Epidemiology of neural tube defects and folic acid
© Shurtleff; licensee BioMed Central Ltd. 2004
Received: 29 September 2004
Accepted: 10 December 2004
Published: 10 December 2004
This review article combines four disparate observations about Neural Tube Defects (NTDs). They are the worldwide decline in the birth incidence that began prior to prenatal diagnosis; family recurrence risks; the effect of prenatal diagnosis and termination of affected pregnancies; and the effect of folic acid.
Variations in birth incidence
Family recurrence risks
Family studies suggest the recurrence risk for first-degree relatives of affected individuals is approximately 1 in 30. For second-degree relatives (the children of the mother's sisters and brothers) the risk is approximately 1 in 220 . However, the authors of the same study state there is not yet agreement upon the accurate recurrence risk data for family members. Others report a recurrence risk among the mother's or an affected child's first-degree relatives is as high as 1 in 70 to 140 [10, 11]. McManus  reports recurrence risks in first and second-degree relatives of 1 in 40 for sisters of the mother of an affected child, and 1 in 90 for the offspring of those sisters. She reported the mother's brothers and the father's sisters and brothers to have lower recurrence risks of 1 in 140 to 1 in 190. Arata et al  report that affected mothers appear to have only a 0.5 to 1% chance of having a child with an NTD. This last observation concurs with our finding that only one mother with myelomeningocele has an affected child. That child is one of 106 otherwise unaffected by an NTD.
Prenatal diagnosis and termination
The third aspect, prenatal diagnosis and termination of affected pregnancies, is one that should be discussed with all women in the reproductive age range and, more importantly, with patients who have a family history of an NTD. Folic acid taken orally on a daily basis is shown to lower the occurrence and recurrence of NTDs in their own offspring and in their relatives. The Medical Research Council  was the first to prove conclusively that when women who had had a previous child affected by an NTD took 4.0 mg of folic acid daily, beginning three months prior to conception, there was a 70% reduction in the recurrence in subsequent offspring. Wald et al  have recommended 5 mg daily. Because of the higher occurrence in first- and second-degree relatives, we recommend 4.0 mg daily, beginning three months prior to a planned conception. We suggest the effect in the United States may be nearer to a 40 – 50% reduction for two reasons. First, Berry et al  demonstrated a 79% reduction in occurrence in north China (an area of high incidence) but only 40% in south China (where there is a low incidence) when the women took 0.4 mg of folic acid periconceptually. The incidence of NTDs in the United States is closer to that seen in south China rather than that in north China. Secondly, recent data from Canada and Mexico are the first to indicate that lower incidence communities on the North American continent can achieve a 45 – 55% reduction in occurrence with a regimen of 5 mg of folic acid per week  and dietary fortification added to recommendations for supplementation periconceptually with 0.4 mg dose of folic acid daily [8, 18].
Folic acid supplementation
When recent trends in the birth incidence of NTDs are reported, they focus additionally on the effect that folic acid has on the early second trimester prevalence of affected fetuses. As for the epidemiological studies noted above, these reports include varying types of cases; some report only "spina bifida", others "spina bifida" and anencephaly, and still others mention these two types and encephalocele with or without hydrocephalus. Some studies report only deaths due to complications in these groups of patients as stillborns, or deaths in the neonatal time period; other reports study all affected newborns, and still others cover selective or spontaneously aborted fetuses. Those that include time intervals after the introduction of intrauterine diagnosis and selective termination do not take into consideration the variations in incidence at different gestational ages and at birth, whether stillborn or live . Creasy and Alberman  reported that 3% of 1216 (30 per 1000) spontaneously aborted fetuses had central nervous system malformations. The majority of the malformations were NTDs. Forty percent also had chromosomal aberrations. The prevalence varied from about 21 per 1000 during each three-week period of gestational age between 8 and 19 weeks, to 105 per 1000 amongst fetuses greater than 27 weeks gestational age. The live born birth incidence at that time was 1.5 per 1000. Nishimura et al , reported 13 per 1000 spina bifida embryos amongst 3402 induced abortion fetuses for social reasons at a gestational age between 3 and 10 weeks old. The live born incidence at the time was 2 per 1000. Adams et al  reported 10 of 34 fertilized ova up to the age of 17 days were malformed (an incidence of 294 per 1000). Studies after the initiation of prenatal diagnosis and before folic acid supplementation and fortification clearly demonstrate a remarkable decrease in live born birth incidence ([1, 20, 21] and Figure 1). In Washington State, USA, prenatal diagnosis and termination of affected pregnancies began in 1980. Beginning in 1991, concerned specialists and the media advised supplementation with 400 mcg (0.4 mg) of folic acid daily for women in the childbearing age group. Fortification with an estimated 140 mcg (0.14 mg) per serving of flour-containing foods was added to the recommendations, beginning in 1996, and implemented over the next three years. The marked increase of 7 fold from 0.03 per 1000 in 2001 to 0.21 in 2002 coincided with the completion of fortification (Figure 1).
Our data and this review clearly demonstrate the effects of intrauterine diagnosis and selective termination prior to the recommendation for supplementation and fortification of foodstuffs with folic acid. Because the reason for termination of a pregnancy is not reportable in our state and the USA, we cannot determine the effect of folic acid on the prevalence of myelomeningocele and anencephaly in first and early second trimester fetuses. Studies of the effect of folic acid in reducing the birth incidence in communities with a low incidence, and active prenatal diagnosis associated with termination of affected fetuses, require longer-term studies than published to date. The differences in data discussed above need to be considered if one is to evaluate the effect of prenatal diagnosis and elective termination as well as the effects of fortification or supplementation with folic acid. We recommend that these variables be discussed with women of reproductive age, particularly if they are relatives of a patient with an NTD. Regardless of the uncertainties, we recommend supplementation of the diet of women, beginning three months prior to an anticipated pregnancy. We recommend all women of childbearing age take at least 400 mcg of folic acid daily when they begin sexual activity. Relatives of a patient with an NTD should take 4.0 mg daily, beginning three months prior to conception.
