Is excess folic acid supplementation a risk factor for autism?

Is excess folic acid supplementation a risk factor for autism?

Medical Hypotheses 77 (2011) 15–17 Contents lists available at ScienceDirect Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy Is e...

127KB Sizes 14 Downloads 145 Views

Medical Hypotheses 77 (2011) 15–17

Contents lists available at ScienceDirect

Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy

Is excess folic acid supplementation a risk factor for autism? C. Mary Beard a,⇑, Laurel A. Panser b, Slavica K. Katusic a a b

College of Medicine, Mayo Clinic, Rochester, MN, USA Social Science Division, Rochester Community & Technical College, Rochester, MN, USA

a r t i c l e

i n f o

Article history: Received 27 January 2011 Accepted 7 March 2011

a b s t r a c t Background: The objective was to assess the association between increasing autism incidence rates and the increasing dose of folic acid in prescription prenatal and pediatric vitamins. Methods: We used published autism incidence rates from the Rochester Epidemiological Project in Rochester, MN, for 1976–1997. Additionally, we used the percent of prescription prenatal vitamins containing 1 mg folic acid and the percent of prescription pediatric vitamins with any folic acid from Physicians’ Desk References for roughly the same time period. Results: The Pearson product moment correlation coefficient (r) for the association between the percentage of prescription prenatal vitamins containing 1 mg folic acid and research-identified autism incidence in Olmsted County was 0.87 [95% confidence interval (CI) = 0.19–0.99]. In contrast, there was a weak association between pediatric vitamins containing any folic acid and autism incidence using the same statistical method (r = 0.62, 95% CI = 0.38–0.95). Conclusions: If it is true that too little folic acid results in nervous tissue damage, as is accepted by the scientific community in regard to neural tube defects (NTDs), then it seems plausible that too much folic acid may result in nervous tissue damage associated with autism. Although the correlations described here do not provide proof of causation, these data provide an impetus for further study. Children who develop autism may be receiving a massive dose of folic acid in utero, as well as, after birth. It would be of interest to carry out a case–control study using medical record data to document folic acid intake for pregnant women whose offspring were later diagnosed with autism and controls. Ó 2011 Elsevier Ltd. All rights reserved.

Introduction This is a short report about the possible association between high dose folic acid exposure and autism. The incidence of autism increased 8.2-fold in Olmsted County, MN, over the years 1976– 1997 [1]. The increase may be influenced by greater awareness, changes in diagnostic definition, or some as yet unidentified deleterious environmental exposure. Autism is a complex, life-long, neuro-developmental condition of unknown etiology. Families with autistic children and society in general, suffer greatly both emotionally and financially, and the costs are endless. During the early 1970s, there was increased interest in the previously known association between maternal anticonvulsant prescription use and congenital malformations in their offspring [2]. These drugs and others are known to leach folate from the body,

Abbreviations: CDC, Centers for Disease Control; CI, confidence interval; FDA, Food and Drug Administration; NTD, neural tube defects; r, Pearson product moment correlation coefficient; PDR, Physicians’ Desk Reference’s; RDAs, recommended daily allowance. ⇑ Corresponding author. (Retired). Address: 2194 Century Hills Ct NE, Rochester, MN 55906, USA. Tel.: +1 507 269 9155. E-mail address: [email protected] (C.M. Beard). 0306-9877/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2011.03.013

consequently prescription prenatal vitamins were fortified with folic acid, synthetic folate. Later, interest focused on neural tube defects (NTDs), such as spina bifida and anencephaly, in children whose mothers lacked adequate folic acid during the periconceptional period [3]. According to Junod [3] the Food and Drug Administration’s charge to evaluate a potential link between folic acid and NTDs came ‘‘out of the blue’’, probably from a Centers for Disease Control (CDC) workshop in the late 1980s. Later in 1996, the FDA mandated that folic acid be added to manufactured cereal products beginning January 1, 1998, to decrease the risk of NTDs [3]. We are not aware of any studies that suggest untoward fetal effects occur as a result of the increased use of high doses of folic acid by pregnant women. It is not always true that more is better. Is it possible that larger doses of folic acid consumed by pregnant women and their offspring result in autistic symptoms in some children so exposed?

