- Email: [email protected]
The influence of maternal weight on human chorionic gonadotropin in the multiple-marker screening test for fetal Down syndrome
The influence of maternal weight on human chorionic gonadotropin in the multiple-marker screening test for fetal Down syndrome Katharine D. Wenstrom, MD, John Owen, MD, Larry Boots, PhD, and Melissa Ethier, MD Birmingham, Alabama OBJECTIVE: Our purpose was to determine the effect of maternal weight on human chorionic gonadotropin concentration in the multiple-marker screening test for fetal Down syndrome. STUDY DESIGN: Two genetics databases were used: database I contained the results of 8297 multiple-marker screening tests and database II contained the results of 1936 multiple-marker screening tests and fetal karyotypes. RESULTS: The overall screen-positive rate in database I was 7.1%; it was 7.5% in patients weighing < 180 pounds and 5.1% in patients weighing -> 180 pounds (p = 0.001). Weight significantly affected the screen-positive rate only in women -> 30 years old (p = 0.003 for 30 to 34 years, p = 0.00004 for -> 35 years). A weight correction formula was derived; when applied to database II it eliminated individual weight-related differences but had no effect on the overall screen-positive rate or Down syndrome detection rate. CONCLUSIONS: Human chorionic gonadotropin concentration is affected by maternal weight. A weight correction formula eliminates individual weight-related differences in the screen-positive rate but has no discernible effect on the overall screen-positive or Down syndrome detection rates. (AM J OBSTETGYNECOL 1995;173:1297-300.)
Key words: Multiple-marker screening test, human chorionic gonadotropin
Second-trimester maternal serum et-fetoprotein (AFP) has been used since the early 1980s as a screening test for fetal Down syndrome and fetal neural tube defects.~-3 Maternal serum AFP is typically measured in nanograms p e r milliliter and then expressed as a multiple of the median value for unaffected pregnancies of the same gestational age. Expressing the maternal serum AFP value as a multiple of the median allows data fi'om different laboratories to be interpreted in a consistent manner and allows adjustment for biologic variables known to affect maternal serum levels of AFP. 4 One of the biologic variables known to affect maternal serum AFP levels is maternal weight. Obese women generally have lower maternal serum AFP levels because the AFP p r o d u c e d by the fetal liver at a fairly predictable rate is diluted in the greater intravascular volume typical of large women. Conversely, small women have spuriously high maternal serum AFP levels because of their small volume of distribution. A weight From the Center for Obstetric Research, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Alabama at Birmingham. Presented in part at the Fifteenth Annual Meeting of the Society of Perinatal Obstetricians, Atlanta, Georgia, January 23-28, 1995. Reprint requests: Katharine D. Wenstrom, MD, University of Alabama at Birmingham, Department of Obstetrics and Gynecology, 618 S. 20th St., UAB Station, Birmingham, AL 35233-7333. Copyright © 1995 by Mosby-Year Book, Inc. 0002-9378/95 $5.00 + 0 6/6/67644
correction formula is therefore used to compensate for disparity in maternal vascular volume, and the weightcorrected multiple of the median is used to determine maternal risk. ~' 6 T h e multiple-marker screening test for Down syndrome has now largely replaced maternal serum AFP alone as a second-trimester screening test for fetal aneuploidy. 7-9 T h e multiple-marker test consists of maternal serum AFP, human chorionic gonadotropin (hCG), unconjugated estriol, and maternal age. hCG is the most predictive serum marker for fetal Down syndrome, with abnormally high values identifying 68% of chromosomally abnormal fetusesJ ° Because hCG is produced at a fairly predictable rate by the placental cytotrophoblast, it is likely that hCG released into the maternal circulation is subject to the same dilutional effects as maternal serum AFP. However, a weight correction formula for hCG is not typically used. The purpose of our study was to determine whether hCG levels are influenced by maternal weight. We also sought to derive a weight correction formula for hCG and to evaluate its effect on both the Down syndrome screen-positive rate and the Down syndrome detection rate. Material and m e t h o d s
Two genetics databases were used. Database I contained the results of 8297 multiple-marker screening 1297
