Anti-epileptics in Pregnancy?

August 7, 2017

What are the risks of anti-seizure meds in pregnancy? Benefits?

What are the risks of anti-seizure meds in pregnancy? Benefits? Scroll through the slides for insights from a new study.

What evidence can you use to counsel this patient?
Seizures pose risks to the health of both mother and fetus. A 2015 US study found that maternal mortality was over 10 times higher in women with epilepsy than in those without.[1] Women with epilepsy also had increased risk of preeclampsia, preterm labor, cesarean section, and stillbirth. [1] Moreover, a meta-analysis of 38 studies in low- and middle-income countries found that maternal epilepsy is also associated with increased odds of spontaneous miscarriage, gestational hypertension, ante- and post-partum hemorrhage, induction of labor, and fetal growth restriction.[2]

For these reasons, AEDs are often continued during pregnancy, despite research suggesting that in utero exposure to AEDs may increase the risk for fetal congenital malformations. In particular, the older generation of AEDs like valproic acid (VPA), carbamazepine, and phenytoin are considered teratogenic.[3]
Research, though, has tended to focus on how AEDs affect infant outcomes, rather than their effect on maternal pregnancy outcomes. That raises the question: what is the effect of continuing AEDs during pregnancy on the mother? How does this weigh against the risk to the fetus of in utero exposure to AEDs? A new study in Sweden looked at the issue.

Retrospective study of singleton births in Sweden 1997-2011
. Over 1.4 million pregnancies
. 5373 pregnancies in 3586 women with active epilepsy
Data on AEDs exposure for children born 7/2005-12/2011
. 42% (n=1363/3231) children born to mothers with epilepsy during this period were exposed to AEDs in utero
Results adjusted for maternal age, country of origin, education, partner cohabitation, height, BMI, smoking, delivery year, maternal pre-gestational diabetes, hypertension, psychiatric disorders

Increased risk of adverse pregnancy outcomes in women with epilepsy vs those without:
. Preeclampsia: 24% increase risk (aRR 1.24; 95%CI, 1.07-1.43)
. Maternal infection: 85% increased risk (aRR 1.85; 95%CI, 1.43-2.29)
. Placental abruption: 68% increased risk (aRR 1.68; 95%CI, 1.18-2.38)
. Induction of labor: 31% increased risk (aRR, 1.31; 95%CI, 1.21-1.40)
. Elective C-section: 58% increased risk (aRR, 1.58; 95%CI, 1.45-1.71)
. Emergency C-section: 9% increased risk (aRR, 1.09; 95%CI, 1.00-1.20)
Increased risk of postpartum hemorrhage, borderline significance (aRR, 1.11, 95% CI,
0.97-1.26)

Increased risk of adverse outcomes in infants of mothers with epilepsy vs those without:
. Stillbirth: 55% increased risk (aRR, 1.55; 95%CI, 1.05-2.30)
. Medically indicated preterm birth: 24% increased risk (aRR, 1.24; 95%CI, 1.08-1.43)
. Spontaneous preterm birth: 34% increased risk (aRR, 1.34; 95%CI, 1.20-1.53)
. Small for gestational age (SGA): 25% increased risk (aRR, 1.25; 95%CI, 1.13-1.30)
. Neonatal infections: 42% increased risk (aRR, 1.42; 95%CI, 1.17-1.73)
. Any congenital malformation: 48% increased risk (aRR, 1.48; 95%CI, 1.35-1.62)
. Major malformations: 61% increased risk (aRR, 1.61; 95%CI, 1.43-1.81)
. Asphyxia-related complications: 75% increased risk (aRR, 1.75; 95%CI, 1.26-2.42)
. Low Apgar score of 4 to 6 at 5 minutes: 34% increased risk (aRR, 1.34; 95%CI, 1.03-1.76)
. Low Apgar score of 0 to 3 at 5 minutes: Almost 2.5 times increased risk (aRR, 2.42; 95% CI, 1.62-3.61)
. Neonatal hypoglycemia: 53% increased risk (aRR, 1.53; 95%CI, 1.34-1.75)
. Respiratory distress syndrome: 48% increased risk (aRR, 1.48; 95%CI, 1.30-1.68)

Risk of adverse pregnancy outcomes not significantly increased in women with epilepsy who used AEDs during pregnancy

. Except: women with epilepsy treated with AEDs had 30% increased risk of induction of labor vs women with epilepsy who did not use AEDs (aRR, 1.30; 95%CI, 1.10-1.55)

. Non-significantly increased risk of preeclampsia in women on AEDs vs without (aRR 1.39, 0.96-2.00)

Non-significantly increased risk of the following with in utero exposure to AEDs vs not exposed:
. Major malformations (aRR 1.25, 95% CI 1.30, 95% CI 0.95-1.77)
. Respiratory distress (6.0% vs 4.5%, aRR 1.30, 95% CI 0.92-1.81)
. SGA (9.5% vs 6.9%, aRR 1.25, 95% CI 0.97-1.61)

Propensity score matched analysis; risk of adverse neonatal outcomes not statistically increased for in utero AED exposure vs not exposed
Results similar when adjusted for AED type, polytherapy, and term vs pre-term delivery

. Used registry data on prescription fills, treatment adherence unknown (no drug levels assessed)
. No data on malformations that may have led to induced abortions
. Could have decreased the association between in utero AED exposure and major malformations
. Cannot determine causal relationship between maternal epilepsy and poor pregnancy and fetal outcomes

Findings contrast with past studies, suggesting increased risk of adverse outcomes in infants with in utero exposure to AEDs.
Differences with past studies:
. 46.1% of women on AEDs in this study used lamotrigine, considered relatively safe regarding teratogenicity
. VPA was used in 19.2% of pregnancies
. Highest rate of major malformations among women on VPA monotherapy (10.6%)

“Our findings reveal that the increased risks of complications during pregnancy, labor, and the neonatal period might be due to pathologic factors related to epilepsy as a chronic disease more than being the effect of AEDs per se... Therefore, women with epilepsy should not be advised to discontinue clinically indicated treatment. Adverse effects of AED use have also been shown to be counterbalanced by the seizure control effect of AEDs.”
-Lead author Sven Cnattingius, MD, PhD, Karolinska Institute, Stockholm, Sweden

Nationwide retrospective Swedish cohort study found pregnancy and infant outcomes are worse in women with epilepsy than in women without epilepsy
. AEDs are not generally associated with adverse maternal pregnancy and infant outcomes
. Increased risk of pregnancy complications may be related to epilepsy itself, not AEDs
. Adverse effects of AEDs on fetal outcomes are counter-balanced by improved seizure control in women with epilepsy; these women should continue AEDs during pregnancy if clinically indicated.

References
1. MacDonald SC, Bateman BT, McElrath TF, Hernandez-Diaz S. Mortality and morbidity during delivery hospitalization among pregnant women with epilepsy in the United States. JAMA Neurol. 2015 Sep;72(9):981-988.
2. Tomson T, Battino D. Teratogenic effects of antiepileptic drugs. Lancet Neurol. 2012;11(9):803-813.
3. LaganÃ AS, Triolo O, D’Amico V, et al. Management of women with epilepsy: from preconception to post-partum. Arch Gynecol Obstet. 2016;293(3):493-503.
4. Razaz N, Tomson T, WikstrÃ¶m AK, Cnattingius S. Association between pregnancy and perinatal outcomes among women with epilepsy. JAMA Neurol. 2017 Jul 3. doi: 10.1001/jamaneurol.2017.1310.

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Anti-epileptics in Pregnancy?

Veronica Hackethal, MD