Teratogen update: valproic acid

Valproic acid use during pregnancy results in an absolute risk for spina bifida of 1-2%. This increased risk is comparable to the recurrence risk for neural tube defects and warrants informed counselling and access to prenatal diagnosis. There is no substantial evidence that valproic acid use increases the risk for other specific major malformations above the increased risk due to maternal epilepsy. Valproic acid may cause a characteristic pattern of minor facial malformations. Further definition and confirmation are required, and the magnitude of the risk needs to be determined. There are inadequate data to assess the magnitude, if any, of the risks for postnatal growth abnormalities and developmental disabilities associated with the use of valproic acid during pregnancy. Birth-defect monitoring programs and international collaboration among the staffs of monitoring programs played a major role in determining that valproic acid is a human teratogen.     

Folic acid supplementation and neural tube defect recurrence prevention

BACKGROUND: It is well established that women who have had a pregnancy affected by a neural tube defect (NTD) have an elevated risk of a subsequent NTD-affected pregnancy and that a high dose (4 mg/day) of folic acid taken around the time of conception prevents most recurrences of NTDs. METHODS: We reviewed the literature to identify studies that quantify the reduction in risk if women with a prior-NTD affected pregnancy consistently take folic acid before and during a subsequent pregnancy and the effectiveness of NTD recurrence prevention programs in increasing the percentage of women who consistently consume folic acid supplements. RESULTS: A meta-analysis of randomized trials of folic acid for the prevention of recurrent NTDs indicates a 69% reduction in recurrence risk if analyzed on an intention-to-treat basis and an 87% reduction among those women who took supplements prior to the beginning of pregnancy. Observational studies report reductions in recurrence risk of 85% to 100% among women taking folic acid prior to subsequent pregnancies. The percentage of women who take folic acid prior to a subsequent pregnancy has been reported to vary from 33% to 85%, varying with the demographic background and the intensity of folic acid counseling efforts. CONCLUSIONS: Targeted folic acid information and counseling provided to women with an NTD-affected pregnancy has been demonstrated to substantially reduce the risk of recurrent NTDs and is feasible to implement on a public health basis.     

Birth prevalence and recurrence rates of neural tube defects in southern Alberta in 1970-81.

Given the observed variation in birth prevalence and recurrence rates of neural tube defects, it is important to obtain such data specific to a given locality for research and genetic counseling purposes. A review of hospital medical charts, the patient lists of the Medical Genetics and Myelomeningocele clinics at Alberta Children''s Hospital and data from the Canadian Congenital Anomalies Surveillance System revealed the annual birth prevalence rate of neural tube defects in southern Alberta in 1970-81 to be 1.62/1000 total births. This figure suggests southern Alberta to be a low-frequency area. There was no significant variation in the annual rates of spina bifida, encephalocele or all neural tube defects combined over the study period. A significant linear decline in the frequency of births of anencephalic infants, however, was noted (p = 0.025). Information on the total reproductive history of the mothers revealed that the empiric risk of recurrence of a neural tube defect was 2.2%, and the risk to all siblings was estimated to be 2.3%. In future prevalence studies multiple sources of case ascertainment should be used, including data on pregnancies terminated because of a fetal neural tube defect.     

Use of multivitamins and folic acid in early pregnancy and multiple births in Sweden.

Folic acid is recommended to reduce the risk of neural tube defects and other congenital malformations. Data from the Swedish Medical Birth Registry were used to study frequency of twinning in women who in early pregnancy reported the use of folic acid. Women (n = 2,569) who in early pregnancy reported the use of folic acid had an increased rate of twin deliveries after consideration of maternal age and of length of involuntary childlessness, both variables being significant confounders. The effect of folic acid was seen also in women who did not report involuntary childlessness. A similar but not statistically significant trend was seen after use of multivitamins without simultaneous use of folic acid tablets (n = 1,979). The increased risk seems to be limited to dizygotic twinning (relative risk = 2.13, 95% CI 1.64-2.74). If this association is causal, wide-spread supplementation with folic acid may represent a hazard larger than the postulated beneficial effect on neural tube defects, at least in low-risk areas.     

