Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers

Campbell, Ellen; Kennedy, Florynce; Russell, Aline; Smithson, W Henry; Parsons, L.; Morrison, Patrick J.; Liggan, Brenda; Irwin, B.; Delanty, Norman; Hunt, Stephen; Craig, John; Morrow, James

doi:10.1136/jnnp-2013-306318

Cited by 259 publications

(252 citation statements)

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“…10 We found no relationship between occurrence of intrauterine death and AED dose, at least for LTG, CBZ, or VPA, whereas an increased occurrence was identified in women exposed to polytherapy. The observation that AED monotherapy, which is the predominant treatment regimen in pregnant women with epilepsy, [7][8][9] had no apparent impact on the rate of spontaneous abortions or stillbirths is also consistent with a previous report from Rochester based on 788 pregnancies in 256 women with epilepsy. 15 That study found no difference in rates of spontaneous abortions between pregnancies of women with epilepsy on (14.6%) or off (13.6%) AED medication or between pregnancies of women with epilepsy and pregnancies of spouses of men with epilepsy.…”

Section: Methodssupporting

confidence: 77%

“…4,5 Registries set up in the late 1990s have enrolled thousands of pregnancies and enabled comparisons of MCM rates between different AEDs at different dose levels. [6][7][8][9] Other observational studies have revealed differences in postnatal cognitive development.5 For both *These authors contributed equally to this work. …”

mentioning

confidence: 99%

“…5 For both types of outcomes, valproic acid (VPA) has been shown to be associated with greater risks than other AEDs, such as carbamazepine (CBZ) and lamotrigine (LTG), and additional AEDs in a dose-related manner. [7][8][9] Less focus has been given to the role of AEDs regarding other adverse pregnancy outcomes, in particular spontaneous abortions and stillbirths. A recent Danish study based on data from national health registries found no association between AED use during pregnancy and spontaneous abortions in women with epilepsy (n 5 2,615) but found a significantly increased risk with AED use in women without epilepsy, 10 leading to the question of a potential impact of unmeasured confounding.…”

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confidence: 99%

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Antiepileptic drugs and intrauterine death

et al. 2015

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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 5 1,910), carbamazepine (n 5 1,713), valproic acid (n 5 1,171), levetiracetam (n 5 324), oxcarbazepine (n 5 262), or phenobarbital (n 5 260), and to polytherapy (n 5 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. Neurology ® 2015;85:580-588 GLOSSARY AED 5 antiepileptic drug; CBZ 5 carbamazepine; CI 5 confidence interval; EURAP 5 International Registry of Antiepileptic Drugs and Pregnancy; LTG 5 lamotrigine; MCM 5 major congenital malformation; RR 5 risk ratio; VPA 5 valproic acid.Ever since the first report of major congenital malformations (MCMs) in the offspring of women taking antiepileptic drugs (AEDs) in pregnancy, 1 research has been dedicated to the assessment of teratogenic risks associated with AEDs. Concerns focused primarily on the risk of MCMs 2,3 and, more recently, on impaired cognitive and behavioral development after prenatal AED exposure. 4,5 Registries set up in the late 1990s have enrolled thousands of pregnancies and enabled comparisons of MCM rates between different AEDs at different dose levels. [6][7][8][9] Other observational studies have revealed differences in postnatal cognitive development.5 For both *These authors contributed equally to this work.

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Section: Methodssupporting

confidence: 77%

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confidence: 99%

mentioning

confidence: 99%

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Antiepileptic drugs and intrauterine death

et al. 2015

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“…Risks of MCMs were higher with VPA and PB at all doses, and with CBZ at > 400 mg/day. The UK and Ireland Epilepsy and Pregnancy Registers published a subsequent report on an even larger number of pregnancies in each medication group and also demonstrated a significant dose effect with VPA-and CBZ-exposed pregnancies, although the dosedependent trend with LTG was not significant [9]. Additionally, the authors reported that the MCM rate for highdose LTG (>400 mg/day) appeared lower than the MCM rate for pregnancies exposed to < 600 mg/day of VPA, but, again, this was not significant (3.4 % vs 5.0 %; p = 0.31).…”

Section: Dose At Conception Matters For MCM Riskmentioning

confidence: 99%

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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“…15 These cognitive deficits can occur without MCMs or MAs. For the second-generation AEDs, the risks of MCMs have been reported as 2.0% to 3.7% for lamotrigine, [16][17][18] 0.7% to 2.4% for levetiracetam, 18,19 2.8% for oxcarbazepine, 20 and 4.2% to 4.8% for topiramate.…”

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confidence: 99%

Antiepileptic drug use by pregnant women enrolled in Florida Medicaid

2015

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Objective: The study aims were to investigate secular trends in antiepileptic drug (AED) use in women during pregnancy, and to compare the use of first-and second-generation AEDs.Methods: Study participants consisted of female Florida Medicaid beneficiaries, older than 15 years, and pregnant within the time period 1999 to 2009. Fifteen AEDs were categorized into first and second generation of AEDs. Continuous use of AEDs was defined as at least 2 consecutive AED prescriptions totaling more than a 30-day supply. Polytherapy was defined as 2 or more AEDs continuously used for at least 30 overlapping days. Annual prevalence was estimated and compared.

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Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers

Cited by 259 publications

References 13 publications

Antiepileptic drugs and intrauterine death

Antiepileptic drugs and intrauterine death

Use of Antiepileptic Drugs During Pregnancy: Evolving Concepts

Antiepileptic drug use by pregnant women enrolled in Florida Medicaid

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