1298 Wenstrom et al.
October 1995 Am J Obstet Gynecol
Table I. Effect of maternal weight and age on Down syndrome screen-positive rate before weight correction of hCG
Screen-positive rate (hCG uncorrected) (%) Maternal age (yr) < 20 20-24 25-29 30-34 ->35 M1
< 180 lb
]
>-180 lb
1.6 2.2 2.4 7.6 32.5 7.5
tests performed at the University of Alabama Obstetrics and Gynecology Research and Diagnostic Laboratory from January 1993 to August 1994. Database II contained the results of multiple-marker screening tests and fetal karyotypes from 1936 women seen at the University of M a b a m a Prenatal Diagnosis Clinic. (Data were obtained prosPectively from 1186 women seen from January 1993 to August 1994 and retrospectively from 750 women seen from 1988 to 1992.) Maternal serum was obtained at 14 to 22 weeks' gestation and analyzed with commercially available radioimmunoassay kits (maternal serum AFP by Sanofi Pasteur, Chaska, Minn.; unconjugated estriol by Diagnostic Systems Laboratory, Webster, Tex.; and hCG by Nichols Institute, San J u a n Capistrano, Calif.). Maternal serum AFP values were corrected for maternal weight, race, and t h e presence of insulin-dependent diabetes. Analyte levels were expressed as multiples of the median, d e t e r m i n e d by comparison with the normal medians at 14 to 22 weeks' established for the patient population served by the University of Alabama at Birmingham. After all three analytes were evaluated with a trivariate gaussian algorithm to correct for slight pairwise correlation, the derived likelihood ratio was used to modify the maternal a g e - r e l a t e d Down synd r o m e risk. T h e test was considered to be Down synd r o m e screen positive if the combined Down syndrome risk was -> 1 : 190. This risk cutoff was chosen because it was estimated to combine a relatively low screenpositive rate (4.7%) with an acceptable detection rate (60%). 'l The" overall Down syndrome screen-positive rate was calculated with database I. Patients were then categorized according to maternal weight. After examining several weight stratification schemes, we elected to divide the study patients into two groups: < 180 pounds and _> 180 p o u n d s . We chose 180 pounds as the cutoff value somewhat arbitrarily but also because it was a compromise between the 75th percentile weight (171 pounds) and the weight equivalent to 1 SD above the mean (188 pounds). The screen-positive rate in each weight group was then calculated. To determine the effect of maternal age on both maternal weight and screen-positive rate, patients within each weight cat-
0.8 1.0 1.6 3.3 20.3 5.1
Significance p p p p p p
= = = = = =
0.480 0.122 0.301 0.003 0.00004 0.001
egory were also g r o u p e d according to 5-year maternal age intervals ( < 20, 20 to 24, 25 to 29, 30 to 34, and -> 35 years), and the screen-positive rate was recalculated. Differences in screen-positive rates between the groups were analyzed with ×2 and Fisher's exact test where appropriate. A p value <0.05 was considered significant. A weight correction formula was then derived by fitting a regression equation to the distribution of hCG multiples of the median in database I. This formula was applied to database I, and its effect on the screenpositive rate in the various weight and age categories was determined. T h e Down syndrome screen-positive rate and detection rate were then calculated in database II. The hCG weight correction formula was applied to database II, and the effect on both the screen-positive rate and the detection rate was determined.
Results In database I the overall screen-positive rate was 7.1% (3.2% for women < 3 5 years, 28.3% for women -> 35 years). T h e screen-positive rate was different in each weight category: 7.5% for women < 180 pounds and 5.1% for women > 180 pounds (p = 0.001). When patients were g r o u p e d by age and weight, weight appeared to significantly influence the screen-positive rate only in women -> 30 years old (Table I). A weight correction formula was then derived by fitting a regression equation to the distribution of hCG multiples of the median in database I. T h e data best fit a polynomial equation: Weight-corrected hCG multiple of the median = Uncorrected hCG multiple of the median/(0.465 + [78.56/Weight in pounds]) (r 2 = 0.86, p < 0.001) (Fig. 1). When this weight correction formula was applied to database I, weight-related differences in the screen-positive rate were eliminated (Table II). T h e Down syndrome screen-positive rate and detec~ tion rate (with uncorrected hCG) were determined for database II. T h e weight correction formula was then applied and the rates were recalculated. Depending on weight, individual patients could experience a change in the calculated risk of Down syndrome. However, the
Volume 173, Number 4 Am J Obstet Gynecol
Wenstrom eta[.
