Prospective evaluation of maternal serum human chorionic gonadotropin levels in 3428 pregnancies Mark H. Bogart, PhD: O.W. Jones, MD: Robin A. Felder, PhD; Robert G. Best, PhD,c Linda Bradley, PhD/ William Butts, PhD," Barbara Crandall, MD,' Wendy MacMahon, BS,g Frank H. Wians, Jr., PhD: and Paulette V. Loeh, BSi La Jolla and Los Angeles, California, Charlottesville, Virginia, Columbia, South Carolina, Chandler, Arizona, Renton, Washington, Decatur, Georgia, and Lackland, Texas As part of a multicenter prospective study, second-trimester human chorionic gonadotropin and a-fetoprotein concentrations were evaluated. Data included maternal age, human chorionic gonadotropin level, a-fetoprotein level, weight, race, and pregnancy outcome of 3428 pregnancies at between 15 and 20 weeks' gestation. The results of the study indicate that human chorionic gonadotropin levels decrease as maternal weight increases, that weight-adjusted human chorionic gonadotropin levels for Oriental and black women are higher than for white or Hispanic women, and that twin pregnancies have higher human chorionic gonadotropin levels than singleton pregnancies. Of 255 pregnancies that did not have normal outcomes, 54 (21.2%) had human chorionic gonadotropin levels >2.0 multiples of the median and 26 (10.2%) had a-fetoprotein levels >2.5 multiples of the median. Of 11 pregnancies with fetal aneuploidy, 6 (54.5%) had human chorionic gonadotropin levels >2.0 multiples of the median. It is concluded that in human chorionic gonadotropin screening programs for fetal Down syndrome, weight and race adjustments are necessary for accurate risk assessment. (AM J OBSTET GVNECOL 1991 ;165:663-7.)
Key words: Human chorionic gonadotropin, a-fetoprotein, Down syndrome, aneuploidy
The decision to prenatally screen pregnant women for fetal Down syndrome and other forms of aneuploidy has traditionally been made on the basis of maternal age. In recent years the use of combined maternal age and maternal serum a-fetoprotein concentrations (AFP) has become routine; it has recently been estimated that approximately 1 million pregnancies are screened according to these parameters. l There is widespread use of maternal serum AFP in spite of a combined maternal serum AFP and age detection rate of 2.0 multiples of the median (54.5%), induding four of six pregnancies with Down syndrome (66.7%). The case of trisomy 20 mosaicism resulted in a normal female infant. Blood chromosome analysis did not reveal any trisomy 20 cells. This case most likely reflects confined mosaicism. Of
Prospective hCG evaluation
Volume 165 Number 3
665
Table II. Weight-adjusted hCG from abnormal pregnancy outcomes hCG > 2.0 MoM Outcome
No.
No.
Fetal death CPD-fetal distress Prematurity-low birth weight Aneuploidy Twins (normal) Twins (abnormal) Others*
43 8 45 11 33 3 112 255
TOTAL
I
AFP >2.5 MoM
I
%
No.
5 5 13
11.6 62.5 28.8
9 0 4
20.9 0 6.2
6 12 0 17 58
54.5 36.4 0 15.2 22.7
1 9 1 2 26
9.1 27.3 33.3 1.8 10.2
%
MoM, Multiples of the median; CPD, cephalopelvic disproportion.
*All other pregnancies reported to be abnormal, including pregnancies involving omphalocele, dysplastic kidneys, gestational diabetes, hydrops, oligohydramnios, polyhydramnios, Potter's syndrome, cleft lip, and clubfoot.
