The incidence of neural tube defects (NTD) among black South Africans living in urban areas is low compared with reports of NTD incidence in rural areas  A NTD incidence of 0.95 per 1000 live births was reported in Cape Town,l while an incidence of 0.99 per 1 000 live births was reported in a study performed at Kalafong Academic Hospital, Pretoria.' In contrast, the prevalence of NTD in the black population in rural Transkei was 6.13 per 1 000 live births,' and in rural Northern Province it was 3.55 per 1 000 live births.' In view of the association between folic acid status and NiD, we  performed a study in rural and urban communities to determine whether folate or vitamin B12 status and/or abnormal homocyst(e)ine metabolism could explain why the incidence of NTD in rural areas is so high. (Homocyst(e)me (tHcy) refers to the sum of concentrations of free homocysteine, protein-bound homocysteine, the disulphide homocystine, and the mixed disulphide homocysteine-cysteine.

Delport, Rhena

Ubbink, Johan B

English

AJOL - African Journals Online

ARTICLES15. de Francisco A, Hall Aj, Annstrong-Schellenberg JRM, Greenwood AM, Greenwood BM. Thepattern of infant and childhood mortality in Upper River Division, The Gambia. Ann TrapPaediatr 1993; 13: 345-352-16. Fauveau V, Stewart MK, Chakraborty J, Khan SA. lmpact on mortality of a commwtity-basedprogramme to control acute lower respiratory tract infections. Bull World Health Organ 1992;7(}. 109-116.17. Pandey MR, Daulaire. MP. Starbuck ES, Houston RM, McPherson K. Reduction in totalunder-five mortality in western Nepal through community-based antimicrobial treatment ofpneumonia. umcet 1991; 338: 993-997.18. Ghana VASr Study Team. Vitamin A supplementation in northern Ghana: effects on clinicattendances, hospital admissions, and child mortality. Lancet 19.93; 342: 7-12.19. West KP jun, Katz J. Shrestha SR, et a1. Mortality of infants < 6 ma of age supplemented withvitamin A: A randomised double-masked trial in Nepal. Am JClin Nutr 1995; 62:. 143-148.20. Bayley N. Bayley Scales of Infant Development. San Antonio: The Psychological Corporation,1993.February 1999, Va!. 89, No. 2 SAMJREVIEW OF CURRENT EVIDENCEFOR FOLATE IN THE PREVENTIONOF NEURAL TUBE DEFECTSRhena Delport, Johan B UbbinkThe incidence of neural tube defects (NTD) among black SouthAfricans living in urban areas is low compared with reports of _"I\TTD incidence in rural areasY A NTD incidence of 0.95 per -;:-1000 live births was reported in Cape Town,l while anincidence of 0.99 per 1 000 live births was reported in a studyperformed at Kalafong Academic Hospital, Pretoria.' Incontrast, the prevalence of NTD in the black population in Jrural Transkei was 6.13 per 1 000 live births,' and in rural ::-'Northern Province it was 3.55 per 1 000 live births.' In view _Qfthe association between folic acid status and NiD, we }performed a study in rural and urban communities todetermine whether folate or vitamin B12 status and/orabnormal homocyst(e)ine metabolism could explain why theincidence of NTD in rural areas is so high. (Homocyst(e)me(tHcy) refers to the sum of concentrations of free homocysteine,protein-bound homocysteine, the disulphide homocystine, andthe mixed disulphide homocysteine-cysteine.)FOLATE, ABNORMAL HOMOCYST(E)INEMETABOLISM AND NTDElevated maternal plasma homocysteine as a causal .agent in NTDThe mechanism by which folate deficiency may cause NTD isby impairing homocysteine metabolism. Elevated plasmahomocyst(e)inel concentrations and elevated homocyst(e)ineconcentrations in amniotic fluid aspirates have been reportedpreviously in mothers with NTD births.5-S Further evidence foran association between abnormal homocysteine metabolism insome NTD cases is given in a report of increased post-methionine load tHcy concentrations in 22% of women with ahistory of NTD! Abnormal homocysteine metabolism may bedue to homozygosity for the 677 C to T mutation in the genecoding for methylene tetrahycirofolate reductase (MTHFR). Themutated enzyme is thermolabile.lo It has a lower level ofactivit'j,"-n which results in ineffective homocysteineremethylation. Homozygosity is associated with higher plasmatotal homocyst(e)ine (tHey) levels,u·14 especially when dietaryfolate intake is.low.l2.14 Furthermore, a 2 - 3-fold increase in theprevalence of homozygosity for the 677 C--7T mutation in theDepartment of Chemical Pathology, University