Dietary folate and the prevalence of neural tube defects in the British Isles: the past two decades

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1 British Journal of Obstetrics and Gynaecology July 0, VO~ 107, pp Dietary folate and the prevalence of neural tube defects in the British Isles: the past two decades *Michael Murphy Director, *David Whiteman Nufield Research Fellow, **David Stone Director,?Beverly Botting Statistician, $Chris Schorah Senior Lecturer, $Jenny Wild Senior Project Oficer *ICRF General Practice Research Group, University of Oxford; **Paediatric Epidemiology and Communiw Health Unit, University of Glasgow;?Census, Population and Health Group, OfJice for National Statistics, London; $School of Medicine, University of keds Objectives To measure the changes in folate consumption and the prevalence of neural tube defects in the British and Irish populations during the past two decades. Design Ecological study. Main outcome measures Average daily hetary folate consumption for Britain for the period was estimated from the National Food Survey. Annual neural tube defect prevalences for the same period were obtained from the Oxford Record Linkage Study Neural hbe Defect register, the Glasgow EUROCAT register, and the three Irish EUROCAT registers (Belfast, Dublin and Galway). Results Dietary folate consumption increased on average by 1.6% per annum in Scotland and 1.4% in England during the study period. The annual rate of decline of neural tube defect prevalence averaged 10.4% in the Irish population, 8.2% in Glasgow, and 5.2% in Oxfordshire and West Berkshire. Conclusions The decline in neural tube defect prevalence observed in all British and Irish populations since the early 1970s continued with the introduction of folate fortification of cereals, which produced measurable increases in average daily folate consumption. Further declines in neural tube defect prevalence may be achieved by targeted folate supplementation during the periconceptual period. INTRODUCTION There is now strong epidemiological and laboratory evidence that folate deficiency is causally related to the pathogenesis of neural tube defects and that periconceptual folic acid supplementation prevents their occurrence2,3. Factors contributing to folate deficiency may include both dietary insufficiency and germline mutations of maternal or fetal enzymes which require folate as a cofactof. Other factors may also play a role, including vitamins B, and B,, *. The Occurrence of neural tube defects in England and Wales, Scotland and Ireland historically has been among the highest in the world, yet total prevalence rates have now fallen to those observed in countries regarded as areas of lower At the population level, geographc variations in the prevalence of neural tube defects observed between the populations of similar genetic heritage (such as in the UK and Australia) are likely to be largely attributable to environmental differences, since the proportion of cases of neural tube defect resulting from inherited metabolic disturbances would be unlikely to vary substantially Correspondence: Dr M. Murphy, ICRF General Practice Research Group, Institute of Health Sciences, Old Road, Headington, Oxford OX3 7LF, UK. among homogeneous populations. If so, then temporal variations in the Occurrence of a putative causal factor should be mirrored by predicted variations in the occurrence of the outcome. We have therefore analysed the available data on changes in the observed levels of folate intake during the past two decades, in relation to changes in the prevalence of neural tube defects among live births, stillbirths and terminations of pregnancy in discrete populations in Scotland, Ireland, and England and Wales during the same period. This coincides with the gradual introduction in Britain of folic-acid fortification of breakfast cereals ( ) and bread (from 1991). In this paper the general temfolute has been applied to members of the class of vitamins with activity similar to pteroylmonoglutamic acid (or folic acid), the synthetic heat-stable chemical used in vitamin supplements and fortified food. METHODS Dietary folate estimation Estimates of average daily intakes of folate for Great Britain (excluding Northern Ireland) were derived from the annual National Food Survey conducted by the Ministry of Agriculture, Fisheries and Food. These 0 RCOG 0 British Journal of Obstetrics and Gynaecology 885

2 886 M. MURPHY ET AL. standardised surveys have recorded nutrient consumption in terms of food purchasing patterns in households across Britain since 1940 folate consumption has been estimated since the late 1970s and has been available in tabulations since The folate levels of bread and cereals (foodstuffs fortified with folate) have been routinely analysed and incorporated into the household estimates since that time. Prevalence of neural tube defects The total prevalence of neural tube defects was assessed at both regional and national level. Regional cases were ascertained from established populationbased registers in the UK and Ireland, (including the Oxford Record Linkage Study neural tube defect register ( ), the Glasgow EUROCAT Register ( , and the three Irish EUROCAT Registers in Dublin, Belfast and Galway ( ). Each of these registers adopted the EUROCAT criteria which specifically excludes cases of spina bifida occulta from calculations of the prevalence of neural tube defect^'^. Neural tube defect prevalence for each population was calculated by dividing the total number of cases of neural tube defects in live births, stillbirths, late second trimester miscarriages and therapeutic terminations by the total number of