audiohope.org - Epidemiologic evidence for low maternal vitamin D as a risk factor of IAD

June 13, 2008
Epidemiologic evidence for supporting the role of maternal vitamin D deficiency as a risk factor for the development of infantile autism
William B. Grant, Ph.D.
Sunlight, Nutrition, and Health Research Center (SUNARC)
P.O. Box 641603
San Francisco, CA 94164, USA
www.sunarc.org
wbgrant@infionline.net

Connie M. Soles
AudioHope
4403 Chesapeake Avenue
Hampton, VA 23669
soles1@cox.net

Abstract
This study will examine whether maternal vitamin D deficiency is a risk factor for infantile autism disease (IAD). I used epidemiologic data seasonal variation of birth rates and prevalence of IAD for cohorts born before 1985. For seven studies reporting spring-to-summer excess birth rates for IAD, the season progressed from broad near 30° N latitude, spring/summer in midlatitudes, to winter at the highest latitude. Also, using data from 10 studies, I found a strong effective latitudinal (related to solar ultraviolet B radiation) increase in IAD prevalence. These findings are consistent with maternal vitamin D deficiency’s being a risk factor for IAD, a factor affecting immune system status.

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Introduction
The etiology of autism is still somewhat of an enigma. Autism is considered an autoimmune disease [Krause et al., 2002]. It also appears to have important risk factors in utero, as evidenced by a highly significant increased frequency of congenital malformations [Lauritsen et al., 2002]; and those with autism have several characteristics associated with schizophrenia [Konstantareas and Hewitt, 2001], which is also linked to in utero risk factors [Mackay-Sim et al., 2004]. Perinatal viral infection of mother or infant is a risk factor for both infantile autism and schizophrenia [Libbey et al., 2005]. Also, several studies have reported seasonality in excess births of those with autism, with March being a peak month in Sweden [Gillberg, 1990], Denmark [Mouridsen et al., 1994], and Boston [Stevens et al., 2000], but without a good explanation for this seasonality.

Schizophrenia is another disease that exhibits excess of births in winter and a deficit in summer [Davies et al., 2003]. This seasonality has sometimes been shown to be linked to influenza epidemics [Adams et al., 1993; McGrath et al., 1994]. Infectious disease during pregnancy has been found to adversely affect rodent brain development in a manner that can lead to schizophrenia as well as autism [Shi et al., 2003; Fatemi et al., 2002, 2005; Meyer et al., 2006, 2007a,b; Fortier et al., 2007]. The hypothesis that the seasonality was related to low levels of maternal serum 25-hydroxyvitamin D (calcidiol) was also advanced [McGrath, 1999]. Support for the maternal vitamin D deficiency hypothesis has been reported based on rat studies [Eyles et al., 2003, 2007; Cui et al., 2007].

It was recently proposed that the annual solar ultraviolet-B (UVB) and vitamin D cycles explained some of the seasonality of epidemic influenza, which peaks in winter [Cannell et al., 2006]. This hypothesis received experimental support in a randomized, prospective, placebo-controlled vitamin D study involving 204 postmenopausal black women living in New York State. Those taking 2000 IU of vitamin D3 per day got very few colds or influenza during the three-year study compared with those taking the placebo [Aloia and Li-Ng, 2007]. More support came from a study of meteorological variables associated with incidence of respiratory syncytial virus that found an effect for solar UVB in addition to temperature and relative humidity, with greatest effect at lower latitude [Yusuf et al., 2007]. Thus, serum calcidiol levels can affect risk of maternal viral disease during pregnancy.

This report examines the evidence supporting the hypothesis that maternal vitamin D deficiency is an important risk factor for the development of infantile autism disease (IAD), through both direct effect and indirect effects in reducing the risk of infectious diseases. The analysis is limited to the period prior to the mid-1980s. There has been a rapid rise in birth rates of autism in countries such as the United Kingdom and the United States since the mid-1980s [Blaxill, 2995]. While there is concern that increased rate of vaccinations, especially those containing Thimerosal, has led to the increases [Geier and Geier, 2006], there is still no general agreement on the cause of the increases.

