History Of Neural Tube Defects Research Articles

Folic acid supplementation and social deprivation

To assess the use of folic acid supplementation in relation to small-area measures of social deprivation. Cohort study. Antenatal clinic, Women's Outpatients Services, Cumberland Infirmary, Carlisle, UK. Four hundred and fifty women attending their 18-week antenatal clinic appointment. No selection criteria were applied. Townsend scores were allocated using postcodes to provide a small-area measure (enumeration district) of social deprivation. Eighty-nine per cent of women took folic acid prior to their 18-week antenatal clinic appointment; 48% of women took folic acid before 4 weeks of gestation. Younger women and more socially deprived women were less likely to use folic acid supplements before 4 weeks of gestation. Women with a family history of neural tube defects were no more likely to take folic acid than were women with no family history of neural tube defects. A high proportion of women reported taking folic acid supplements during pregnancy but less than half took them at the most important time in early pregnancy. Younger women and women who were more socio-economically deprived were much less likely to take folic acid during the critical periconceptional period. Future strategies should promote prenatal folic acid supplementation in women under the age of 24 and in women of low socio-economic status. Further attention should also be given to the use of folic acid supplements in women with a family history of neural tube defects.

Folate Intake and the Risk of Neural Tube Defects: An Estimation of Dose-Response

Folic acid supplements in the form of multivitamins, taken in the periconceptional period, lower the risk of neural tube defects (NTDs), but few studies have demonstrated a clear dose-response relationship. This prospective study analyzed data from 23,228 women, chiefly from the northeastern United States, who enrolled from 1984 through 1987. Diet and vitamin intake were assessed by telephone interviews early in the second trimester of pregnancy. Dietary folate was estimated using a 50-item food frequency questionnaire. Women using the highest-dose supplements in the first 5 weeks of pregnancy tended to be older and college-educated, and to have used multivitamins before becoming pregnant. They also were likelier than others to have a history of diabetes or a family history of NTDs. No dose-response relationship was noted when analyzing folic acid intake from supplements alone. The estimated reduction in NTD risk ranged froth 44% to 71%. Women with the lowest dietary folate intake had the highest risk of having an infant with an NTD (4 cases per 1000). There were indications that a higher intake of folate from foods is protective, but any protective effect was not linear. Women taking the least folate had a prevalence of NTDs of 3.4 cases per 1000. The risk declined as total folate increased, and the risk for those taking the most folate was 0.8 cases per 1000, a 77% reduction in risk. The prevalence of NTDs declined by 0.78 cases for every additional 500 dietary folate equivalents consumed per day. It appears that the NTD risk decreases substantially with a modest increase in total folate, from both food and supplements, in early pregnancy. Total folate intake is the critical parameter when formulating public health guidelines.

Folic acid — changes in women's knowledge

Taking folic acid supplements in the peri-conceptional period and during the first trimester of pregnancy is associated with a reduced incidence of neural tube defects. This study aimed to investigate changes in knowledge and attitudes to folic acid supplementation following advice to health professionals about the recommended use of folic acid supplements by all women of childbearing age. A questionnaire-based survey was conducted in 1996 and 2002 on 450 women. Most women were not offered folic acid before conception and but were offered supplements on confirmation of their pregnancy. There was a 2.5-fold increase in the number of women buying their own supplements, the majority of whom took these before conception. There was a decline in the number of women receiving no advice at all about folic acid supplementation and supplementation in women with a family history of neural tube defects increased 2-fold. The findings of this study support an increased awareness of the benefits of peri-conceptional folic acid supplementation, however, this was primarily observed in primagravida women and supplementation compliance decreased with pregnancy parity.

Frequency of Down's syndrome and neural-tube defects in the same family

There is evidence that some mothers of infants with Down's syndrome have abnormal metabolism of folate and methyl, as well as mutations in folate genes, which are features that are also seen in neural-tube defects (NTD). We therefore investigated whether Down's syndrome and NTD arise more often in the same family than would be expected from the incidence of each disorder considered separately. We studied two series of families using information obtained from medical records about maternal age, pregnancy outcome, congenital malformations, and karyotype: the first, 493 families from Israel who were at high risk of NTD (445 with a history of NTD and 48 with isolated hydrocephalus); and the second, 516 families from the Ukraine at high risk of Down's syndrome. In the families at risk of NTD, there were a total of 11 pregnancies affected by Down's syndrome in 1492 at-risk pregnancies (compared with 1.87 expected on the basis of maternal age), which was a significant increase (p<0.00001). In the families at risk of Down's syndrome, there were seven NTD pregnancies in 1847 at risk, compared with 1.37 expected (p<0.001). In this study, we provide direct evidence of a link between Down's syndrome and NTD. Folate supplementation before conception has the potential to reduce the frequency of Down's syndrome.