ofPretoriaRhena Delport, PhDJohan B Ubbink, DScARTICLESgene coding for the enzyme MTHFR was observed in parentsof neonates with NTD,lO and fibroblast cultures from fetuseswith NTD showed that homozygosity for the 677 C->Tmutation was associated with a 7.2-fold increased risk ofNTD.15Folate supplementation and NTDFolate supplementation in the peri-conceptual period appearsto reduce the frequency of NTD.16,17 Although the findings arenot entirely consistent, a recent review concluded that NTDwere associated with decreased folate concentrations duringthe first trimester of pregnancy.IS Early in pregnancy serum andred-cell folate concentrations were reported to be significantlylower in women who delivered babies with NTD comparedwith controls,19 and a continuous dose-response relationbetween a risk of NTD and red-eell folate levels wasestablished.20RURAL BLACK SOUTH AFRICAN MOTHERSWITH A HISTORY OF NTDAs folate and/or vitamin B12 deficiencies are considered to becausally related to NTD/' we hypothesised that differences infolate/vitamin B12 nutritional status could explain thedifferences in NTD incidence in rural and urban blackpopulations. Folate deficiency is common in pregnant ruralblack women'" and in rural black children.'" It is not knownwhether impaired homocysteine metabolism exists in blackwomen with a history of NTD pregnancies, or whetherhomozygosity for the thermolabile variant of MTHFR increasesthe risk of NTD. We therefore investigated whether vitamin B12and/or folate status and elevated homocysteine concentrationscould explain the high incidence of NTD in rural blackpopulations by determining plasma tHcy, vitamin B12 andfolate concentrations in apparently healthy rural black womenand urbanised black women. We also studied folate andvitamin B12 status, homocyst(e)ine metabolism and MTHFRgenotypes (677 C->T mutation) in 54 rural black women withhistories of NTD.Population survey of rural and urban womenApparently healthy, urbanised black women (mean (SD) age25.4 (3.9) years, N = 101) from the Pretoria area had lowerplasma folate concentrations (P < 0.001) compared with ruralblack women (mean (SD) age 31.3 (7.5) years, N = 107) wholived in Northern Province, Lower plasma tHey concentrationswere observed in the rural population but the difference wasnot statistically significant (P = 0.09).Homocysteine metabolism and MTHFR genotype inwomen with a history of NTDSince 1990, the Department of Human Genetics, University ofPretoria, has provided a clinical genetic service to seven ruralhospitals in Northern Province. Fifty-four black women with arecorded history of NTD between 1990 and 1995 wereapproached to participate in the study. Of the 54 NTD cases, 30were documented as spina bifida, 10 as anencephaly, 7 ascranioracheischisis, and 7 as encephalocoele. Age and bodymass paired controls were selected from the rural populationsample described above. None of the cases or controls werereceiving vitamin supplementation. Methionine load tests wereperformed on these subjects and no significant differences wereobserved in plasma vitamin B12, folate, fasting homocyst(e)ine,methionine, and the post-methionine load increase in plasmahomocyst(e)ine concentrations between NTD cases andcontrols. More than 50% of both NTD cases and controls had apost-methionine load increase in plasma tHcy concentrationsbelow the 5th percentile calculated in a healthy white controlgroup (64 apparently healthy white women with no history ofNTD or previous miscarriages (mean (SD) age 35.9 (8.1) years)recruited from major employers in Pretoria).The finding that black rural women with a history of ITDdo not differ significantly from controls supports the conceptthat a frank folate deficiency is not a prerequisite for NTDoccurrence.'" Abnormal homocysteine metabolism in NTD hasbeen reported for Caucasian populations,5-S but our resultsquestion the assumption that homocyst(e)ine metabolism iscausally related to NTD in black subjects. Black subjects have ahigh incidence of NTD, while they appear to metabolisemethionine much more effectively than white subjects, as wasobserved in the present study as well as in previous studies."The presence of 677 C->T mutation in the MTHFR gene wasinvestigated in women with a history of NTD and in controlsby polymerase chain reaction (PCR) of genomic DNA and Hinfldigestion of the PCR product. Of the controls 9/54 (16.6%)were heterozygous