Materials and methods
I searched the literature for relevant reports relating to prevalence of and seasonality of birth of childhood autism. For prevalence, several reviews were useful, including Sponheim and Skjeldal [1998], Fombonne [1999], Gillberg and Wing [1999], and Fombonne [2003]. Several ideas were readily apparent in reviewing the published prevalence data:

1. both IAD (defined as developing autism prior to 30 months of age) and pervasive developmental disorders (PDD) were studied;
2. the criteria for determination changed several times since the original criteria developed by Kanner [1951] for “nuclear autism”;
3. the prevalence rates varied geographically;
4. the autism rates determined in Japan and other Asian countries were considerably higher than those determined in primarily white countries; and
5. the prevalence rates increased when the DSM-III criteria were replaced by the DSM-III-R criteria [APA, 1987]. This finding is related to a broadening of the diagnostic boundaries [Charman, 2002, 2003]. On the basis of these observations, the prevalence data used to investigate a possible latitudinal variation were restricted to those gathered using DSM-III and earlier criteria. Some of the subsequent data were used separately.

Tables 1 and 2 give the prevalence data used in this study. I omitted data for Asian countries since the prevalence values are much higher than those in Western developed countries. For Utah, an educated guess was to associate the prevalence stated as for “autism” with that for PDD since in Table 1 of that paper, many of the prevalence values from other reports are listed as associated with autism but are, in fact, associated with PDD. Also, the report states merely that DSM-III criteria were used. Also, some adjustments had to be made to account for different age ranges included in the various studies since even though IAD develops prior to 30 months of age, health officials often do not learn about student IAD status until the children attend school. The variation in observed prevalence rate versus age tabulated in Cialdella and Mamelle [1989] was used to determine an effective prevalence for those values that included those younger than 5 years, 1.2 starting at age 3 years, and 1.33 starting at 0 years.

Several reports have looked for seasonality in autistic births. Table 3 summarizes the results of searching the National Library of Medicine’s PubMed database. The winter and spring quarters had the highest rate of autistic births, with March being the month mentioned most often.

The approaches used here to test the hypothesis that maternal vitamin D deficiency is a risk factor for IAD and PDD include trying to find a link between vitamin D and IAD and PDD prevalence and interpreting the reported results regarding the seasonal variation in birth rates. Thus, a suitable index for vitamin D at the population level must be used. The simplest index is latitude. Solar UVB radiation is the primary source of vitamin D for many people on Earth, especially in tropical and temperate climate zones. The well-documented seasonal variation of serum calcidiol shows the largest variation in countries, such as France, that do not fortify foods with vitamin D or encourage the use of vitamin D supplements [Ovesen et al., 2003]. However, in Europe in winter, serum calcidiol levels actually increase with latitude [van der Wielen et al., 1995].

There are two simple indices for serum calcidiol assuming that solar UVB is the primary source. The simplest one is latitude for latitude greater than about 30°. For example, those living near 30° can produce vitamin D from solar UVB during the entire year, whereas those living at 42° N cannot produce vitamin D from solar UVB for 4–5 months of the year [Webb and Engelsen, 2006]. However, this simple index cannot explain the geographic variation in U.S. cancer mortality rates [Grant, 2002; Grant and Garland, 2006]: July UVB is much higher at the same latitude west of the Rocky Mountains than east of them [Leffell and Brash, 2006]. Both lower column ozone and higher surface elevation west of the range explain the difference. The shift west of the Rockies is approximately 7o (770 km) [Leffell and Brash, 2006]. Also, from the finding that a state’s degree of urbanization was an added risk factor for seven types of cancer for which UVB is a risk-reduction factor [Grant and Garland, 2006], living in an urban versus a rural environment apparently reduces the total dose of UVB. Thus, latitude is used as the primary index for vitamin D, with slight adjustments for high summertime UVB levels and for living in a primarily rural region. Changes made to yield effective latitude for the prevalence data include the following:

North Dakota, from 47.5° to 41° N
Utah, from 41° to 35° N
Rural Bohuslän near Göteborg, from 57.7° N to 55° N

I ran multiple linear regressions with SigmaStat version 2.0, applying normality (Kolmogorov–Smirnov) and constant variance tests. For each linear regression, I give the values of the adjusted r2, F (accounts for the number of degrees of freedom), and p.