Importance of folate in human nutrition.

From a public health perspective, some of the new insights into folic acid nutrition are of significance. Folate intake recommendations vary under different conditions. Intake of 350 microg is required to maintain plasma homocysteine levels, 650 microg for those with elevated plasma homocysteine, about 400 microg for women planning to become pregnant and 4000 microg for those with history of neural tube defect affected pregnancy. This raises the question whether the folate intake is adequate for the general population, particularly in the vulnerable groups or whether there is a need for scientists to take a fresh view of the requirements, recommended dietary intakes, and consider intervention measures which will have impact on the folate nutritional status. The recommendations should provide a margin of safety to allow for decreased intake, increased requirements, individual variability and bioavailability of natural food folates. The folate intake and nutriture in relation to India and other developing countries needs careful consideration to reduce anemia, neural tube defects and possibly impact on the high incidence of cardiovascular diseases.

Rare association of polysplenia with anencephaly

ABSTRACT Anencephaly is usually observed without association of severe malformations of other organs. A case of polysplenia, which was experienced in a 20-week-old anencephalic female fetus, was reported. The families of the parents had no history of neural tube defects. There was no consanguinity between the parents. The fetus showed a typical anencephaly with absent cranial vault, exophthalmus, hyperplastic thymus and hypoplastic adrenals. There was an atypical polysplenia consisting of five small spleens, absent gall bladder, short pancreas, small intestinal atresia and Fallot tetralogy. No visceral heterotaxy was observed in bronchi, lungs, liver or stomach. Though no direct association has been recognized between anencephaly and polysplenia, recent progresses in the studies of human fetuses and animal experiments help explain the relationship between anencephaly and heterotaxy syndrome. The mother of the present fetus had no history of hyperthermia, drug take or diabetes mellitus. She also had no infections such as virus and toxoplasma before and during pregnancy. There were no clues that would elucidate the etiology of the present anencephalic fetus with polysplenia. Precise surveillance and records of such cases should be advisable.

Absorption of Dietary and Supplemental Folate in Women with Prior Pregnancies with Neural Tube Defects and Controls

Background: The Public Health Service of the United States recommends that all women capable of childbearing consume .4 mg (400 μg) folic acid per day to decrease the risk of having a pregnancy affected by a neural tube defect such as spina bifida or anencephaly. Three strategies are available to women to achieve this goal: use of dietary supplements; use of fortified foods; and/or increased intake of naturally occurring folate from foods. Identification of the most effective vehicle for delivery of folate to all women is critical in order to prevent these devastating congenital defects.Objective: To investigate the difference in response to an oral load of folate both from naturally occurring food sources and synthetic supplements among women with prior pregnancies affected by neural tube defects and controls.Methods: We compared the absorption of test doses of 400 μg pteroylglutamic acid (unconjugated or synthetic folic acid found in supplements) and 400 μg pteroylpolyglutamic acid (conjugated or food folate) in 10 women with a history of neural tube defect affected pregnancies and eight controls with normal birth outcomes. The folate test dose was given as either 32 fluid ounces of orange juice or a folic acid single supplement pill. All participants received each test dose at separate clinic visits. The response to each test dose was measured by constructing an area under the curve (AUC) from the serum folate levels at 1, 2 and 3 hours post dose and applying a t-test to compare within and between cases and controls. We also compared red cell folate, vitamin B12, zinc and homocysteine between cases and controls.Results: Within group comparisons showed that the area under the curve was significantly greater for the pteroylglutamic acid dose compared to the pteroylpolyglutamic acid dose for both cases and controls (p=0.02 and p=0.03, respectively). In a between group comparison, control women had a greater serum folate response to both forms of the vitamin compared to the case women, but the difference reached statistical significance only for the pteroylglutamic acid dose (p=0.02). Other measured nutrients differed between cases and controls, but did not reach statistical significance.Conclusion: We conclude that for all women synthetic folic acid as supplements or fortified foods may be the best way to increase acute folate levels in the blood, and thus delivery to the developing embryo. Further, since case women had a diminished response to both forms of the vitamin, and some case women had almost no response, we speculate that women with prior affected pregnancies may need a larger dose of folate to elicit a plasma response equivalent to the general population.