Method The incidence rates for research-identified, age- and sex-adjusted autism were available from published data from the Rochester Epidemiological Project in Rochester, MN, for

16

C.M. Beard et al. / Medical Hypotheses 77 (2011) 15–17

1976–1997 [1]. That study used medical as well as private and public school records to obtain the data to identify cases. To be included the records of the children had to contain information that would fulfill the criteria for DSM-IV guidelines for a diagnosis of autism. The details of case ascertainment are already published [1]. These incidence rates were data entered into Minitab, statistical software available at Rochester Community & Technical College in Rochester, MN [2]. These rates per 100,000 children were 0, 5.5, 7.9, 11.8, 29.4, and 44.9, during the time periods, 1976–1979, 1980–1983, 1984–1987, 1988–1991, 1992–1994, 1995–1997, respectively [1]. Similarly the percent of prescription prenatal vitamins containing 1 mg of folic acid was estimated from data gathered from the prenatal vitamin list in the Drug Classification, or Product Category section of Physicians’ Desk Reference’s (PDR) for 1970, 1975, 1980, 1985, 1990 and 1994 [5–10] Similarly, we obtained the percent of prescription pediatric vitamins that were fortified with folic acid from the PDRs [11–16]. The PDRs we used were the only ones readily available to us; they roughly corresponded to the incidence data. We entered these PDR data into Minitab [4]. A Pearson product moment correlation coefficient [17] was estimated to assess the association between the percentage of prescription prenatal vitamins containing 1 mg of folate and research-identified, age- and sex-adjusted autism incidence rates per 100,000 population in Olmsted County, MN from 1976–1997 using Minitab [4]. Similarly, a Pearson product moment correlation coefficient [17] was estimated to assess the association between the percentage of prescription pediatric vitamins containing any folate and the same incidence rates. Results The percent of prescription prenatal vitamins with 1 mg of folic acid increased over the study period from 21.9%, 28.6%, 53.3%, 53.8%, 63.2%, 72.7% over the years from 1970, 1975, 1980, 1985, 1990, and 1994, respectively [5–10]. The percent of prescription pediatric vitamins with any folic acid increase over the study period from 2.1%, 14.7%, 26.3%, 27.8%, 28.6% and 26.7% over the years from 1970, 1975, 1980, 1985, 1990, and 1994, respectively [11–16]. As shown in Tables 1 and 2, the increase in autism incidence was associated with an increase in the percent of prescription prenatal vitamins with 1 mg folate over the study period. The Pearson product moment correlation coefficient for the association between the percentage of prescription prenatal vitamins containing 1 mg folic acid and research-identified autism incidence in Olmsted County was 0.87 [95% confidence interval (CI) = 0.19–0.99]. As shown in Tables 1 and 3, the increase in autism incidence was weakly associated with the percent of prescription pediatric vitamins with any folic acid over the study period. The Pearson product moment correlation coefficient for the association between pediatric vitamins containing any folic acid and researchidentified autism incidence in Olmsted County was 0.62 (95% CI = 0.38–0.95). This result may be due to the fact that many chilTable 1 Age-and sex-adjusted autism incidence rates per 100,000 children in Olmsted County, MN 1976–1997. Time Period

1976–79 1980–83 1984–87 1988–91 1992–94 1995–97

Incidence 0.0 rate/100,000

5.5

7.9

11.8

29.4

44.9

Table 2 Percent of prescription prenatal vitamins containing 1 mg. folic acid by year. Year

1970

1975

1980

1985

1990

1994

% with 1 mg folic acid

21.9

28.6

53.3

53.8

63.2

72.7

Table 3 Percent of prescription pediatric vitamins containing 1 mg. folic acid by year. Year

1970

1975

1980

1985

1990

1994

% with 1 mg folic acid

2.1

14.7

26.3

27.8

28.6

26.7

dren’s vitamins were no longer sold by prescription, and could be obtained over the counter by 1985.

