Genetic link for folic acid supplementation: Study

Genetic link for folic acid supplementation: Study: "A link between changes in the DNA of newborn babies, folic acid supplementation during pregnancy, and birth weight, has been identified for the first time, researchers claim."

Use of clomiphene citrate and birth defects, National Birth Defects Prevention Study, 1997–2005

BACKGROUND
Clomiphene citrate (CC) is the first line drug for subfertility treatment. Studies assessing the association between CC and birth defects have been inconclusive.

METHODS
We used data from the National Birth Defects Prevention Study, a population-based, multi-site case–control study of major birth defects. Women from 10 US regions with deliveries affected by at least one of >30 birth defects (cases) and mothers of live born infants without a major birth defect (controls) who delivered October 1997–December 2005 were interviewed. The exposure of interest was reported CC use in the period from 2 months before conception through the first month of pregnancy. Women who conceived using assisted reproductive technology were excluded. Thirty-six birth defect categories with at least three exposed cases were studied. Multiple logistic regression was used to control for potential confounders.

RESULTS
CC use was reported by 1.4% of control mothers (94/6500). Among 36 case-groups assessed, increased adjusted odds ratios (aOR) were found [all: aOR, 95% confidence interval (CI)] for anencephaly (2.3, 1.1–4.7), Dandy–Walker malformation (4.4, 1.7–11.6), septal heart defects (1.6, 1.1–2.2), muscular ventricular septal defect (4.9, 1.4–16.8), coarctation of aorta (1.8, 1.1–3.0), esophageal atresia (2.3, 1.3–4.0), cloacal exstrophy (5.4, 1.6–19.3), craniosynostosis (1.9, 1.2–3.0) and omphalocele (2.2, 1.1–4.5).

CONCLUSIONS
Several associations between CC use and birth defects were observed. However, because of the small number of cases, inconsistency of some findings with previous reports, and the fact that we cannot assess the CC effect separately from that of the subfertility, these associations should be interpreted cautiously.

Journal Reference:
J. Reefhuis, M.A. Honein, L.A. Schieve, S.A. Rasmussen, and the National Birth Defects Prevention Study
Use of clomiphene citrate and birth defects, National Birth Defects Prevention Study, 1997–2005
Hum. Reprod. 2010 : deq313v1-deq313.

Maternal fumonisin exposure and risk for neural tube defects: Mechanisms in an in vivo mouse model

Background:
Fumonisin B1 (FB1) is a mycotoxin produced by the fungus Fusarium verticillioides, a common contaminant of corn worldwide. FB1 disrupts sphingolipid biosynthesis by inhibiting the enzyme ceramide synthase, resulting in an elevation of free sphingoid bases and depletion of downstream glycosphingolipids. A relationship between maternal ingestion of FB1-contaminated corn during early pregnancy and increased risk for neural tube defects (NTDs) has recently been proposed in human populations around the world where corn is a dietary staple. The current studies provide an in vivo mouse model of FB1 teratogenicity.

Methods:
Pregnant LM/Bc mice were injected with increasing doses of FB1 on GD 7.5 and 8.5, and exposed fetuses were examined for malformations. Sphingolipid profiles and 3H-folate concentrations were measured in maternal and fetal tissues. Immunohistochemical expression of the GPI-anchored folate receptor (Folbp1) and its association with the lipid raft component, ganglioside GM1, were characterized. Rescue experiments were performed with maternal folate supplementation or administration of gangliosides.

Results:
Maternal FB1 administration (20 mg/kg of body weight) during early gestation resulted in 79% NTDs in exposed fetuses. Sphingolipid profiles were significantly altered in maternal and embryonic tissues following exposure, and 3H-folate levels and immunohistochemical expression of Folbp1 were reduced. Maternal folate supplementation partially rescued the NTD phenotype, whereas GM1 significantly restored folate concentrations and afforded almost complete protection against FB1-induced NTDs.

Conclusions:
Maternal FB1 exposure altered sphingolipid metabolism and folate concentrations in LM/Bc mice, resulting in a dose-dependent increase in NTDs that could be prevented when adequate folate levels were maintained.