Results
Prevalence
Table 4 gives the regression results for IAD and their difference versus latitude. Figure 1 also shows the regression results for IAD. Effective latitude was highly correlated with prevalence; i.e., prevalence increased at the higher latitudes, which are associated with lower vitamin D produced by solar UVB in summer. Actual latitude was also correlated with prevalence data, but at lower levels of significance.

However, people born between 1988 and 1995 showed little variation with latitude for IAD and an insignificant inverse correlation with latitude for PDD.

Season of birth
Figure 2 graphs the months of excess birth rate versus latitude, with December counted as month zero; when two adjacent quarters were listed as having excess birth rates, I omitted the two extreme months of these quarters. At the lower latitudes, there is a large spread, decreasing to 3–4 months for the other latitudes; also, there is a trend toward the beginning of the year with increasing latitude. New York does not fall into this pattern.

Discussion
Prevalence
The data for seasonal variation of prevalence of those born prior to 1985 are consistent with an increased risk during pregnancy in winter. From the timing, risk is most likely affecting the mother during the third trimester of pregnancy since serum calcidiol values are lowest in late winter/early spring, and risk of influenza and other viral diseases is highest then. The brain develops mostly in the later stages of pregnancy, so a vitamin D deficiency would exert more effect during this period [Meyer et al., 2006]. The prevalence of IAD quadruples in going from Israel to Sweden. The earlier period to the north is consistent with colder temperatures and lower solar UVB doses arriving earlier there than to the south. The fact that a similar effect was not found for the non-IAD portion of PDD, which develops after 30 months of age, is further evidence pointing to IAD’s association with a maternal vitamin D deficiency.

The IAD prevalence data for France are somewhat above the regression line in Figure 1, perhaps partly because food there is not vitamin D fortified. On this basis, the French appear the largest winter/spring drop in serum calcidiol level of any country studied [Guillemant et al., 1999]. People living near the Arctic Circle are more likely to consume fish, an important source of vitamin D, and to take vitamin D supplements.

Multiple sclerosis (MS) is another disease for which risk increases rapidly with latitude [Kurtzke, 1979; van der Mei et al., 2001; Wallin et al., 2004]. The geographic variation in the United States is more highly correlated with latitude, an index for wintertime UVB and vitamin D, than with July UVB [Leffell and Brash, 1996; Grant and Holick, 2005]. Risk of MS is linked to the Epstein-Barr virus [Ascherio and Munger, 2007], and both solar UVB [Ponsonby et al., 2005] and vitamin D [Munger et al., 2006] reduce the risk. It has also been proposed that higher calcidiol levels reduce the risk of MS by reducing the risk of Epstein-Barr infection [Holmoy, 2007].

Season of birth
The seasonal excess of autistic births has an interesting variation with latitude. The general coherence to the data indicates that there are seasonal influences on the risk of autism. The large spread in months of excess births for Israel—March, August, and October—may be related to the fact that the latitude is low enough that there is not a pronounced seasonal variation of serum calcidiol levels. That the season of excess autistic birth is generally from December to April is consistent with a maternal vitamin D deficiency during the last 3–5 months of pregnancy. Serum calcidiol levels tend to be lowest in the spring at mid-to-higher latitudes as the body depletes vitamin D stores built up in the fatty tissues and photoproduction from solar UVB has not yet resumed [Webb and Engelsen, 2006]. Curiously, however, serum calcidiol levels in Europe increase with increasing latitude in winter [van der Weilen et al., 1995], which is probably due to increased vitamin D fortification of food, use of supplements, and use of solaria [Boldeman et al., 2003].

Role of vitamin D in reducing the risk of IAD
Vitamin D could reduce the risk of IAD by (1) aiding proper development of the brain and/or (2) strengthening the immune system. The best evidence for a role of maternal calcidiol on brain development comes from the study of rat brain development for maternal vitamin D deficiency. Several adverse effects were found, such as reductions in brain content of nerve growth factor and glial cell line–derived neurotrophic factor, as well as structural differences of the cortex and lateral ventricles [Eyles et al., 2003]. Other effects on rat brain development were reported more recently [Cui et al., 2007].

