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RACIAL DIFFERENCE AND BIOLOGICAL SIGNIFICANCE OF MATERNAL SERUM ALPHA-FETOPROTEIN
573 RACIAL DIFFERENCE AND BIOLOGICAL SIGNIFICANCE OF MATERNAL SERUM
ALPHA-FETOPROTEIN
SIR,-A report of significantly lower maternal serum ot-fetoprotein (MSAFP) concentration in Indians than whites1 was followed by other reports of no difference between American blacks and whites23 as well as ones claiming higher values in blacks.4,5
There may be an interrelation between the amount of the factor carried by AFP, its requirement by the fetus, and the concentration of AFP. When the availability of the factor is limited, the concentration of AFP may critically affect the occurrence of NTD. The hypothesis also suggests that other populations (ethnic, trisomic) may exhibit a similar, inverse correlation between the mean MSAFP and the prevalence of NTD.
However, no correction for race appears to be made in programmes
serving mixed populations elsewhere. In Connecticut’s AFP screening programme, where about 7% of sera are from blacks, race discriminant until this year. That programme uses computer algorithms for an automatic determination of raised (or low) MSAFP concentrations and the interpretations made contain a strong racial bias. In 1981-85 there were 39 259 initial serum samples from white women and 3057 from blacks, of which 1710 (4-4%) and 290 (95%); respectively, were interpreted as raised (p < 0 001, test). A similar difference was found for women whose weight was available for adjustment of MSAFP, as well as for those whose weight was available and who were 20-34 years old (p < 0-001 in both cases). Among the latter group, the prevalence of an increased risk of Down’s syndrome was calculated in 6-1% of white women but only 3-3% of blacks (p<0-001). Differences in MSAFP concentrations for women of various gestational ages are represented in the table. The average maternal weight remained similar for each race throughout the examined gestational interval, though’it was higher for blacks (68-5 kg) than whites (64-4 kg), which would have tended to yield lower MSAFPs in blacks. The difference in MSAFP concentration between the races, expressed as a percentage of the MSAFP at a given percentile, was greatest at the highest percentile. Therefore, MSAFP concentrations appear to be distributed differently in the two races, and a higher multiple of the median may be required to exclude a similar percentage of blacks as whites in screening for NTD. Two issues emerge from this study. First, that misinterpretation of data can follow omission of race as a factor in the assessment of MSAFP in initial specimens, both in selection for increases that can be associated with neural tube defect (NTD) and for low values that can accompany trisomy. Indeed, the effect on selection of low values may be more important, especially in blacks, in whom the frequency of NTD is less than it is in whites6 whereas the incidence of trisomy is similarThe higher MSAFP in blacks cannot be attributed to a greater incidence offetomatemal haemorrhage or, probably, other placental lesions; the proportion of raised MSAFP in subsequent specimens of serum from women who had a raised MSAFP in the first was comparable. Second, the racial difference in MSAFP may imply different fetal serum concentrations and have a biological significance—eg, in explaining the prevalence of NTD. It is noteworthy that, as with diabetes so with race, a lower mean MSAFP concentration for the population8,9 is associated with a higher prevalence of NTD.9,10 It has been postulated that an environmental factor, possibly a nutrient, has a contributory role in the causation of NTD. This was not used as a
nutrient
(or its active metabolite)
may be
transported
and its
effective concentration modulated by AFP. AFP binds arachidonic acid," which may prevent embryopathy," and retinoidsll which assist cellular maturation and that, in turn, reduce the production of AFP.13
Department of Laboratory Medicine, Yale Medical School, New Haven, Connecticut 06504, USA
A. BAUMGARTEN
1.
Shapiro LM, Skinner LG, Philips HV, Whitfield CR. Racial variations in maternal serum alpha-fetoprotein. Lancet 1975; ii: 1142. 2. Macri JN, Weiss RR, Elligers KW, Federgreen WR. Racial differences in maternal serum alpha-fetoprotein. Lancet 1976; i: 207-08. 3. Milunsky A, Alpert E, Neff RK, Frigoletto FD. Prenatal diagnosis of neural tube defects IV: Maternal serum alpha-fetoprotein screening. Obstet Gynecol 1979; 55: 60-66. 4. Crandall BF, Lebherz TB, Schroth PC, Matsumoto M. concentrations in maternal serum: Relation to race and body
Alpha-fetoprotein weight. Clin Chem
1983; 29: 531-33. Johnson AM. Racial differences in maternal serum alpha-fetoprotein screening. In: Mizejewski GJ, Porter IH, eds. Alpha-fetoprotein and congenital disorders. New York: Academic Press, 1985: 183-96. 6. Chung CS, Myrianthopoulos NC. Racial and prenatal factors in major congenital malformations. Am J Hum Genet 1968; 20: 44-60. 7. Sever JL, Gilkeson MR, Chen TC, Ley AC, Edmonds D. Epidemiology of mongolism in the collaborative project. Ann NY Acad Sci 1970; 171: 328-40 8. Wald NJ, Cuckle H, Boreham J, Stirrat GM, Turnbull AC. Maternal serum alpha-fetoprotein and diabetes mellitus. Br J Obstet Gynaecol 1979; 86: 101-05. 9. Milunsky A, Alpert E, Kitzmiller JL, Younger MD, Neff RV. Prenatal diagnosis of neural tube defects VIII: The importance of serum alpha-fetoprotein screening in diabetic pregnant women. Am J Obstet Gynecol 1982; 142: 1030-32. 10. Mills JL, Baker L, Goldman AS. Malformations in infants of diabetic mothers occur before the seventh gestational week. Implications for treatment. Diabetes 1979; 28: 5.