and of the NTD cases 12/58 (20.7%) wereheterozygous, while no homozygotes for the 677 C->T mutationin the MTHFR gene were found in either group. A populationgenetic test showed that this black population sample was inHardy-Weinberg equilibrium. Homozygosity for the 667 C->Tmutation in the gene coding for MTHFR may not be a geneticrisk factor for NTD in black subjects, as was reported forCaucasians.lO,lSCONCLUSIONNo explanation can be derived from this study for the highincidence of NTD in rural black women since neither folate orvitamin B12 deficiency, nor aberrant homocysteine metabolismwere evident in NTD subjects compared with controls. Theprevalence of folate deficiency (plasma folate levels < 6.75nmol/I) was high in rural non-pregnant black women (21 %)and even higher in the urban population group (46%). In aprevious study performed in Northern Province 48% of blackwomen in the second or third trimester of pregnancy wereARTICLES-.----ReferencesDqJartmenf of Chemical Pafhology, University of Pretoria, PretoriaRhena Delport, PhDRhena DelportThe prevalence of coronary heart disease (CAD) reported in thelate seventies was high in whites by world standards incontrast to blacks, who had a very low prevalence.I;! Thedifference in prevalence was ascribed to differences in lifestyleand diet, as blacks were reported to take in a high-fibre andlow-fat dietY Due to increased urbanisation, a trend towards aWesternised lifestyle was observed in the black populatiOJfwith a concomitant increase in hypertension,''' obesitysmoking7 aI).d diabetes; which are all recognised risk factors forvascular disease. Despite the high prevalence of CAD riskfactors, the incidence of the disease is still remarkably low inthis population group..n in contrast to whites. 'D The lowprevalence of CAD in black subjects despite a high prevalenceof major risk factors shows that our understanding ofatherogenesis and its clinical presentation(s) is still incomplete.Even more puzzling is the observation that atherosclerosis inblack subjects appears to affect the cerebral circulation ratherthan extracranial and peripheral arteries.12-15 Cerebrovasculardisease (CVD) is regarded as a major cause of morbidity andmortality in this ethnic groupl6-IS and approximately 32 - 50% ofstrokes are related to atherothrombosis.'6-'9 Against thisbackground the study on homocysteine as a CVD/CAD riskfactor in both black and white South African subjects was·performed in order better to understand the underlyingdifferences in these vascular disease expressions. Elevatedplasma total homocysteine (tHey) concentrations haverepeatedly been associated with increased vascular diseaserisk,2021 and explaining ethnic differences in CVD/CAD interms of prevalence by differences in homocysteine metabolismis possible.Homocysteine is an intermediate sulfhydryl a-amino acidformed during conversion of methionine to cysteine and isformed when transmethylation occurs between 5-adenosylmethionine and a methyl group acceptor. Plasma levels of tHeyHOMOCYST(E)INE AND DETERMINANTS OFPLASMA TOTAL HOMOCYST(E)INE (THCY)CONCENTRATIONSMICRONUTRIENTS IN THEPREVENTION AND TREATMENT OFCARDIOVASCULAR DISEASEPREVALENCE OF VASCULAR DISEASE IN SOUTHAFIDCANS ~reported to be folate-deficient." A significant trend to lowerfolate intake with urbanisation" may explain why the urbangroup in our study had significantly lower folateconcentrations compared with the rural group. Although theurban group had a higher prevalence of folate deficiency thanthe rural group, the NTD prevalence was only 0.99/1000 livebuths/ compared with the 1\TTD prevalence in rural areasranging from 3.55 - 6.13 per 1 000 live births.'"'Folate deficiency does not appear to increase the risk of NTDin black subjects. As our data question the role of folatedeficiencies and abnormal homocysteine metabolism in theaetiology of NTD in black subjects, the relevance of folatesupplementation in this population group to prevent NTDneeds further investigation.1. Buccimazza SS, Molteno CD, Durme IT, Viljoen DL Prevalence of neural tube defects inCape Town, South Africa. Teratology 1994; 50: 194-199.2. Delport SO, Christianson AL Van den Berg HJS, Wolmarans L, Gericke CS. Congenitalanomalies in black South African livebom neonates born in an urban academic hospital. 5 AJrMed 11995; 85, 11-15..). Ncayiyana DJ. Neural tube defects among rural blacks in a Transkei district. 