- Shurtleff DB, Lemire RJ: Epidemiology, etiologic factors, and prenatal diagnosis of open spinal dysraphism. Neurosurg Clin N Am. 1995, 6: 183-193.PubMedGoogle Scholar
- Creasy MR, Alberman ED: Congenital malformations of the central nervous system in spontaneous abortions. J Med Genet. 1976, 13: 9-16.PubMed CentralView ArticlePubMedGoogle Scholar
- Luthy DA, Wardinsky T, Shurtleff DB, Hollenbach KA, Hickok DE, Nyberg DA, Benedetti TJ: Cesarean section before the onset of labor and subsequent motor function in infants with meningomyelocele diagnosed antenatally. N Engl J Med. 1991, 324: 662-666.View ArticlePubMedGoogle Scholar
- Nishimura H, Takano K, Tanimura T, Yasuda M, Uchida T: High incidence of several malformations in the early human embryos as compared with infants. Biol Neonat. 1966, 10: 93-107.View ArticlePubMedGoogle Scholar
- Roberts CJ, Lowe CR: Where have all the conceptions gone?. The Lancet. 1975, March 1: 498-499. 10.1016/S0140-6736(75)92837-8.View ArticleGoogle Scholar
- Leck I: Changes in the incidence of neural-tube defects. Lancet. 1966, 2: 791-793. 10.1016/S0140-6736(66)90383-7.View ArticlePubMedGoogle Scholar
- Elwood JM, Elwood JH: Epidemiology of anencephalus and spina bifida. 1980, New York, Toronto, Oxford University Press, 85-119.Google Scholar
- Persad VL, Van Den Hof MC, Dube JM, Zimmer P: Incidence of open neural tube defects in Nova Scotia after folic acid fortification. CMAJ. 2002, 167: 241-245.PubMed CentralPubMedGoogle Scholar
- Toriello HV, Higgins JV: Occurrence of neural tube defects among first-, second-, and third-degree relatives of probands: results of a United States study. Am J Med Genet. 1983, 15: 601-606.View ArticlePubMedGoogle Scholar
- Chatkupt S, Skurnick JH, Jaggi M, Mitruka K, Koenigsberger MR, Johnson WG: Study of genetics, epidemiology, and vitamin usage in familial spina bifida in the United States in the 1990s. Neurology. 1994, 44: 65-70.View ArticlePubMedGoogle Scholar
- Timson J: A study of the first degree relatives of the parents of spina bifida children. Clin Genet. 1972, 3: 99-102.PubMedGoogle Scholar
- McManus S: Neural tube defects: identification of 'high risk' women. Ir Med J. 1987, 80: 166-168.PubMedGoogle Scholar
- Arata M, Grover S, Dunne K, Bryan D: Pregnancy outcome and complications in women with spina bifida. J Reprod Med. 2000, 45: 743-748.PubMedGoogle Scholar
- Group MRCVSR: Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group. Lancet. 1991, 338: 131-137. 10.1016/0140-6736(91)90133-A. [http://PM:1677062]View ArticleGoogle Scholar
- Wald NJ, Law MR, Morris JK, Wald DS: Quantifying the effect of folic acid. Lancet. 2001, 358: 2069-2073. 10.1016/S0140-6736(01)07104-5.View ArticlePubMedGoogle Scholar
- Berry RJ, Li Z, Erickson JD, Li S, Moore CA, Wang H, Mulinare J, Zhao P, Wong LY, Gindler J, Hong SX, Correa A: Prevention of neural-tube defects with folic acid in China. China-U.S. Collaborative Project for Neural Tube Defect Prevention. N Engl J Med. 1999, 341: 1485-1490. 10.1056/NEJM199911113412001.View ArticlePubMedGoogle Scholar
- Martinez V, Perez JZ, Vazquez PA, Herrera RH, Campos MR, Lopez RA, Ramirez JL, Sanchez JM, Villarreal JJ, Garza MT, Limon A, Lopez AG, Barcenas M, Garcia JR, Dominguez AS, Nunez RH, Ayala JL, Martinez JG, Gonzalez MT, Alvarez CG, Castro RN: Decline of neural tube defects cases after a folic acid campaign in Nuevo Leon, Mexico. Teratology. 2002, 66: 249-256. 10.1002/tera.10094.View ArticlePubMedGoogle Scholar
- Gucciardi E, Pietrusiak MA, Reynolds DL, Rouleau J: Incidence of neural tube defects in Ontario, 1986-1999. CMAJ. 2002, 167: 237-240.PubMed CentralPubMedGoogle Scholar
- ADAMS EC, HERTIG AT, ROCK J: A description of 34 human ova within the first 17 days of development. Am J Anat. 1956, 98: 435-493.View ArticlePubMedGoogle Scholar
- Laurence KM: The apparently declining prevalence of neural tube defect in two counties in South Wales over three decades illustrating the need for continuing action and vigilance. Z Kinderchir. 1985, 40 Suppl 1: 58-60.PubMedGoogle Scholar
- Omran M, Stone DH, McLoone P: The Chief Scientist reports.... Pattern of decline in prevalence of anencephaly and spina bifida in a high risk area. Health Bull (Edinb ). 1992, 50: 407-413.Google Scholar
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