Table III. Median hCG values and number of pregnancies White Weeks' gestation
hCG value
15 16 17 18 19 20
32.80 27.49 22.41 20.21 20.21 18.13
I
Black
No. of pregnancies
hCG value
237 1222 633 261 91 61
34.77 26.65 24.63 22.51 18.70 15.12
I
Hispanic
No. of pregnancies
hCG value
37 112 58 61 28 14
41.63 26.20 24.30 19.82 18.31 27.80
J
Oriental
No. of pregnancies
hCG value
10 94 42 16 12 11
4.1.60 38.12 28.00 29.10 21.04
I
No. of pregnancies
7 45 19 13 9
hCG values are before weight adjustment. the white women with pregnancies having normal outcomes, 9.82% had weight-adjusted hCG levels >2.0 multiples of the median. The median age of patients in this study was 28 years. There was no correlation between hCG values and maternal age (correlation coefficient = 0.028). There were insufficient data to determine any correlation between maternal diabetes and hCG levels. Comment
The results of this study indicate that maternal weight acljustment is needed in routine hCG screening for fetal aneuploidy. The weight-adjustment formula we developed for hCG values takes the same form previously described for maternal weight adjustment for maternal serum AFP evaluation II showing a decrease in median hCG levels with increasing maternal weight. After weight adjustment, hCG levels from the normal singleton pregnancies of Oriental women were 16% higher than those for white women. However, because we evaluated hCG levels in the pregnancies of only 93 Oriental women with normal outcomes, further studies with larger numbers of Oriental women are needed before an accurate adjustment for Oriental-race factor can be calculated. It is interesting to note that the incidence of trophoblastic disease is greater in Orientals
Table IV. Median weights Group
White Hispanic Oriental Black
I
Median weight (lb)
No.
P*
139 133 115 147
2505 180 90 310
0.008 0.0001 0.0001
*Significance between median weights of white women and other groups (P < 0.05 is considered to be significant). than in whites. 12 Whether the increased level of hCG contributes to or reflects a significant risk factor for trophoblastic disease should be the subject of further study. Our results confirm the report by Petrocik et al. b that there is no statistically significant difference in hCG levels between white and black patients; however, this conflicts with a recently reported study in which significantly different levels were observed between these two racial groupS.13 On the other hand, we did observe a significant difference between the weight-adjusted multiples of the median for blacks and whites, with blacks having 9.8% higher weight-adjusted hCG levels. Although our data are taken from only 310 pregnant black women, it appears that the placenta of black
666
Bogart et al.
1.5
Septeillber 1991 Am .J Obstet Gynecol
I
I
I
*
1.4 I-
2 o 2
**
1.3 I-
1.1
r- r-
-
r- fo-
-
r- r-
1.2 t-
Table V. Weight-adjusted heG values for aneu ploid pregnancies
I
-
+
-
I-
Abnormality
47,+21 47,+21 47,+2 1 47,+2 1 47,+2 1 47,+2 1 47,+ 18 47,+ IS 47,+ 13 45, X 46,XX/47, + 20*
MuM 16 16 18 19.5 20.7 20.5 16 20 16 16 16
3 1.0 11 8.3 41.8 72.6 39.8 10.5 10.0 12.0 31.0 106.8 76.4
1.1 3 4.29 2.07 3.59 2.20 0.58 0.36 0.59 1.1 3 3.S9 2.78
MoM, Multiples of the median.
1.0
185
2505
310
93
Hispanic
White
Black
Oriental
Race Fig. 1. Weight-adjusted multiples of the median (mean :±: SEM) of different racial groups. Numbers within bars equal number of patients. One asterisk, Significance between white and Oriental women (p = 0.0 I); two asterisks, significance between white and black women (j) = 0.008).
women produces 9.8% more heG than the placenta of white women . Whether the increased amount of heG is due to increased placenta size or increased production cannot be determined from this study. It is worth noting that the heG levels recently reported for blacks by Simpson et al.,13 using the same assay system that was used in our study, are nearly the same as we report for whites. It appears that the median heG levels for whites in the study by Simpson et aI., are less than the levels we observed. Such geographic variation in heG levels in the pregnancies with normal outcomes of white women have previously been reported by Bartels et aLI I and most likely reflect differences in maternal weight rather than a true difference in heG production by the placenta. In this regard we observed a significantly lower weight in women enrolled in this study in Washington and a higher weight in women from Virginia. We believe that the use of weight-adjustment formulas is critical to accurate assessment of maternal heG levels and that the use of such formu las is appropriate both for comparative studies and for clinical evaluation of Down syndrome risk. Additional factors such as smoking ma y also affect heG levels"" IGand result in differences among subgroups wit hin the population. Although there is no documented difference in the incidence of fetal aneuploidy between different racial groups, screening programs that do not account for racial differences in weight, heG production, and perhaps smoking habits may result in different detection and false-positive rates.