5 Afr Med / 1986;69,618-620.4. Venter PA, Christianson Al, Hutamo CM, Makhura MP.. Gencke CS. Congenital anomalies inrural black South African neonates - a silent epidemic? 5 Aft Med J1995; 85: 15-20.5. Steegers-Thewtissen RPM, Boers CHJ. Trijbels FJM, et al. Maternal hyperhomocysteinernia: Arisk factor for neural-tube defects? Metabolism 1994; 43: 1475-1480.6. Mills IL, McPartlin"JM, Kirke PN.. et af. Homocysteine metabolism in pregnancies complicatedby neural-tube defects. Limcet 1995; 345: 149-151.7. Lucock MD, 'vVild J, Lumb CH, et al. Risk of neural tube defect-affected pregnancy isassociated with a block in maternal one-carbon metabolism at the level of N-5--methyltetrahydrofolate: homocysteine methyltransferase. Biochem Mol Med 1997; 61: 28-40.8. Steegers-Theunissen RP. Boers CH, Blom HJ, et al. Neural tube defects and elevated. homocysteine levels in amniotic fluid. Am I Ohstet Gynecoll995; 172: 1436-1441.9. Frosst P, Blom HJ, Milos R, et a1. A candidate genetic risk factor for vascular disease: acommon mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10: 111-113.10. Van der Put I\.TM], Steegers-Theunissen RPM, Frosst P, et al. Mutatedmethylenetetrahydrofolate reductase as a risk factor for spina bifida. umcet 1995; 346: 1070-1071.Nishio H, Lee MJ, Fujii M, et a1. A common mutation in methylenetetrahydrofolate reductasegene among the Japanese population. Ipn I Hum Genetics 1996; 41: 247-251.Jacques PF, Bostom AG, Williams RR, et a1. Relation behveen folate status, a commonmutation in methylenetetrahydrofolate reductase and plasma homocysteine concentrations.CircuLation 1996; 93: 7-9.Harmon DL, Woodside JV.. Yamell JW, et al. The common "thermolabile" variant ofmethylenetetrahydrofolate reductase is a major detenninant of mild hyperhomocysteinaemia.QlM 1996; 89, 571-577.Malinow MR, Nieto Fj, Kruger WD, et al. The effects of folic acid supplementation on plasmatotal homocysteine are modulated by multivitamin use and methylenetetrahydrofolatereductase genotypes. Arterioscler Thromb Vase 8ioI1997; 17: 1157-1162.Du CY, Stevenson RE, Brown VK, et al. 5,10 Methylenetetrahydrofolate reductase geneticpolymorphism as a risk factor for neural tube defects. Am I Med Genet 1996; 63: 610-614.Medical Research Council Research Group. Prevention of neural tube defects: Results of theMedical Research Council vitamin study. Loncef 1991; 338: 131-137.Czeizel AE, Dudas I. Pre\'ention of the first occurrence of neural-tube defects bypericonceptional vitamin supplementation. N Engl JMed 1992; 327: 1832-1835.Wald !J, Hackshaw AK, Stone R, Sourial NA. Blood folic acid and vitamin B12 in relation toneural tube defects. Br I Obstet GynaecoI1996; 103: 319-324.Kirke PN,-MoUoy AM, Daly LE, Burke H, Weir DG, Scott JM. Maternal plasma folate andvitamin Bu are independent risk factors for neural tube defects. Q1M 1993; 86: 703--708.Daly LE, Kirke PN, Molioy A, Weir DG, Scott JM. Folate levels and neural tube defects.ImplicatiOns for prevention. lAMA 1995; 274: 1698-1702.Kirke P " Molloy AM, Daly LE, Burke H, Weir DC, Scott JM. Maternal plasma folate andvitamin B12 are independent risk factors for neural tube defects. QJM 1993; 86: 703--708.Baynes RD, Meriwether WO, Bothwell TH, Costa FJF, Bezwoda WR, MacPhail AP. Iron andfolate status of pregnant black women in Gazankulu. 5 AI' Med I 1986; 70, 14&-151.Van der Westhuyzen J, van Tonder 5, Gilbertson I, Metz J. Iron, folate and vitamin Bt2nutrition and anaemia in black preschool children in the northern TransvaaL 5 Aft Med J1986; 71T.143-145.Allen WP. Folic acid in the prevention of birth defects. eurr Opi,r Pedilltr 1996; 8: 630-634.Ubbink JB, Vermaak lA'}H, van der Merwe A, Becker PJ, Potgieter H. Effective homocysteinemetabolism may protect South African Blacks against coronary heart disease. Am I Clin Nutr1995; 620 802-808.Boume LT, Boume DE, Sayed AR, Wolfaardt D. Folate levels in an urban population-implications for supplementation for the prevention of neural tube defects. 5 Aft Med 11997;87,932-933.11.12.13.14.15.16.17.18.19.20.21.- 22.23.24.25.26.February 1999, Vo!. 89, No. 2 SAMJ .

Review of current evidence for folate in the prevention of neural tube defects

https://www.ajol.info/index.php/samj/article/download/156939/146547

Review of current evidence for folate in the prevention of neural tube defects

Abstract

Similar works

Full text

Available Versions

AJOL - African Journals Online