New Irish study finds that ‘continued effort is needed’ in reducing valproate risks

A new study which investigated the awareness, knowledge, and practice of healthcare professionals in implementing the Sodium Valproate (Epilim) Pregnancy Prevention Program (PPP) has been published in the medical journal Expert Opinion on Drug Safety.

The study was conducted by researchers from the Royal College of Surgeons in Ireland and funded by the Health Research Board (HRB) and the Health Products Regulatory Authority (HPRA). Epilepsy Ireland and OACS Ireland were members of the project’s steering committee.

The Valproate PPP was established in February 2018 and consists of measures to ensure that a woman does not become pregnant while on Sodium Valproate. Up to 40% of children exposed to Valproate in-utero will experience neurodevelopmental delays, while 10% of children will have congenital malformations.

The study focused on healthcare professionals (HCPs) experience and knowledge of the Valproate PPP. The researchers issued an anonymous survey to HCPs across Ireland who are involved in the care of women with epilepsy, including GPs, specialist consultants and pharmacists. In total, 1,544 GPs, 224 specialists and 2,052 community pharmacists were asked to complete the survey. Response rates were low from all three groups and the data is based on responses from 90 GPs, 219 pharmacists and 17 specialists.

Study Findings

Key findings from the study include:

  • 66% of GPs, 82% of community pharmacists, and 59% of specialists indicated that they had received information relating to the PPP, mainly as a result of the repeated “Dear Doctor/ Pharmacist” letters approved by the HPRA in recent years.
  • Knowledge of the magnitude of the risks associated with valproate use in pregnancy varied across the three HCP groups. 20% of GPs, 33% of pharmacists and 60% of specialists correctly identified the risk of malformations. For the risk of developmental disorders, 13% of GPs, 27% of pharmacists, and 40% of specialists correctly identified the extent of this risk.
  • Over 80% of HCPs were aware of the need for patients to be referred to a specialist before starting on valproate. However, only 42% of GPs, 62% of pharmacists and 60% of specialists were aware of the need for an annual review in line with the PPP.
  • Key aspects of the PPP are the information guides for HCPs and patients, which have been circulated regularly to HCPs. The study found ‘varied’ awareness and use of these materials. Over 80% of pharmacists were aware of the guides, and 60% said that they used them. However, just 60% of GPs were aware of the guides. Less than 40% of GPs said that they used the HCP guide in their practice and 20% said they used the patient guide.
  • Since the implementation of the PPP, 100% of neurologists said that they ensured patients understood the risks and the need for contraception. 83% said that they completed the annual risk acknowledgement form (ARAF). However, only two-thirds reported that they had requested their patient to have a pregnancy test before starting treatment.
  • Since the implementation of the PPP, 62% of GPs had reviewed their patient lists and 44% said they had recalled patients. 60% had ensured the patient understood the risks and 59% discussed the need to comply with contraception. 97% of GPs said they would advise their patient to seek specialist advice urgently in the case of an unplanned pregnancy.
  • 96% of pharmacists said that they had dispensed valproate in the past 12 months. 46% reported that they checked if the patient had received the Patient Guide and provided a copy if necessary while 30% stated that they reminded their patients about the need for annual treatment review. However, less than 20% said that they counsel female patients at each dispensing.

The authors point out a number of limitations to their study. The low response rate makes the results difficult to generalise and the respondents may not be representative of their wider professions. Another major weakness is that it did not survey Specialist Nurses, who regularly conduct reviews, consultations and provide counselling to patients taking Valproate. Finally, data was gathered within a year of the introduction of the PPP’s introduction, which may not have allowed sufficient time for it to be embedded in clinical practice. 

Analysis

While acknowledging the potential weaknesses in the study, Epilepsy Ireland nonetheless considers many of these findings to be deeply concerning.

Although we agree with the authors that the HCPs surveyed had a good awareness of the PPP and good knowledge of some of the key aspects of its implementation, the data also highlights significant gaps in implementing the PPP, which is mandatory for all women of childbearing potential taking valproate.

Despite numerous communications from the HPRA, the HSE, the Pharmaceutical Society and others, as well as the increased profile of the issue in the medical and consumer media, it is perplexing that significant numbers are not aware of the PPP, the extent of the risks involved or basic resources such as the HCP/ patient guides.

The responses from GPs are of particular concern. 1 in 3 said they had not received communications about the PPP; 4 out of 5 said they did not use the patient guide, while just 60% ensured their patients understood the risks and used effective contraception.

Despite this, 22% of GPs said that they prescribe valproate “occasionally to frequently”. 78% said they renewed a valproate prescription in the past 12 months and 4/73 GPs indicated they had initiated valproate treatment. The PPP states that “In girls and women of childbearing potential, valproate must be initiated and supervised by a specialist experienced in the management of epilepsy or bipolar disorder”.