*See article text.
Our results indicate no correlation between maternal age and heG levels; these results are consistent with previous reports'" and indicate that age and heG levels are independent factors useful in screening for fetal aneuploidy. Because of the increased placenta volume in twin as opposed to singleton pregnancies, the level of maternal serum heG has been reported to be higher in twin pregnancies. I' In our group of33 twin pregnancies with normal outcomes, weight-adjusted heG levels were significantly elevated (p = 0.001), with the median weight-adjusted heG level a pproximately 1.5 times the singleton median. In our study 6 of II pregnancies (54.5%) with fetal aneu ploidy had abnormal heG levels, including four of six pregnancies (66 .7 %) with Down syndrome (Table IV). These results are consistent with previous reports"']"; however, because of the limited number of cases of aneuploidy in this stud y, the statistical validity of the detection percentage is unreliable. To more accurately evaluate the relationship between h eG, AFP, age, and ane uploid y, we have evaluated 49 Down syndrome pregnancies between 15 and 20 weeks' gestation using a probability risk calculation similar to that of Petrocik et aU We observed a detection rate of 65.3%, with a false-positive rate of 7.85% (data not presented). This is quite similar to the findings of Petrocik et al. of approximately 68% detection at a 5 % false-positive rate. Our fa lse-positive rate is somewhat higher but is primarily based on gestational age estimation from the date of the mother's last menstrual period. It is wetl documented that approximately one third of women with abnormal maternal serum AFP levels have incorrect gestational age estimation when date of last menstrual period is compared with ultrasonographic evaluation. I" Assuming that there is a similar occurrence in our study of one third of the women with abnormal heG levels having incorrect ges-
Volume 165 Number 3
tational age estimates, our false-positive rate would drop to approximately 5.2% after ultrasonographic evaluation. Had this been an intervening study 7.8% of the women would have been referred for ultra sonographic evaluation, but only 5.2% would have had amniocentesis. Screening programs can be expected to lead to the detection of approximately 65% of fetal aneuploidy, including Down syndrome, within the approximately 5% to 7% of women offered amniocent~sis when calculation of combined-risk rates include evaluation of maternal age and hCG level. The findings of Wald et aI.' and Petrocik et al. 6 indicate that addition of maternal serum AFP evaluation to hCG and age only minimally increases detection of fetal aneuploidy; however, the value of maternal serum AFP in detecting other types of abnormalities is well known. The addition of other biochemical parameters such as the gonadotropin a-subunit,3,4 unconjugated estriol,"19 and pregnancyspecific 131-g1ycoprotein (SPl)20 for increasing detection of fetal aneuploidy have been proposed. There are conflicting claims regarding the value of unconjugated estriol'9 21 and SP 1,14,20,22 and the findings of Bogart et al. 3 ,4 on the free a-subunit have not been independently verified. Thus the value of these biochemical tests in addition to or as a replacement for maternal serum AFP in age-hCG-AFP risk evaluation for fetal aneuploidy remains to be proved. Decisions regarding the incorporation of one or more of the alternative biochemical tests depend on judgment of cost, accuracy, consistency, available assay systems, and ease of use. At this time there is insufficient evidence to determine which protocol is most efficacious. Regardless of conflicting claims regarding the addition of alternative biochemical tests, all screening protocols primarily depend on hCG evaluation. Thus it is important to establish baseline data on race differences, to establish weightadjustment formulas, and to begin recognizing other pregnancy complications that are associated with elevated levels of hCG. We acknowledge the assistance ofJai Dev, Pam King, Peggy Grau, MD, and Effrain Valladolid. REFERENCES 1. Palomaki GE, Knight G], Holman MS. Haddow]E, Maternal serum a-fetoprotein screening for fetal Down syndrome in the United States: results of a survey. AM] OBSTET GVNECOL 1990;162:317-21. 2, Cuckle HS, Wald N], Lindenbaum RH, et al. Maternal serum alpha-fetoprotein measurement: a screening test for Down syndrome. Lancet 1984; 1:926-9,
