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Analyse commentée d’articles

Prevention of neural tube defects: evaluation of policy options

RÉFÉRENCES DES ARTICLES

— Botto LD, Lisi A, Robert-Gnansia E, Erickson JD, Vollset

SE, Mastroiacovo P, et al. International retrospective cohort

study of neural tube defects in relation to folic acid

recommendations: are the recommendations working? BMJ

2005; 330 (7491):571. Epub 2005, Feb 18.

— Busby A, Abramsky L, Dolk H, Armstrong B. Preventing

neural tube defects in Europe: population based study. BMJ

2005; 330 (7491):574-5.

Two recent articles [1, 2] published in the British Medical Jour-nal highlight some of the important policy questions related toprevention of neural tube defects (NTDs) by folic acid supplemen-tation.

The etiology of the overwhelming majority of birth defects is notknown. Therefore, other than avoidance of known teratogenssuch as lithium or some of the anti-epileptic medications, primaryprevention of by far the majority of birth defects is not currentlyfeasible. An important exception concerns the heterogeneousgroup of anomalies classified as NTDs [3], which include anen-cephaly, spinal bifida and encephalocele.

Each year, NTDs affect about a quarter of a million pregnanciesworldwide. Results from both observational [4-6] and randomi-zed controlled trials [7, 8] have provided convincing evidence forefficacy of periconceptional (before conception and during thefirst trimester of pregnancy) supplementation with folic acid forprevention of NTDs. Folic acid supplementation reduces the riskof first occurrence of an NTD [7] as well as the risk of recurrence[8]. Folic acid may also prevent other congenital anomalies,however most studies on this subject have evaluated the effects ofmultivitamin supplements including folic acid rather than folicacid supplementation alone [9].

Following the findings on efficacy of folic acid in prevention ofNTDs, several countries adopted policies regarding periconcep-tional folic acid supplementation. These policies have includedrecommendations to raise folate levels by dietary means only orin combination with folic acid supplements when planning a pre-gnancy or throughout childbearing age. The first European go-vernments to implement such policies were the United Kingdom(1992), Ireland (1993) and the Netherlands (1993). In France, fol-lowing initial recommendations by pediatric (1995) and obstetric(1997) professional bodies, official recommendations for dietarychanges and folic acid supplementation (0.4 mg per day) aimedat increasing serum folate levels for women planning a pregnancywere made in the year 2000. In a few countries including theUnited States, in addition to recommendations for folic acid sup-plementation (CDC, 1992), widespread fortification of staplefoods has been implemented (since 1998) in order to ensure aminimum level of increase in folate levels regardless of supple-ment use. Fortification has the added advantage that it may also

diminish socioeconomic disparities in folic acid intake and therisk of NTDs [10].

In the recent articles published in BMJ, Botto et al. [1], and Busbyet al. [2] assess time trends in the prevalence of NTDs in Europeancountries in relation to recommendations for periconceptional folicacid supplementation.

Botto et al. studied a database from 13 birth registries monito-ring rates of NTDs for the period 1988 to 1998 in a base popula-tion of approximately 13 million births. The registries includedthose in Norway, Finland, Northern Netherlands, England andWales, France (three registries: Paris, Strasbourg, Central East),Hungary, Italy, Portugal, and Israel. Folic acid policies during thestudy period varied from no recommendations (Italy and Israel) ordietary recommendations only (Norway until 1998), to dietary re-commendations plus use of supplements among selected women(Finland) or use of supplements for women planning a pregnancy(France) or all those of childbearing age (Portugal). Timing of re-commendations also varied among countries.

Overall, the study by Botto et al. included 8,636 cases of NTDsamong 13 million births. Prevalence of NTDs was higher in Ire-land, Northern Netherlands and France (Paris). Differences in theprevalence of NTDs among registries were in part related todifferential reporting of pregnancy terminations. In most areasprevalence of NTDs were stable and in those with an overalldecreasing trend (Northern Netherlands, England and Wales,Ireland), the rates of decrease were similar in the periods beforeand after local recommendations. In France, recommendationshad no discernable impact on the prevalence of NTDs. This was alsothe case for other European countries that made recommendationsregarding dietary changes and periconceptional supplementationwith folic acid.

Busby et al. assessed prevalence of NTDs in 31 European regis-tries in 16 countries (Eurocat network) for the period 1980 to2001. The study included 8,913 cases of NTD in a base popula-tion of approximately nine million births. Annual prevalence ofNTDs declined substantially in the United Kingdom and Ireland,from 45 per 10,000 births in 1980 to 10 to 15 per 10,000 in the1990s. Prevalence of NTD in other European countries however,was fairly stable during the study period and remained at approxi-mately 10 per 10,000 births.

