Ruber H Arias C

Resident of clinical toxicology

U de A

Antiepileptics and pregnancy Carbamazepine D category. Compatible with

breastfeeding.

Phenobarbital D category. Moderate risk with

breastfeeding.

Lamotrigine C category. Moderate risk with breastfeeding.

Valproic acid D category. Compatible with breastfeeding.

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Seizures in pregnancy were reported from 1882 women participating in the European Pregnancy Registry. Seizure control remained unchanged in 63.6% of whom 92.7% remained seizure free during the whole pregnancy. Of the remainder, whose seizure control had altered, 17.3% had an increase, and 15.9 a decrease in seizures. Seizures occurred during delivery in 60 pregnancies (3.5%), more commonly in women with seizures during pregnancy.

more than five convulsions poses a risk for the child’s cognitive development.

data suggest that VPA is more effective than LTG but this may be related to the fact that LTG clearance increases during pregnancy, with a decline in the serum levels of LTG.

Hazards of uncontrolled seizures is the loss of fetus. Hypoxia of the fetus may result in spontaneous abortion, and potential cognitive damage.

The dose of an AED may be a less accurate marker of exposure and production of abnormalities than plasma concentrations.

Valproic acid exhibits more incidence of teratogenic effects.

There is a beneficial effect of folic acid in preventing neural tube defects.

appropriate tests to observation of the fetus includes ultrasound, blood tests such as α -fetoprotein measurements, amniocentesis.

VPA teratogenicity is dose related, and extends from physical malformations to cognitive developmental problems.

Polytherapy, by all accounts, is undesirable but often necessary.

LTG has significant limitations as a substitute

Described adverse outcomes include major congenital malformations, minor anomalies and dysmorphism, growth retardation, and impaired cognitive development.

all of the major old generation AEDs such as phenobarbital, phenytoin, valproate and carbamazepine, have been reported to be associated with increased risks for major congenital malformations.

Women with epilepsy have been estimated to account for 0.3% up to 0.7% of all pregnancies.

Reduced birth weight, in the offspring of women treated with phenytoin was reported already in the 1970´s.

The malformations related to the exposure includes microcephaly, growth retardation, hypertelorism, depressed nasal bridge, low set ears, micrognathia and distal digital hypoplasia.

Valproate exposure has been claimed to cause a dysmorphic syndrome characterized by thin arched eyebrows broad nasal bridge, short anteverted nose, and a smooth long filtrum with thin upper lip.

The prevalence of major congenital malformations in children exposed to AEDs has ranged from 4 to 10%.

It is possible that more frequent use of AED monotherapy as opposed to polytherapy, use of lower doses, changes in AED preferences, and pre-conceptional counselling has contributed to reduced fetal risks.

In 26 cohort studies that included pregnancies of women with treated as well as untreated epilepsy, the average malformation rate among children exposed to AEDs in utero was 6.1% compared to 2.8% among children of mothers with untreated epilepsy and 2.2% in infants of healthy controls.

Neural tube defects and hypospadia are more common among offspring of mothers who used valproate during pregnancy.

An increased risk of neural tube defects of 0.5–1% has also been reported after carbamazepine exposure.

A dose–effect relationship has been shown for teratogenicity with valproate. Dosages above 800–1,000 mg/day have been associated with significantly greater risks.

The 5,10 methylene tetrahydrofolate reductase (MTHFR) gene has been suggested as one candidate to explain genetic susceptibility to folate sensitive malformations.

Some mutations have been associated with increased risks of malformations such as neural tube defects, cleft palate and congenital heart disease that are often seen in relation to exposure to AEDs.

Reactive epoxides could be the result of CYP450 mediated oxidation of phenytoin, carbamazepine or phenobarbital.

Deficiency of free radical scavenging enzymes, responsible for eliminating ROS, has been associated with malformations in the offspring of epileptic mothers exposed to AEDs.

phenytoin, trimethadione, carbamazepine, phenobarbital, and possibly lamotrigine may exert their teratogenic effects by inducing embryonic cardiac arrhythmia during specific sensitive restricted periods.

Objective

To determine the frequency of malformations among infants born to women who had taken lamotrigine or carbamazepine as part of polytherapy during the first trimester of pregnancy.

A cohort of women enrolled during pregnancy in the North American AED (Antiepileptic Drug) Pregnancy Registry.

Greater risk of birth defects in politherapy against monotherapy.

Risk of birth defects in monotherapy 10.7% with valproate, phenobarbital 6.5% and lamotrigine 2.3%.

Methods

women were interviewed 3 times: at enrollment, at 7 months’ gestation, and 8 to 12 weeks after the expected date of delivery.

They asked about epilepsy treatment, habits, medications, other exposures, family history and folic acid treatment.

A woman was classified as being a “pure” prospective enrollee if she had not had any prenatal screening that could have identified malformations at the time of enrollment and, therefore, could not have known whether her fetus had a malformation.

Participants were eligible for analyses if they completed the follow-up and had a live-born or stillborn (20 weeks’ gestational age) infant, an infant who died in the first 28 days of life (neonatal death), or an elective termination of pregnancy for which the findings in postmortem examinations were available.

The exposure time was the first 16 weeks of pregnancy.

A major malformation was defined as a structural abnormality with surgical, medical, or cosmetic importance. The written descriptions in the pediatricians’ examinations were reviewed separately by the clinical teratologist who was blinded to exposure status.

They exclude minor anomalies (eg, simian crease); deformations

or positional deformities ; features due to prematurity ; birthmarks (eg, hemangiomas); genetic disorders ; chromosome abnormality ; functional deficits (eg, a failed hearing test during newborn screening); any finding by prenatal sonography or at surgery or autopsy (eg, absence of 1 kidney) that was not identified by an examining pediatrician; and anomalies detected only by prenatal ultrasonography (and not during the physical examination by the pediatrician.)

Comparisons groups

Internal group: woman recruited among friends and family of the patients.

External group: live-born and stillborn infants, as well as elective terminations because of fetal anomalies, surveyed by the Active Malformations Surveillance Program at Brigham and Women’s Hospital.

They compared the risk with monotherapy, politherapy and the two control groups of not exposed mothers.

They calculated the risks through multivariate logistic regression using SAS statistical software.

Discussion

Previous studies:

UK Epilepsy and Pregnancy Register 8.8% among 62 patients with

carbamazepine and valproic acid. 9.6% among 141 patients with

lamotrigine and valproic acid.

International lamotrigine pregnancy registry

12.5% among 88 patients with lamotrigine and valproate.

2.7% among 182 patients with lamotrigine without valproate.

In conclusion, counseling for fetal risks from exposure to AED polytherapy should be based on the specific drugs included in the combinations. Polytherapies that include valproate pose a higher risk to the fetus than those without this drug.

Limitations The criteria of pediatricians about physical

examination.

They did not include functional impairments.

The criteria of the external group (same investigator) and the risk of bias.

Good study, size sample, OR were significant.

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