Teratogenic effects of antiepileptic drugs

doi:10.1016/S1474-4422(12)70103-5

The Lancet Neurology

Volume 11, Issue 9, September 2012, Pages 803-813

https://doi.org/10.1016/S1474-4422(12)70103-5 Get rights and content

Summary

Most women with active epilepsy need treatment with antiepileptic drugs during pregnancy. Antiepileptic drugs are also frequently used for other indications, such as migraine, pain syndromes, and psychiatric disorders, which are prevalent among women of childbearing age. Possible teratogenic effects of antiepileptic drugs are therefore of wide concern and the risks imposed by the drugs must be weighed against the risks associated with the disorder being treated. Adverse drug effects on the fetus can present as fetal loss, intrauterine growth retardation, congenital malformations, impaired postnatal development, and behavioural problems. For optimum use of antiepileptic drugs in women of childbearing age and rational management of epilepsy during pregnancy, a thorough understanding of the teratogenic effects of antiepileptic drugs and knowledge of the differences in risks between various treatment options are needed.

Introduction

50 years have passed since the first report of thalidomide embryopathy,¹ the disaster that led to the establishment of modern teratology. A few years later, Meadow² reported hare-lip, cleft palate, and other abnormalities among babies of mothers who received primidone, phenytoin, or phenobarbital. Findings from subsequent studies have confirmed higher birth defect rates than expected among children of mothers with epilepsy.³ The cause is probably multifactorial, but antiepileptic drugs (AEDs) are the main reason for the increased risk.4, 5

Despite these risks, physicians need to prescribe AEDs to women with epilepsy who are considering becoming pregnant because seizures can harm the mother as well as her fetus. Epilepsy is a serious disorder and seizures can occasionally be fatal.⁶ The report of the Confidential Enquiries into Maternal Deaths in the United Kingdom noted that of 261 maternal deaths, 14 (5%) were from epilepsy.⁷ Fetal risks associated with maternal seizures are less well delineated, but generalised tonic-clonic seizures can induce fetal lactic acidosis and hypoxia⁸ and status epilepticus can cause fetal death.⁹ Frequent tonic-clonic seizures during pregnancy have been associated with poor cognitive performance in childhood.10, 11

The challenge for clinicians is to balance these risks and to select a treatment that is effective in preventing major seizures while minimising adverse fetal drug effects.¹² Treatment options have increased with the number of available AEDs, but clarifying the teratogenic potential of a new drug takes a long time, and data comparing the safety of different treatment options have been scarce. The past decade has seen intensified clinical research on the subject, with several studies reporting pregnancy outcomes after maternal use of AEDs. Possible manifestations of second-generation drug effects include spontaneous abortions, intrauterine growth retardation, birth defects, and adverse effects on cognitive development and behaviour.3, 4 In this Review, we focus on clinical data on the links between AED exposure in utero and the occurrence of major congenital malformations in the offspring and alterations in postnatal cognitive development. With an emphasis on published work from the past decade, we present comparative outcome data on individual drugs and on the relation between dose and risks—information that should facilitate rational management decisions.

Section snippets

Pregnancy loss

Estimating the rate of spontaneous abortions in women receiving AEDs is difficult because many occur in early pregnancy and can pass unrecognised. Additionally, in general, a large proportion of spontaneous abortions are associated with chromosomal abnormalities, but these abnormalities have not been studied in populations with epilepsy. Published data on obstetric risks in women with epilepsy are also scarce and conflicting.¹³ In a recent study from India,¹⁴ women with epilepsy (n=718) and

Intrauterine growth

AEDs might affect fetal growth. Limited data suggest a slightly increased risk of small-for-gestational-age outcomes among newborn babies exposed to AEDs during pregnancy.⁴ In particular, interest has been paid to the possibility of reduced head circumference in newborn babies because this could be associated with functional deficits. Results from hospital-based cohort studies16, 17 and population-based register studies18, 19, 20 have shown increased proportions of newborn babies with small

Fetal anticonvulsant syndromes

Many investigators have described an association between exposure to certain AEDs and dysmorphic features of the child, sometimes in combination with major malformations and learning and behavioural problems. Such syndromes have been described in association with phenytoin,²¹ carbamazepine,²² and valproate.²³ Findings from some reports suggest that the features of these syndromes are specific depending on the type of AED used by the mother. Distinctive facial features that are seen after

