Valproic acid in epilepsy pregnancy-related issues

The use of valproic acid for the treatment of epilepsy during pregnancy should be extremely limited.

Women with epilepsy are at risk for adverse pregnancy outcomes. Nevertheless, the majority of children born to sick mothers do not differ from their peers. In studies performed in experimental animals, demonstrated that prenatal appointed antiepileptic drugs (PET) in doses not to cause the formation of structural anomalies in fetuses, lead to a breach in the future children of behavioral and cognitive functions, changes in the fine neurochemical processes and contribute to reduce the mass of brain matter. It was established that the person on the effect of the probe fetus may show impaired nerve - psychic development, but the use of these medications during pregnancy is justified due to the undoubtedly greater risk to mother and fetus because of seizures. Results of published studies do not allow us to recommend one or another probe pregnant or planning pregnancy.

In a recent agreement, worked out jointly by the American Academy of Neurology, American College of Obstetricians and Gynecologists and the International League against Epilepsy, does not give preference to the use of - or the drug, taking into account the risk of teratogenic effects. In this regard, the team conducted an assessment of psychomotor development of children exposed to some of the probes during fetal development.

Methods and progress in the study.
Effect of antiepileptic drugs on the Psychomotor Development (The Neurodevelopmental Effects of Antiepileptic Drugs - NEAD) - a prospective descriptive study, which included pregnant women who received monotherapy with PET. The study was performed between October 1999 and February 2004 in 25 centers epilepsy United States and Britain. Scientists in both countries, working in isolation from each other, subsequently joined the results. The main estimated results - evaluation of intellectual abilities of the child reaches the age of six years. In this study, an interim analysis conducted assuming examination of children when they reach the age of three.
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From each patient were obtained informed written consent to participate in the study. Include pregnancy, epilepsy, about which monotherapy one of the following drugs: carbamazepine, lamotrigine, phenytoin, or valproic acid (VC). Women who received other drugs not included in the study because of the small number of clinical observations. Furthermore, do not take into account the observation that was multi-component treatment due to adverse effects of poly therapy, and because of technical difficulties did not allow to evaluate the possible negative impact of a combination of several drugs. In accordance with the recommendations of the National Institutes of Health has been performed in a set of the control group of children whose mothers did not receive treatment during pregnancy probe. Because the maternal intellectual coefficient (IQ) is the most significant prognostic factor for IQ child from the study excluded patients with the value of this indicator is below 70. In addition, excluding women with positive results of serological tests for syphilis and human immunodeficiency virus, the presence of progressive brain diseases, severe extragenital pathology (e.g., diabetes mellitus), exposed to teratogens, poor tolerance to probe who use illicit trafficking in drug's history and / or current pregnancy.

Carefully recorded information about factors that could influence the subsequent psychomotor development of children: IQ mother and her age at the time of birth, educational level, employment status, race, ethnicity, clinical variant of epilepsy, the nature and frequency of seizures, the dose of PEP, treatment tolerability , social - economic situation, the use of folic acid during pregnancy planning, the use during pregnancy alcohol and other drugs, tobacco. Consider the location of a particular center - UK or U.S.. Recorded also such factors as the planned or unplanned pregnancy, pathology, or complications in the present or previous pregnancy, gestational age at enrollment and at delivery, body weight at birth, the presence of breastfeeding, especially the child's development.

Trained professionals who are not knowledgeable about the nature of antiepileptic treatment during pregnancy, assessed the mental abilities of children using the Index of Mental Development Scales of infant Bayley second revision (in the child's age from 21 to 34 months) and the Differential Abilities Scales (aged children from 33 to 45 months of life). Based on the tests was calculated point scoring on each of the scales. Evaluation of maternal IQ was carried out using several tests for the subsequent comparison of results obtained in the UK and the USA. In 267 patients used non-verbal Abilities Test Ratings, 18 - Scale Wechsler intelligence, 18 - National Reading Test for Adults. Conducting these tests carefully monitored for quality and completeness of execution. In this case, all the experts conducting the survey annually with individual instruction on using these tests. In addition, in order to avoid methodological errors and to make the appropriate correction was carried videotape of the testing process.