live births and stillbirths in each population for each year of comparison. As such, the observed prevalence of neural tube defects is likely to underestimate the true occurrence among all fetuses, since the numerator includes only those fetuses surviving to the middle of the second trimester. Annual numbers of cases of neural tube defects (births and terminations) for England and Wales were obtained from the Office for National Statistics for , and included cases of spina bifida occulta. The latter were notified at a consistently very low rate throughout , and even lower rate from , and their exclusion would make no material difference to the trends shown for England and Wales. The degree of incompleteness of the national register of neural tube defects was estimated by comparison with the register of the Oxford Record Linkage Study using capture-recapture methodology during the reporting periods , and O. Statistical analyses Temporal changes in both folate consumption and the prevalence of neural tube defects from (for which comparable data were available for all registers, and which coincided with the folate dietary estimation from the Ministry of Agriculture, Fisheries and Food) were estimated from the slope of the best-fitting line representing the logarithm of the measured event (folate intake level or prevalence of neural tube defects) as a linear function of timei4. The average annual rate of change was calculated by subtracting one from the exponential of the p coefficient. The multiple-partial F test was used to test for differences among the rates of change at each register. Linear regression models were fitted by the method of weighted least squares using the generalised linear models procedure in SASI5. RESULTS Dietary folate consumption Table 1 shows the estimated average dietary intakes of folate for Scotland, England and Wales for each year during the period 1980 to Figure 1 illustrates the pooled data for the population of Great Britain plotted against calendar year, which are less affected by sampling variation than the estimates of component countries. For each population (and for Britain as a whole), a decline in folate intake was recorded between 1980 and 1983/1984, from which time there were progressive gains in average folate intake. For the whole period (198&1996), the average daily folate intake increased at the rate of 1.6% per year (95% CI 0.4%, 2.9%) in Scotland, 1.6% per year (95% CI 0-8%, 2.4%) in Wales, and at the rate of 1.4% per year (95% CI 0-9%, 1.9%) in England. Average folate intake in Scotland rose faster between 198Ck1990 than in England and Wales but from a historically lower baseline, so that by 1990 average intake in each of England, Wales and Scotland was substantially the same. The gap reappears in the 1990s however. Table 1. National Food Survey estimates: average daily intakes of folate (pglday) for Great Britain, England, Wales and Scotland, Values are given as n. Average daily intake of folate (kg/day) Year Great Britain England Wales Scotland

3 DIETARY FOLATE AND NEURAL TUBE DEFECTS L m al 3 70 c r = 0 o_ 60 0 r 50 L 0) n 8 40 C - 0) 30 2 n g I LL 150 2c 1C lq Year ~~ NTD Reglaby Ireland *-*--C Oxon and W Beck -e Glaagow.o-..o England and w* - Fig. 1. Prevalence of neural tube defect in four registries in the British Isles ( ), and estimated folate intake levels for the period Oxfordshire and West Berkshire denominator populations for 1995 and 1996 are estimated. 0 = Ireland; 0 = Glasgow; A = Oxon and West Berkshire; 0 = England and Wales. Prevalence of neural tube defects The changes in the prevalence of neural tube defects over time among the populations served by the Oxford Record Linkage Study, and the Glasgow, Ireland and England and Wales registers are depicted in Fig. 1. For each register, a simple linear model of change in prevalence over time provided the best fit to the data. While substantial declines in the prevalence of neural tube defects were observed in each of the populations during the study period ( ), the three Irish EUROCAT registries recorded the steepest decline in the prevalence of neural tube defects (-10.4% per year; 95% CI -10.6% to -11.2%), followed by the Glasgow EUROCAT register (-7.8% per year; 95% CI -5.3% to -10.2%) and the Oxfordshire and West Berkshire register (-3.2% per year; 95% CI -0.6% to -5.7%). For England and Wales as a whole, the prevalence of neural tube defects declined at an average annual rate of -8.8% (95% CI -8.0% to -9.7%). Adjustment for maternal age had almost no impact on the crude trends shown. The rates of decrease of neural tube defects differed significantly across the registries (0.01 < P < 0.005). DISCUSSION These data indicate that during the past two decades, rapid and substantial reductions have occurred in the reported prevalence of neural tube defects among populations of the British Isles. The decline in the rates of neural tube defects may be due to either changes in the environment, changes in allelic frequency or some interaction of the two. The genetic explanations, while theoretically possible, could not plausibly account for population effects of this magnitude within such a short time span. The strongest environmental determinant of neural tube defects yet identified is folate deficiency at the time of conception (see review by Wald et ul.'). The data from the National Food Survey indicate that average folate intakes in the British population have increased substantially since the mid 1980s, coinciding with the accelerated fortification of breakfast cereals during the period , and fortification of bread from Nevertheless, the decline in the prevalence of neural tube defects in all three regional populations predated the introduction of fortified cereals. One explanation is that changes in consumption of other dietary factors, including B-group vitamins, may

