in several respects. It states that valproate ‘must not be used’ in pregnancy, with rare exceptions for individual women: a) having epilepsy and b) for whom there is no effective alternative medication. The EMA calls for stronger, more ubiquitous warnings, patient reminder cards and updated educational materials. 

Equally important, it underscores the pressing need for a ‘new valproate prevention programme’. This includes assessing pregnancy potential/intentions, pregnancy tests before and during treatment with valproate, individualised counselling, informed consent using a new ‘risk acknowledgement form’, regular reviews of treatment and effective contraception while taking valproate. Crucially, there is now equal emphasis on all women of childbearing potential, replacing the previous focus on already pregnant women.

There is an urgent need for a valproate prevention programme

 Strengthening valproate’s preconception, preventative element is a welcome development.  Whether these European recommendations will be implemented in the UK is yet another post-Brexit mystery. The signs are positive. A senior official within the UK’s MHRA chairs the PRAC at present. In February 2018, following media attention and pressure upon Westminster politicians, the Prime Minister and the UK’s Health Secretary announced a major review of valproate. As it is not in the EMA’s remit, there was no action recommended about the treatment of, or compensation for, past valproate victims. This presents a continuing challenge for campaigners in both the UK and Europe.

One oft-forgotten impediment to avoiding valproate harm is confusion about the name. People are becoming increasingly familiar with valproate as a medication to be avoided if pregnant, of if trying/likely to conceive. But, very few women of childbearing age are given a generic prescription for ‘valproate’ or ‘valproic acid’. Instead, women in Europe/UK read on the box or label that they are taking: Absenor, Convival Chrono, Convulex, Delepsine, Depakin, Depakine, Depakote, Depamag, Depamide, Deprakine, Diplexil, Dipromal, Epilim, Episenta, Epival, Ergenyl, Espa-Valept, Hexaquin, Kentlim, Leptilan, Micropakine L.P., Orfiril, Petilin, Valepil, Valhel PR, Valpal, Valpro or Valprolek. This disconnects the active ingredient from the brand name, which can easily contribute to confusion and unintentional risk-taking.

What should be done about teratogenic agents other than valproate?

Of course, valproate is not the only teratogenic medication prescribed in the UK, Europe or worldwide (Bastow et al., 2017). Will the EMA limit itself to this one medication or is this the beginning of an effort by national and international regulatory agencies to deal better with all drugs known to create risks for adverse pregnancy and birth outcomes?

As health professionals know, but many in the general public do not, teratogens exist in very different forms. They can be environmental, e.g. radiation or hazardous chemicals in the workplace, neighbourhood or home; or, communicable diseases, e.g. rubella or zika virus, as well as medications and other consumable products.

Teratogens of any kind jeopardise what anyone intending to become a mother or father deeply desires: a safe pregnancy, a thriving baby and rewarding parenthood. Sadly, these positive outcomes are far too often not achieved, while the harm is inequitably distributed (Sher, 2016a). While beyond the remit of the EMA, alcohol remains one of the most common and potentially most potent teratogens. Across the UK, in particular, there is a continuing ‘blind spot’ about preventing or identifying Fetal Alcohol Spectrum Disorder (FASD), or properly supporting those already affected (May et al., 2018; British Medical Association, 2017; de Caestecker & Sher, 2017; Jonsson et al., 2014). 

Neither ‘crying wolf’ nor ‘burying one’s head in the sand’ is helpful in preventing the risks of valproate or any other teratogen. Both extremes are counterproductive for prospective mothers and fathers. What they want and need is respectful support to make genuinely informed, empowering choices about preparing for pregnancy and parenthood. 

Dr Jonathan Sher can be reached at: This email address is being protected from spambots. You need JavaScript enabled to view it.


Best practice guidelines for warning about the risks of all proven teratogens

When discussing the risks of proven teratogens in pregnancy, advice given should be:

Respectful and compassionate
Toward every individual being cautioned about established risks. 
Naming, shaming and blaming people when their behaviours (often inadvertently) undermine their good intentions is both cruel and ineffective.

Proportionate to the proven risks 
Warnings and other primary prevention activities should have at their core information that is accurate, easily understood and, most importantly, explains clearly why the advice being given is worth heeding. 