Prevalence of neural tube defects in South Australia, 1966-91: effectiveness and impact of prenatal diagnosis.

OBJECTIVE--To determine trends in total prevalence of neural tube defects in South Australia during 1966-91, the impact of prenatal diagnosis on birth prevalence, and the effectiveness of prenatal screening for neural tube defects in 1986-91. DESIGN--All births and terminations of pregnancy affected by neural tube defects and information on prenatal screening were ascertained from multiple sources including the South Australian perinatal and abortion statistics collections, birth defects register, and state maternal serum alpha fetoprotein screening programme. SETTING--Southern Australia. SUBJECTS--All 1058 births and terminations of pregnancy affected by neural tube defects in 1966-91. MAIN OUTCOME MEASURES--Total prevalence and birth prevalence of individual and all neural tube defects. The proportion of screened cases detected prenatally. RESULTS--Total prevalence of neural tube defects during 1966-91 was 2.01/1000 births with no upward or downward trend. However, birth prevalence fell significantly (by 5.1% a year), with an 84% reduction from 2.29/1000 births in 1966 to 0.35/1000 in 1991 (relative risk = 0.16, 95% confidence interval 0.07 to 0.34). The fall was 96% for anencephaly and 82% for spina bifida. 85% of defects, both open and closed, were detected before 28 weeks'' gestation in women screened by serum alpha fetoprotein or mid-trimester ultrasonography, or both, in 1986-91 (99.0% for anencephaly and 75.7% for spina bifida). CONCLUSIONS--While the total prevalence of neural tube defects in South Australia remained stable, prenatal diagnosis and termination of pregnancy resulted in an 84% fall in birth prevalence during 1966-91. Screening detected over four fifths of cases in 1986-91.     

Neural tube defects and first trimester operations

Swedish health care registries were used to identify women who had surgery during pregnancy and their offspring. Among the 2,252 infants born to women who had first trimester operations during 1973-1981, six had definite diagnoses of neural tube defects (expected number, 2.5). Scrutiny of the records showed that 572 operations occurred during gestational weeks 4-5, the period of neural tube formation, and that the mothers of five of the six infants with neural tube defects had an operation during that period (expected number of neural tube defects, 0.6) although one of the offspring probably had Meckel's syndrome. The relationship between neural tube defects and operation during pregnancy is discussed including the possibility that the association may be random.     

Maternal Serum α-Fetoprotein Screening for the Detection of Neural Tube Defects—Report of a Pilot Program

We tested 10,715 low-risk pregnancies in a voluntary maternal serum α-fetoprotein screening program for the detection of neural tube defects in California. In all, 5.3 percent of women had one elevated serum level, 3.3 percent were referred for sonography and 1.5 percent for amniocentesis. There were 12 cases of open neural tube defects (1.1 per 1,000); all of the mothers had one elevated serum αfetoprotein level: nine (75 percent) completed the protocol and the neural tube defects were correctly identified. No normal pregnancies were terminated. The risk of an open neural tube defect occurring was about 1 in 50 after the first abnormal serum level and 1 in 15 at amniocentesis. We found significantly increased risk for fetal death and low birth weight after one elevated serum α-fetoprotein level, though the likelihood of a normal pregnancy outcome was about 80 percent. Maternal serum screening was also useful in identifying twin pregnancies and correcting underestimated gestational dates.     