1299
1.35Weight corrected hCGMOM = Uncorrect(pd hCGMOM
1,3"
0.4654. 78.56
Maternal
1.25:! 1,2O ~; 1,15-; ¢-) ¢,.
1.1i
c 1.05-
~
10.95i 0.9~ 0.85 100
. . . .
I
. . . .
120
I
. . . .
140
I
. . . .
160
I
. . . .
180
I
. . . .
200
I
. . . .
220
I
. . . .
240
260
Mean Weight (pounds) Fig. 1. hCG weight correction formula. MOM, Multiples of the median.
Table I L Effect of maternal weight and age on Down syndrome screen-positive rate after weight correction of hCG
Screen-positive rate (hCG corrected) (%) Maternal age (yr) < 20 20-24 25-29 30-34 >_35 All
l
< 180 lb
>_180 lb
1.4 1.8 2.3 7.0 32.0 7.2
0.8 2.0 2.5 4.7 26.0 6.9
1
Significance p p p p p p
= = = = = =
0.57 0.80 0.80 0.11 0.06 0.73
Table I I I . Effect of weight correction of hCG on Down syndrome screen-positive rate and detection rate (n = 1936)
Screen-positive rate Down syndrome detection rate
Without correction (%)
With correction (%)
S~gnificance
18.5 68 (36/53)
18.9 68 (36/53)
NS NS
NS, Not significant.
overall screen-positive rate and Down syndrome detection rate were u n c h a n g e d (Table III). Of note, only 11 of the 53 women with fetal Down syndrome weighed -> 180 pounds, and eight of 11 already had positive Down syndrome screening tests before weight correction.
Comment Our analysis confirms that, analogous to maternal serum AFP, hCG values are affected by maternal weight and volume of distribution. T h e inequity in screenpositive rates between women weighing < 180 and >- 180 pounds can be eliminated with a weight correction formula. Although weight correction did not have an effect on the overall Down syndrome screen-positive and detection rates in our database, it did distribute the
positive screening tests more equitably among women of all weights. Weight correction of hCG had the most significant effect on women _ 30 years old. This p h e n o m e n o n is most easily explained by considering the maternal a g e related risk of Down syndrome. Maternal age is a strong predicter of fetal aneuploidy. ~' A woman < 30 years old is at such low risk by virtue of her age that a small change in the hCG multiple of the median is unlikely to significantly a l t e r her estimated risk of fetal Down syndrome. Conversely, a woman _>30 years old already has such a high age-related risk that a small change in the hCG multiple of the median might be sufficient to change her combined risk relative to the chosen cutoff. Should maternal weight correction of hCG be insti-
1300
October 1995 Am J Obstet Gynecol
Wenstrom et al.