Discussion The increased prevalence of autism has been documented and this literature has been reviewed by others and will not be repeated here [1]. The prevalence of disease is important to public health personnel for planning purposes. In contrast, the incidence of disease measures new cases, which indicates whether a disease or condition is increasing in the population. Barbaresi [1] et al., reported an 8.2-fold increase in autism over the 22 year period 1976–1997; the age- and sex-adjusted incidence was 5.5 per 100,000 children for 1980–83 (95% CI: 1.4–9.5) compared to 44.9 per 100,000 children for 1995–97 (95% CI: 32.9–56.9). This increased incidence of autism may be influenced by a new deleterious exposure, increased awareness, and increased availability of diagnostic and care services, or a combination of some of these. The apparent increase in incidence of autism parallels the increased percentage of prescription prenatal vitamins containing 1 mg of folic acid over time in this study. In 1975, 28.6% of prenatal vitamins contained 1 mg folate [6]. By 2002, all prescription prenatal vitamins marketed in the US were fortified with 1 mg of folate according to the PDRs [18]. This was despite the fact that the recommended daily allowances (RDAs) are lower and have not changed over this time period; specifically the RDAs are 0.40 mg for non-pregnant women, 0.15 mg children aged 1–3 years, 0.20 mg children aged 4–8, while the RDA for infants is less than 0.10 mg (2009 e-mail to author, un-referenced). Further, even small children began to be exposed to added folic acid in pediatric formula, and pediatric vitamins, beginning in 1975 [12] and by 2009, some children’s over-the-counter vitamins, as seen on pharmacy shelves had up to 0.50 mg of added folic acid. The data presented here do not support an association between pediatric folic acid exposure and autism probably due to the fact that by 1985 many children’s vitamins were obtainable over-the-counter. Little is known about the effect of too much folic acid on humans. Although data from Canada and US comparing the preand post-cereal fortification program suggested that rather modest amounts of periconceptional folic acid exposure decreased the risk of NTDs [19,20], that does not address the concern that there may be an upper limit to safe folic acid consumption. There are a number of nutrients that can cause untoward effects if consumed to excess. For example, too much iron can cause hemachromatosis in children, and too much vitamin A can cause liver damage. Further, overdoses of vitamin C can result in gastrointestinal problems, and excess niacin may result in jaundice or liver damage. This suggests that too much folic acid may lead to health problems, perhaps autism. The result presented here may represent an ecological fallacy. The data presented do not provide proof, but rather a suggestion for further exploration. We used correlation statistics to assess the simultaneous increase in autism incidence and the increase in the dose of folic acid in prescription prenatal vitamins as well as prescription pediatric vitamins over time. Correlation statistics are known to provide significance that in reality may be very misleading. Nonetheless, the rather remarkable parallel increase in both the incidence of autism and prenatal folic acid exposure over time may be an important observation.

C.M. Beard et al. / Medical Hypotheses 77 (2011) 15–17

The present study used information from the incidence study of autism in Olmsted County, MN [1] and information regarding the percent of prescription prenatal vitamins containing 1 mg folic acid and pediatric vitamins containing any folic acid over time from PDRs [5–16]. Ideally, it would be best to have folic acid exposure for pregnant mothers and their offspring, autism status in offspring, as well as pertinent confounding and interaction variables; we had none of these data in this preliminary study. A case–control study would be useful to assess folic acid exposure among newlydiagnosed patients with autism and controls using medical record information. It would be important to update the study of the incidence of autism to see if it has continued to increase after fortification of cereals with folic acid took place in Olmsted County, MN. Conflicts of interest statement This research was not funded. None of the authors have financial or conflicts of interest as it pertains to the research submitted. We have no personal relationships that would have biased the work. All authors participated in the conception and design, analysis and interpretation of data, revising of the manuscript, and approved the manuscript as submitted. Further, this manuscript has been read and approved by all of the authors. This manuscript is only being submitted to Medical Hypotheses, and it will not be submitted elsewhere while under consideration at your journal. The data submitted do not pertain to a clinical trial. References [1] Barbaresi WJ, Katusic SK, Colligan RC, Weaver AL, Jacobsen SJ. The Incidence of Autism in Olmsted County, MN 1976–1996. J. Pediatr. Adolesc. Med. 2005;159:37–44.

