Dr. Gagan Sabharwal
Oro Facial Clefts (OFC) is one of the most commonly seen congenital anomaly after congenital cardiac anomalies. Various studies have been conducted and several factors have been attributed to the pathogenesis of OFC the commonly proposed etiological factors being genetics, drug abuse during pregnancy, stress and nutritional deficiencies during the gestational phase, consanguineous marriages. The role of folic acid in the prevention of clefts has been proven beyond doubt by various studies. The aim of this article is spread awareness about the effect of folic acid in the prevention of neural tube defects its mechanism of action in preventing OFC and its value as an important micronutrient in a balanced diet.
The face is an important source of information in interpersonal communication. It is the focus of attention in face-to-face interaction, and gives us information on which we form initial, automatic impression of other people. Cleft lip and palate forms a group of facial anomalies that have an additional disadvantage of being located in the nose mouth area and can have a significant physical and psychological impact on the patient. Oro Facial Clefts (OFC) is one of the most commonly seen congenital anomaly after congenital cardiac anomalies.1
In humans, a finely choreographed cascade of gene expression, cell migration, cell transformation and apoptosis between 14 and 60 days post conception creates the soft and hard tissues of the face from the originating oropharyngeal membrane. By 48 days the upper lip is continuous and by 60 days palatal shelf fusion completes facial embryogenesis. Disruption of any of the tightly regulated processes occurring in this time frame by environmental and/or genetic abnormalities may then predispose to cleft lip and/or palate.2
OFC include cleft lip with or without the palate (CLP) as well as palate only (CP). OFC occur in both isolated and non-isolated forms. Isolated or nonsyndromic forms involve no other major structural or developmental impairments and represent the majority of cases with CL. The non-isolated or syndromic forms with CLP occur due to more than 450 causes including chromosomal anomalies, single gene conditions, environmental exposures, and syndromes of unknown cause. OFC impose significant health, psychosocial, and economic burdens, both at them individual and family levels. 3
Various studies have been conducted and several factors have been attributed to the pathogenesis of OFC, the commonly proposed etiological factors being genetics, drug abuse during pregnancy, stress and nutritional deficiencies during the gestational phase, consanguineous marriages, etc .4-7
OFC deformities are completely correctable and provide the patient a chance to get back into normalcy with predictable quality of life. But, prevention of a condition when options are available is a much better option than the correction of the problem. The role of folic acid in the prevention of clefts has been proven beyond doubt by various studies.8-10
Incidence of Oro facial Clefts
There has been a lack of an established registry for craniofacial deformities in India, therefore the exact incidence is not available. The last dedicated multicenter study involving three cities in India and 94,906 births was conducted between 1994 and 1996.11 The present incidence of cleft deformities however is around 1 in 800 live births in India12 which translates to around 30,000 new patients every year. This is a large number and when added to the number of individuals, who have not been treated, gives us a huge figure as backlog.
The aim of this article is spread awareness about the effect of folic acid in the prevention of neural tube defects its mechanism of action in preventing OFC and its value as an important micronutrient in a balanced diet.
Role of Folic acid
The discovery of the role of folic acid as the single most important prophylactic supplement was around two decades back; the benefits of the discovery are yet to be realized. The incidence of OFC has remained the same and the associated benefits too have not been utilized solely due to the lack of awareness among the health care providers themselves. The use of folic acid as a prophylactic therapy to any woman of child-bearing age has been proven to decrease the incidence of orofacial cleft by as much as 85%, besides the other proven benefits of folic acid as a nutritional supplement.13-15
There is strong evidence from clinical trials for a large preventive effect of folic acid on both recurrence and occurrence of Neural tube defects (NTDs). The strongest evidence for a preventive effect of high dose folic acid supplementation on recurrence of NTDs comes from the Medical Research Council (MRC) double-blinded randomized study, where women with a previous child with NTD were randomly assigned to groups of 4 mg folic acid, vitamins other than folic acid, vitamins with 4 mg folic acid, and placebo, taken daily at preconception and throughout the first trimester of pregnancy. The study reported a significant reduction of about 72% in the rate of NTDs in the groups supplemented with folic acid compared to the other study groups. No significant decreases in NTD recurrence were observed in the group receiving vitamins without folic acid, indicating that preventive effects were due the folic acid component.16
Multivitamin supplementation with a 0.8 mg folic acid at preconception and through at least two months post conception was also shown to lower the risk of first occurrence of NTDs by up to 100% in a randomized clinical trial in Hungary using a sample of women with no history of NTDs among their children. This same study showed no decrease in the occurrence of OFC though the overall rate of congenital anomalies was reported to have decreased with the multivitamin supplementation.17