Hypothesis: folate-responsive neural tube defects and neurocristopathies

BACKGROUND: What accounts for the wide spectrum of folate-responsive dysmorphogeneses? Both embryonic and fetal cells are entirely dependent on maternal folate to support their requirement for precisely timed proliferative bursts during gestation. Folate receptors (FRs) mediate transport into cells and are central to transplacental maternal-to-fetal folate transport. FRs are also critical for neural tube and neural crest development because recent murine "knock-out" and "knock-down" of FRs results in a high percentage of folate-responsive neural tube defects (NTDs) and neurocristopathies. HYPOTHESIS: Central to our hypothesis is the fact that folate deficiency is accompanied by a reduction in the proliferative capacity of highly mitotic neural tube or neural crest cells. Therefore, depending on when in pregnancy various cohorts of highly proliferative cells are deprived of folate, and the origin of the affected cells will determine the type of developmental dysmorphogenesis. Thus, selective folate deficiency in early pregnancy of only highly proliferative neural tube or neural crest cells predisposes to NTDs or gross dysmorphogenesis, respectively. Folate deficiency that compromises placental development will predispose to small-for-date babies due to an overall nutrient deficiency, and the development of folate insufficiency later in pregnancy could predispose to more subtle midline birth defects involving atresia of neural crest cell-derived structures. Finally, a congenital folate transport defect would only be corrected by suprapharmacological doses of folate, which ensures passive diffusion. CONCLUSION: This hypothesis can explain the results of several earlier and more recent clinical trials on folate supplementation in pregnancy, but it also raises the possibility that there may be several as yet undiscovered neurocristopathies that are folate responsive. Teratology 62:42-50, 2000. Published 2000 Wiley-Liss, Inc.     

Pregnancies of mothers with a neural tube defect child: outcomes and recurrence risks

Ninety-four mothers who had been in contact with the Center for Human Genetics of the University of Leuven (Belgium) after the birth of a child with neural tube defect were questioned about the outcomes of their pregnancies. To this end a structured interview and a mailed questionnaire were used. The recurrence rate for neural tube defects after the birth of one affected child was 2.9%. This number is at the lower border of the risk rates (between 3% and 5%) generally given to parents during genetic counseling sessions. The relative amount of miscarriages was larger in the interviewed group than in the Belgian population in general.     

Epidemiology and genetics of neural tube defects: an application of the Utah Genealogical Data Base

The distribution and prevalence of births with neural tube defects in Utah from 1940 to 1979 are analyzed with regard to prevalence rates, secondary sex ratios, seasonality, yearly rates, and time-space clustering. The overall prevalence rate of 1.00 per thousand live births is comparable to that of other populations in the western United States. Analysis of sex ratios indicates a substantially higher proportion of females than males. No significant secular trends or time-space clustering are observed. No seasonality is seen for spina bifida; however, the anencephaly cases are delivered more frequently in the early spring and fall months. Following linkage of the neural tube defect cases to the Utah Genealogical Data Base, application of the genealogical index method shows substantial familial clustering of the disease. The average inbreeding coefficient of the neural tube defect cases is not elevated over that of matched controls. The empirical recurrence risk for the disease is calculated to be 3%, and the heritability estimate is 70%. Likelihood analysis of pedigrees containing spina bifida occulta and spina bifida cystica indicates that they may segregate as an autosomal dominant trait with a penetrance of 75%.     

Effect of infection with the ts22 mutant of Semliki Forest virus on development of the central nervous system in the fetal mouse.

The A7 strain of Semliki Forest virus induces rapid fetal death in pregnant mice, whereas the ts22 mutant derived from it is teratogenic for a proportion of fetuses. Both A7 and ts22 induce viremia and infect the central nervous systems and fetuses of pregnant mice. Using immunogold-silver staining, a cDNA probe for a Semliki Forest virus nonstructural sequence, and a riboprobe derived from the same sequence, we showed that the skin and musculoskeletal systems of fetuses from mothers infected with ts22 were often heavily infected but the central nervous systems were not labeled before day 17 of pregnancy. Damage to the neural tube, including open-neural-tube defects, was detected in fetuses following infection of the mother at days 8 and 10 of pregnancy with both A7 and ts22. For ts22, neural tube damage induced by fetal infection before day 17 of pregnancy appeared to be indirect and caused by virus infection of mesenchymal cells surrounding the developing neural tube.     

Antenatal diagnosis of neural tube defects in Canada: extension of a collaborative study.