Prospective hCG evaluation
667
3. Bogart MH, Pan dian MR,]ones OW, Abnormal maternal serum chorionic gonadotropin levels in pregnancies with fetal chromosome abnormalities. Pre nat Diagn 1987; 7:623-30, 4. Bogart MH, Golbus MS, Sorg ND, Jones OW. Human chorionic gonadotropin levels in pregnancies with aneuploid fetuses, Pre nat Diagn 1989;9:379-84. 5. Wald N], Cuckle HS, Densem ]W, et al. Maternal serum screening for Down's syndrome in early pregnancy. BM] 1988;297:833-7, 6, Petrocik E, Wassman ER, Kelly]C. Prenatal screening for Down syndrome with maternal serum human chorionic gonadotropin levels, AM ] OBSTET GV;\IECOL 1989; 161:1168-73, 7. Osathanondh R, Canick ]A, Abell KB, et al. Second trimester screening for trisomy 21. Lancet 1989;2:52, 8. White I, Papiha SS, Magnay D. Improving methods of screening for Down's syndrome, N Engl ] Med 1989;320:401-2. 9, Norgaard-Pedersen B, Larsen SO, Arends .I, et al. Maternal serum markers in screening for Down syndrome. Clin Genet 1990;37:35-43. 10. Suchy SF, Yeager MT. Down syndrome screening in women under 35 with maternal serum hCG. Obstet Gynecol 1990;76:20-4, 11. Knight G], Palomaki GE, Haddow .IE. Use of alphafetoprotein measurements to screen for Down's syndrome. Clin Obstet Gynecol 1988;31:306-27, 12, Grimes DA, Epidemiology of gestational trophoblastic disease. AM] OBSTET GVNECOL 1984;150:309-18. 13, Simpson ]L, Elisa S, Morgan CD, et al. Second trimester maternal serum human chorionic gonadotropin and unconjugated oestriol levels in blacks and whites. Lancet 1990;335: 1459-60. 14, Bartels I, Thiele M, Bogart MH. Maternal serum hCG and SPI in pregnancies with fetal aneuploidy, Am] Med Genet 1990;37:261-4. 15. Bernstein L, Pike MC, Lobo RA, et al. Cigarette smoking in pregnancy results in marked decrease in maternal hCG and oestradiol levels. Br ] Obstet Gynaecol 1989;96: 92-6, 16. Cuckle HS, Wals N], Densem ]W, et al. The effect of smoking in pregnancy on maternal serum alpha-fetoprotein, unconjugated oestriol, human chorionic gonadotropin, progesterone and dihydroepiandrosterone sulphate levels, Br] Obstet Gynaecol 1990;97:272-6. 17. Reuter AM, Gaspard U], Deville ]L, et al. Serum concentrations of human chorionic gonadotropin and its alpha and beta subunits. 1, During normal singleton and twin pregnancies, Clin Endocrinol (Oxf) 1980;13:305-18, 18, Lustig L, Clarke S, Cunningham G, et al. California's experience with low MS-AFP results, Am .I Med Genet 1988;31 :211-22. 19. Canick .lA, Knight G], Palomaki GE, et aL Low second trimester maternal serum unconjugated oestriol in pregnancies with Down's syndrome, Br .I Obstet Gynaecol 1988;95:334-41. 20, Bartels I, Lindemann A. Maternal levels of pregnancyspecific J3 1-glycoprotein (SP-l) are elevated in pregnancies affected by Down's syndrome, Hum Genet 1988;80:46-8. 21. Macri ]N, Kasturi RV, Krantz DA, et al. Maternal serum Down syndrome screening: lInconjugated estriol is not useful. AM] OBSTET GV;\IECOL 1990; 162:672-3, 22, Wald N, Clickle H, Densem J. Maternal serum specific beta I-glycoprotein in pregnancies associated with Down's syndrome, Lancet 1989;2:450.
Key words: Human chorionic gonadotropin, a-fetoprotein, Down syndrome, aneuploidy
The decision to prenatally screen pregnant women for fetal Down syndrome and other forms of aneuploidy has traditionally been made on the basis of maternal age. In recent years the use of combined maternal age and maternal serum a-fetoprotein concentrations (AFP) has become routine; it has recently been estimated that approximately 1 million pregnancies are screened according to these parameters. l There is widespread use of maternal serum AFP in spite of a combined maternal serum AFP and age detection rate of 2.0 multiples of the median (54.5%), induding four of six pregnancies with Down syndrome (66.7%). The case of trisomy 20 mosaicism resulted in a normal female infant. Blood chromosome analysis did not reveal any trisomy 20 cells. This case most likely reflects confined mosaicism. Of
Prospective hCG evaluation
Volume 165 Number 3
665
Table II. Weight-adjusted hCG from abnormal pregnancy outcomes hCG > 2.0 MoM Outcome
No.