Recent reports indicate that vitamin D reduces the risk of respiratory diseases caused by viral infections [Cannell et al., 2006; Aloia and Li-Ng, 2007; Yusuf et al., 2007], which are most common in winter. Other reports indicate that maternal influenza during pregnancy can adversely affect brain development [McGrath et al., 1994; Shi et al., 2003]. Taken together, these studies provide good evidence that vitamin D can affect development of the brain in utero by improving the immune system to reduce the risk of infectious diseases. 
Possible role of infectious agents
Maternal viral infection is known to increase the risk for schizophrenia and autism in the offspring [Libbey et al., 2005]. Animal models support this finding. Mice exposed to human influenza virus on Day 9 of pregnancy produced offspring with adverse effects on the developing brain including altered pyramidal and nonpyramidal cell density values; atrophy of pyramidal cells despite normal cell proliferation rate and final enlargement of brain [Fatemi et al., 2002]. In a subsequent study, prenatal viral infection showed significant upregulation of 21 genes and downregulation of 18 genes in the affected neonatal brain homogenates spanning gene families affecting cell structure and function [Fatemi et al., 2005]. Another study found that infection of mice with human influenza virus yielded offspring that displayed highly abnormal behavioral responses as adults. The effect was attributed to an effect of maternal immune response on the fetus [Shi et al., 2003].

Application of these findings
The finding that vitamin D can reduce the risk of infectious diseases and that seasonal and latitudinal variations in solar UVB doses seems to explain some of the epidemiology of IAD prior to 1985 suggests that increased calcidiol levels during pregnancy, breast feeding, and infancy could reduce the risk of autism. While the role of vaccinations in the etiology of autism is not clear, higher levels of calcidiol could reduce the risk of adverse reactions to vaccinations, based on reports that calcidiol reduces the risk of respiratory viral infections and that calcitriol enhances the effectiveness of vaccinations [Reinhardt et al., 1999; Hayes et al., 2003; Cantorna, 2004; Ivanov et al., 2006].

Summary and conclusion
The results presented here for season of birth and prevalence variation with effective latitude are consistent with maternal vitamin D’s being a risk factor for development of IAD. However, in the late 1990s, the rates of IAD prevalence became several times higher than those prior to 1985, to the point where maternal vitamin D deficiency is no longer discernible in the epidemiologic data. Further work is required to determine whether vitamin D could be used to reduce the risk of autism, perhaps by reducing the risk of infectious disease or adverse reactions to vaccinations.

Disclosure
W.B.G. receives funding from the UV Foundation (McLean, VA) and the Vitamin D Society (Canada) and the European Sunlight Association.

Note added after preparation of this paper.
John Cannell has added further evidence for a role of vitamin D in reducing the risk of autism.

Cannell JJ. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9.

Cannell JJ, Hollis BW. Use of vitamin D in clinical practice. Altern Med Rev. 2008 Mar;13(1):6-20.

Also, see his ongoing discussion of the topic at his web site, http://vitamindcouncil.org/

References
Adams W, Kendell RE, Hare EH, Munk-Jorgensen P. Epidemiological evidence that maternal influenza contributes to the aetiology of schizophrenia. An analysis of Scottish, English, and Danish data. Br J Psychiatry. 1993 Oct;163:522-34.

Aloia JF, Li-Ng M. Re: epidemic influenza and vitamin D. Epidemiol Infect. 2007 Oct;135(7):1095-6; author reply 1097-8.

American Psychiatric Assoc. Diagnostic and statistical manual of mental disorders, revised 3rd edn. Washington, DC. American Psychiatric Assoc. 1987.

Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol. 2007 Apr;61(4):288-99.

Atlas JA. Birth seasonality in developmentally disabled children. Psychol Rep. 1989;64:1213-1214.

Barak Y, Ring A, Sulkes J, Gabbay U, Elizur A. Season of birth and autistic disorder in Israel. Am J Psychiatry. 1995 May;152(5):798-800.

Bartlik BD. Monthly variation in births of autistic children in North Carolina. J Am Med Womens Assoc. 1981;36:363-368.

Blaxill MF. What's going on? The question of time trends in autism. Public Health Rep. 2004 Nov-Dec;119(6):536-51.