292-93. 11. Aussel C, Masseyeff R. Interaction of retinoids and bilirubin with the binding of arachidonic add to human alpha-fetoprotein. Biochem Biophys Res Comm 1984; 119: 1122-27. 12. Pinter E, Reece EA, Leranth CZ, Garcia-Segura M, Hobbins JC, Mahoney MJ, Naftolin F. Arachidonic add prevents hyperglycemia—associated yolk sac damage and embryopathy. Am J Obstet Gynecol (in press). 13. Chou JY, Ito F. Role of retinoic add in maturation of fetal liver cells in vitro. Biochem Biophys Res Comm 1984; 118: 168-75.
NEURAL TUBE DEFECTS AND SEX RATIO
SIR,-Dr Seller (July 26, p 227) presents data on the sexes and pathological categories of an unselected series of 147 fetuses with neural tube defects. In all categories except one there was an excess of females. The remaining category ("lower" spina bifida, thorax not involved) had a striking male excess of 15 males to 5 females. Seller cites evidence that in mice, males
are more
advanced
developmentally than females of the same presumed age, and she speculates that if this were true of man, this differential may be the key to the differing propensities of the sexes to defective processes of formation of the neural tube. I should like to enlarge on this. There seems good evidence that in man, male zygotes are formed earlier in the cycle than female zygotes,l,2 and that this is related to maternal hormone levels.3 Closure of the neural tube proceeds caudally. So, if maternal hormone levels are taken as time origin, the pathological process which leads to a spina bifida (thorax not involved) in a male embryo occurs at the same (maternal) time as
MSAFP CONCENTRATION IN AMERICAN BLACKS (B) AND WHITES (W) AS FUNCTION OF GESTATIONAL AGE AND PERCENTILE OF POPULATION
*Dated from last menstrual period. t(B-W)
as
00 of W.
ALPHA-FETOPROTEIN
SIR,-A report of significantly lower maternal serum ot-fetoprotein (MSAFP) concentration in Indians than whites1 was followed by other reports of no difference between American blacks and whites23 as well as ones claiming higher values in blacks.4,5
There may be an interrelation between the amount of the factor carried by AFP, its requirement by the fetus, and the concentration of AFP. When the availability of the factor is limited, the concentration of AFP may critically affect the occurrence of NTD. The hypothesis also suggests that other populations (ethnic, trisomic) may exhibit a similar, inverse correlation between the mean MSAFP and the prevalence of NTD.
However, no correction for race appears to be made in programmes
serving mixed populations elsewhere. In Connecticut’s AFP screening programme, where about 7% of sera are from blacks, race discriminant until this year. That programme uses computer algorithms for an automatic determination of raised (or low) MSAFP concentrations and the interpretations made contain a strong racial bias. In 1981-85 there were 39 259 initial serum samples from white women and 3057 from blacks, of which 1710 (4-4%) and 290 (95%); respectively, were interpreted as raised (p < 0 001, test). A similar difference was found for women whose weight was available for adjustment of MSAFP, as well as for those whose weight was available and who were 20-34 years old (p < 0-001 in both cases). Among the latter group, the prevalence of an increased risk of Down’s syndrome was calculated in 6-1% of white women but only 3-3% of blacks (p<0-001). Differences in MSAFP concentrations for women of various gestational ages are represented in the table. The average maternal weight remained similar for each race throughout the examined gestational interval, though’it was higher for blacks (68-5 kg) than whites (64-4 kg), which would have tended to yield lower MSAFPs in blacks. The difference in MSAFP concentration between the races, expressed as a percentage of the MSAFP at a given percentile, was greatest at the highest percentile. Therefore, MSAFP concentrations appear to be distributed differently in the two races, and a higher multiple of the median may be required to exclude a similar percentage of blacks as whites in screening for NTD. Two issues emerge from this study. First, that misinterpretation of data can follow omission of race as a factor in the assessment of MSAFP in initial specimens, both in selection for increases that can be associated with neural tube defect (NTD) and for low values that can accompany trisomy. Indeed, the effect on selection of low values may be more important, especially in blacks, in whom the frequency of NTD is less than it is in whites6 whereas the incidence of trisomy is similarThe higher MSAFP in blacks cannot be attributed to a greater incidence offetomatemal haemorrhage or, probably, other placental lesions; the proportion of raised MSAFP in subsequent specimens of serum from women who had a raised MSAFP in the first was comparable. Second, the racial difference in MSAFP may imply different fetal serum concentrations and have a biological significance—eg, in explaining the prevalence of NTD. It is noteworthy that, as with diabetes so with race, a lower mean MSAFP concentration for the population8,9 is associated with a higher prevalence of NTD.9,10 It has been postulated that an environmental factor, possibly a nutrient, has a contributory role in the causation of NTD. This was not used as a
nutrient
(or its active metabolite)
may be
transported
and its
effective concentration modulated by AFP. AFP binds arachidonic acid," which may prevent embryopathy," and retinoidsll which assist cellular maturation and that, in turn, reduce the production of AFP.13
Department of Laboratory Medicine, Yale Medical School, New Haven, Connecticut 06504, USA
A. BAUMGARTEN
1.