For the 23 registries with data going back to at least 1990, Busbyet al. compared changes in NTD prevalence before and after1991, i.e., the year when the results of randomized controlledtrials proving efficacy of folic acid supplementation for preventionof NTDs were published. Statistical analyses included a randomeffects meta analysis of prevalence ratios in 1999-2001 ascompared with 1989-1991 in countries with similar policies. Re-sults showed a significant decrease in the prevalence of NTDs in1999-2001 as compared with 1989-1991 in the United Kingdomand Ireland. This trend was a continuation of the decrease in theprevalence of NTDs observed in the United Kingdom and Irelandprior to implementation of policies for folic acid supplementation.For other European countries, fairly small (and statistically insigni-ficant) differences were found in the NTD prevalence trends.

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Both studies concluded that recommendations alone areunlikely to be an effective strategy for prevention of NTDs. Thepossible reasons for this lack of effectiveness include the fol-lowing: i) women may not receive or respond to recommenda-tions for dietary modifications and/or supplementation intendedto increase folic acid intake; ii) dietary modifications alone areunlikely to raise serum folate levels sufficiently for effective pre-vention of NTDs, and iii) a large proportion of pregnancies areunplanned. Neither study however, provided an explicit analysisof the relative importance of the various possible reasons for theapparent inefficacy of recommendations.

Both studies noted that the observed decrease in the prevalenceof NTDs in the United Kingdom and Ireland were a continuationof the decreases observed prior to implementation of policies forfolic acid supplementation. This in turn suggested that the recom-mendations had no impact on trends in the prevalence of NTDsin the UK and Ireland. However, neither study forwarded an ex-planation or a specific hypothesis as to why the prevalence ofNTDs might have declined both prior and after recommendationsfor folic acid supplementation in the United Kingdom and Ireland.Therefore, based on the studies by Botto et al. and Busby et al.alone, it is not possible to evaluate the reasons for apparent failureof recommendations or to suggest alternative ways for a moreoptimal implementation of the existing recommendations and po-licies aimed at increasing folic acid intake in European countries.

Notwithstanding these limitations, both studies implicitly (andreasonably) concluded that if recommendations have not workedthus far they are unlikely to be effective in the future. Hence theauthors suggest that widespread fortification of staple foodsshould be implemented for effective prevention of NTDs. Busbyet al. further suggest that health effects of both supplementationand fortification should continue to be monitored.

An unresolved question of potentially substantial importanceconcerns the optimum levels of supplementation and fortification[11, 12]. Wald et al. have suggested that higher doses of folic acidthan those currently recommended will be substantially moreeffective in preventing NTDs. Accordingly, the currently recom-mended dose of 0.4mg of folic acid per day would prevent ap-proximately 36% of NTDs as compared with 82% prevented with4 mg, and 85% with 5 mg per day. Higher doses (> 5 mg per day)would produce little additional benefit. These estimates are basedon a two-stage dose-response model which specifies the relationbetween dietary folic acid and plasma folate level in the first stageand the relation between plasma folate and the risk of NTDs inthe second stage. The dose-related estimates of efficacy notedabove assume a baseline serum folate level of 5 ng/mL and seemconsistent with the results obtained in the MRC vitamin supple-mentation study [8].

Notwithstanding the call for higher doses of folic acid supple-mentation, current guidelines of the Centers for Disease Preven-tion and Control (CDC) remain a folic acid supplementation of0.4 mg per day for all women capable of becoming pregnant and4 mg per day for those with a previous pregnancy affected by anNTD. The current level of fortification of flour and other grainproducts in the United States leads to an additional increase ofabout 0.2 mg per day of folic acid. In Chile, a higher level of for-

tification has been adopted, which results in an additional folicacid intake of about 0.4 mg per day. Wald [12] recommends aminimum fortification level equivalent to 0.6 to 0.8 mg per day offolic acid supplementation. In addition to greater efficacy for pre-vention of NTDs, this higher level of fortification is advocated asa means of providing a minimal fully effective dose for loweringhomocysteine levels to decrease the risk of ischemic cardiacevents, stroke, deep venous thrombosis and pulmonary embolus[13].