Boldeman C, Jansson B, Dal H, Ullen H. Sunbed use among Swedish adolescents in the 1990s: a decline with an unchanged relationship to health risk behaviors. Scand J Public Health. 2003;31:233-237.

Bolton P, Pickles A, Harrington R, Macdonald H, Rutter M. Season of birth: issues, approaches and findings for autism. J Child Psychol Psychiatry. 1992 Mar;33(3):509-30.

Brask BH. A prevalence investigation of childhood psychoses. Nordic Symposium on the Care of Psychotic Children, 1970.

Burd L, Fisher W, Kerbeshian J. A prevalence study of pervasive developmental disorders in North Dakota. J Am Acad Child Adolesc Psychiatry. 1987;26:700-3.

Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S, Garland CF, Giovannucci E. Epidemic influenza and vitamin D.Epidemiol Infect. 2006 Dec;134(6):1129-40.

Cantorna MT, Zhu Y, Froicu M, Wittke A. Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system. Am J Clin Nutr. 2004 Dec;80(6 Suppl):1717S-20S.

Charman T. The prevalence of autism spectrum disorders; Recent evidence and future challenges. Eur Child Adolescent Psychiatry. 2002;11:249-256.

Charman T. Epidemiology and early identification of autism: research challenges and opportunities. Autism: neural basis and treatment possibilities. Wiley, Chichester (Novartis Foundation Symposium 251). 2003:10-25.

Cialdella P, Mamelle N. An epidemiological study of infantile autism in a French department (Rhone): a research note. J Child Psychol Psychiatry. 1989 Jan;30(1):165-75.

Cui X, McGrath JJ, Burne TH, Mackay-Sim A, Eyles DW. Maternal vitamin D depletion alters neurogenesis in the developing rat brain. Int J Dev Neurosci. 2007 Jun;25(4):227-32.

Davies G, Welham J, Chant D, Torrey EF, McGrath J. A systematic review and meta-analysis of Northern Hemisphere season of birth studies in schizophrenia. Schizophr Bull. 2003;29:587-593.

Eyles D, Brown J, Mackay-Sim A, McGrath J, Feron F. Vitamin D3 and brain development. Neuroscience. 2003;118:641-653.

Eyles D, Almeras L, Benech P, Patatian A, Mackay-Sim A, McGrath J, Feron F. Developmental vitamin D deficiency alters the expression of genes encoding mitochondrial, cytoskeletal and synaptic proteins in the adult rat brain. J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):538-45.

Fatemi SH, Earle J, Kanodia R, Kist D, Emamian ES, Patterson PH, Shi L, Sidwell R. Prenatal viral infection leads to pyramidal cell atrophy and macrocephaly in adulthood: implications for genesis of autism and schizophrenia. Cell Mol Neurobiol. 2002 Feb;22(1):25-33.

Fatemi SH, Pearce DA, Brooks AI, Sidwell RW. Prenatal viral infection in mouse causes differential expression of genes in brains of mouse progeny: a potential animal model for schizophrenia and autism. Synapse. 2005 Aug;57(2):91-9.

Fombonne E. The epidemiology of autism: a review. Psychol Med. 1999;29:769-786.

Fombonne E. Epidemiological surveys of autism and other pervasive developmental disorders: an update. J Autism Dev Disord. 2003;33:365-582.

Fombonne E, du Mazaubrun C. Prevalence of infantile autism in four French regions. Soc Psychiatry Psychiatr Epidemiol. 1992;27:203-210.

Fortier ME, Luheshi GN, Boksa P. Effects of prenatal infection on prepulse inhibition in the rat depend on the nature of the infectious agent and the stage of pregnancy. Behav Brain Res. 2007 Aug 6;181(2):270-7.

Geier DA, Geier MR. A meta-analysis epidemiological assessment of neurodevelopmental disorders following vaccines administered from 1994 through 2000 in the United States. Neuro Endocrinol Lett. 2006 Aug;27(4):401-13.

Gillberg C. Do children with autism have March birthdays? Acta Psychiatr Scand. 1990 Aug;82(2):152-6.

Gillberg C, Wing L. Autism: not an extremely rare disorder. Acta Psychiatr Scand. 1999 Jun;99(6):399-406.

Grant WB. An estimate of premature cancer mortality in the United States due to inadequate doses of solar ultraviolet-B radiation, Cancer. 2002;94:1867-1875.