Folate intake in Europe: recommended, actual and desired intake.

To evaluate possible inconsistencies between recommended, actual and desired folate intake in European adult populations. Review of dietary recommendations, of food consumption surveys, and of intervention and observational studies relating folate intake to the risk of neural tube defects and plasma homocysteine levels. In Europe, mean dietary folate intake in adults is 291 micrograms/d (range 197-326) for men and 247 micrograms/d (range 168-320) for women. The recommended intakes vary between 200-300 micrograms/d (men) and 170-300 micrograms/d (women). However, women with a previous pregnancy affected by a neural tube defect (NTD), are recommended to take 4000 micrograms/d of supplemental folic acid when planning a subsequent pregnancy. For those without a history of NTD, the use of 400 micrograms/d of supplemental folic acid is the best option to prevent the occurrence of NTDs. A daily dose of 650 micrograms supplemental folic acid normalises elevated plasma homocysteine levels, which is a risk factor for cardiovascular diseases. A dietary folate intake of at least 350 micrograms/d is desired to prevent an increase in plasma homocysteine levels of the adult population in general. Mean dietary folate intake in Europe is in line with recommendations, but the desired dietary intake of > 350 micrograms/d is only reached by a small part of studied European populations. It is considered unethical to investigate whether supplements with a dose lower than 400 micrograms/d of folic acid are also protective against NTDs. However, research to establish the lowest effective dose of dietary folate/supplemental folic acid to optimise homocysteine levels and research on the bioavailability of folate is required. This will enable the choice of a strategy to achieve desired folate intakes in the general population. In the meantime, consumption of plant foods like vegetables, fruits, and cereals should be stimulated to reach the desired level of 350 micrograms of dietary folate per day.

Heterogeneity of spina bifida.

Splitting birth defects into dysmorphologically homogeneous groups might improve the ability to detect a genetic risk factor or teratogenic exposure. With regard to spina bifida, recent studies suggest that etiologic heterogeneity exists within the group of spina bifida, although exogenous risk factors have been sparsely evaluated for subgroups. In the present study, 210 spina bifida patients were classified into relatively homogeneous groups, based on retrospective information on appearance and functional aspects of the lesion abstracted from medical records of the patients. We compared high with low spina bifida, and open with closed spina bifida, and investigated whether risk factors for spina bifida such as maternal age, antiepileptic drug use, parental occupation, and genetic factors were specifically associated with these homogeneous subclasses. For these comparisons, a referent group of 671 children was used. Although classifying spina bifida into homogeneous subclasses presented some difficulties and numbers were small, this study provides some evidence for different risk profiles for subclasses of spina bifida. The sex ratio, the proportion of miscarriages of siblings, and maternal age did not differ among the different subclasses of spina bifida. However, children with a positive family history of neural tube defects (NTDs) had a higher risk of high spina bifida [odds ratio (OR) = 6.3, 95% confidence interval (CI): 1.7-19.2] than of low spina bifida (OR = 2.1, 95% CI: 1.0-4.2). Siblings with NTDs were more common in cases with high spina bifida and cases with open spina bifida. A strongly increased risk of high spina bifida was found for male welders (OR = 12.1, 95% CI: 1.5-64.2), whereas the risk of low spina bifida was much lower (OR = 1.6, 95% CI: 0.2-7.9). For mothers with agricultural occupations, a strongly increased risk was observed for open spina bifida (OR = 14.3, 95% CI: 2.9-77.7), whereas none of 107 cases with closed spina bifida had a mother with an occupation in agriculture. Due to small numbers, the results must be interpreted with caution.