Given and received early
And shared widely enough to reach all relevant people (especially those of reproductive potential) to allow sufficient time for necessary changes and primary prevention to occur. 

The means getting the right information at the right time to the right people instead of, for instance, waiting until the ‘first booking appointment’ when a pregnancy is already underway. Prescribers of teratogenic medications have a responsibility to provide the information and counselling necessary for there to be meaningful informed consent before the first prescription is written for any girl or woman of reproductive potential.

Accompanied by assistance
There should be easy access to opportunities to receive the help needed to make necessary life-style changes, including switching medications. In addition, valproate and some other medications can supress folate levels, which means increased Vitamin B9 (folic acid) supplementation should be routinely encouraged before and early in pregnancy (Meador, 2018). Public health campaigns should be combined with relationship-based preconception and antenatal counselling. While well-constructed, broadly distributed, key messages are helpful in raising societal awareness and cultural sensitivity, they are not enough by themselves. People are persuaded by, and act upon, personalised information and advice from trusted, respected sources (Sher, 2017; Allen et al., 2012; Nolan, 2009).


References

Adedinsewo, D.A., Thurman, D.J., Luo, Y-H., Williamson, R.S., Odewole, O.A. et al. (2013) Valproate prescriptions for nonepilepsy disorders in reproductive-age women, Birth Defects Research, 97(6),403-408. 

Agence nationale de securite du medicament et des produits de santé [ANSM] (2017) Available at:  http://ansm.sante.fr/content/download/111303/1410275/version/1/file/Enquete-Valproate-Synthese-ANSM.pdf <accessed 28 February, 2018>

Allen, K., Collier, S., Kelly, C., Pates, A., Sher, J. et al (2012) Exploration of the information support needs of parents. NHS Health Scotland. Available at: http://www.healthscotland.com/uploads/documents/19013-RE001ExecSum.pdf <accessed 28 February, 2018>

Atturu, H., Odelola, A. (2015) Valproate prescribing in women of childbearing age: An audit of clinical practice. Advances in Psychiatry. Available at: https://www.hindawi.com/archive/2015/520784/ <accessed 28 February, 2018>

Bastow, B.D., Holmes, J.L. (2017) Teratology and Drug Use During Pregnancy. Available at: https://emedicine.medscape.com/article/260725-overview <accessed 28 February, 2018>

British Medical Association (2016) Alcohol and pregnancy: Preventing and managing fetal alcohol spectrum disorders. Available at: https://www.bma.org.uk/collective-voice/policy-and-research/public-and-population-health/alcohol/alcohol-and-pregnancy <accessed 28 February, 2018>

de Caestecker, L., Sher, J. (2017) We need facts not fiction on FASD. Children in Scotland. Available at:  http://bit.ly/FASDCiSmagazine <accessed 28 February, 2018>

European Medicines Agency (2014) CMDh agrees to strengthen warnings on the use of valproate medicines in women and girls. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2014/11/news_detail_002220.jsp&mid=WC0b01ac058004d5c1 <accessed 28 February, 2018>

European Medicines Agency [EMA] (2017) PRAC List of Questions on Valproate. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Valproate_2017_31/Procedure_started/WC500223243.pdf <accessed 28 February, 2018>

European Medicines Agency (2017a) Summary of the EMA public hearing on valproate in pregnancy. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Other/2017/10/WC500236051.pdf <accessed 1 March, 2018>

European Medicines Agency (2017b) Full EMA Public Hearing on Valproate. Available at: https://www.youtube.com/watch?v=07LlmEpwY9g&feature=youtu.be <accessed 28 February, 2018>

European Medicines Agency (2018) PRAC recommends new measures to avoid valproate exposure in pregnancy. Available at: -http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2018/02/news_detail_002903.jsp&mid=WC0b01ac058004d5c1 <accessed 1 March, 2018>

Health News (2016) France sets up fund for Sanofi drug epilepsy victims. Health News. Available at: https://www.reuters.com/article/us-sanofi-france-compensation/france-sets-up-fund-for-sanofi-epilepsy-drug-victims-idUSKBN13B1FN <accessed 12 March, 2018>