Given what we know about the risks of valproate use in pregnancy and the potentially devastating impact of failing to ensure effective risk management, many of the study’s findings cannot be considered acceptable.

Yet they do not come entirely as a surprise. Last year, an Epilepsy Ireland survey of over 150 women with epilepsy who have been prescribed Sodium Valproate since the introduction of the PPP found similar shortcomings.

In our survey, almost 30% of respondents said they had never had a discussion with a health professional about the risks of valproate in pregnancy. Just 39% of all respondents said they had a discussion with a HCP since the introduction of the PPP (approx. 18 months). 1 in 3 women who had met with their GP about their epilepsy in that period said that their GP did not discuss valproate risks, although the figure was far better in relation to consultants or epilepsy specialist nurses (77% and 83% respectively). Less than 1/3 had been given a copy of the Patient Guide and a majority (62%) had not been asked to sign the annual risk acknowledgement form.

These findings, which closely correlate to the RCSI data, prompted Epilepsy Ireland and OACS Ireland to call for the establishment of a stakeholder group consisting of representatives from all those involved in the care of a women with epilepsy to review and strengthen the current risk reduction measures. We discussed this with the Minister for Health in November 2020 and the Minister agreed to pursue the matter. Unfortunately, there has been no further progress on this since the Minister’s commitment. Together with our colleagues in OACS Ireland, we recently wrote to the Minister urging him to act on this and other outstanding commitments. You can read our correspondence HERE.

In light of the RCSI findings, we are renewing our call for the URGENT establishment of this stakeholder group. The group should report to the Minister and should have representation from medical professionals (epilepsy and mental health), patient organisations, HSE, HPRA, Pharmaceutical Society of Ireland and representative groups such as the ICGP and IPU. While bodies such as the HSE, HPRA and PSI have all individually taken positive steps since 2018 to minimise risks, it is clear that actions to date have not been as successful as intended. A renewed, focused and co-ordinated approach across all stakeholders is required if we are to be successful.

In addition, we are calling for the IMMEDIATE recruitment of unfilled Epilepsy Specialist Nursing posts approved by the HSE in 2018 for the specific purpose of implementing the PPP. To date, just two of the six posts have been filled. This additional capacity MUST be added to enable the HSE's epilepsy service meet the requirements of the PPP for every woman taking valproate, including the need for annual treatment reviews.

In their paper, the authors of the RCSI study highlight a number of implications for policy and practice. They highlight the need for:

  • Knowledge reinforcement and process optimization, including the need for regular discussion between all HCPs and valproate patients, increased use of educational materials and better recognition by HCPs of their roles in implementing the PPP.
  • Continuing periodic outreach and dissemination of information to support PPP implementation in clinical practice.
  • New, targeted education initiatives for HCPs
  • Better linkages and communications (including e-health initiatives) between HCPs involved in the care of women prescribed valproate
  • A national database of women taking valproate to support systematic data collection

The authors concluded that continued effort is required to ensure optimal implementation of [the PPP] into clinical practice, including the need for further targeted education and collaborative learning among HCPs potentially involved in the care of women of childbearing potential prescribed valproate.”

We agree wholeheartedly with these conclusions. The most effective and perhaps only way to ensure positive change is through a collaborative effort to implement actions such as those above and others (e.g. patient awareness campaigns, practice audits etc).

It is unthinkable that in 2021, there is still a risk of children being born in Ireland with avoidable valproate-related disabilities. It must be acknowledged that for this to occur, a patient would need to have been prescribed, dispensed, and have taken Valproate without any of the professionals involved in her care (GP, pharmacist, specialist nurse, consultant) implementing the PPP. It would also most likely require the patient to have no prior knowledge of the risks involved herself.

This “Swiss Cheese” effect may give some comfort. However, with c. 1,600 women of childbearing potential currently taking valproate in Ireland, the risk is not insignificant. Enough is enough – this is a solvable problem, and it needs to be solved now.

Women and girls should not stop taking valproate without first discussing it with their doctor. More information can be found HERE or by calling Epilepsy Ireland at 01 4557500. OACS Ireland can be contacted via www.oacsireland.com.

Reference: John E. Hughes, Niamh Buckley, Yvonne Looney, Gráinne Kirwan, Sinead Curran, Colin P Doherty, Maeve Mullooly & Kathleen E. Bennett (2021) Awareness, knowledge and practice of healthcare professionals following implementation of a Pregnancy Prevention Program for sodium valproate in Ireland: a multi-stakeholder cross-sectional study, Expert Opinion on Drug Safety, 20:8, 965-977, DOI: 10.1080/14740338.2021.1933429