Risk of Recurrence of Craniospinal Anomalies

The authors analyzed 1,655 situations from their Genetic Counseling Service over a 15 year period where the reason for counseling was craniospinal anomaly (neural tube defects and/or hydrocephalus) in the family. Excluding the obviously monogenically inherited cases, they investigated pregnancies undertaken after 1,285 isolated and 177 multiple forms of craniospinal abnormalities. The recurrence rate of craniospinal defects was found to be 3.66%, which is about ten times higher than the general population risk, supporting the theory of the multifactorial threshold model in the inheritance of these anomalies. The recurrence risks of neural tube defects and of hydrocephalus were 3.47% and 2.95%, respectively. The authors concluded that recurrence risk is mainly influenced by the pathoanatomic severity of the involved anomaly, the degree of relationship, and the number of affected relatives in the family. There is a positive correlation between the pathoanatomic severity of the anomaly in the proband and the offspring. At least in one-half of the cases the same type of anomaly was observed again in the offspring as in the proband. Attention is drawn to the fact that hydrocephalus (ventriculomegaly) is often manifested only in the second half of gestation. Therefore, performing ultrasound examination is strongly recommended not only at the 18th but at the 24th week of gestation, as well in pregnancies with a positive history of neural tube defects and/or hydrocephalus.

Risk of recurrence of craniospinal anomalies

The authors analyzed 1,655 situations from their Genetic Counseling Service over a 15 year period where the reason for counseling was craniospinal anomaly (neural tube defects and/or hydrocephalus in the family. Excluding the obviously monogenically inherited cases, they investigated pregnancies undertaken after 1,285 isolated and 177 multiple forms of craniospinal abnormalities. The recurrence rate of craniospinal defects was found to be 3.66%, which is about ten times higher than the general population risk, supporting the theory of the multifactorial threshold model in the inheritance of these anomalies. The recurrence risks of neural tube defects and of hydrocephalus were 3.47% and 2.95%, respectively. The authors concluded that recurrence risk is mainly influenced by the pathoanatomic severity of the involved anomaly, the degree of relationship, and the number of affected relatives in the family. There is a positive correlation between the pathoanatomic severity of the anomaly in the proband and the offspring. At least in one-half of the cases the same type of anomaly was observed again in the offspring as in the proband. Attention is drawn to the fact that hydrocephalus (ventriculomegaly) is often manifested only in the second half of gestation. Therefore, performing ultrasound examination is strongly recommended not only at the 18th but at the 24th week of gestation, as well in pregnancies with a positive history of neural tube defects and/or hydrocephalus. J. Matern.-Fetal Med. 6:53–57, 1997. © 1997 Wiley-Liss, Inc.

The factors associated with effective folic acid prophylaxis in the peri-conceptional period in women attending an ante-natal clinic

Summary The aim of this study was to examine whether folic acid supplements had been taken and dietary folate intake increased in 662 pregnant women attending the antenatal clinic at St Mary's Hospital, Portsmouth. An assessment was also made of the factors that influenced correct compliance with the recommendations of the Expert Advisory Group on folic acid. Thirty-seven percent (245/662) women had taken folic acid supplements and 26.4% (175/ 662) increased their dietary folate before or during early pregnancy. The majority of women who commenced folic acid supplements after conception did so after the neural tube had closed (220/247). Women were more likely to have adhered to the Expert Advisory Group'srecommendations if the pregnancy was planned, the woman was primiparous, there was no past or family history of neural tube defect and the patient had the correct existing knowledge of folic acid prophylaxis. The relevance of these findings to the current Health Education Authority's folic awareness campaign is discussed.

Risk of recurrence of craniospinal anomalies.

The authors analyzed 1,655 situations from their Genetic Counseling Service over a 15 year period where the reason for counseling was craniospinal anomaly (neural tube defects and/or hydrocephalus) in the family. Excluding the obviously monogenically inherited cases, they investigated pregnancies undertaken after 1,285 isolated and 177 multiple forms of craniospinal abnormalities. The recurrence rate of craniospinal defects was found to be 3.66%, which is about ten times higher than the general population risk, supporting the theory of the multifactorial threshold model in the inheritance of these anomalies. The recurrence risks of neural tube defects and of hydrocephalus were 3.47% and 2.95%, respectively. The authors concluded that recurrence risk is mainly influenced by the pathoanatomic severity of the involved anomaly, the degree of relationship, and the number of affected relatives in the family. There is a positive correlation between the pathoanatomic severity of the anomaly in the proband and the offspring. At least in one-half of the cases the same type of anomaly was observed again in the offspring as in the proband. Attention is drawn to the fact that hydrocephalus (ventriculomegaly) is often manifested only in the second half of gestation. Therefore, performing ultrasound examination is strongly recommended not only at the 18th but at the 24th week of gestation, as well in pregnancies with a positive history of neural tube defects and/or hydrocephalus.