tuted even though it doesn't a p p e a r to change the overall Down syndrome screen-positive rate or the detection rate? We believe that it should for two (theoretic) reasons. First, the multiple-marker screening test is becoming increasingly important to older gravid women. Women who have delayed childbearing or who have conceived after treatment of infertility may not wish to j e o p a r d i z e a highly valued pregnancy by undergoing genetic amniocentesis unless they are demonstrated to be at clearly increased risk. Because weight tends to increase with age, the Down syndrome risk of older gravid women may be consistently underestimated without weight correction of hCG. If an older pregnant woman relies on the (falsely) lower risk estimated by the uncorrected multiple-marker screening test, she may decline an amniocentesis for advanced maternal age, and fetal aneuploidy may be missed. T h e second theoretic advantage of weight correction of hCG is that it results in fewer false-positive screening tests in below-average-weight women. T h e specificity of the multiple-marker screening test is already quite l o w . 7 , s W o m e n with abnormal screening test results, even if the results turn out to be falsely abnormal, u n d e r g o tremendous stress and an (possibly unnecessary) amniocentesis. Weight correction of hCG should result in the recommendation of fewer unnecessary procedures for slender women and may ultimately reduce the procedure-related loss rate of unaffected fetuses. In summary, we found that hCG is affected by maternal weight and that a weight correction formula could be derived and applied to more equitably distribute the abnormal Down syndrome screening test results among women of all weights. O u r results will need to be verified by the directors of other reference laboratories,
who may also want to derive and evaluate their own hCG weight correction formulas. REFERENCES
1. United Kingdom Collaborative Study on Alpha-fetoprotein in Relation to Neural-tube Defects. Maternal serum alpha-fetoprotein measurement in antenatal screening for anencephaly and spina bifida in early pregnancy. Lancet 1977;2:1323-32. 2. Cuckle HS, Wald NJ, Lindenbaum RH. Maternal serum alpha-fetoprotein measurement: a screening test for Down syndrome. Lancet 1984;1:926-9. 3. DiMaio MS, Baumgarten A, Greenstein RM, Saal HM, Mahoney MJ. Screening for fetal Down's syndrome in pregnancy by measuring maternal serum alpha-fetoprotein levels. N EnglJ Med 1987;317:342-6. 4. Burton BK. Elevated maternal serum alpha-fetoprotein (MSAFP): interpretation and follow-up. Clin Obstet Gynecol 1988;31:293-305. 5. Wald NJ, Cuckle H, Boreham J, Terzian E, Redman C. The effect of maternal weight on maternal serum alphafetoprotein levels. Br J Obstet Gynaecol 1981;80:1094-6. 6. Haddow JE, Kloza EM, Knight GJ, Smith DE. Relation between maternal weight a n d serum aipha-fetoprotein concentration during the second trimester. Clin Chem 1981;27:133-4. 7. Haddow JE, Palomaki GE, Knight GJ, et al. Prenatal screening for Down's syndrome with use of maternal serum markers. N Engl J Med 1992;327:588-93. 8. Cheng EY, Luthy DA, Zebelman AM, Williams MA, Lieppman RE, Hickok DE. A prospective evaluation of a secondtrimester screening test for fetal Down syndrome using maternal serum alpha-fetoprotein, hCG, and unconjugated estriol. Obstet Gynecol 1993;81:72-7. 9. Wenstrom KD, Williamson RA, Grant SS, Hudson JD, Getchell JP. Evaluation of multiple-marker screening for Down syndrome in a statewide population. AM J OBSTET GYNECOL1993;169:793-7. 10. Bogart MH, Pandian MR, Jones OW. Abnormal maternal serum chorionic gonadotropin levels in pregnancies with fetal chromosome abnormalities. Prenat Diagn 1987;7: 623-30. 11. Wald NJ, Cuckle HS, Densem JW, et al. Maternal serum screening for Down's syndrome in early pregnancy. BMJ 1988;297:883-7.
Key words: Multiple-marker screening test, human chorionic gonadotropin
Second-trimester maternal serum et-fetoprotein (AFP) has been used since the early 1980s as a screening test for fetal Down syndrome and fetal neural tube defects.~-3 Maternal serum AFP is typically measured in nanograms p e r milliliter and then expressed as a multiple of the median value for unaffected pregnancies of the same gestational age. Expressing the maternal serum AFP value as a multiple of the median allows data fi'om different laboratories to be interpreted in a consistent manner and allows adjustment for biologic variables known to affect maternal serum levels of AFP. 4 One of the biologic variables known to affect maternal serum AFP levels is maternal weight. Obese women generally have lower maternal serum AFP levels because the AFP p r o d u c e d by the fetal liver at a fairly predictable rate is diluted in the greater intravascular volume typical of large women. Conversely, small women have spuriously high maternal serum AFP levels because of their small volume of distribution. A weight From the Center for Obstetric Research, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Alabama at Birmingham. Presented in part at the Fifteenth Annual Meeting of the Society of Perinatal Obstetricians, Atlanta, Georgia, January 23-28, 1995. Reprint requests: Katharine D. Wenstrom, MD, University of Alabama at Birmingham, Department of Obstetrics and Gynecology, 618 S. 20th St., UAB Station, Birmingham, AL 35233-7333. Copyright © 1995 by Mosby-Year Book, Inc. 0002-9378/95 $5.00 + 0 6/6/67644