4 888 M. MURPHY ET AL. have been protective. Population data to test this hypothesis are scarce, but estimates of vitamin consumption from the National Food Survey suggest an increase in vitamin B6 intake only in the 1990s and a long slow decline in vitamin B,* intake since the 1980s. In contrast, National Food Survey data also suggest that steady increases occurred in the consumption of fruit juice and fruits in British households during the past three decadesi6, which may have offset the small declines in vegetable consumption, and which may have been benefi~ial'~. Some degree of measurement error is inescapable in these nutritional estimates. Average folate intakes derived from the National Food Survey reflect household purchasing patterns rather than actual per capita consumption among pregnant adult females. Furthermore, the estimation of average intake depends heavily upon analytical measurements of folate levels in the range of foods purchased by British households, not all of which have been subject to precise measurement (Dr Susan Church, Ministry of Agriculture, Fisheries and Food, personal communication). However, as long as the magnitude of the error of folate estimates has not changed systematically over time (due, for example, to changes in survey methodology), the estimation of rates of change of folate intake is unlikely to be seriously biased. The increases in dietary folate consumption do not simply reflect patterns in other micronutrients such as calcium and iron, for which intakes have declined during the same period'*. Moreover, independent cross-sectional data have broadly corroborated point estimates from the National Food Survey", providing reasonable assurance that the purchasing survey reflects patterns of folate consumption. The steady declines in the rates of neural tube defect observed in each population are also likely to be real, since alternative explanations can effectively be excluded. Chance is unlikely to account for the observed declines in the prevalence of neural tube defects, given the precision of the estimates of each of the regression coefficients. It is known that terminations of affected pregnancies with neural tube defects stated as the indication for the procedure are under-estimated in the national data, but we are confident about the completeness of the local registers2"s2'. Throughout the entire period of , the Oxford Record Linkage Study register was estimated to be more than 90% complete, compared with the national figure of about 60% complete". There were no major changes in the methods of ascertainment or registration of numerator and denominator data by any of the registries during the study period, with the exception of a minor change in the definition of stillbirth in England and Wales from October 1992, which had a negligible effect on birth statistics. The decline in the prevalence of neural tube defects recorded between 1995 (7.3 per 10,000) and 1996 (6.6 per 10,000) for England and Wales also seems to be real, and is the largest relative fall (9.6%) observed in a single year for several years. In the absence of demonstrable error, the trends in average folate intake during the 1980s and early 1990s provide a plausible explanation for the decline in the occurrence of neural tube defects during that period. While folate data from the National Food Survey are an indirect marker of intake by the population of pregnant women, and provide no information about nonfood sources of folate, there is evidence that folate supplementation prior to conception was very infrequent in the early 1990s (at less than 2% of pregnant British women in ), and was almost nonexistent before then, during which time steep declines in the occurrence of neural tube defects were observed. By 1996 however, about 30% of women attending antenatal clinics reported taking folate supplements before conception22, coinciding with the noticeable decline in the national prevalence of neural tube defects observed between 1995 and Provisional figures for 1997 suggest a further 15% decline on the 1996 figures (data from the Office for National Statistics not shown). Although there is evidence that increasing the levels of folic acid consumption has health benefits beyond neural tube development, such as reducing the risk of cardiovascular disease through lowering homocysteine level^^^.^^, the strategy of food fortification is not without risks to some members of the population. For example, those taking medication for epilepsy and persons at risk of subacute combined degeneration of the spinal cord may be adversely affected by high dietary intakes of folic acid17. In view of the recent important decline in the occurrence of neural tube defects in England and Wales, further strategies targeted at periconceptual folic acid supplementation might be the most effective way to produce a further reduction from the current estimate of 600 affected pregnancies per year reaching the mid-second trimester or beyond. Acknowledgements This article contains material which is Crown Copyright and is reproduced with the permission of the Office for National Statistics. The Glasgow EUROCAT Register is supported by the Greater Glasgow Health Board, and EUROCAT is supported by the European Commission. The ORLS NTD Register project was supported by the Association for Spina Bifida and Hydrocephalus (ASBAH) and the Department of Health. Dr D. Whiteman was supported by a University of Oxford Nuffield Medical Research Fellowship.