Overall malformation rates

Major congenital malformations are generally defined as structural abnormalities of surgical, medical, functional, or cosmetic importance. Such structural abnormalities are established during organogenesis, within the first 8–10 weeks of gestation, often before the woman is aware that she is pregnant. Findings from several studies have confirmed greater risks of such malformations in children exposed to AEDs in utero; the risk was about three times that in the children of healthy women,

Cognitive outcomes after AED exposure

Although the crucial period for all structural abnormalities caused by drug exposure or other reasons is limited to the first trimester, drug exposure throughout pregnancy might affect the cognitive development of the fetus and the child. Whether treatment with AEDs during pregnancy can adversely affect the mental development of the exposed child has been discussed since the 1970s. Early studies were inconclusive and conflicting because of shortcomings such as poor statistical power or failure

Behavioural outcomes

Maternal use of AEDs during pregnancy has also been suggested to affect the behaviour of the exposed child. A retrospective study assessed 242 children aged between 6 and 16 years whose mothers had epilepsy during pregnancy.⁹² Children who had been exposed to valproate had lower scores on tasks relating to daily living and socialisation skills than children exposed to other AEDs, suggesting that valproate exposure in utero is a risk factor for maladaptive behaviour. In a prospective cohort

Dose dependence of teratogenic effects

Several studies have reported that the risk of major malformations increases with the prescribed dose of valproate, in general with greater risks at doses above 600–1500 mg/day.25, 28, 38, 75, 95, 96, 97 In a study from the UK Epilepsy and Pregnancy Register, greater risks of malformations were reported with lamotrigine doses above 200 mg/day than with lower doses,²⁸ although this finding was not confirmed in the NAAPR or the International Lamotrigine Pregnancy Registry.27, 58 The most

Conclusions

Our knowledge of the second-generation effects of three frequently used AEDs—carbamazepine, lamotrigine, and valproate—has increased substantially in recent years. One striking finding is that the risk for major malformations with use of carbamazepine and lamotrigine in monotherapy seems to be less than the previously reported three times increased risk with AEDs compared with the general population.³ Another consistent finding is significantly lower rates of malformation with exposure to

Search strategy and selection criteria

References for this Review were identified from the authors’ files and from a PubMed search (from 1966 to March, 2012) using at least one of the following terms (by searching as text words): “epilep*”, “seizure*”, “antiepileptic*”, “anti-epileptic*”, “anticonvuls*”, “anti-convuls*”, “barbit*, and specific drug names. Publications found were limited to those retrieved by searching as text word at least one of the following terms: “pregnan*”, “maternal”, “mother”, “parent*”, “fetal”, “foetal”,