correction formula is therefore used to compensate for disparity in maternal vascular volume, and the weightcorrected multiple of the median is used to determine maternal risk. ~' 6 T h e multiple-marker screening test for Down syndrome has now largely replaced maternal serum AFP alone as a second-trimester screening test for fetal aneuploidy. 7-9 T h e multiple-marker test consists of maternal serum AFP, human chorionic gonadotropin (hCG), unconjugated estriol, and maternal age. hCG is the most predictive serum marker for fetal Down syndrome, with abnormally high values identifying 68% of chromosomally abnormal fetusesJ ° Because hCG is produced at a fairly predictable rate by the placental cytotrophoblast, it is likely that hCG released into the maternal circulation is subject to the same dilutional effects as maternal serum AFP. However, a weight correction formula for hCG is not typically used. The purpose of our study was to determine whether hCG levels are influenced by maternal weight. We also sought to derive a weight correction formula for hCG and to evaluate its effect on both the Down syndrome screen-positive rate and the Down syndrome detection rate. Material and m e t h o d s
Two genetics databases were used. Database I contained the results of 8297 multiple-marker screening 1297
1298 Wenstrom et al.
October 1995 Am J Obstet Gynecol
Table I. Effect of maternal weight and age on Down syndrome screen-positive rate before weight correction of hCG
Screen-positive rate (hCG uncorrected) (%) Maternal age (yr) < 20 20-24 25-29 30-34 ->35 M1
< 180 lb
]
>-180 lb
1.6 2.2 2.4 7.6 32.5 7.5
tests performed at the University of Alabama Obstetrics and Gynecology Research and Diagnostic Laboratory from January 1993 to August 1994. Database II contained the results of multiple-marker screening tests and fetal karyotypes from 1936 women seen at the University of M a b a m a Prenatal Diagnosis Clinic. (Data were obtained prosPectively from 1186 women seen from January 1993 to August 1994 and retrospectively from 750 women seen from 1988 to 1992.) Maternal serum was obtained at 14 to 22 weeks' gestation and analyzed with commercially available radioimmunoassay kits (maternal serum AFP by Sanofi Pasteur, Chaska, Minn.; unconjugated estriol by Diagnostic Systems Laboratory, Webster, Tex.; and hCG by Nichols Institute, San J u a n Capistrano, Calif.). Maternal serum AFP values were corrected for maternal weight, race, and t h e presence of insulin-dependent diabetes. Analyte levels were expressed as multiples of the median, d e t e r m i n e d by comparison with the normal medians at 14 to 22 weeks' established for the patient population served by the University of Alabama at Birmingham. After all three analytes were evaluated with a trivariate gaussian algorithm to correct for slight pairwise correlation, the derived likelihood ratio was used to modify the maternal a g e - r e l a t e d Down synd r o m e risk. T h e test was considered to be Down synd r o m e screen positive if the combined Down syndrome risk was -> 1 : 190. This risk cutoff was chosen because it was estimated to combine a relatively low screenpositive rate (4.7%) with an acceptable detection rate (60%). 'l The" overall Down syndrome screen-positive rate was calculated with database I. Patients were then categorized according to maternal weight. After examining several weight stratification schemes, we elected to divide the study patients into two groups: < 180 pounds and _> 180 p o u n d s . We chose 180 pounds as the cutoff value somewhat arbitrarily but also because it was a compromise between the 75th percentile weight (171 pounds) and the weight equivalent to 1 SD above the mean (188 pounds). The screen-positive rate in each weight group was then calculated. To determine the effect of maternal age on both maternal weight and screen-positive rate, patients within each weight cat-
0.8 1.0 1.6 3.3 20.3 5.1
Significance p p p p p p
= = = = = =
0.480 0.122 0.301 0.003 0.00004 0.001
egory were also g r o u p e d according to 5-year maternal age intervals ( < 20, 20 to 24, 25 to 29, 30 to 34, and -> 35 years), and the screen-positive rate was recalculated. Differences in screen-positive rates between the groups were analyzed with ×2 and Fisher's exact test where appropriate. A p value <0.05 was considered significant. A weight correction formula was then derived by fitting a regression equation to the distribution of hCG multiples of the median in database I. This formula was applied to database I, and its effect on the screenpositive rate in the various weight and age categories was determined. T h e Down syndrome screen-positive rate and detection rate were then calculated in database II. The hCG weight correction formula was applied to database II, and the effect on both the screen-positive rate and the detection rate was determined.
