Grand Rounds

CMECNE

Antiepileptic Drugs: What is the Impact on Risk for Birth Defects

Learning Objectives and CME/Disclosure Information

This activity is intended for healthcare providers delivering care to women and their families.

After completing this activity, the participant should be better able to:

1. State which AEDs are most highly associated with major congenital malformations
2. Discuss reasons why, based on the results of this study, providers should be cautious in the use of VPA in pregnancy

Estimated time to complete activity: 0.25 hours

Faculty:

Susan J. Gross, MD, FRCSC, FACOG, FACMG
President and CEO, The ObG Project

Disclosure of Conflicts of Interest

Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.

Faculty: Susan J. Gross, MD, receives consulting fees from Cradle Genomics, and has financial interest in The ObG Project, Inc.

Planners and Managers: The PIM planners and managers, Trace Hutchison, PharmD, Samantha Mattiucci, PharmD, CHCP, Judi Smelker-Mitchek, MBA, MSN, RN, and Jan Schultz, MSN, RN, CHCP have nothing to disclose.

Method of Participation and Request for Credit

Fees for participating and receiving CME credit for this activity are as posted on The ObG Project website. During the period from Dec 31 2017 through Dec 31 2020, participants must read the learning objectives and faculty disclosures and study the educational activity.

If you wish to receive acknowledgment for completing this activity, please complete the post-test and evaluation. Upon registering and successfully completing the post-test with a score of 100% and the activity evaluation, your certificate will be made available immediately.

For Pharmacists: Upon successfully completing the post-test with a score of 100% and the activity evaluation form, transcript information will be sent to the NABP CPE Monitor Service within 4 weeks.

Joint Accreditation Statement

In support of improving patient care, this activity has been planned and implemented by the Postgraduate Institute for Medicine and The ObG Project. Postgraduate Institute for Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

Physician Continuing Medical Education

Postgraduate Institute for Medicine designates this enduring material for a maximum of 0.25 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Continuing Nursing Education

The maximum number of hours awarded for this Continuing Nursing Education activity is 0.2 contact hours.

Designated for 0.1 contact hours of pharmacotherapy credit for Advance Practice Registered Nurses.

Read Disclaimer & Fine Print

BACKGROUND AND PURPOSE:

Most women with epilepsy will continue to take antiepileptic drugs (AEDs) throughout pregnancy based on medical advice and the balance of risks/benefits
Weston et al. (Cochrane Database Syst Rev, 2016) examined the AED exposure and prevalence of congenital malformations in offspring

METHODS:

Systematic review and meta-analysis
Relevant literature included prospective cohort studies, RCTs and registry studies
Intervention group
- Women with epilepsy receiving AEDs as monotherapy
Control groups
- Women without epilepsy
- Women with epilepsy not on treatment
Primary outcome
- Presence of a major congenital malformation
Secondary outcome
- Specific types of major congenital malformation (NTDs, cardiac defects, orofacial clefting/craniofacial anomalies and skeletal or limb malformations)
- Minor malformations (e.g., low set ears or digital hypoplasia)

RESULTS:

Risk of Malformation

50 studies were selected, 31 of which contributed to meta-analysis
Carbamazepine (CBZ): Increased risk of malformation vs controls
- Without epilepsy: Risk ratio (RR) 2.01, 95% confidence interval (CI) 1.20 to 3.36
- Untreated epilepsy: RR 1.50, 95% CI 1.03 to 2.19)
Phenobarbital (PB): Increased risk of malformation vs control
- Without epilepsy: RR 2.84, 95% CI 1.57 to 5.13
Phenytoin (PHT): Increased risk of malformation vs controls
- Without epilepsy: RR 2.38, 95% CI 1.12 to 5.03
- Untreated epilepsy: RR 2.40, 95% CI 1.42 to 4.08)
Topiramate (TPM): Increased risk of malformation vs control
- Without epilepsy: RR 3.69, 95% CI 1.36 to 10.07
Valproate (VPA): Increased risk of malformation vs controls
- Without epilepsy: RR 5.69, 95% CI 3.33 to 9.7
- Untreated epilepsy: RR 3.13, 95% CI 2.16 to 4.54)
No increased risk of malformations for the following (limited data for meds with *)
- Lamotrigine (LTG)
- *Gabapentin (GBP)
- *Levetiracetam (LEV)
- *Oxcarbazepine (OXC)
- *Primidone (PRM)
- *Zonisamide (ZNS)

Prevalence of Major Malformations

CBZ: 4.93% (95% CI 3.84 to 6.16)
GBP: 1.47% 1.47% (95% CI 0.26 to 3.64)
LEV: 1.77% 1.77% (95% CI 0.98%-2.79)
LTG: 2.31% (95% CI 1.87 to 2.78)
OXC: 2.39% (95% CI 0.85% to 4.68%)
PB: 7.10% (95% CI 5.36 to 9.08)
PHT: 6.26% (95% CI 4.37 to 8.47)
PRM: 8.49% (95% CI 4.13 to 14.22)
TPM: 4.28% (95% CI 2.65 to 6.29)
VPA: 10.93% (95% CI 8.91 to 13.13)
ZNS: 0.28% (95% CI 0.25 to 2.39) / only 1 small study

Comparing AEDs

VPA: increased risk of malformation compared to
- CBZ: RR 2.44, 95% CI 2.00 to 2.94
- GBP: RR 6.21, 95% CI 1.91 to 20.23
- LEV: RR 5.82, 95% CI 3.13 to 10.81)
- LTG: RR 3.56, 95% CI 2.77 to 4.58
- TPM: RR 2.35, 95% CI 1.40 to 3.95
- OXC: RR 3.71, 95% CI 1.65 to 8.33
- PB: RR 1.59, 95% CI 1.11 to 2.29
- PHT: RR 2.00, 95% CI 1.48 to 2.71
- ZNS: RR 17.13, 95% CI 1.06 to 277.48
CBZ: increased risk of malformation compared to
- LEV: RR 1.84, 95% CI 1.03 to 3.29
- LTG: RR 1.34, 95% CI 1.01 to 1.76
PB: Increased risk of malformation compared to
- GBP: RR 8.33, 95% CI 1.04 to 50.00
- LEV: RR 2.33, 95% CI 1.04 to 5.00
- LTG: RR 3.13, 95% CI 1.64 to 5.88)
PHT: Increased risk of malformation compared to
- LTG: RR 1.89, 95% CI 1.19 to 2.94
TPM: Increased risk of malformation compared to
- LEV: RR 2.00, 95% CI 1.03 to 3.85
- LTG: RR 1.79, 95% CI 1.06 to 2.94

Specific Malformations

PB exposure was associated with cardiac malformations
VPA exposure with NTD, cardiac, clefting/craniofacial anomalies, and skeletal and limb malformations
Risk of malformation was dosage dependent for VPA exposure
Limited data may have contributed to lack of statistically significant associations with specific malformations in other AEDs

CONCLUSION:

AEDs are associated with increased risk of congenital malformation in children, with VPA ranking the highest risk and LEV and LTG the lowest
- Concurs with previous studies and professional guidelines to be cautious using VPA
- NOTE: Consider higher dose of folic acid (4mg daily) for women on VPA
Further studies are needed to define specific malformations associated with LEV and LTG
Few studies provided sufficient data on minor malformations

Learn More – Primary Sources:

Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child.

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