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Higher healthcare utilization in epilepsy correlates with better clinical and quality of life outcomes. Women Veterans with epilepsy (WVE) have unique characteristics that may affect access and utilization of care. This study investigates epilepsy care in WVE, with respect to utilization of outpatient, inpatient, and emergency room care.
Data were collected from 58,525 Veterans with epilepsy using the Veterans Health Administration (VHA) Corporate Data Warehouse administrative data. Overall, 8.5% of the sample were women (n = 4983). Neurology visits, comprehensive epilepsy care, neuroimaging, ASM prescription and hospital and emergency care were analyzed, and comparisons were made with men Veterans with epilepsy to identify gender differences.
Compared to men, a greater proportion of WVE utilized services including neurology (73.8% vs. 62.0%), comprehensive epilepsy care (16.1% vs. 11.7%), epilepsy monitoring unit evaluation (EMU; 6.1% vs. 2.9%), neuroimaging (CT: 39.1% vs. 36.6%; MRI: 43.7% vs. 32.5%), and electroencephalograms: (EEG: 36.5% vs. 29.1%). WVE also evidenced higher percentages of seizure-related emergency room care usage vs. men (15.2 vs. 12.6) and hospitalizations (12.3 vs. 10.0) and were prescribed a greater number of ASMs (average:2.3 vs. 1.9). Valproate was prescribed to 17.6% of WVE, despite potential teratogenic concerns.
WVE have greater utilization of epilepsy care within the VHA system compared to men, which could lead to better epilepsy management and quality of life. However, higher rates of emergency care, hospitalizations, and concurrent ASMs among WVE highlight the clinical complexity and raise concern for potentially comorbid conditions including psychogenic non-epileptic seizures.
Antiseizure Medications in Pregnancy
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Gene–environment interactions underlying the etiology of neural tube defects
2023, Current Topics in Developmental Biology
Neural tube defects (NTDs) consist of severe structural malformations of the brain and spinal cord and are the second most common structural birth defect in humans, accounting for approximately 2700 affected pregnancies every year in the United States. These numbers are highly significant, considering that birth defects remain a leading cause of infant mortality in the United States, affecting approximately 120,000 babies born annually. Survivors of these congenital malformations face long-term disability and lifelong challenges imposed by severe physical burdens compromising the afflicted individual's overall quality of life. Clearly, birth defects, and especially NTDs remain a global public health challenge, and the source of significant financial repercussions for healthcare systems worldwide. In order to better understand the role gene–environment interactions play in the etiology of NTDs, this chapter provides an overview of NTD phenotypes and their embryonic origins, discusses the genetic landscape of NTDs as it is currently understood, with a focus on experimental models that best illustrate how environmental factors modulate individual susceptibility to these birth defects. As folic acid interventions have proven to be effective in reducing the prevalence of NTDs, the chapter ends with a discussion on the impact that maternal dietary status has on NTD prevalence from a population perspective.
Effects of antiepileptic drugs polytherapy on pregnancy outcomes in women with epilepsy: An observation study in northwest China
2022, Epilepsy and Behavior
The management of pregnant women with epilepsy (WWE) treated with antiepileptic drugs (AEDs) polytherapy poses a great challenge. The purpose of this study was to evaluate the major congenital malformations (MCMs) associated with AED polytherapy, to assess the impacts of polytherapy regimens on seizure control and breastfeeding, and to determine the potential predictors for pregnancy outcomes.
This study was based on prospectively acquired data from a registry enrolling WWE in early pregnancy from Feb 2010 to July 2019, in which 123 pregnancies in 110 WWE were exposed to 27 different AED combinations.
There were 123 pregnancies in 110 WWE analyzed in our study. The live birth rate was 86.2 % and the risk of MCMs was 10.4 %. Multivariate analysis indicated that prenatal exposure to phenobarbital (odds ratio [OR], 17.424; 95 %CI, 1.510–201.067; P = 0.022) and topiramate (OR, 9.469; 95 %CI, 1.149–62.402; P = 0.036) was associated with increased risk of MCMs. Valproate (OR, 4.441; 95 %CI, 1.165–16.934; P = 0.029), phenobarbital (OR, 13.636; 95 %CI, 2.146–86.660; P = 0.006) and topiramate (OR, 7.527; 95 %CI, 1.764–32.118; P = 0.006) were significantly correlated with adverse pregnancy outcomes. Among 67 pregnancies in four combinations over 10 patients, 15 (22.4 %) remained seizure free through pregnancy, seizure frequency increased in 17 (25.4 %), decreased in 24 (35.8 %) women, in 26 (38.8 %) remained unchanged. Only 23.6 % of mothers undertook exclusive breastfeeding. Planned pregnancy was the only independent factor significantly associated with decreased risk of adverse pregnancy outcomes (OR, 0.139; 95 % CI, 0.051–0.382; P < 0.001). Notably, no adverse pregnancy outcome was recorded in pregnancies exposed to the combination of lamotrigine plus levetiracetam.
Prenatal exposure to the combinations containing valproate, phenobarbital, or topiramate was associated with increased risk of adverse pregnant outcomes. AED-related teratogenicity may be reduced by planned pregnancy in WWE exposed to polytherapy. Our findings also suggest the combination of lamotrigine and levetiracetam seems to be most desirable to balance seizure control and fetal safety.
Characterizing differences in psychiatric profiles between male and female veterans with epilepsy and psychogenic non-epileptic seizures
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While previous studies have described psychiatric profiles in patients with psychogenic non-epileptic seizures (PNES) and epileptic seizures (ES), a well-matched comparison between males and females has been lacking. To address this shortcoming, the present study sought to explore sex differences between male and female Veterans with ES and PNES in terms of psychiatric diagnoses, trauma histories, and psychiatric treatment.
A male Veteran sample (PNES n = 87, ES n = 28) was identified matching age and seizure diagnosis with our previously-gathered female Veteran sample (PNES n = 90, ES n = 28). Retrospective chart review was used to obtain demographic, psychiatric, and seizure-related variables. Group differences between PNES and ES were first assessed among males followed by differences between males and females.
Males with PNES were more likely to receive psychiatric treatment (82.6 % vs. 60.7 %, p = 0.017), be prescribed more psychotropics (1.6 vs. 0.9, p = 0.003), and more likely to have childhood physical abuse (27.9 % vs. 3.6 %, p = 0.007) than those with ES. Compared to PNES, males with ES presented to the epilepsy monitoring unit (EMU) significantly later (12.8 years vs. 6.1 years, p = 0.009), and were prescribed more anti-seizure medications (ASMs) previously (2.1 vs. 0.8, p = 0.009) and currently (1.6 vs. 1.0, p = 0.001). Between males and females with PNES, females evidenced more depression (76.7 % vs. 26.3 %, p < 0.001), borderline personality disorder (18.9 % vs. 4.7 %, p = 0.004), suicidality (65.6 % vs. 33.7 %, p < 0.001), and childhood sexual abuse (37.8 % vs. 11.6 %, p < 0.001), while males had higher rates of substance use disorders (37.2 % vs. 8.9 %, p < 0.001).
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ReviewTeratogenic effects of antiepileptic drugs