Shapiro LM, Skinner LG, Philips HV, Whitfield CR. Racial variations in maternal serum alpha-fetoprotein. Lancet 1975; ii: 1142. 2. Macri JN, Weiss RR, Elligers KW, Federgreen WR. Racial differences in maternal serum alpha-fetoprotein. Lancet 1976; i: 207-08. 3. Milunsky A, Alpert E, Neff RK, Frigoletto FD. Prenatal diagnosis of neural tube defects IV: Maternal serum alpha-fetoprotein screening. Obstet Gynecol 1979; 55: 60-66. 4. Crandall BF, Lebherz TB, Schroth PC, Matsumoto M. concentrations in maternal serum: Relation to race and body
Alpha-fetoprotein weight. Clin Chem
1983; 29: 531-33. Johnson AM. Racial differences in maternal serum alpha-fetoprotein screening. In: Mizejewski GJ, Porter IH, eds. Alpha-fetoprotein and congenital disorders. New York: Academic Press, 1985: 183-96. 6. Chung CS, Myrianthopoulos NC. Racial and prenatal factors in major congenital malformations. Am J Hum Genet 1968; 20: 44-60. 7. Sever JL, Gilkeson MR, Chen TC, Ley AC, Edmonds D. Epidemiology of mongolism in the collaborative project. Ann NY Acad Sci 1970; 171: 328-40 8. Wald NJ, Cuckle H, Boreham J, Stirrat GM, Turnbull AC. Maternal serum alpha-fetoprotein and diabetes mellitus. Br J Obstet Gynaecol 1979; 86: 101-05. 9. Milunsky A, Alpert E, Kitzmiller JL, Younger MD, Neff RV. Prenatal diagnosis of neural tube defects VIII: The importance of serum alpha-fetoprotein screening in diabetic pregnant women. Am J Obstet Gynecol 1982; 142: 1030-32. 10. Mills JL, Baker L, Goldman AS. Malformations in infants of diabetic mothers occur before the seventh gestational week. Implications for treatment. Diabetes 1979; 28: 5.
292-93. 11. Aussel C, Masseyeff R. Interaction of retinoids and bilirubin with the binding of arachidonic add to human alpha-fetoprotein. Biochem Biophys Res Comm 1984; 119: 1122-27. 12. Pinter E, Reece EA, Leranth CZ, Garcia-Segura M, Hobbins JC, Mahoney MJ, Naftolin F. Arachidonic add prevents hyperglycemia—associated yolk sac damage and embryopathy. Am J Obstet Gynecol (in press). 13. Chou JY, Ito F. Role of retinoic add in maturation of fetal liver cells in vitro. Biochem Biophys Res Comm 1984; 118: 168-75.
NEURAL TUBE DEFECTS AND SEX RATIO
SIR,-Dr Seller (July 26, p 227) presents data on the sexes and pathological categories of an unselected series of 147 fetuses with neural tube defects. In all categories except one there was an excess of females. The remaining category ("lower" spina bifida, thorax not involved) had a striking male excess of 15 males to 5 females. Seller cites evidence that in mice, males
are more
advanced
developmentally than females of the same presumed age, and she speculates that if this were true of man, this differential may be the key to the differing propensities of the sexes to defective processes of formation of the neural tube. I should like to enlarge on this. There seems good evidence that in man, male zygotes are formed earlier in the cycle than female zygotes,l,2 and that this is related to maternal hormone levels.3 Closure of the neural tube proceeds caudally. So, if maternal hormone levels are taken as time origin, the pathological process which leads to a spina bifida (thorax not involved) in a male embryo occurs at the same (maternal) time as
MSAFP CONCENTRATION IN AMERICAN BLACKS (B) AND WHITES (W) AS FUNCTION OF GESTATIONAL AGE AND PERCENTILE OF POPULATION
*Dated from last menstrual period. t(B-W)
as
00 of W.