Journal Reference:
Gelineau-van Waes, J., Starr, L., Maddox, J., Aleman, F., Voss, K. A., Wilberding, J. and Riley, R. T. (2005), Maternal fumonisin exposure and risk for neural tube defects: Mechanisms in an in vivo mouse model. Birth Defects Research Part A: Clinical and Molecular Teratology, 73: 487–497. doi: 10.1002/bdra.20148



Study Looks At Suspected Link Between Corn Mycotoxin And Birth Defects


A Creighton University School of Medicine researcher has been awarded a $2.7 million grant by the National Institutes of Health (NIH) to investigate a possible link between the ingestion of tortillas and corn-based food products contaminated with a fungal toxin and increased risk for birth defects.

The three-year award is a collaborative effort among investigators at Creighton, the U.S. Department of Agriculture-Agricultural Research Service (USDA-ARS) in Athens, Georgia; Duke University Medical Center in Durham, N.C., and Centro de Investigaciones en Nutricion y Salud (CIENSA) in Guatemala.

Janee Gelineau-van Waes, D.V.M., Ph.D., principal investigator and associate professor in Creighton's Department of Pharmacology, will use the grant to continue her research studying a potential connection between exposure to fumonisin during early pregnancy and an increased risk for having a baby with a neural tube defect (NTD).

NTDs are one of the most common congenital malformations (one per 1,000 births) and include defects such as anencephaly and spina bifida. NTDs occur when the embryonic neural tube, which forms the brain and spinal cord, fails to close properly during the first few weeks of pregnancy.

Fumonisin is a mycotoxin produced by a common fungal contaminant of corn worldwide.

In animals, the toxin disrupts sphingolipid metabolism, causing diseases such as leukoencephalomalacia in horses, pulmonary edema in pigs and cancer in laboratory rodents. In humans, ingestion of fumonisin-contaminated corn is associated with increased risk for esophageal cancer and having a baby with a NTD.

An unusually high incidence of NTDs (six to 10 cases per 1,000 births) has been observed in regions of Guatemala, China, and South Africa where corn is a dietary staple and fumonisin contamination is frequent.

Gelineau-van Waes and USDA scientists have shown that early gestational exposure to the toxin disrupts sphingolipid metabolism and induces NTDs in mice.

In the new study, preliminary data obtained from mice will be used to validate biomarkers of exposure in blood and urine samples collected from women in Guatemala. The human samples, collected by CIENSA scientists, will be analyzed by the USDA-ARS Mycotoxin Research Unit.

Creighton researchers will use mouse models to investigate underlying signaling mechanisms that result in failure of neural tube closure after fumonisin exposure, and collaborative studies with Duke University will focus on identifying genetic mutations that increase susceptibility.

Gelineau-van Waes' research program is supported by the Nebraska Tobacco Settlement Biomedical Research Program (LB-692). Her current NIH grant was awarded under the American Recovery and Reinvestment Act of 2009, in response to the NIH Director's Opportunity for Research on Global Health.

Background on fumonisin:

-- Fumonisin contamination of corn is periodically a problem in the U.S. In 1990, a cluster of babies born with NTDs was reported among Hispanic women living along the south Texas border. The incident occurred a year after very high levels of fumonisin were reported in the corn crop used to make tortillas, prompting scientists at the Texas Department of Health to suspect a possible connection.

-- In 2001, the U.S. Food and Drug Administration (FDA) established industry guidelines containing recommended maximum levels for fumonisin in corn used to prepare human and animal foods. However, the FDA guidelines do not contain enforceable regulatory limits.

-- In 2002, the World Health Organization (WHO) released provisional maximum tolerable daily intake (PMTDI) for fumonisins and suggested that further research was needed to examine the potential for this compound to cause birth defects.

-- In areas where corn is consumed in large quantities, such as Mexico and Guatemala, a significant percentage of the population exceeds (by more than 20 times) the WHO daily intake limit for fumonisin. In the U.S., a recent analysis of corn tortilla and masa flour samples from various retail sources in southern California indicates that fumonisin contamination of corn-based foods is common, and, depending on the amount an individual consumes, it is possible to exceed the WHO recommended daily limit.