Hunt, J. (2018) Parliamentary Debate on Medicines Safety Review. Available at:

https://hansard.parliament.uk/commons/2018-02-21/debates/7DA2E2F3-E1E6-40CB-8061-680E0399CA97/MedicinesAndMedicalDevicesSafetyReview and https://www.youtube.com/watch?v=kiGKIy8_Vac <accessed 1 March, 2018>

Jonsson, E., Salmon, A., Warren, K.R. (2014) The international charter on prevention of fetal alcohol spectrum disorders. The Lancet, 2(3),e135–e137.

Martin, M. (2017) Testimony at the EMA Public Hearing on Valproate. Available at: https://www.youtube.com/watch?v=tN4jlxLLiL0 <accessed 1 March, 2018>

May, P., Chambers, C.D., Kalberg, W.O., Zellner, J., Feldman, H. et al. (2018) Prevalence of Fetal Alcohol Spectrum Disorders in 4 US communities. Journal of the American Medical Association (JAMA) 319(5),474-482.

Meador, K.J. (2016) Valproic acid: Reducing the risks of pre-natal exposure. The Lancet Neurology, 15(2),132-133.

Meador, K.J., Baker, G.A., Browning, N., Cohen, M.J., Bromley, R.L. et al. (2013) Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): A prospective observational study. The Lancet Neurology, 12(3),244-252. 

Meador, K.J., Loring, D.W. (2016) Developmental effects of antiepileptic drugs and the need for improved regulations. Neurology, 86(3).  Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4733155/ <accessed 1 March, 2018>

Meador, K.J. (2018) Periconceptional folate supplementation and the risk of autism following antiepileptic drug exposure. JAMA Neurology. Available at: https://jamanetwork.com/journals/jamaneurology/article-abstract/2666185?redirect=true <accessed 2 March, 2018>

MRHA (2016) Valproate and risk of abnormal pregnancy outcomes: New communication materials. Available at:

https://www.gov.uk/drug-safety-update/valproate-and-of-risk-of-abnormal-pregnancy-outcomes-new-communication-materials <accessed 1 March, 2018>

MRHA (2016a) Toolkit on the risks of valproate medicines in female patients. Available at: https://www.gov.uk/government/publications/toolkit-on-the-risks-of-valproate-medicines-in-female-patients <accessed 1 March, 2018>

Murphy, S., Bennett, K., Doherty, C.P. (2016) Prescribing trends for sodium valproate in Ireland. Seizure, 36,44-48. 

NHS Digital (2015) Prescriptions Dispensed in the Community: Statistics for England (2004-2014). Available at: http://digital.nhs.uk/catalogue/PUB17644 <accessed 1 March, 2018> See especially Table 7 and Figure 61.

NHS England (2017) Sodium Valproate Prescribing. Available at: https://www.england.nhs.uk/publication/prescribing-for-sodium-valproate/ <accessed 1 March, 2018>

Nolan, M. (2009) Information giving and education in pregnancy: A review of qualitative studies. Journal of Perinatal Education, 18(4),21-30.

Sher, J. (2016) Prepared for Pregnancy? NHS Greater Glasgow and Clyde (Public Health). Available at: 

http://www.nhsggc.org.uk/media/237841/prepared-for-pregnancy-j-sher-may-2016.pdf  <accessed 1 March, 2018>

Sher, J. (2016a) Missed Periods: Scotland’s opportunities for better pregnancies, healthier parents and thriving babies the first time . . . and every time. NHS Greater Glasgow and Clyde (Public Health). Available at:  http://www.nhsggc.org.uk/media/237840/missed-periods-j-sher-may-2016.pdf <accessed 1 March, 2018>

Sher, J. (2017) Making preconception health, education and care real. International Journal of Birth and Parent Education, 4(4),4-8.

Wen, X., Meador, K.J., Hartzema, A. (2015) Antiepileptic drug use by pregnant women enrolled in Florida Medicaid. Neurology, 84(9). Available at: https://www.ncbi.nlm.nih.gov/pubmed/25653296 <accessed 1 March, 2018>


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