Experience with the diagnosis of neural tube defects from alpha1-fetoprotein (AFP) concentrations in amniotic fluid is reported from a prospective study of five laboratories testing for 13 Canadian genetic centres. The results of the study indicate that antenatal diagnosis of open neural tube defects is being carried out effectively in Canada (in 99.2% of cases the AFP measurements were interpreted correctly). Amniocentesis should be recommended to women at high risk for having a child with a neural tube defect (i.e., those who have a child, a parent or a sibling with a neural tube defect). The rate of neural tube defects in 182 high-risk pregnancies was 2.2% for an open defect and 1.1% for a closed defect, whereas the rate in 673 pregnancies in which amniocentesis was being performed for other reasons was 0.3%. This suggests that the AFP concentration should be measured in any sample of amniotic fluid collected for other reasons (usually fetal karyotyping). There were three instances of false-negative results, for a rate of 0.4%. Two closed neural tube defects were not detected; this limitation of the test has also been found by others. One of the six fetuses with an open neural tube defect, who died in utero, had a large myelocele in the neck that was not recognized. There were also four instances of false-positive results, for a rate of 0.5%. The findings suggest that AFP values that are more than 2 but less than 7 standard deviations (SDs) above the mean may indicate a neural tube defect, and that values 7 or more SDs above the mean very likely indicate such a defect, although other reasons for such high values (e.g., fetal erythrocytes in the amniotic fluid, intrauterine death and mistaken gestational age) must be ruled out by other methods.     

Methylenetetrahydrofolate reductase mutations, a genetic cause for familial recurrent neural tube defects

Methylenetetrahydrofolate reductase (MTHFR) gene mutations have been implicated as risk factors for neural tube defects (NTDs). The best-characterized MTHFR genetic mutation 677C→T is associated with a 2-4 fold increased risk of NTD if patient is homozygous for this mutation. This risk factor is modulated by folate levels in the body. A second mutation in the MTHFR gene is an A→C transition at position 1298. The 1298A→C mutation is also a risk factor for NTD, but with a smaller relative risk than 677C→T mutation. Under conditions of low folate intake or high folate requirements, such as pregnancy, this mutation could become of clinical importance. We present a case report with MTHFR genetic mutation, who presented with recurrent familial pregnancy losses due to anencephaly/NTDs.     

More folic acid, the five questions: why, who, when, how much, and how

In recent years, a number of studies have been performed to evaluate the possible health benefits of an increased intake of folic acid (FA) on human health. However, the only well-documented benefit emerging from randomized controlled trials, nonrandomized interventions trials, and observational studies is the risk reduction of neural tube defects (NTDs). NTDs are congenital malformations that include anencephaly, encephalocele, and spina bifida caused by the failure of fusion of the neural tube that normally closes between 22nd and 28th day since conception (on an average 40-42th day after the first day of last menstrual period). The occurrence of NTDs varies among population between 0.8 and 3 per 1,000, and it is estimated that 324,000 pregnancies are affected every year worldwide. More FA can decrease the NTDs risk up to 0.6 per 1,000 births. Other malformations as congenital heart defects, cleft lip, and limb deficiencies can be most probably also reduced. To decrease the NTDs risk, it is recommended that all women capable of becoming pregnant should have more FA. The goal is that every woman could start her pregnancy with an optimal folate status, estimated today to be as more than 906 nmol/L of red blood cell folate concentration. More FA can be obtained through a strict Mediterranean pattern of nutrition and healthy life style, fortified food, supplements. Women and health authorities can choose the most appropriate strategy. Monitoring folate status of women during the periconceptional period is an essential way to evaluate the success of the preferred strategy.     

Maternal fever and neural tube defects

It has been proposed that hyperthermia in the pregnant woman is associated with neural tube defects in her offspring. We analyzed retrospective interview data for a maternal history of probable febrile illness during the first trimester of pregnancy among mothers of infants with anencephaly or spina bifida. There were two control groups--mothers of infants with Down syndrome and mothers of infants with cleft lip or palate. With the Down syndrome group serving as controls, the incidence of febrile illness among mothers of all infants with neural tube defects was significantly elevated. With the cleft group as controls, the fever incidence was not significantly increased in the neural tube defect groups. When the combined cleft and Down syndrome controls were used, only mothers of the spina bifida group had an elevated fever incidence. Epidemiology data suggest an association of maternal fever during pregnancy with neural tube defects in the offspring.     