Source: Creighton University

Further evidence for a maternal genetic effect and a sex-influenced effect contributing to risk for human neural tube defects

Background:
Neural tube defects (NTDs), including spina bifida and anencephaly, are the second most common birth defect with an incidence of 1/1000. Genetic factors are believed to contribute to NTD risk and family-based studies can be useful for identifying such risk factors.

Methods:
We ascertained 1066 NTD families (1467 affected patients), including 307 multiplex NTD families. We performed pedigree analysis to describe the inheritance patterns, pregnancy outcomes, and recurrence risks to relatives of various types.

Results:
Myelomeningocele or spina bifida (66.9%) and cranial defects (17.7%) were the most common NTD subtypes observed. The overall male:female ratio for affected individuals was 0.82, and there were even fewer males among individuals with an upper level NTD (0.62). Among twins, 2 of the 5 monozygotic twins and only 3 of 35 dizygotic twins were concordant, while 27% of the same sex twins were concordant, but none of the different sex twins. The estimated 6.3% recurrence risk to siblings (CI 0.04–0.08) is consistent with previous reports. Families with two or more affected individuals show a higher proportion of female transmitters (p = 0.0002). Additionally, the number of affected relatives in maternal compared to paternal lineages was more than double (p = 0.006). There were significantly more miscarriages, infant deaths, and stillborn pregnancies of the maternal aunts and uncles (p < 0.0001) and of first cousins (p = 0.04).

Conclusions:
Our data provide several lines of evidence consistent with a maternal effect, as well as a sex-influenced effect, in the etiology of NTDs.

Journal Reference:
Deak, K. L., Siegel, D. G., George, T. M., Gregory, S., Ashley-Koch, A. and Speer, M. C. (2008), Further evidence for a maternal genetic effect and a sex-influenced effect contributing to risk for human neural tube defects. Birth Defects Research Part A: Clinical and Molecular Teratology, 82: 662–669. doi: 10.1002/bdra.20511

Loss of Nutrients Following Gastric Bypass Surgery in Adolescent Girls Increases Risk for Neural Tube Defects

SAN FRANCISCO – An increasing number of obese adolescents, particularly females, are undergoing gastric bypass surgery. Yet a case study presented Sunday, Oct. 3, at the American Academy of Pediatrics (AAP) National Conference and Exhibition in San Francisco, highlights the possible link between gastric bypass surgery in adolescent girls and an increased risk for neural tube defects, which can lead to varying degrees of disability such as paralysis and mental retardation due to damage to the nervous system, in their future children.

Neural tube defects in the brain and spinal cord can be due to nutritional deficiencies. The report, “Neural Tube Defects: An Unforseen Consequence of Gastric Bypass Surgery in Young Female Patients?” reviewed the case of a young patient who had undergone gastric bypass surgery prior to becoming pregnant. She presented to the Fetal Treatment Center at UCSF Benioff Children’s Hospital to discuss the possibility of fetal surgery as her fetus had spina bifida. A literature review found six additional documented cases of children born with neural tube defects thought to be due to maternal nutritional deficiencies, particularly malabsorption (when the body cannot absorb nutrients), following bypass surgery.

It is well documented that gastric bypass surgery leads to malabsorption causing multiple nutritional deficiencies, including folate (folic acid), which is a key element in the prevention of neural tube defects. Although daily folate replacement can reverse this deficiency, adolescents often don’t comply with medication regimens.

This situation is especially critical because adolescents who have undergone gastric bypass surgery are at an increased risk of unintended pregnancies.

“We postulate that the malabsorption of folate, poor compliance with nutritional supplements and a higher risk of unintended pregnancies places young women at an increased risk for pregnancies complicated with neural tube defects,” said senior study author Diana L. Farmer, MD.

“Although obesity is epidemic in this country, we believe non-reversible gastric bypass surgery should be avoided in adolescent women given the potential increased risk of fetal neural tube defects,” Farmer said. “If gastric bypass is performed on an adolescent female, great efforts must be made to minimize the risks of both
unintended pregnancies and nutritional deficiencies. This should include extensive pre-surgery counseling and frequent post-operative follow-up, as well as consideration of highly efficacious contraceptives such as an intrauterine device.”

Source

Valproic Acid Monotherapy in Pregnancy and Major Congenital Malformations

Abstract:

Background:
The use of valproic acid in the first trimester of pregnancy is associated with an increased risk of spina bifida, but data on the risks of other congenital malformations are limited.