17

[2] Annegers JF, Elveback LR, Hauser WA, Kurland LT. Do anticonvulsants have a teratogenic effect? Arch. Neurol. 1974;31:364–73. [3] SW. Junod. Folic Acid Fortification: Fact and Folly. Food and Drug Administration Law Institute 2009 April 4. [4] Minitab, INC. Minitab Statistical Software, Release 15.1.0.0 For Windows, State College Pennsylvania. 2006. [5] Physicians’ Desk Reference. 24th Ed. Oradell, NJ: PDR; 1970. 582, 629, 690, 785-6, 804, 836, 878, 897, 955-6, 1007, 1072-73, 1127, 1138–39, 1146–47, 1212, 1247, 1323-24, 1347. [6] Physicians’ Desk Reference. 29th Ed. Oradell, NJ: PDR; 1975. 555, 613–4, 620, 762–3, 873–4, 926–7, 971, 1005, 1076-78, 1134, 1199, 1275, 1283-84, 1291, 1387. [7] Physicians’ Drug Reference. 34th Ed. Oradell, NJ: PDR; 1980. 778, 864, 978, 983, 1039–40, 1098, 1119–20, 1224, 1226, 1328, 1356, 1404, 1510, 1626, 1648, 1705. [8] Physicians’ Desk Reference. 39th Ed. Oradell, NJ: PDR; 1985. 838–9, 914–5, 942, 1093, 1098, 1196, 1224, 1416, 1419, 1545, 1640, 1775, 1824, 2042–43. [9] Physicians’ Desk Reference. 44th Ed. Oradell, NJ: PDR; 1990. 681, 856, 941, 1004, 1161, 1297, 1519–20, 1743, 1897–98, 2171–72. [10] Physicians’ Desk Reference. 49th Ed. Montvale, NJ: PDR; 1994. 791, 925, 1167– 68, 1375, 1622, 2008–9, 2124, 2309, 2607–8. [11] Physician’ Desk Reference. 24th Ed. Oradell, NJ: PDR; 1970. 669–70, 810, 830– 1, 893, 899, 900, 904, 960, 1118–19, 1141–43, 1314, 1319, 1320–21, 1343–44, 1348–49. [12] Physician’ Desk Reference. 29th Ed. Oradell, NJ. PDR: 1975. 555, 657–8, 944–5, 1008, 1013, 1080, 1263–64, 1287–88, 1467–69, 1508. [13] Physicians’ Desk Reference. 34th Ed. Oradell, NJ: PDR; 1980. 562, 738–9, 901, 1067– 68, 1107–10, 1230, 1488, 1514–16, 1700, 1702. [14] Physicians’ Desk Reference. 39th ED. Oradell, NJ: PDR; 1985. 914–5, 1243–46, 1247–48, 1709–10, 1782–84, 1994, 2039. [15] Physicians’ Desk Reference. 44th Ed. Oradell, NJ: PDR; 1990. 939, 1149, 1303– 8, 1902–4, 2169. [16] Physicians’ Desk Reference, Montvale, NJ: PDR; 1994, 2015–17, 2335. [17] Osborn CE. Essentials of Statistics in Health Information Technology. Sudbury: Mass: Jones & Bartlett; 2008. [18] Physicians’ Desk Reference. 54th Ed. Montvale, NJ: PDR; 2002. 1351, 1769, 1862, 2231, 3094, 3096–97, 3312–13, 3364. [19] De Wals P, Fassiatou T, Van Allen MI, Uh SH, Lowry RB, Sibbald B, et al. N. Engl. J. Med. 2007;357(2):135. [20] Honein MA, Paulozzi LJ, Mathews TJ, Erickson JD, Wong LYC. Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects. JAMA 2001;285(23):2981–6.