Intrauterine growth in the offspring of epileptic women: a prospective multicenter study.

The aim of the present study was to evaluate the risk of intrauterine growth delay in the offspring of epileptic mothers and to quantify the risks of intrauterine exposure to antiepileptic drugs (AEDs). Data concerning 870 newborns, prospectively collected in Canada, Japan and Italy, using the same study design, were pooled and analyzed. The overall proportion of newborns whose body weight (7.8%) or head circumference (11.1%) at birth were below the 10th percentile was not increased. However, logistic regression analysis showed that the risk of small head circumference was significantly higher in Italian than in Japanese (RR 4.2; 95% CI: 2.2-8.0) or Canadian children (RR 2.6; 95% CI: 1.1-6.5), and in children exposed to polytherapy (RR 2.7; 95% CI: 1.2-6.3), phenobarbital (PB) (RR 3.6; 95% CI: 1.4-9.4) and primidone (PRM) (RR 4.5; 95% CI: 1.5-13.8). Country was also the only factor affecting low body weight, with Italian children having a higher risk than Japanese (RR 5.2; 95% CI: 2.6-10.4) or Canadian (RR 8.8; 95% CI: 2.0-38.1) children. Due to the small categories, the influence of AED doses and plasma concentrations was studied for each individual AED, without adjustment for the other potential confounding factors. A clear dose-dependent effect was found for PB and PRM in terms of both small head circumference and low body weight, and a concentration-dependent effect for PB in terms of small head circumferences. The size of the difference between the Italian and the other two populations, which is only partially explained by differences in therapeutic regimens, suggests that genetic, environmental and ethnic factors also need to be taken into account when considering possible explanations.

Congenital malformations due to antiepileptic drugs.

To identify the major risk factors for the increased incidence of congenital malformations in offspring of mothers being treated for epilepsy with antiepileptic drugs (AEDs) during pregnancy and, to determine the relative teratogenic risk of AEDs, we prospectively analyzed 983 offspring born in Japan, Italy, and Canada. The incidence of congenital malformations in offspring without drug exposure was 3.1%, versus an incidence with drug exposure of 9.0%. The highest incidence in offspring exposed to a single AED occurred with primidone (PRM; 14.3%), which was followed by valproate (VPA; 11.1%), phenytoin (PHT; 9.1%), carbamazepine (CBZ; 5.7%), and phenobarbital (PB; 5.1%). The VPA dose and level positively correlated with the incidence of malformations. This study first determined a cut-off value of VPA dose and level at 1000 mg/day and 70 microg/ml, respectively, to avoid the occurrence of malformations. The incidence of malformations increases as the number of drugs increases, and as the total daily dose increases. Specific combinations of AEDs such as VPA + CBZ and PHT + PRM + PB produced a higher incidence of congenital malformations. The incidence of malformations was not associated with any background factors studied except for the presence of malformations in siblings. These results indicate that the increased incidence of congenital malformations was caused primarily by AEDs, suggesting that malformations can be prevented by improvements in drug regimen, and by avoiding polypharmacy and high levels of VPA (more than 70 microg/ml) in the treatment of epileptic women of childbearimg age.

Impact of a Menninger training experience.

In light of her experience working with victims of severe physical and psychological trauma, the author comments on the benefits of her training in psychodynamic psychology. She highlights in particular the value of understanding the complexity of diagnosis and the importance of psychodynamically informed thinking in all treatment approaches.

Torture and war trauma survivors in primary care practice.

Close to 1 million refugees from around the world have entered the United States, fleeing repression, war, terrorism, and disease. It has been estimated that among these are thousands who have experienced torture. Many refugees and immigrants will appear in the offices of health care professionals with symptoms that may be related either directly or indirectly to torture. Both physical and psychological torture may result in long-term sequelae. Physical effects may be found in every organ system, but psychological effects are most commonly manifest in the symptoms of the post-traumatic stress disorder. For physicians to recognize how torture can affect health status, it is important to understand that history taking may be difficult and that little information may emerge that would explain the origins of scars, fractures, or disabilities. Recognizing the clues to a torture history allows physicians to assist patients in describing the trauma. In addition, knowing the subacute and chronic signs and symptoms of torture enables physicians to diagnose and treat often obscure symptoms with a much clearer understanding of the sources of the difficulty. Paying special attention to the interview process will support torture survivors in detailing often horrific events.

Improved pregnancy outcome in epileptic women in the last decade: relationship to maternal anticonvulsant therapy.