Methods:
We first combined data from eight published cohort studies (1565 pregnancies in which the women were exposed to valproic acid, among which 118 major malformations were observed) and identified 14 malformations that were significantly more common among the offspring of women who had received valproic acid during the first trimester. We then assessed the associations between use of valproic acid during the first trimester and these 14 malformations by performing a case–control study with the use of the European Surveillance of Congenital Anomalies (EUROCAT) antiepileptic-study database, which is derived from population-based congenital-anomaly registries. Registrations (i.e., pregnancy outcomes with malformations included in EUROCAT) with any of these 14 malformations were compared with two control groups, one consisting of infants with malformations not previously linked to valproic acid use (control group 1), and one consisting of infants with chromosomal abnormalities (control group 2). The data set included 98,075 live births, stillbirths, or terminations with malformations among 3.8 million births in 14 European countries from 1995 through 2005.

Results:
Exposure to valproic acid monotherapy was recorded for a total of 180 registrations, with 122 registrations in the case group, 45 in control group 1, and 13 in control group 2. As compared with no use of an antiepileptic drug during the first trimester (control group 1), use of valproic acid monotherapy was associated with significantly increased risks for 6 of the 14 malformations under consideration; the adjusted odds ratios were as follows: spina bifida, 12.7 (95% confidence interval [CI], 7.7 to 20.7); atrial septal defect, 2.5 (95% CI, 1.4 to 4.4); cleft palate, 5.2 (95% CI, 2.8 to 9.9); hypospadias, 4.8 (95% CI, 2.9 to 8.1); polydactyly, 2.2 (95% CI, 1.0 to 4.5); and craniosynostosis, 6.8 (95% CI, 1.8 to 18.8). Results for exposure to valproic acid were similar to results for exposure to other antiepileptic drugs.

Conclusions:
The use of valproic acid monotherapy in the first trimester was associated with significantly increased risks of several congenital malformations, as compared with no use of antiepileptic drugs or with use of other antiepileptic drugs.

Journal Reference:
Jentink J. et al. Valproic Acid Monotherapy in Pregnancy and Major Congenital Malformations, NEJM Volume 362:2185-2193 June 10, 2010 Number 23

The Antifolate Activity of Tea Catechins

Abstract:
A naturally occurring gallated polyphenol isolated from green tea leaves, ( )-epigallocatechin gallate (EGCG), has been shown to be an inhibitor of dihydrofolate reductase (DHFR) activity in vitro at concentrations found in the serum and tissues of green tea drinkers (0.1-1.0 Mmol/L). These data
provide the first evidence that the prophylactic effect of green tea drinking on certain forms of cancer, suggested by epidemiologic studies, is due to the inhibition of DHFR by EGCG and could also explain why tea extracts have been traditionally used in ‘‘alternative medicine’’ as anticarcinogenic/antibiotic agents or in the treatment of conditions such
as psoriasis. EGCG exhibited kinetics characteristic of a slow, tight-binding inhibitor of 7,8-dihydrofolate reduction with bovine liver DHFR (KI = 0.109 Mmol/L), but of a classic, reversible, competitive inhibitor with chicken liver DHFR (KI = 10.3 MAmol/L). Structural modeling showed that EGCG can bind to human DHFR at the same site and in a similar orientation to that observed for some structurally characterized DHFR inhibitor complexes. The responses of lymphoma cells to EGCG and known antifolates were similar, that is, a dose-dependent inhibition of cell growth (IC50 = 20 Mmol/L for EGCG), G0-G1 phase arrest of the cell cycle, and induction of apoptosis. Folate depletion increased the sensitivity of these cell lines to antifolates and EGCG. These effects were attenuated by growing the cells in a medium containing hypoxanthine-thymidine, consistent with DHFR being the site of action for EGCG.

Extract:
Our data may also explain why neural tube defects such as anencephaly and spina bifida, which are usually associated with folic acid deficiency, have been linked to high levels of maternal green tea consumption during the periconceptional
period

Journal Reference:
Enma Navarro-Pera´n et al. The Antifolate Activity of Tea Catechins. Cancer Res 2005; 65(6): 2059-64