Understanding and Responding to Prescribing Patterns of Sodium Valproate-Containing Medicines in Pregnant Women and Women of Childbearing Age in Western Cape, South Africa

Abstract

Introduction Growing evidence of the teratogenic potential of sodium valproate (VPA) has changed prescribing practices across the globe; however, the impact of this research and the consequent dissemination of a Dear Health Care Professional Letter (DHCPL) in December 2015, recommending avoidance of the teratogen VPA in women of childbearing age (WOCBA) and pregnant women in South Africa, is unknown. We explored trends and reasons for VPA use among pregnant women and WOCBA in the public sector in Western Cape Province from 1 January 2015 to 31 December 2017. Methods Using the provincial health information exchange that collates routine electronic health data via unique patient identifiers, we analysed clinical and pharmacy records from 2015 to 2017 to determine prescription patterns of VPA and other antiepileptic drug (AED) and mood-stabilising medicine (MSM) use in WOCBA and pregnant women. Senior clinicians and policy makers were consulted to understand the determinants of VPA use. Results At least one VPA prescription was dispensed to between 8205 (0.79%) and 9425 (0.94%) WOBCA from a cohort of approximately 1 million WOCBA attending provincial health care facilities per year. Prescriptions were more likely in HIV-infected women compared with HIV-uninfected women (1.1–1.3% vs. 0.7–0.9%; p < 0.001). VPA use in WOCBA remained stable at 0.8–0.9% over the review period despite the 2016 DHCPL. VPA was the most prescribed AED/MSM, constituting 43.2–45.5% of all WOCBA taking at least one such agent, while lamotrigine, the other recommended first-line agent, was only prescribed in 7.8–8.9% of WOCBA. Over 3 years, approximately 663 pregnancies were exposed to VPA, with a steady rise in the number of exposures each year ( n = 204, 214 and 245, respectively). Conclusion Despite warnings, VPA remained the most frequently prescribed AED or MSM in WOCBA. Contributing factors are described. Electronic supplementary material The online version of this article (10.1007/s40264-020-00987-4) contains supplementary material, which is available to authorized users.

A description of sodium valproate, lamotrigine and levetiracetam consumption in the Western Cape public sector

“…A local study attributed tardiness of switching WOCBA from valproate to safer alternatives to fear of breakthrough seizures, challenges in initiating lamotrigine, overburdened health system and inadequate access to specialists. 21 Similarly, in this study, the bulk of patients on valproate were at PHC level/Level 1 under the management of medical doctors and having limited access to specialists. Lamotrigine requires slow titration over an approximately 8-week period to prevent serious side effects, which is a major challenge in a resource-constrained health system and for patients who may default therapy.…”

“…20 In the WCGH, over a 3-year period, sodium valproate remained the most frequently prescribed antiepileptic in women of childbearing age (WOCBA) compared with other anti-epileptics and mood stabilisers available in the public sector (carbamazepine, risperidone, phenytoin, lamotrigine, olanzapine, lithium and levetiracetam), that is, 43.2% in 2015, 45.4% in 2016 and 44.8% in 2017. 21 Furthermore, sodium valproate was the most frequently prescribed antiepileptic in WOCBA primarily for the treatment of epilepsy in the retroviral disease positive population. 21 As a consequence of safety warnings and the high use of sodium valproate, the WCGH introduced a policy on the use of valproate in epilepsy in May 2019, which suggested alternatives and promoted the safe use of valproate in epilepsy in WOCBA.…”

“… 21 Furthermore, sodium valproate was the most frequently prescribed antiepileptic in WOCBA primarily for the treatment of epilepsy in the retroviral disease positive population. 21 As a consequence of safety warnings and the high use of sodium valproate, the WCGH introduced a policy on the use of valproate in epilepsy in May 2019, which suggested alternatives and promoted the safe use of valproate in epilepsy in WOCBA. 22 The policy was shared electronically with healthcare professionals in the public sector and accompanied by a series of information or training sessions for relevant staff.…”

Cohort profile: the Western Cape Pregnancy Exposure Registry (WCPER)

“…We are currently investigating the impact of data source on gestational age (Malaba T, manuscript in preparation) and hypertensive disorders of pregnancy 34. PER data have contributed to population-based analyses describing the use and safety of sodium valproate and isoniazid for tuberculosis preventive therapy in pregnancy 35 36. In addition, initiation of the PER provided the opportunity to host a workshop, Building Teratovigilance Capacity in Africa, which provided networking and training opportunities to 60 delegates from sub-Saharan Africa https://globalpharmacovigilance.tghn.org/resources/building-teratovigilance-capacity-africa/.…”

Measures to Mitigate Sodium Valproate Use in Pregnant Women With Epilepsy

“…Hence, due to its high-risk profile, valproate is indicated for epilepsy only for females in the reproductive age group who are either not tolerant to it or to those who do not respond well to other medications that are prescribed for epilepsy (those who are more likely to suffer from puerperal psychosis or are more likely to relapse) [17] and to those who thoroughly follow a proper pregnancy prevention program. However, it is indicated as a first-line drug in women who have tested positively for HIV and are undergoing antiretroviral therapy along with lamotrigine [18]; the chief reason being that the rest of the drugs used for antiepileptic therapy may reduce the levels of antiretrovirals in the body by inducing p50 enzyme [19].…”