Concerns have been raised regarding possible adverse effectsrelated to folic acid supplementation. These concerns have inclu-ded a higher risk of twin gestations [14-16] and possible maskingof vitamin B12 deficiency due to partial correction of the associa-ted anemia. However, available evidence suggests that folic acidfortification in the United States has not had such a masking effect[17] and detection of vitamin B12 deficiency does not depend onanemia alone.

With regard to risk of twin births, recent studies [18, 19] suggestlittle, if any, effects on the risk for multiple births associated withfolic acid supplementation after adjustment for confoundingfactors including, most importantly, use of infertility treatments.Moreover, an assessment of trends in twin births in the UnitedStates suggests that fortification has not resulted in an increase inthe prevalence of twin births [20]. Nevertheless, a consensus onthe issue has not been reached in the literature and inconsisten-cies persist in the results of studies, including recent ones [16, 18,19, 21-23], regarding the risk of multiple births associated withfolic acid intake. Notwithstanding these inconsistencies, the sumof the available evidence seems to converge towards the conclu-sion that the recommended dose of folic acid does not apprecia-bly increase the risk of multiple births.

A final area of concern for adverse effects associated with folicacid has been an increase in the risk of cancer. Specifically, arecent article reported an association between folic acid intakeand risk of breast cancer [24]. However, this finding may havebeen due to chance [25] and in any case remains controversial[26]. In addition, several other studies have found an inverse re-lation between folic acid intake and the risk of breast [27, 28], aswell as, colorectal [29, 30] cancer.

In summary, the available evidence from the literature suggeststhat widespread fortification of staple foods with folic acid maybe the only effective strategy for prevention of NTDs. In addition,fortification may have added benefits in terms of diminishingsocioeconomic differences in the risk of NTDs, prevention ofother congenital anomalies, and a decrease in the risk for ische-mic heart disease and other adverse cardiovascular events [13,31]. Current evidence suggests that folic acid supplementationand fortification pose little, if any, risk. Therefore, a policy offortification of grains and other staple foods, along with recom-mendations and educational campaigns to promote higher levelsof folic acid intake by supplements and dietary changes, shouldbe considered in France and other European countries.

Several questions regarding folic acid supplementation remainunresolved. The issue of optimal level of fortification and dose ofsupplementation is of potentially substantial importance andneeds to be further studied. Higher levels of fortification may be

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more effective for prevention of NTDs and have the added benefitof reducing the risk of adverse cardiovascular events at the popu-lation level by lowering homocysteine levels. It should be notedhowever, that the exact role of homocysteine as a causal riskfactor for cardiovascular disease remains controversial [31]. There-fore, the potentially beneficial effects of folic acid supplementationon the risk of cardiovascular disease need to be further examined.Finally, fortification policies should be combined with monitoringof health outcomes, including those other than the NTDs.

B. KHOSHNOOD

Unité 149, INSERM, 16, avenue Paul-Vaillant-Couturier, 94807

Villejuif. Email: khoshnood@vjf.inserm.fr

Références

1. Botto LD, Lisi A, Robert-Gnansia E, Erickson JD, Vollset SE,Mastroiacovo P, et al. International retrospective cohort study ofneural tube defects in relation to folic acid recommendations: arethe recommendations working? BMJ 2005; 330 (7491): 571. Epub2005, Feb 18.

2. Busby A, Abramsky L, Dolk H, Armstrong B. Preventing neuraltube defects in Europe: population based study. BMJ 2005; 330(7491): 574-5.

3. Marks JD, Khoshnood B. Epidemiology of common neurosurgi-cal diseases in the neonate. Neurosurg Clin N Am 1998; 9 (1): 63-72.

4. Smithells RW, Sheppard S, Schorah CJ. Vitamin dificiencies andneural tube defects. Arch Dis Child 1976; 51 (12): 944-50.

5. Smithells RW, Sheppard S, Schorah CJ, Seller MJ, Nevin NC,Harris R, et al. Possible prevention of neural-tube defects by peri-conceptional vitamin supplementation. Lancet 1980; 1 (8164):339-40.

6. Smithells RW, Nevin NC, Seller MJ, Sheppard S, Harris R, ReadAP, et al. Further experience of vitamin supplementation for pre-vention of neural tube defect recurrences. Lancet 1983; 1 (8332):1027-31.

7. Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. NEngl J Med 1992; 327 (26): 1832-5.

8. Prevention of neural tube defects: results of the Medical ResearchCouncil Vitamin Study. MRC Vitamin Study Research Group.Lancet 1991; 338 (8760): 131-7.

9. Botto LD, Olney RS, Erickson JD. Vitamin supplements and therisk for congenital anomalies other than neural tube defects. AmJ Med Genet C Semin Med Genet 2004; 125 (1): 12-21.