Results In database I the overall screen-positive rate was 7.1% (3.2% for women < 3 5 years, 28.3% for women -> 35 years). T h e screen-positive rate was different in each weight category: 7.5% for women < 180 pounds and 5.1% for women > 180 pounds (p = 0.001). When patients were g r o u p e d by age and weight, weight appeared to significantly influence the screen-positive rate only in women -> 30 years old (Table I). A weight correction formula was then derived by fitting a regression equation to the distribution of hCG multiples of the median in database I. T h e data best fit a polynomial equation: Weight-corrected hCG multiple of the median = Uncorrected hCG multiple of the median/(0.465 + [78.56/Weight in pounds]) (r 2 = 0.86, p < 0.001) (Fig. 1). When this weight correction formula was applied to database I, weight-related differences in the screen-positive rate were eliminated (Table II). T h e Down syndrome screen-positive rate and detec~ tion rate (with uncorrected hCG) were determined for database II. T h e weight correction formula was then applied and the rates were recalculated. Depending on weight, individual patients could experience a change in the calculated risk of Down syndrome. However, the
Volume 173, Number 4 Am J Obstet Gynecol
Wenstrom eta[.
1299
1.35Weight corrected hCGMOM = Uncorrect(pd hCGMOM
1,3"
0.4654. 78.56
Maternal
1.25:! 1,2O ~; 1,15-; ¢-) ¢,.
1.1i
c 1.05-
~
10.95i 0.9~ 0.85 100
. . . .
I
. . . .
120
I
. . . .
140
I
. . . .
160
I
. . . .
180
I
. . . .
200
I
. . . .
220
I
. . . .
240
260
Mean Weight (pounds) Fig. 1. hCG weight correction formula. MOM, Multiples of the median.
Table I L Effect of maternal weight and age on Down syndrome screen-positive rate after weight correction of hCG
Screen-positive rate (hCG corrected) (%) Maternal age (yr) < 20 20-24 25-29 30-34 >_35 All
l
< 180 lb
>_180 lb
1.4 1.8 2.3 7.0 32.0 7.2
0.8 2.0 2.5 4.7 26.0 6.9
1
Significance p p p p p p
= = = = = =
0.57 0.80 0.80 0.11 0.06 0.73
Table I I I . Effect of weight correction of hCG on Down syndrome screen-positive rate and detection rate (n = 1936)
Screen-positive rate Down syndrome detection rate
Without correction (%)
With correction (%)
S~gnificance
18.5 68 (36/53)
18.9 68 (36/53)
NS NS
NS, Not significant.
overall screen-positive rate and Down syndrome detection rate were u n c h a n g e d (Table III). Of note, only 11 of the 53 women with fetal Down syndrome weighed -> 180 pounds, and eight of 11 already had positive Down syndrome screening tests before weight correction.
Comment Our analysis confirms that, analogous to maternal serum AFP, hCG values are affected by maternal weight and volume of distribution. T h e inequity in screenpositive rates between women weighing < 180 and >- 180 pounds can be eliminated with a weight correction formula. Although weight correction did not have an effect on the overall Down syndrome screen-positive and detection rates in our database, it did distribute the
positive screening tests more equitably among women of all weights. Weight correction of hCG had the most significant effect on women _ 30 years old. This p h e n o m e n o n is most easily explained by considering the maternal a g e related risk of Down syndrome. Maternal age is a strong predicter of fetal aneuploidy. ~' A woman < 30 years old is at such low risk by virtue of her age that a small change in the hCG multiple of the median is unlikely to significantly a l t e r her estimated risk of fetal Down syndrome. Conversely, a woman _>30 years old already has such a high age-related risk that a small change in the hCG multiple of the median might be sufficient to change her combined risk relative to the chosen cutoff. Should maternal weight correction of hCG be insti-
1300
October 1995 Am J Obstet Gynecol
Wenstrom et al.
