Antiepileptic drugs and intrauterine death

Torbjörn Tomson, Dina Battino, Erminio Bonizzoni, John J. Craig, Dick Lindhout, Emilio Perucca, Anne Sabers, Sanjeev V. Thomas, Frank Vajda

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Objective: To compare the risk of spontaneous abortions and stillbirth associated with maternal use of different antiepileptic drugs (AEDs). Methods: The EURAP registry is an observational international cohort study primarily designed to determine the risk of major congenital malformations (MCMs) after prenatal AED exposure. Using EURAP data, we prospectively monitored pregnancies exposed to the 6 most common AED monotherapies and to polytherapy. Intrauterine death (spontaneous abortion and stillbirth combined) was the primary endpoint. Results: Of 7,055 pregnancies exposed to monotherapy with lamotrigine (n 1,910), carbamazepine (n 1,713), valproic acid (n 1,171), levetiracetam (n 324), oxcarbazepine (n 262), or phenobarbital (n 260), and to polytherapy (n 1,415), 632 ended in intrauterine deaths (592 spontaneous abortions and 40 stillbirths). Rates of intrauterine death were similar across the different monotherapies (8.2%; 95% confidence interval [CI] 7.5%-8.9%), higher with polytherapy (12.1%; 95% CI 10.5%-13.9%), but showed no relationship with AED dose in monotherapy at conception. Multivariable analysis including 11 covariates in addition to the different AED exposures showed that the risk was greater with polytherapy vs monotherapy (risk ratio [RR] 1.38; 95% CI 1.14-1.66), parental history of MCMs (RR 1.92; 1.20-3.07), maternal age (RR 1.06; 1.04-1.07), and number of previous intrauterine deaths (RR 1.09; 1.00-1.19). The risk was greater with early enrollment and decreased with later gestational week at enrollment (RR 0.84; 0.82-0.86). Conclusions: The most important risk factors for intrauterine death in pregnancies of women with epilepsy include maternal exposure to AED polytherapy and the presence of MCMs in at least one of the parents.

Original languageEnglish
Pages (from-to)580-588
Number of pages9
JournalNeurology
Volume85
Issue number7
DOIs
Publication statusPublished - Aug 18 2015

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Anticonvulsants
Odds Ratio
Stillbirth
Spontaneous Abortion
etiracetam
Confidence Intervals
Pregnancy
Maternal Exposure
Carbamazepine
Maternal Age
Valproic Acid
Phenobarbital
Combination Drug Therapy
Registries
Epilepsy
Cohort Studies
Parents
Mothers
Mortality

ASJC Scopus subject areas

  • Clinical Neurology
  • Medicine(all)

Cite this

Tomson, T., Battino, D., Bonizzoni, E., Craig, J. J., Lindhout, D., Perucca, E., ... Vajda, F. (2015). Antiepileptic drugs and intrauterine death. Neurology, 85(7), 580-588. https://doi.org/10.1212/WNL.0000000000001840

Antiepileptic drugs and intrauterine death. / Tomson, Torbjörn; Battino, Dina; Bonizzoni, Erminio; Craig, John J.; Lindhout, Dick; Perucca, Emilio; Sabers, Anne; Thomas, Sanjeev V.; Vajda, Frank.

In: Neurology, Vol. 85, No. 7, 18.08.2015, p. 580-588.