Neural Tube Defects and Chromosome Deletions

Patients with neural tube defects (NTDs) complicated by congenital heart defects, facial anomalies, thymic hypoplasia, cleft lip or palate, or hypocalcemia and a family history of NTDs and other anomalies were tested for 22qll deletions at the Departments of Pediatrics and Molecular Genetics, Oregon Health Sciences University, Eugene, Oregon.

Antenatal detection of neural tube defects: Comparison of biochemical and immunofluorescence methods

The aim of this study was to determine whether identification of glial cells in amniotic fluid samples could form a useful supplementary test in the antenatal diagnosis of neural tube defects (NTDs). In a 5-year study, 1452 samples of middle trimester amniotic fluid were examined blind to the results of other antenatal diagnostic tests and to the outcome of pregnancy. Reason of amniocentesis included raised serum alpha-fetoprotein (329), previous NTD (73), and a family history of NTDs (71). Duplicate cytospin preparations were stained with Giemsa and an antibody to glial fibrillary acidic protein (GFAP), and on this basis a prediction of fetal NTD status was made which was not communicated to clinicians. Subsequent management of pregnancies was influenced only by the results of routine antenatal testing for NTDs. Twenty cases of NTDs occurred among the 1406 cases in which the outcome was subsequently known. Of these 20 cases, only five (four anencephalic, one spina bifida) were correctly predicated by immunofluorescent identification of GFAP-positive cells in the amniotic fluid. The remaining 15 cases (two anencephalic, 13 spina bifida) were not so identified. In a further 18 cases, apparently GFAP-positive cells were identified in the absence of NTDs. We conclude that GFAP immunofluorescence examination of routine amniocentesis samples of amniotic fluid is not a useful predictive test for NTDs.

Megadose carbamazepine during the period of neural tube closure

Analyses of the frequency of congenital anomalies among infants born to women who used carbamazepine during organogenesis have not yielded consistent results. Because the drug is used to treat epilepsy, any association is confounded by the underlying condition.A nonepileptic 44-year-old multigravid woman attempted suicide by ingesting 24 200-mg carbamazepine tablets (approximately 4.8 g). By last menstrual period and sonogram dates, the megadose occurred during the third to fourth week post-conception. Maternal drug levels were elevated above therapeutic ranges for 2 days. Maternal serum alpha-fetoprotein was elevated, and high-resolution fetal sonography demonstrated a large myeloschisis that was verified at autopsy. No family history of neural tube defects or any other malformations was reported by the patient. Megadose carbamazepine ingestion during the period of neural tube closure was the only known risk factor.Although no other published reports of megadose carbamazepine during pregnancy were located, the neural tube defect is consistent with the recently reported risks for congenital anomalies in infants born to women who used this anticonvulsant in therapeutic doses during pregnancy.

"Why don't you sue?"

Our daughter was born with spina bifida. She has a large lumbosacral myelomeningocele with an associated neuropathic bladder, patulous anus, and neurological deficits of her legs. Fortunately the lesion is closed with excellent skin cover and Emily shows no signs, as yet, of developing hydrocephalus. We were not expecting our first child to be born in anything other than perfect health. I had done all the right things, including taking folic acid supplements as had just been recommended by the Department of Health when we were planning the pregnancy. We have no family history of neural tube defects and I had had an uncomplicated antenatal period. My husband, who was working in France at the time, returned home to be at my side when I went for my routine 20 week ultrasound scan, our discussed intention being that he could be with me for a termination of pregnancy if the worst happened. The worst did not happen then. Normal vertebrae, normal kidneys, we were told, so off we went happily to await the …

Investigation of factors influencing folate status in women who have had a neural tube defect-affected infant

Objective To investigate folate intake and blood levels of vitamins in women with and without a history of neural tube defect (NTD)-affected infant and to explore the relation between red cell and serum folate in those women. Subjects Twenty-nine women with a history of NTD-affected infant, who had taken periconceptional vitamin supplements one year or more prior to the study and twenty-nine controls with no such history. Main outcome measures Dietary intake of folate was assessed by questionnaire and blood levels of folate, vitamin B12 and vitamin C were measured. Results Neither dietary intake of folate nor any of the blood vitamins measured were lower in the women with a history of NTD infant. The majority of women who had received periconceptional vitamin supplementation subsequently had adequate folate intakes and red blood cell folates greater than 160 ug/l. Smokers had lower plasma Vitamin C levels than nonsmokers. Multiple regression analysis suggested that the relation between red blood cell (RBC) and serum folate may differ between women with and without a history of NTD. Conclusions Women with a history of NTD-affected infants may have different folate metabolism from those who have not.