Evaluation of mental retardation performed in 258 children aged 2 and / or 3 years old, born to 252 mothers of them during pregnancy in 73 of the mothers' receiving carbamazepine, in 84 - lamotrigine, in 48 - and phenytoin in 53 - VC. This group accounts for 83.5% of all children whose mothers were originally included in the study: 309 infants born to 303 mothers. At the same time, get pregnant following treatment PET: in 93 observations - carbamazepine, 100 - lamotrigine, in 55 - and phenytoin in 61 - VC. These differences reflect the diversity in approaches to treatment in clinical centers participating in the study NEAD. Initially, the centers of the UK have not conducted a survey of children aged two years. As a consequence, 63 children in Britain have not been examined in the present age. In general, it surveyed 187 children aged two years and 232 - in three years. The relative amount of missing data and the assessment methodology IQ mothers in all four groups, which were treated by any other probes were not significantly different.

In assessing the maternal demographic factors was significant correlation (p <0,05) of the VC with maternal age, dose of antiepileptic drugs, the nature of seizures, a clinical variant of epilepsy, the location of the clinical inter in the U.S. or the UK, the frequency of breastfeeding. Average IQ values ​​in children aged three years were characterized by significant differences depending on the type used in pregnancy PEP: Using VC (n = 53) average IQ - 92 (the boundary values ​​of 88 - 97)for carbamazepine (n = 73)- 98 ( boundaries of the 95 - 102), for phenytoin (n = 48)- 99 (the boundary values ​​of 94 - 104) for lamotrigine (n = 84)- 101(boundary values ​​of 98 - 104).

Based on the regression model revealed that a statistically significant independent effect on IQ of the child had the type of probe, IQ mother and her age, used a standard dose of the drug, the gestational age at delivery, and use of folic acid during pregnancy planning. For the remaining factors accounted for this relationship is not revealed.

During pregnancy in two patients completed the replacement of one probe to another, and in 12, it became necessary to appointment of the second drug. With the exclusion of data analysis 14 cases the final results have not undergone any changes.

The researchers found that the average IQ of children exposed to VC during fetal development, was down 9 points, compared with lamotrigine (95% confidence interval [CI] - 3,1 - 14,6 p = 0, 009), 7 points - compared to the use of phenytoin (95% CI - 0.2 - 14.0, p = 0.04) and by 6 points - in the treatment of carbamazepine (95% CI - 0.6 - 12.0, p = 0, 04). At the same time, the IQ of children whose mothers during pregnancy were treated with either of the drugs, but the VC did not differ significantly (p = 0.68).

In assessing the impact of dose on IQ probe child aged three-year significant negative relationship is established only for VC (r =- 0, 38; p = 0.005) such a relationship remained true when considering the average dose of the drug at most during the third trimester of pregnancy.

During pregnancy in 38 patients was carried out determining the level of VC in plasma, while A significant correlation with the received dose of the drug (r = 0, 42; p = 0.008) at the same time, the correlation between the level of VC in the blood plasma and IQ of the child in the future in the present of a small subgroup were found.

In addition, when using low-dose PET no significant differences in IQ of children in the future. Child IQ was in the line of reliability depending on the mother's IQ and did not depend on the type of probe, except for VC.

Unlike the other most commonly used PET, VC during pregnancy has a negative, dose - dependent influence on subsequent intellectual development of children.
The present study is not randomized, that is its limitation. Nevertheless, establishing a relationship of an adverse finding by using the VC during pregnancy showed no relevant change through the introduction of amendments to the numerous significant factors.
For a comprehensive assessment of the risk of PEP during pregnancy and understanding the mechanisms of their negative influence, in our opinion, necessary to conduct additional studies.
Researchers believe that the VC in any case should not be used during pregnancy as first-line agents. At the same time, a number of clinical situations, only the VC can achieve adequate control of seizures. In this situation, the pregnant woman should receive the necessary valuable information regarding potential risks and benefits of such treatment, including that it should not independently make the decision to refuse treatment from the VC without consulting with a specialist.

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