The prevalence of abnormal pregnancy outcomes in the offspring of 103 epileptic women, followed prospectively during pregnancy between 1982 and 1989, was compared with that in the previous study of 119 pregnancies by Dansky et al from the same institution. Our results have shown a significant decrease in the prevalence of major malformations, as compared with the previous study: 8.8% vs 24.1% (P < 0.01). Monotherapy was more frequent and the mean number of drugs used during pregnancy was significantly smaller in the present study. Phenytoin, phenobarbital and primidone were prescribed less frequently in the present study, whereas carbamazepine and valproic acid were used more frequently. Plasma levels of valproic acid during pregnancy were higher in mothers of malformed babies. In the present study, plasma folate levels were significantly higher, and more patients were taking folate supplements during pregnancy. In conclusion, the type and number of drugs used during pregnancy, as well as the plasma concentrations and serum folate levels, may determine the frequency of abnormal outcomes.

Mechanisms of teratogenesis: folic acid and antiepileptic therapy.

Gestational folate deficiency has been associated with abnormal growth and development in both experimental animal and human studies and has been postulated as a putative mechanism for the teratogenic effects of antiepileptic drugs (AEDs). Animal studies have shown that the administration of AEDs results in folate depletion and teratogenic effects. Attempts to prevent the teratogenic effects of AEDs by coadministration of folate have shown variable results, perhaps because of a lack of understanding about the specific effects of AEDs on folate metabolism. Our prospective study of women with epilepsy showed that blood folate levels decreased with increasing plasma AED levels and with the number of AEDs. Low blood folate levels before and/or early in pregnancy were significantly associated with spontaneous abortion and the occurrence of developmental anomalies in the offspring. These findings suggest that folate supplementation might be one means of preventing the occurrence of abnormal pregnancy outcome in women with epilepsy, including neural-tube defects in the offspring.

Parental epilepsy, anticonvulsant drugs, and reproductive outcome: epidemiologic and experimental findings spanning three decades; 1: Animal studies.

In conclusion, it is clear that the experimental animal literature has been extremely beneficial in validating the teratogenicity of selected anticonvulsant drugs such as phenytoin and valproic acid, and in providing much needed information on pharmacokinetic parameters that are involved in altering normal embryogenesis. Continued efforts are needed to further elucidate the mechanism of teratogenic action for these drugs. It is clear from the work on phenytoin that reactive intermediates are important, and care must be taken to either avoid drug therapies that promote the formation of or inhibit the rapid degradation of toxic oxidative metabolites. For valproic acid and carbamazepine the pathogenesis of congenital defects remains much less defined. Until adequate information is ascertained on just how antiepileptic drugs disrupt normal development, it will be difficult, if not impossible, to develop either alternative medications or treatment strategies that maximize clinical effectiveness without the risk of an adverse pregnancy outcome. Such information emanating from animal studies shall, hopefully, be available in the not-too-distant future.

Parental epilepsy, anticonvulsant drugs, and reproductive outcome: epidemiologic and experimental findings spanning three decades; 2: Human studies.

Evidence accumulated over the past three decades has established AEDs as human teratogens. Important developments in the delineation of these compounds as human teratogens include: the demonstration of a consistent association between in utero exposure to AEDs and an increased occurrence of single major malformations, the description of AED-induced dysmorphogenic syndromes; demonstration of a dose-response relationship, both in terms of the number and dosage of AEDs; and evidence that pharmacogenetic differences in the metabolism of AEDs are strongly correlated with the occurrence of congenital malformations. Furthermore, the experimental animal findings, having accumulated in parallel to those of human studies, strongly support the teratogenic role of AEDs. Areas that require further amplification and clarification in future studies are the relative contribution of AEDs and other factors, such as genetic predisposition and maternal seizures, particularly with respect to the occurrence of minor anomalies, growth retardation, and developmental outcome; the relative teratogenicity of specific monotherapies and polytherapies; the predictive role of pharmacogenetic differences in the metabolism of AEDs in the occurrence of structural and functional abnormalities; and characterization of the precise nature of the pharmacogenetic defect underlying the aforementioned differences in AED metabolism. Attempts should also be made in future prospective studies to monitor metabolite levels of AEDs, particularly the oxidative metabolites, in order to further elucidate the relative contribution of individual differences in metabolism in the determination of adverse fetal outcome. Similarly, further efforts should be made to assess the clinical significance of decreased growth parameters in terms of mental and neurologic development, and to ascertain whether there is any risk for such abnormalities in children who do not display overt or persistent reductions in physical growth parameters. This is critically important in light of the animal studies that have shown functional abnormalities at doses that do not necessarily produce structural defects. Future investigations would be conducted through collaborative studies that would encompass sufficiently large numbers of women to provide adequate power to the statistical analyses of the data obtained. Care would have to be exercised to establish a uniform protocol for the collaborating centers. Regionally based investigations would be preferable to studies based at special centers, in order to assess the relative role of risk factors associated with abnormal pregnancy outcomes in the epileptic population at large.(ABSTRACT TRUNCATED AT 400 WORDS)

Evaluation of placental morphology and growth factor receptors in women receiving antiepileptic drugs: a pilot study.