Summary

Introduction

Section snippets

Pregnancy loss

Intrauterine growth

Fetal anticonvulsant syndromes

Overall malformation rates

Cognitive outcomes after AED exposure

Behavioural outcomes

Dose dependence of teratogenic effects

Conclusions

Search strategy and selection criteria

Lancet

Epilepsy Res

Lancet

Am J Obstet Gynecol

Epilepsy Behav

Seizure

Epilepsy Res

Seizure

Lancet

Lancet Neurol

Epilepsy Res

Epilepsy Behav

Epilepsy Behav

Reprod Toxicol

Reprod Toxicol

Epilepsy Res

Seizure

Lancet

Lancet

Lancet

Lancet

J Neurol Sci

Epilepsy Behav

Lancet

Epilepsy Behav

Epilepsy Res

J Clin Neurosci

Thalidomide embryopathy

Arch Environ Health

Neurology

The teratogenicity of anticonvulsant drugs

N Engl J Med

Saving mothers’ lives: reviewing maternal deaths to make motherhood safer: 2006–2008. The Eighth Report of the Confidential Enquiries into Maternal Deaths in the United Kingdom

BJOG

Seizure control and treatment in pregnancy: observations from the EURAP epilepsy pregnancy registry

Neurology

Common antiepileptic drugs in pregnancy in women with epilepsy

Cochrane Database Syst Rev

Neurodevelopment of children exposed in utero to lamotrigine, sodium valproate and carbamazepine

Arch Dis Child

Navigating toward fetal and maternal health: the challenge of treating epilepsy in pregnancy

Epilepsia

Spontaneous abortion and the prophylactic effect of folic acid supplementation in epileptic women undergoing antiepileptic therapy

J Neurol

Epilepsy and pregnancy: effect of antiepileptic drugs and lifestyle on birthweight

BJOG

Pregnancy, delivery, and outcome for the child in maternal epilepsy

Epilepsia

Body dimensions of infants exposed to antiepileptic drugs in utero: observations spanning 25 years

Epilepsia

Pattern of malformations in the children of women treated with carbamazepine during pregnancy

N Engl J Med

The fetal valproate syndrome

Am J Med Genet

Dysmorphic features: an important clue to the diagnosis and severity of fetal anticonvulsant syndromes

Arch Dis Child Fetal Neonatal Ed

Antiepileptic drug use of women with epilepsy and congenital malformations in offspring

Neurology

Major malformations in infants exposed to antiepileptic drugs in utero, with emphasis on carbamazepine and valproic acid: a nation-wide, population-based register study

Acta Paediatr

Final results from 18 years of the International Lamotrigine Pregnancy Registry

Neurology

Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register

J Neurol Neurosurg Psychiatry

Comparative safety of antiepileptic drugs during pregnancy

Neurology

Newer-generation antiepileptic drugs and the risk of major birth defects

Review
Teratogenic effects of antiepileptic drugs