Research output: Contribution to journalArticle

Tomson, T, Battino, D, Bonizzoni, E, Craig, JJ, Lindhout, D, Perucca, E, Sabers, A, Thomas, SV & Vajda, F 2015, 'Antiepileptic drugs and intrauterine death', Neurology, vol. 85, no. 7, pp. 580-588. https://doi.org/10.1212/WNL.0000000000001840
Tomson T, Battino D, Bonizzoni E, Craig JJ, Lindhout D, Perucca E et al. Antiepileptic drugs and intrauterine death. Neurology. 2015 Aug 18;85(7):580-588. https://doi.org/10.1212/WNL.0000000000001840
Tomson, Torbjörn ; Battino, Dina ; Bonizzoni, Erminio ; Craig, John J. ; Lindhout, Dick ; Perucca, Emilio ; Sabers, Anne ; Thomas, Sanjeev V. ; Vajda, Frank. / Antiepileptic drugs and intrauterine death. In: Neurology. 2015 ; Vol. 85, No. 7. pp. 580-588.
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abstract = "Objective: To compare the risk of spontaneous abortions and stillbirth associated with maternal use of different antiepileptic drugs (AEDs). Methods: The EURAP registry is an observational international cohort study primarily designed to determine the risk of major congenital malformations (MCMs) after prenatal AED exposure. Using EURAP data, we prospectively monitored pregnancies exposed to the 6 most common AED monotherapies and to polytherapy. Intrauterine death (spontaneous abortion and stillbirth combined) was the primary endpoint. Results: Of 7,055 pregnancies exposed to monotherapy with lamotrigine (n 1,910), carbamazepine (n 1,713), valproic acid (n 1,171), levetiracetam (n 324), oxcarbazepine (n 262), or phenobarbital (n 260), and to polytherapy (n 1,415), 632 ended in intrauterine deaths (592 spontaneous abortions and 40 stillbirths). Rates of intrauterine death were similar across the different monotherapies (8.2{\%}; 95{\%} confidence interval [CI] 7.5{\%}-8.9{\%}), higher with polytherapy (12.1{\%}; 95{\%} CI 10.5{\%}-13.9{\%}), but showed no relationship with AED dose in monotherapy at conception. Multivariable analysis including 11 covariates in addition to the different AED exposures showed that the risk was greater with polytherapy vs monotherapy (risk ratio [RR] 1.38; 95{\%} CI 1.14-1.66), parental history of MCMs (RR 1.92; 1.20-3.07), maternal age (RR 1.06; 1.04-1.07), and number of previous intrauterine deaths (RR 1.09; 1.00-1.19). The risk was greater with early enrollment and decreased with later gestational week at enrollment (RR 0.84; 0.82-0.86). Conclusions: The most important risk factors for intrauterine death in pregnancies of women with epilepsy include maternal exposure to AED polytherapy and the presence of MCMs in at least one of the parents.",
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AU - Battino, Dina

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AU - Lindhout, Dick

AU - Perucca, Emilio

AU - Sabers, Anne

AU - Thomas, Sanjeev V.

AU - Vajda, Frank

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N2 - Objective: To compare the risk of spontaneous abortions and stillbirth associated with maternal use of different antiepileptic drugs (AEDs). Methods: The EURAP registry is an observational international cohort study primarily designed to determine the risk of major congenital malformations (MCMs) after prenatal AED exposure. Using EURAP data, we prospectively monitored pregnancies exposed to the 6 most common AED monotherapies and to polytherapy. Intrauterine death (spontaneous abortion and stillbirth combined) was the primary endpoint. Results: Of 7,055 pregnancies exposed to monotherapy with lamotrigine (n 1,910), carbamazepine (n 1,713), valproic acid (n 1,171), levetiracetam (n 324), oxcarbazepine (n 262), or phenobarbital (n 260), and to polytherapy (n 1,415), 632 ended in intrauterine deaths (592 spontaneous abortions and 40 stillbirths). Rates of intrauterine death were similar across the different monotherapies (8.2%; 95% confidence interval [CI] 7.5%-8.9%), higher with polytherapy (12.1%; 95% CI 10.5%-13.9%), but showed no relationship with AED dose in monotherapy at conception. Multivariable analysis including 11 covariates in addition to the different AED exposures showed that the risk was greater with polytherapy vs monotherapy (risk ratio [RR] 1.38; 95% CI 1.14-1.66), parental history of MCMs (RR 1.92; 1.20-3.07), maternal age (RR 1.06; 1.04-1.07), and number of previous intrauterine deaths (RR 1.09; 1.00-1.19). The risk was greater with early enrollment and decreased with later gestational week at enrollment (RR 0.84; 0.82-0.86). Conclusions: The most important risk factors for intrauterine death in pregnancies of women with epilepsy include maternal exposure to AED polytherapy and the presence of MCMs in at least one of the parents.

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