The NTD research provides a model for developing clinical trials aimed at assessing preventive effects of folic acid on recurrence and occurrence of OFC, which is of direct relevance for clinical practice. A connection between NTDs and OFC can be supported by their similar time of occurrence during embryogenesis, their status as defects involving the midline of the embryo, their near identical population genetic characteristics (variable by geographic origin but with near identical recurrence risks and very similar birth prevalence rates overall), evidence of similar gene and environment contributions and the failure to identify major genetic factors for either.18
|Category of women
|No history of a previous NTD
|With history of previous NTD
|Other high risk patients
|Women with close relative with NTD
Type 1 DM
With seizure disorders
Public health program- supplementation/food fortification
NTD: Neural tube defects, DM: Diabetes mellitus
Table 1 :Folic acid dosage regimens for women of child-bearing age 18
Normal adults are prescribed a daily intake of 400 μg of folate. Administration of folic acid in excess of 1,000 μgm may mimic symptoms of Vitamin B12 deficiency, especially the changes in the nervous system in elderly people.18
Mechanism of action
Folic acid is an essential component in the development and maintenance of cells and tissues. It is necessary for homocysteine metabolism. Folic acid also plays a vital role in the synthesis of DNA and RNA, which are the building blocks of cells. They are essential for the synthesis of puridine, thymidylate and methionine.18
Other benefits of folic acid
- Preventive role in neural tube defects apart from OFC
- Helps in prevention of cardiovascular diseases, especially fetal coronary heart diseases
- Helps in prevention of age-related hearing loss
- Helps combat adverse effects of methotrexate in anti-cancer therapy
- Important role in the prevention of psychological depression
- Has been proven to have a role in the prevention of psoriasis19-21
Any factor that could prevent the facial processes from reaching each other by slowing down migration, multiplication or both of neural crest cells by stopping tissue growth and development for a time or by killing some cells that are already in that location, would cause a persistence of a cleft.22
There are several lines of evidence suggesting the folate-hemocysteine metabolism to be implicated in the risk of orofacial clefts. However the explanation for this association is unknown but recent information shows endothelial nitric oxide synthase (NOS3) genetic variants expressing NOS3 involvement in folate homocysteine metabolism which inhibits nitric oxide resulting in hypertension and fetal growth retardation in pregnant rats.23, 24
There is some suggestive evidence for a possible role of folic acid in prevention of OFC. However, several important questions remain unanswered including confirming whether folic acid prevents OFC, whether it prevents occurrence or recurrence or both, whether it prevents CLP, CP or both, and identifying whether low or high doses are effective for prevention. Studies to date have provided mixed results particularly in regards to whether low or high dose folic acid can prevent primary occurrence. Most case-control observational studies indicating a preventive effect are likely to have evaluated low to moderate doses of folic acid though the majority did not measure or report the dose.26
These findings suggest that daily periconceptional intake of 400 μg of folic acid (the dose most commonly contained in over-the-counter multivitamin preparations) reduces the risk of occurrent NTDs by approximately 60%. 25 It was noted that in women who took 400 μg of folic acid in the time between their pre-marital examination and their first trimester, there was a decreased incidence of neural tube defects by more than 85% in a region with a high risk and by 40% in regions with low risk.13
Although the importance of folic acid in the prevention of OFC was recognized and accepted worldwide, 13-15its practical implementation has eluded reality; the main reason for this is the extremely low degree or, in certain cases, lack of awareness among the medical population and health care providers who actually interact with people affected by OFC.It has been found that proper counseling of prospective mothers and their education is the best means of achieving the goal of prevention.18
- Wyszynski DF. Cleft lip and palate - from origin to treatment. Vol. 35. Oxford: Oxford University Press; 2002. p. 458-67.
- Geoffrey Sperber (2002 ): Wyszynski, DF., editor. Cleft Lip and Palate: From Origin to Treatment. Oxford University Press; 2002.p5-12
- Marazita, ML. Segregation analysis. In: Wyszynski, DF. editor. Cleft Lip and Palate: From Origin to Treatment. Oxford University Press; 2002. p. 222-233
- Beaty TH, Maestri NE, Hetmanski JB, Wyszynski DF, Vanderkolk CA, Simpson JC,et al. Testing for interaction between maternal smoking and TGFA genotype among oral cleft cases born in Maryland 1992-1996. Cleft Palate Craniofac J 1997;34:447-54.
- Kondo A, Kamihira O, Ozawa H. Neural tube defects; prevalence, etiology and prevention. Int J Urol 2009; 16:49-57.
- Murray JC. Gene/Environmental causes of cleft lip and/or palate. Clin Genet 2002;61:248-56.
- Zeiger JS, Beaty TH, Liang KY. Oral clefts, maternal smoking and TGFA: A meta-analysis of gene-environment interaction. Cleft Palate Craniofac J 2005;42:58-63.
- Folic acid for the prevention of neural tube defects. American Academy of Pediatrics. Committee on Genetics. Pediatrics 1999;104:325-7.
- Berry RJ, Li Z, Erickson JD, Li S, Moore CA, Wang H,et al. Prevention of neural tube defects with folic acid in China. N Engl J Med 1999;341:1485-90.
- Czeizel E, Timar L, Sarkozi A. Dose dependent effect of folic acid on the prevention of orofacial clefts. Pediatrics 1999;104:e66.
More References are available on request