10. Wasserman CR, Shaw GM, Selvin S, Gould JB, Syme SL. Socio-economic status, neighborhood social conditions, and neuraltube defects. Am J Public Health 1998; 88 (11): 1674-80.

11. Wald NJ, Law MR, Morris JK, Wald DS. Quantifying the effect offolic acid. Lancet 2001; 358 (9298): 2069-73.

12. Wald NJ. Folic acid and the prevention of neural-tube defects. NEngl J Med 2004; 350 (2): 101-3.

13. Wald DS, Law M, Morris JK. Homocysteine and cardiovasculardisease: evidence on causality from a meta-analysis. BMJ 2002;325 (7374): 1202.

14. Czeizel AE, Metneki J, Dudas I. Higher rate of multiple birthsafter periconceptional vitamin supplementation. N Engl J Med1994; 330 (23): 1687-8.

15. Mathews F, Murphy M, Wald NJ, Hackshaw A. Twinning andfolic acid use. Lancet 1999; 353 (9149): 291-2.

16. Czeizel AE, Vargha P. Periconceptional folic acid/multivitaminsupplementation and twin pregnancy. Am J Obstet Gynecol 2004;191 (3): 790-4.

17. Mills JL, Von Kohorn I, Conley MR, Zeller JA, Cox C, William-son RE, et al. Low vitamin B-12 concentrations in patientswithout anemia: the effect of folic acid fortification of grain. AmJ Clin Nutr 2003; 77 (6): 1474-7.

18. Li Z, Gindler J, Wang H, Berry RJ, Li S, Correa A, et al. Folic acidsupplements during early pregnancy and likelihood of multiplebirths: a population-based cohort study. Lancet 2003; 361 (9355):380-4.

19. Vollset SE, Gjessing HK, Tandberg A, Ronning T, Irgens LM,Baste V, et al. Folate supplementation and twin pregnancies. Epi-demiology 2005; 16 (2): 201-5.

20. Waller DK, Tita AT, Annegers JF. Rates of twinning before andafter fortification of foods in the US with folic acid, Texas, 1996to 1998. Paediatr Perinat Epidemiol 2003; 17 (4): 378-83.

21. Lumley J, Watson L, Watson M, Bower C. Modelling the poten-tial impact of population-wide periconceptional folate/multivita-min supplementation on multiple births. BJOG 2001; 108 (9):937-42.

22. Kallen B. Use of folic acid supplementation and risk for dizygotictwinning. Early Hum Dev 2004; 80 (2): 143-51.

23. Berry RJ, Kihlberg R, Devine O. Impact of misclassification of invitro fertilisation in studies of folic acid and twinning: modellingusing population based Swedish vital records. BMJ 2005; 330(7495): 815.

24. Charles D, Ness AR, Campbell D, Davey SG, Hall MH. Takingfolate in pregnancy and risk of maternal breast cancer. BMJ 2004;329 (7479): 1375-6.

25. Oakley GP, Mandel JS. Folic acid fortification remains an urgenthealth priority. BMJ 2004; 329 (7479): 1376.

26. Stirrat G. Taking folate in pregnancy and risk of maternal breastcancer: authors and publishers must not disclaim ethical respon-sibility. BMJ 2005; 330 (7491): 600-1.

27. Shrubsole MJ, Jin F, Dai Q, Shu XO, Potter JD, Hebert JR, et al.Dietary folate intake and breast cancer risk: results from theShanghai Breast Cancer Study. Cancer Res 2001; 61 (19): 7136-41.

28. Zhang SM, Willett WC, Selhub J, Hunter DJ, Giovannucci EL,Holmes MD, et al. Plasma folate, vitamin B6, vitamin B12, homo-cysteine, and risk of breast cancer. J Natl Cancer Inst 2003; 95 (5):373-80.

29. La Vecchia C, Negri E, Pelucchi C, Franceschi S. Dietary folateand colorectal cancer. Int J Cancer 2002; 102 (5): 545-7.

30. Sanjoaquin MA, Allen N, Couto E, Roddam AW, Key TJ. Folateintake and colorectal cancer risk: a meta-analytical approach. IntJ Cancer 2005; 113 (5): 825-8.

31. Blacher J, Czernichow S, Horrellou MH, Conad J, David P,Chadefaux-Vekemans B, et al. [Homocysteine, folic acid, groupB vitamins and cardiovascular risk]. Arch Mal Coeur Vaiss 2005;98 (2): 145-52.