tuted even though it doesn't a p p e a r to change the overall Down syndrome screen-positive rate or the detection rate? We believe that it should for two (theoretic) reasons. First, the multiple-marker screening test is becoming increasingly important to older gravid women. Women who have delayed childbearing or who have conceived after treatment of infertility may not wish to j e o p a r d i z e a highly valued pregnancy by undergoing genetic amniocentesis unless they are demonstrated to be at clearly increased risk. Because weight tends to increase with age, the Down syndrome risk of older gravid women may be consistently underestimated without weight correction of hCG. If an older pregnant woman relies on the (falsely) lower risk estimated by the uncorrected multiple-marker screening test, she may decline an amniocentesis for advanced maternal age, and fetal aneuploidy may be missed. T h e second theoretic advantage of weight correction of hCG is that it results in fewer false-positive screening tests in below-average-weight women. T h e specificity of the multiple-marker screening test is already quite l o w . 7 , s W o m e n with abnormal screening test results, even if the results turn out to be falsely abnormal, u n d e r g o tremendous stress and an (possibly unnecessary) amniocentesis. Weight correction of hCG should result in the recommendation of fewer unnecessary procedures for slender women and may ultimately reduce the procedure-related loss rate of unaffected fetuses. In summary, we found that hCG is affected by maternal weight and that a weight correction formula could be derived and applied to more equitably distribute the abnormal Down syndrome screening test results among women of all weights. O u r results will need to be verified by the directors of other reference laboratories,
who may also want to derive and evaluate their own hCG weight correction formulas. REFERENCES
1. United Kingdom Collaborative Study on Alpha-fetoprotein in Relation to Neural-tube Defects. Maternal serum alpha-fetoprotein measurement in antenatal screening for anencephaly and spina bifida in early pregnancy. Lancet 1977;2:1323-32. 2. Cuckle HS, Wald NJ, Lindenbaum RH. Maternal serum alpha-fetoprotein measurement: a screening test for Down syndrome. Lancet 1984;1:926-9. 3. DiMaio MS, Baumgarten A, Greenstein RM, Saal HM, Mahoney MJ. Screening for fetal Down's syndrome in pregnancy by measuring maternal serum alpha-fetoprotein levels. N EnglJ Med 1987;317:342-6. 4. Burton BK. Elevated maternal serum alpha-fetoprotein (MSAFP): interpretation and follow-up. Clin Obstet Gynecol 1988;31:293-305. 5. Wald NJ, Cuckle H, Boreham J, Terzian E, Redman C. The effect of maternal weight on maternal serum alphafetoprotein levels. Br J Obstet Gynaecol 1981;80:1094-6. 6. Haddow JE, Kloza EM, Knight GJ, Smith DE. Relation between maternal weight a n d serum aipha-fetoprotein concentration during the second trimester. Clin Chem 1981;27:133-4. 7. Haddow JE, Palomaki GE, Knight GJ, et al. Prenatal screening for Down's syndrome with use of maternal serum markers. N Engl J Med 1992;327:588-93. 8. Cheng EY, Luthy DA, Zebelman AM, Williams MA, Lieppman RE, Hickok DE. A prospective evaluation of a secondtrimester screening test for fetal Down syndrome using maternal serum alpha-fetoprotein, hCG, and unconjugated estriol. Obstet Gynecol 1993;81:72-7. 9. Wenstrom KD, Williamson RA, Grant SS, Hudson JD, Getchell JP. Evaluation of multiple-marker screening for Down syndrome in a statewide population. AM J OBSTET GYNECOL1993;169:793-7. 10. Bogart MH, Pandian MR, Jones OW. Abnormal maternal serum chorionic gonadotropin levels in pregnancies with fetal chromosome abnormalities. Prenat Diagn 1987;7: 623-30. 11. Wald NJ, Cuckle HS, Densem JW, et al. Maternal serum screening for Down's syndrome in early pregnancy. BMJ 1988;297:883-7.