The developmental potentials of the caudalmost part of the neural crest are restricted to melanocytes and glia

The avian spinal cord is characterized by an absence of motor nerves and sensory nerves and ganglia at its caudalmost part. Since peripheral sensory neurons derive from neural crest cells, three basic mechanisms could account for this feature: (i) the caudalmost neural tube does not generate any neural crest cells; (ii) neural crest cells originating from the caudal part of the neural tube cannot give rise to dorsal root ganglia or (iii) the caudal environment is not permissive for the formation of dorsal root ganglia. To solve this problem, we have first studied the pattern of expression of ventral (HNF3beta) and dorsal (slug) marker genes in the caudal region of the neural tube; in a second approach, we have recorded the emergence of neural crest cells using the HNK1 monoclonal antibody; and finally, we have analyzed the developmental potentials of neural crest cells arising from the caudalmost part of the neural tube in avian embryo in in vitro culture and by means of heterotopic transplantations in vivo. We show here that neural crest cells arising from the neural tube located at the level of somites 47-53 can differentiate both in vitro and in vivo into melanocytes and Schwann cells but not into neurons. Furthermore, the neural tube located caudally to the last pair of somites (i.e. the 53rd pair) does not give rise to neural crest cells in any of the situations tested. The specific anatomical aspect of the avian spinal cord can thus be accounted for by limited developmental potentials of neural crest cells arising from the most caudal part of the neural tube.     

Prevalence of periconceptional folic acid use and perceived barriers to the postgestation continuance of supplemental folic acid: survey results from a Teratogen Information Service

BACKGROUND: Fewer than 40% of U.S. women are taking folic acid supplements periconceptionally at a time when the risk of neural tube defects (NTDs) can be reduced by supplementation. A better understanding of the vitamin-taking habits of childbearing-age women and effective methods for improving periconceptional supplement use are needed. METHODS: A telephone survey conducted through the California Teratogen Information Service (TIS) between August 2003 and January 2004 assessed the prevalence and characteristics of pregnant callers who did not use folic acid supplements in the periconceptional period, and explored attitudes toward advice to continue vitamin use following pregnancy in order to be protected in a future pregnancy. RESULTS: A total of 327 pregnant women who called the TIS for information agreed to participate in the survey. More than half (53.2%) were not taking folic acid-containing supplements in the periconceptional period. Predictors of lack of use included a higher prepregnancy body mass index, younger maternal age, non-white race/ethnicity, lower education level, and unplanned pregnancy. One-quarter of the women said they would be willing to continue taking vitamins after the pregnancy if advised to do so by a physician. The remainder identified obstacles to following that advice--notably, not planning to become pregnant again and the belief that enough folate is derived from diet alone. CONCLUSIONS: More than half of the callers to the TIS were not compliant with recommendations regarding periconceptional folic acid supplementation. This represents an opportunity for TIS specialists and physicians to intervene in a current pregnancy to encourage maintenance of supplement use in the subsequent interpregnancy interval.     

Risks of hyperthermia associated with hot tub or spa use by pregnant women

There are a limited number of human studies linking hot tub or spa use during early pregnancy to increased risks for neural tube defects (NTDs) or spontaneous abortion. However, these data can be considered in the context of human studies that have demonstrated an association between high maternal fever in early pregnancy and NTDs. In addition, there is a large volume of animal literature suggesting that, regardless of the heat source, an elevated core maternal temperature at or above the threshold of 2 degrees C over baseline, as well as timing and duration of exposure, are the critical factors in conferring risk. Therefore, the potential for hot tub or spa use to increase core maternal body temperature to risky levels and thus increase the risk for NTDs is likely. A woman who knows or who may not yet be aware that she is pregnant should be advised of the recommended limits of exposure. She should also be aware of the possible variability in hot tub or spa temperature readings and be able to accurately monitor maximum water temperature in the hot tub or spa so that her body temperature can be maintained below 38.9 degrees C.