Grant WB, Holick MF. Benefits and requirements of vitamin D for optimal health: a review. Altern Med Rev. 2005;10:94-111.

Grant WB, Garland CF. The association of solar ultraviolet B (UVB) with reducing risk of cancer: multifactorial ecologic analysis of geographic variation in age-adjusted cancer mortality rates. Anticancer Res. 2006 Jul-Aug;26(4A):2687-99.

Guillemant J, Taupin P, Le HT, et al. Vitamin D status during puberty in French healthy male adolescents. Osteoporos Int. 1999;10:222-5.

Gurney JG, Fritz MS, Ness KK, Sievers P, Newschaffer CJ, Shapiro EG. Analysis of prevalence trends of autism spectrum disorder in Minnesota. Arch Pediatr Adolesc Med. 2003;157:622-627.

Hayes CE, Nashold FE, Spach KM, Pedersen LB. The immunological functions of the vitamin D endocrine system. Cell Mol Biol (Noisy-le-grand). 2003;49:277-300.

Holmoy T. Vitamin D status modulates the immune response to Epstein Barr virus: Synergistic effect of risk factors in multiple sclerosis. Med Hypotheses. 2007 Jun 13; [Epub ahead of print]

Ivanov AP, Dragunsky EM, Chumakov KM. 1,25-dihydroxyvitamin d3 enhances systemic and mucosal immune responses to inactivated poliovirus vaccine in mice. J Infect Dis. 2006 Feb 15;193(4):598-600.

Kanner L. Autistic disturbances of affective contact. Nervous Child. 1943;2:217-250.

Konstantareas MM, Hauser P, Lennox C, Homatidis S. Season of birth in infantile autism. Child Psychiatry Hum Dev. 1986 Fall;17:53-65.

Konstantareas MM, Hewitt T. Autistic disorder and schizophrenia: diagnostic overlaps. J Autism Dev Disord. 2001;31:19-28.

Krause I, He XS, Gershwin ME, Shoenfeld Y. Brief report: immune factors in autism: a critical review. J Autism Dev Disord. 2002;32:337-345.

Kurtzke JF. Geographic distribution of multiple sclerosis: An update with special reference to Europe and the Mediterranean region. Acta Neurol. Scand. 1980;62:65-80.

Lauritsen MB, Mors O, Mortensen PB, Ewald H. Medical disorders among inpatients with autism in Denmark according to ICD-8: a nationwide register-based study. J Autism Dev Disord. 2002;32:115-119.

Leffell DJ, Brash DE. Sunlight and skin cancer. Sci Am. 1996 Jul;275(1):52-3, 56-9. http://toms.gsfc.nasa.gov/ery_uv/dna_exp.gif (accessed July 31, 2007)

Libbey JE, Sweeten TL, McMahon WM, Fujinami RS. Autistic disorder and viral infections. J Neurovirol. 2005 Feb;11(1):1-10.

Lotter V. Epidemiology of autistic conditions in young children. Soc Psychiatry Psychiatric Epidemiol. 1966;1:124-135.

Mackay-Sim A, Feron F, Eyles D, Burne T, McGrath J. Schizophrenia, vitamin D, and brain development. Int Rev Neurobiol. 2004;59:351-380.

McCarthy P, Fitzgerald M, Smith MA. Prevalence of childhood autism in Ireland. Ir Med J. 1984;77:129-130

McGrath J. Hypothesis: is low prenatal vitamin D a risk-modifying factor for schizophrenia? Schizophr Res. 1999;40:173-177.

McGrath JJ, Pemberton MR, Welham JL, Murray RM. Schizophrenia and the influenza epidemics of 1954, 1957 and 1959: a southern hemisphere study. Schizophr Res. 1994 Dec;14(1):1-8.

Meyer U, Nyffeler M, Engler A, Urwyler A, Schedlowski M, Knuesel I, Yee BK, Feldon J. The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology. J Neurosci. 2006 May 3;26(18):4752-62.

Meyer U, Yee BK, Feldon J. The neurodevelopmental impact of prenatal infections at different times of pregnancy: the earlier the worse? Neuroscientist. 2007 Jun;13(3):241-56.