A direct teratogenic effect of antiepileptic drugs (AEDs) on the fetus has been postulated. However, there may also be a primary effect of AEDs on placenta, with secondary consequences to the fetus. Thirteen carefully medically controlled epileptic women were followed prenatally and perinatally. Placentas from all were investigated morphologically and in two with electronmicroscopy. In nine patients, the placentas were studied with respect to insulin and insulin-like growth factor (IGF-I and IGF-II) receptor activity. In this pilot study of a group of carefully medically controlled epileptic women with low levels of AEDs, the results did not differ from normal controls. The possibility of adverse effects of higher concentrations of AEDs cannot be excluded, however.

Anticonvulsants, folate levels, and pregnancy outcome: a prospective study.

Folate levels in serum and red cells, as determined by a microbiological assay using Lactobacillus casei, and plasma anticonvulsant concentrations were monitored concurrently in nonpregnant (50 subjects) and pregnant (49 pregnancies in 46 subjects) epileptic women. Twenty-three (46%) nonpregnant women had subnormal serum folate levels and 4 nonpregnant women (8%) showed subnormal red cell folate levels. In pregnant women not taking folate supplements, the incidence of folate deficiency increased as the pregnancy advanced. Pregnant women taking folate supplements achieved normal or supranormal blood folate concentrations. In both nonpregnant and pregnant women, serum and red cell folate levels were inversely correlated with plasma concentrations of phenytoin and of phenobarbital, and with the number of anticonvulsants. In 49 pregnancies, there were 10 abnormal outcomes (20.4%): 4 spontaneous abortions (8.2%) and 6 children with major congenital malformations (12.2%). Blood folate levels were significantly lower in pregnancies with an abnormal outcome than in those with a normal outcome. The results suggest a dose-response relationship among anticonvulsants, folate, and adverse pregnancy outcome.

Use of the adult developmental relationship in prescreening for developmental hazards.

The overwhelming majority of chemicals already in commerce or brought into use each year have not been evaluated for their potential to adversely affect in utero development. Data from those that have been evaluated thus far in pregnant laboratory animals establish that most, but not all, were no more hazardous to the conceptus than they were to adult homeostasis. Most did not need standard developmental toxicity testing because avoidance of adult toxic exposure levels would have precluded abnormal in utero development. The six general principles of teratology when modified, expanded, and placed into this type of context of contemporary developmental toxicology allow an updating of the present testing sequence which was devised prior to 1966. The developmental hazard index (A/D ratio) calculated from the adult and developmental NOELs of standard Segment II evaluations is predicted by in vitro means. This determination, when coupled with adequate considerations of exposure can be used to prioritize chemicals for more elaborate developmental toxicity tests. Those chemicals with large ratios, i.e., disruptive of embryogenesis at treatment levels too low to produce overt effects in the mother and/or with significant concern regarding exposure, can be identified and tested in pregnant laboratory animals as high priority items. Those with low ratios and those for which there is a low level of concern regarding exposure potential also can be identified and are not high priority items for testing in pregnant animals. The proposed tier system establishes priorities of testing based on exposure and the concept of target organ toxicity applied to the embryo. It provides intensive in vivo evaluations of those chemicals for which developmental effects testing is most needed and avoids use of resources and animals for unnecessary testing of agents that do not pose threats to the conceptus.

Genetic predisposition to phenytoin-induced birth defects.

To find out whether arene oxide metabolites of phenytoin and a genetic defect in arene oxide detoxification contribute to susceptibility to phenytoin-induced birth defects, lymphocytes from 24 children exposed to phenytoin throughout gestation and from their families were challenged in a blind protocol with phenytoin metabolites generated by a murine hepatic microsomal drug-metabolising system. 14 of the children had a "positive" assay result--ie, a significant increase in cell death associated with phenytoin metabolites. Each child with a positive result had one parent whose cells also were positive. A positive in-vitro challenge was highly correlated with major birth defects, including congenital heart disease, cleft lip/palate, microcephaly, and major genitourinary, eye, and limb defects. There was no difference between children with positive and negative results in the number or distribution of minor birth defects, including stigmata of the fetal hydantoin syndrome. Although many factors contribute to the outcome of pregnancies in epileptic women treated with phenytoin, a genetic defect in arene oxide detoxification seems to increase the risk of the baby having major birth defects.

Marriage and fertility in epileptic patients.

Marital status and fertility were compared for 100 epileptic females and 100 epileptic males. The marriage rate among male patients was 59% of expected (p less than 0.001) as compared to 83% for female patients (p less than 0.10). Patients with early onset of seizures, particularly males, had lower marriage rates than expected, unlike patients with onset after age 20. Married female patients had only 69% of the expected number of live-born children (p less than 0.001) as compared to 100% for married male patients. Marriage and fertility rates of epileptic females have improved in the last generation, while those of epileptic males have remained constant.