Title: Protective Effect of Periconceptional Folic Acid Supplements on the Risk of Congenital Heart Defects: A Registry-Based Case-Control Study in the Northern Netherlands
Topic: Congenital Heart Disease
Date Posted: 12/31/2009
Author(s): van Beynum IM, Kapusta L, Bakker MK, den Heijer M, Blom HJ, de Walle HE.
Citation: Eur Heart J 2009;Dec 1:[Epub ahead of print].
Clinical Trial: No
Study Question: Is there a protective effect of periconceptional folic acid use on the risk of congenital heart disease (CHD)?
Methods: A case control study was performed using the EUROCAT–Northern Netherlands registry. All infants registered with CHD from 1996-2005 were included. Patients with CHD were categorized as having either: 1) an isolated single heart defect, 2) multiple heart defects, 3) heart defects associated with other congenital anomalies, or 4) a genetic anomaly with associated cardiac defect, such as in trisomy 21. Parents of registered infants completed questionnaires with items related to demographics, medications, vitamin intake, smoking habits, and alcohol consumption. Mothers were defined as using periconceptional folic acid if they took folic acid supplementation through the entire advised period of 4 weeks prior to conception and 8 weeks post-conception, or if they took folic acid following conception, regularly through the advised period. Others were categorized as nonusers, except when the use of folic acid was unknown or when a folic acid antagonist use was reported, which resulted in exclusion from the analysis. Analysis for potential confounders, including association of folic acid use with maternal age, maternal body mass index (BMI), smoking, ethyl alcohol (ETOH) use, year of birth, and maternal education level, was performed. Relative risk for CHD was calculated with odds ratios from logistic regression models.
Results: Complete data were available from the registry on 3,836 mothers, with 3,012 remaining after exclusion for maternal diabetes, reported use of folic acid antagonists, or presence of defects, which can be reduced with the use of folic acid (neural tube defects, oral clefts, hypospadias, and limb reduction anomalies). There were 611 cases with CHD, and 2,401 controls. The controls included infants with chromosomal or genetic aberrations or other congenital anomalies. There were no differences between cases and controls in maternal age, BMI, educational level, smoking, ETOH use, or year of birth. Adequate use of periconceptional folic acid was found in 56% of cases, and 61% of controls. Mothers who had periconceptional folic acid use were 18% less likely to deliver an infant with any type of CHD, and 38% less likely to deliver an infant with a septal defect. Subgroup analysis did not demonstrate a lower risk with the use of folic acid for conotruncal defects, atrioventricular septal defects, right-sided obstruction, or left-sided obstruction lesions. With adjustment for previously described potential confounders (maternal age, BMI, smoking, ETOH, educational level, and year of birth), the odds ratio was 0.82 (95% confidence interval, 0.68-0.997).
Conclusions: The use of periconceptional folic acid was found to reduce the risk of CHD compared to other nonfolic acid–related malformations. The overall risk reduction from this case control study was 18%, with 38% reduction in risk for septal defects.
Perspective: Reduction of risk for CHD with the use of folic acid has been debated in the literature. The investigators have demonstrated in this well-described study the risk reduction for CHD that is accompanied by the use of folic acid in the periconceptional period. Although a randomized trial on folic acid intake would provide a more certain answer to this research question, because folic acid is recommended during the periconceptional period to reduce other birth defects including neural tube defects, such a trial would be unethical. Case control trials are limited by the ability to adjust for potential confounders. In this study, van Bynum and colleagues did adjust for major confounders including the use of folic acid antagonists. The control group was a group of patients with anomalies thought unrelated to folic acid use. This is not a perfect substitute for the general population, but likely provides a more conservative estimate of the effect of folic acid. In conclusion, these data are supportive of a role of folic acid during the periconceptional period to reduce the risk of CHD by nearly 20%, with a 38% reduction in the rate of septal defects. The optimal dose and method of intake of folic acid through supplemented food, multivitamins, or an isolated folic acid supplement remains unclear. Caren S. Goldberg, M.D., F.A.C.C.
Title: Use of Genetics in the Clinical Evaluation of Cardiomyopathy
Topic: Heart Failure/Transplant
Date Posted: 12/29/2009
Author(s): Judge DP.
Citation: JAMA 2009;302:2471-2476.
Clinical Trial: No
Perspective: The following are 10 points to remember about use of genetics in the clinical evaluation of cardiomyopathy:
1. Dilated cardiomyopathy (DCM) occurs in approximately 1 in 2,500 persons in the United States, and at least 20-35% of these patients have an affected family member. Every patient presenting with DCM should have a family history taken, including information about CM, sudden cardiac death, and syndromic features over at least three generations. DCM in a single additional family member establishes the diagnosis of familial DCM, in the absence of other factors associated with CM such as severe hypertension, severe coronary artery disease, and excessive chronic ethyl alcohol use.
2. Since early treatment with angiotensin-converting enzyme (ACE) inhibitors has been shown to be beneficial in patients with left ventricular (LV) dysfunction, recognition of patients predisposed to DCM is clinically important. For example, a small study showed that incident CM was reduced in patients with Duchenne muscular dystrophy if they were treated with an ACE inhibitor prior to the onset of LV dysfunction.
3. Marked genetic heterogeneity complicates genetic testing for CM. Mutations in more than 35 genes have been associated with DCM, and genetic testing is clinically available for about half of these.
4. Mutations in the lamin A/C gene are found in 5-20% of patients with DCM, and may result in a worse prognosis. Ten percent of DCM patients have a mutation in a sarcomere gene.
5. Hypertrophic CM (HCM) occurs in about 1 in 500 persons in the United States, and is the most common cause of sudden death in young athletes. Most mutations identified are found in sarcomere genes. Sarcomere mutations can thus cause either HCM or DCM.
6. Fabry disease is an X-linked lysosomal storage disease due to deficiency of α-galactosidase A that may lead to LV hypertrophy, which is difficult to distinguish from HCM due to other mutations. Other features associated with Fabry disease include skin angiokeratomas, corneal clouding, neuropathy, anhidrosis, and renal failure. The Food and Drug Administration has approved recombinant enzyme treatment for this disease.
7. Familial amyloidosis may present with similar features to other forms of HCM, but with echocardiograms showing LV hypertrophy and electrocardiograms showing low voltage. Monoclonal light chains should be measured in the serum and urine in these cases, and a cardiac biopsy can confirm the diagnosis with appropriate staining. Familial cardiac amyloid is often due to mutations in the transthyretin gene, and may be associated with neuropathy and chronic diarrhea.
8. The development of genomic DNA sequencing chips will reduce the cost and increase the feasibility of genetic testing to become more widely applied in clinical practice; however, translating the information into clinical practice will be a major hurdle.
9. Genetic testing may provide the diagnostic gold standard for screening of relatives, thus allowing for more vigilant follow-up of those with positive testing. However, decisions not to undergo screening are based on issues such as: a) concern about establishing a pre-existing condition, b) potential negative impact on future insurance premiums and employment (although subjects should be protected by the Genetic Information Nondiscrimination Act [GINA]), and c) uncertainty regarding mutation pathogenicity.
10. Genetic counseling should be provided prior to genetic testing. Daniel T. Eitzman, M.D., F.A.C.C.