Twin pregnancies in the second trimester in women in an alpha-fetoprotein screening program: sonographic evaluation and outcome.

We correlated sonographic findings with fetal outcomes in women with unsuspected twin pregnancies who had sonography in the second trimester as part of a screening program for maternal serum alpha-fetoprotein (MSAFP) level and history of neural tube defect. The study group consisted of 97 women with twin pregnancies who participated in a screening program for MSAFP level and history of neural tube defect. Seventy-three had normal MSAFP levels, 21 had elevated MSAFP levels, and two had low MSAFP levels. One patient had a family history of anencephaly. All 97 patients had sonography during their second trimester of pregnancy. Sonographic findings were reviewed retrospectively for information on gestational age, fetal anomalies, sex of the fetus, location of the placenta, presence and thickness of a dividing membrane, and interpretation of amnionicity and chorionicity. Information on fetal outcome included gestational age at delivery, survival, birth weight, sex, congenital anomalies, obstetric complications, amnionicity, chorionicity, and placental abnormalities. Amnionicity and chorionicity were correctly detected on sonograms in 44 (90%) of 49 diamniotic-dichorionic gestations, 23 (72%) of 32 diamniotic-monochorionic gestations, and two (50%) of four monoamniotic-monochorionic gestations. Fetal anomalies were present at delivery in five neonates and had been correctly detected at sonography in one (hemivertebra); one fetus with duodenal atresia had abnormal sonographic findings in the third trimester. Missed anomalies included absent forearm, cleft lip and palate, and imperforate anus. Sex of the fetuses was correctly predicted on the basis of sonographic findings in 40 of 43 pairs. Nine twin pairs had possible twin-twin transfusion syndrome suspected sonographically on the basis of abnormal fluid volumes, discrepant growth measurements, and abnormal findings on Doppler studies. Outcomes included two confirmed cases of the syndrome (two survivors, two deaths) and three probable cases (six deaths); four pregnancies resulted in eight survivors who were delivered after 34.4 weeks' gestation and had birth weights in the 25th percentile or higher. Survival rates for diamniotic-dichorionic, diamniotic-monochorionic, and monoamniotic-monochorionic gestations were 90%, 91%, and 50%, respectively. Fetuses in women with MSAFP levels greater than 4.5 multiples of the median and with monochorionic placentation had lower survival rates than fetuses in women with normal MSAFP levels and monochorionic placentation (67% vs 96%). Half the fetuses delivered after 20 weeks' gestation had birth-weight discordance of less than 10%. Premature deliveries occurred in 56% of pregnancies. The results suggest that (1) sonography is useful in predicting placentation, (2) placentation may be helpful in predicting fetal outcome, (3) increased MSAFP levels correlate with increased perinatal mortality in diamniotic-monochorionic pregnancies, and (4) caution should be taken in diagnosing and determining prognosis for suspected twin-twin transfusion syndrome in the second trimester.

Megadose carbamazepine during the period of neural tube closure

Analyses of the frequency of congenital anomalies among infants born to women who used carbamazepine during organogenesis have not yielded consistent results. Because the drug is used to treat epilepsy, any association is confounded by the underlying condition. A nonepileptic 44-year-old multigravid woman attempted suicide by ingesting 24 200-mg carbamazepine tablets (approximately 4.8 g). By last menstrual period and sonogram dates, the megadose occurred during the third to fourth week post-conception. Maternal drug levels were elevated above therapeutic ranges for 2 days. Maternal serum alpha-fetoprotein was elevated, and high-resolution fetal sonography demonstrated a large myeloschisis that was verified at autopsy. No family history of neural tube defects or any other malformations was reported by the patient. Megadose carbamazepine ingestion during the period of neural tube closure was the only known risk factor. Although no other published reports of megadose carbamazepine during pregnancy were located, the neural tube defect is consistent with the recently reported risks for congenital anomalies in infants born to women who used this anticonvulsant in therapeutic doses during pregnancy.