5 DIETARY FOLATE AND NEURAL TUBE DEFECTS 889 The authors wish to thank the Nutrition Unit and National Food Survey Branch of the Ministry for Agriculture, Fisheries and Food for assistance in compiling the nutritional information. The authors would also like to thank the following: the Irish EUROCAT Register leaders (Dr D. Lillis, Galway; Dr 2. Johnson, Dublin; Professor N. Nevin, Northem Ireland); the EUROCAT Central Registry Staff, and Ms M. O Donnell, Mrs K. Hey and Ms N. Jones who played an important role in construction of the ORLS NTD Register. References Wald NJ, Hackshaw AK, Stone R, Sourini NA. Blood folic acid and vitamin B,, in relation to neural tube defects. Br J Obstet Gynaecol 1996; 103: The MRC Vitamin Study Group. Prevention of neural tube defects: results of the MRC Vitamin Study. Lancet 1991; Czeizel AE, Dudas 1. Prevention of the first occurrence of neural tube defects by periconceptional vitamin supplementation. N Engl J Med 1992; 327: Wilcken D. MTHFR677 C-T mutation, folate intake, neural tube defect and risk of cardiovascular disease. Lancet 1997; 350: van der Put NMJ, Steegers-Theunissen RPM, Frosst P et al. Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet 1995; 346: Mills JL, McParlin JM, Kirke PN et al. Homocysteine metabolism in pregnancies complicated by neural tube defects. Lancet 1995; 345: Steegers-Theunissen RPM, Boers GHJ, Trijbels FJM, Eskes TKAB. Neural tube defects and derangement of homocysteine metabolism. N EnglJMed 1991; 324: Schorah CJ, Smithells RW. Maternal vitamin nutrition and malformations of the neural tube. Nutr Res Rev 1991; 4: Little J, Elwood JM. Geographical variation. In: Elwood JM. Little J, Elwood JH, editors. Epidemiology and Control of Neurul Tube Defects. Oxford: Oxford University Press, 1992: Murphy M, Seagroatt V, Hey K et al. Neural tube defects down but not out. Arch Dis Child 1996; 75: F133-F134. Bower C, Raymond M, Lumley J, Bury G. Trends in neural tube defects Med JAust 1993; 158: Chan A, Robertson EF, Haan EA, Ranieri E, Camay A. Prevalence of neural tube defects in South Australia : Effectiveness and impact of prenatal diagnosis. EMJ 1993; EUROCAT Working Group. 15 years of surveillance of congenital anomalies in Europe EUROCAT Report 7. Brussels: Scientific Institute of Public Health-Louis Pasteur, Esteve J, Benhamou E, Raymond L. Statistical Methods in Cancer Research Volume N: Descriptive Epidemiology. Lyon: International Agency for Research on Cancer, SAS Version Cary, North Carolina: The SAS Institute, Rayner M, Mockford C, Bow A. Coronary heart disease statistics. London: British Heart Foundation, 1998: 58. Expert Advisory Group. Folic acid and the prevention of neural tube defects. London: Department of Health, Charlton I, Quaife K. Trends in diet In: Charlton J, Murphy M, editors. The Health of Adult Britain , volume 1. London: Offce for National Statistics, 1997: Gregory J, Foster K, Tyler H, Wiseman M. The dietary and nutritional survey of adults. London: Office of Population Censuses and Surveys, Cuckle HS, Wald NJ. The impact of screening for open neural tube defect in England and Wales. Prenat Diag 1987; 7: Cuckle HS, Wald NJ, Cuckle PM. Prenatal screening and diagnosis of neural tube defect in England and Wales in Prenut Diag 1989; 9: Wild J, Sutcliffe M, Schorah CJ, Levene MI. Prevention of neural tube defects. Lancet 1997; 350: Homocysteine Lowering Trialists Collaboration. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. BMJ 1998; 316: Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med 1998; 338: Accepted 8 September 1999