Meyer U, Murray PJ, Urwyler A, Yee BK, Schedlowski M, Feldon J. Adult behavioral and pharmacological dysfunctions following disruption of the fetal brain balance between pro-inflammatory and IL-10-mediated anti-inflammatory signaling. Mol Psychiatry. 2007 Jun 19; [Epub ahead of print]

Mouridsen SE, Nielsen S, Rich B, Isager T. Season of birth in infantile autism and other types of childhood psychoses. Child Psychiatry Hum Dev. 1994 Fall;25:31-43.

Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006 Dec 20;296(23):2832-8.

Ovesen L, Andersen R, Jakobsen J. Geographical differences in vitamin D status, with particular reference to European countries. Proc Nutr Soc. 2003 Nov;62(4):813-21.

Ponsonby AL, Lucas RM, van der Mei IA. UVR, vitamin D and three autoimmune diseases--multiple sclerosis, type 1 diabetes, rheumatoid arthritis. Photochem Photobiol. 2005 Nov-Dec;81(6):1267-75.

Reinhardt TA, Stabel JR, Goff JP. 1,25-dihydroxyvitamin D3 enhances milk antibody titers to Escherichia coli J5 vaccine. J Dairy Sci. 1999 Sep;82(9):1904-9.

Ritvo ER, Freeman BJ, Pingree C, et al. The UCLA-University of Utah epidemiologic survey of autism: prevalence. Am J Psychiatry. 1989;146:194-199.

Shi L, Fatemi SH, Sidwell RW, Patterson PH. Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J Neurosci. 2003 Jan 1;23(1):297-302.

Sponheim E, Skjeldal O. Autism and related disorders: epidemiological findings in a Norwegian study using ICD-10 diagnostic criteria. J Autism Dev Disord. 1998;28:217-227.

Steffenburg S, Gillberg C. Autism and autistic-like conditions in Swedish rural and urban areas: a population study. Br J Psychiatry. 1986;149:81-87.

Stevens MC, Fein DH, Waterhouse LH. Season of birth effects in autism. J Clin Exp Neuropsychol. 2000;22:399-407.

Tanoue Y, Oda S, Asano F, Kawashima K. Epidemiology of infantile autism in southern Ibaraki, Japan: differences in prevalence in birth cohorts. J Autism Dev Disord. 1988;18:155-166.

Ticher A, Ring A, Barak Y, Elizur A, Weizman A. Circannual pattern of autistic births: reanalysis in three ethnic groups. Hum Biol. 1996;68:585-592.

Treffert DA. Epidemiology of infantile autism. Arch Gen Psychiatry. 1970 May;22(5):431-8.

van der Mei IA, Ponsonby AL, Blizzard L, Dwyer T. Regional variation in multiple sclerosis prevalence in Australia and its association with ambient ultraviolet radiation. Neuroepidemiology. 2001;20:168-174.

van der Wielen RP, Lowik MR, van den Berg H, et al. Serum vitamin D concentrations among elderly people in Europe. Lancet. 1995;346:207-210.

Wallin MT, Page WF, Kurtzke JF. Multiple sclerosis in US veterans of the Vietnam era and later military service: race, sex, and geography. Ann. Neurol. 2004;55:65-71.

Webb AR, Engelsen O. Calculated ultraviolet exposure levels for a healthy vitamin D status. Photochem Photobiol. 2006 Nov-Dec;82(6):1697-703.

Wing L, Yeates SR, Brierley LM, Gould J. The prevalence of early childhood autism: comparison of administrative and epidemiological studies. Psychol Med. 1976;6:89-100.

Yeates-Frederikx MH, Nijman H, Logher E, Merckelbach HL. Birth patterns in mentally retarded autistic patients. J Autism Dev Disord. 2000 Jun;30(3):257-62.

Yusuf S, Piedimonte G, Auais A, Demmler G, Krishnan S, VAN Caeseele P, Singleton R, Broor S, Parveen S, Avendano L, Parra J, Chavez-Bueno S, Murguia DE Sierra T, Simoes EA, Shaha S, Welliver R. The relationship of meteorological conditions to the epidemic activity of respiratory syncytial virus. Epidemiol Infect. 2007 Oct;135(7):1077-90.