Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry

Tomson, Torbjörn; Battino, Dina; Bonizzoni, Erminio; Craig, John; Lindhout, Dick; Sabers, Anne; Perucca, Emilio; Vajda, Frank J. E.

doi:10.1016/s1474-4422(11)70107-7

Cited by 711 publications

(736 citation statements)

References 32 publications

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“…The European and International Registry of Antiepileptic Drugs and Pregnancy (EURAP) confirmed that in addition to the type of AED, dose of the AED at conception also affects rates of MCM [8]. MCM rates in pregnancies exposed to CBZ, LTG, VPA, and PB were analyzed by dose at time of conception (not throughout the first trimester or entire pregnancy).…”

Section: Dose At Conception Matters For MCM Riskmentioning

confidence: 99%

“…The findings reported by EURAP that the dose at conception is important for all AEDs studied [8], suggest that a woman's preconception dose should be scrutinized prior to pregnancy and reduced if possible based upon her seizure history and personal characteristics. It is helpful to measure baseline serum concentration in the nonpregnant state, and use that for guidance if she has good seizure control without side effects, and if it is thought that her dose cannot be lowered further.…”

Section: Establishing Individual Aed Target Concentrationsmentioning

confidence: 99%

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Use of Antiepileptic Drugs During Pregnancy: Evolving Concepts

Pennell

2016

Neurotherapeutics

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Although prenatal exposure to antiepileptic drugs (AEDs) is known to impart relatively higher risks of major congenital malformations, prospective studies have provided refined data that allow us to differentiate the risks of different types and doses of AEDs. As the number of AED prescriptions has dramatically increased in reproductive-aged women with a variety of neuropsychiatric indications, the evolving concepts learned from studies in women with epilepsy can be applied to a much larger group of pregnant women to improve child outcomes while maintaining maternal disease control. In addition to careful selection of the type of medication, the amount of fetal exposure at conception and in the first trimester probably matters across all AEDs. Some AED polytherapy regimens are not associated with a higher risk of malformations, although other outcomes have not yet been formally studied. The individual woman's drug target concentration should be established preconception and maintained during pregnancy, to prevent seizure worsening. Substantial pharmacokinetic changes occur with many of the medications during pregnancy and postpartum, and interindividual variability supports the use of therapeutic drug monitoring for most AEDs. During pregnancy, vigilance and close monitoring should also include intrauterine fetal growth, obstetric complications, and neonatal complications. Breastfeeding can provide additional neurodevelopmental benefit and should be an option for women on AEDs. Knowledge of these key principles enhances our ability to make treatment recommendations with resultant improved maternal and child outcomes. Additional prospective studies are needed to further define the risk-benefit ratio across a variety of medications, dosing strategies, and neuropsychiatric disorders.

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Section: Dose At Conception Matters For MCM Riskmentioning

confidence: 99%

Section: Establishing Individual Aed Target Concentrationsmentioning

confidence: 99%

Use of Antiepileptic Drugs During Pregnancy: Evolving Concepts

Pennell

2016

Neurotherapeutics

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“…Several case and population studies have together provided strong evidence that prenatal valproate exposure creates a vulnerability to structural malformations, developmental delay, mental disability, and autism (Christianson et al, 1994;Moore et al, 2000;Williams et al, 2001;Rasalam et al, 2005;Bromfield et al, 2008;Diav-Citrin et al, 2008;Tomson and Battino, 2008;Tomson et al, 2011). Nevertheless, valproate continues to be in common use, given the need to balance teratogenic risks with the risks of uncontrolled seizures or mood disorders.…”

Section: Introductionmentioning

confidence: 99%

Synaptic and Intrinsic Balancing during Postnatal Development in Rat Pups Exposed to Valproic Acidin Utero

Walcott¹,

Higgins²,

Desai³

2011

J. Neurosci.

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Valproic acid (VPA) is among the most teratogenic of commonly prescribed anticonvulsants, increasing the risk in humans of major malformations and impaired cognitive development. Likewise, rats exposed prenatally to VPA exhibit a variety of neuroanatomical and behavioral abnormalities. Previous work has shown that pyramidal neuron physiology in young VPA-exposed animals is marked by two strong abnormalities: an impairment in intrinsic neuronal excitability and an increase in NMDA synaptic currents. In this study, we investigated these abnormalities across postnatal development using whole-cell patch recordings from layer 2/3 neurons of medial prefrontal cortex. We found that both abnormalities were at a peak soon after birth but were gradually corrected as animals matured, to the extent that normal excitability and NMDA currents had been restored by early adolescence. The manner in which this correction happened suggested coordination between the two processes. Using computational models fitted to the physiological data, we argue that the two abnormalities trade off against each other, with the effects on network activity of the one balancing the effects of the other. This may constitute part of the nervous system's homeostatic response to teratogenic insult: an attempt to maintain stability despite a strong challenge.

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“…It can be concluded that sodium valproate is best avoided during pregnancy if other alternatives are available. The risk of malformations can be minimised by using the lowest effective dose of sodium valproate, monotherapy of lamotrigine less than 300 mg/day or monotherapy of carbamazepine less than 400 mg/day as well as the use of folic acid supplements [14,26].…”

Section: Discussionmentioning

confidence: 99%

Medications Used by Pregnant Women: Any Safety Concerns?

Kho

Chua

Dallumal

et al. 2017

Int J Pharm Pharm Sci

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Objective: The use of medications during pregnancy may impose a potential risk to the fetus. Therefore, this study was conducted to determine the prevalence and safety of medications used by pregnant women. Methods:A cross-sectional study was conducted on pregnant women who attended the antenatal clinic of a major teaching hospital in Malaysia, from January to April 2013. Data was collected via face-to-face interviews using a structured questionnaire. Results:Of the 500 respondents in this study, 62% (95% confidence interval, CI: 57.7%, 66.3%) used at least one medication during their pregnancy and 30.8% (95% CI: 26.8%, 34.8%) took the medications during the first trimester. The classes of medications commonly used were analgesics (26.8%), followed by cough and cold medications (18.6%) and medications for gastrointestinal disorders (11.8%). Among the 697 medications used by the respondents during pregnancy, most of them were relatively safe, with approximately 50% being classified under the Food and Drug Administration of the United States (FDA, US)-assigned pregnancy category B. However, seven potentially teratogenic medications were identified, including four antiepileptic drugs and an antimigraine medication which contained ergotamine. Conclusion:This study found that a high proportion of pregnant woman consumed at least one medication during their pregnancy. The use of antimigraine medications containing ergotamine in pregnant women is of major concern as this medication could be obtained without a prescription in some countries, including in Malaysia. Therefore, it is essential for health care professionals to educate and counsel pregnant women on the safety of medications used.

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Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry

Cited by 711 publications

References 32 publications

Use of Antiepileptic Drugs During Pregnancy: Evolving Concepts

Use of Antiepileptic Drugs During Pregnancy: Evolving Concepts

Synaptic and Intrinsic Balancing during Postnatal Development in Rat Pups Exposed to Valproic Acidin Utero

Medications Used by Pregnant Women: Any Safety Concerns?

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