No.
Fetal death CPD-fetal distress Prematurity-low birth weight Aneuploidy Twins (normal) Twins (abnormal) Others*
43 8 45 11 33 3 112 255
TOTAL
I
AFP >2.5 MoM
I
%
No.
5 5 13
11.6 62.5 28.8
9 0 4
20.9 0 6.2
6 12 0 17 58
54.5 36.4 0 15.2 22.7
1 9 1 2 26
9.1 27.3 33.3 1.8 10.2
%
MoM, Multiples of the median; CPD, cephalopelvic disproportion.
*All other pregnancies reported to be abnormal, including pregnancies involving omphalocele, dysplastic kidneys, gestational diabetes, hydrops, oligohydramnios, polyhydramnios, Potter's syndrome, cleft lip, and clubfoot.
Table III. Median hCG values and number of pregnancies White Weeks' gestation
hCG value
15 16 17 18 19 20
32.80 27.49 22.41 20.21 20.21 18.13
I
Black
No. of pregnancies
hCG value
237 1222 633 261 91 61
34.77 26.65 24.63 22.51 18.70 15.12
I
Hispanic
No. of pregnancies
hCG value
37 112 58 61 28 14
41.63 26.20 24.30 19.82 18.31 27.80
J
Oriental
No. of pregnancies
hCG value
10 94 42 16 12 11
4.1.60 38.12 28.00 29.10 21.04
I
No. of pregnancies
7 45 19 13 9
hCG values are before weight adjustment. the white women with pregnancies having normal outcomes, 9.82% had weight-adjusted hCG levels >2.0 multiples of the median. The median age of patients in this study was 28 years. There was no correlation between hCG values and maternal age (correlation coefficient = 0.028). There were insufficient data to determine any correlation between maternal diabetes and hCG levels. Comment
The results of this study indicate that maternal weight acljustment is needed in routine hCG screening for fetal aneuploidy. The weight-adjustment formula we developed for hCG values takes the same form previously described for maternal weight adjustment for maternal serum AFP evaluation II showing a decrease in median hCG levels with increasing maternal weight. After weight adjustment, hCG levels from the normal singleton pregnancies of Oriental women were 16% higher than those for white women. However, because we evaluated hCG levels in the pregnancies of only 93 Oriental women with normal outcomes, further studies with larger numbers of Oriental women are needed before an accurate adjustment for Oriental-race factor can be calculated. It is interesting to note that the incidence of trophoblastic disease is greater in Orientals
Table IV. Median weights Group
White Hispanic Oriental Black
I
Median weight (lb)
No.
P*
139 133 115 147
2505 180 90 310
0.008 0.0001 0.0001
*Significance between median weights of white women and other groups (P < 0.05 is considered to be significant). than in whites. 12 Whether the increased level of hCG contributes to or reflects a significant risk factor for trophoblastic disease should be the subject of further study. Our results confirm the report by Petrocik et al. b that there is no statistically significant difference in hCG levels between white and black patients; however, this conflicts with a recently reported study in which significantly different levels were observed between these two racial groupS.13 On the other hand, we did observe a significant difference between the weight-adjusted multiples of the median for blacks and whites, with blacks having 9.8% higher weight-adjusted hCG levels. Although our data are taken from only 310 pregnant black women, it appears that the placenta of black
666
Bogart et al.
1.5
Septeillber 1991 Am .J Obstet Gynecol
I
I
I
*
1.4 I-
2 o 2
**
1.3 I-
1.1
r- r-
-
r- fo-
-
r- r-
1.2 t-
Table V. Weight-adjusted heG values for aneu ploid pregnancies
I
-
+
-
I-
Abnormality
47,+21 47,+21 47,+2 1 47,+2 1 47,+2 1 47,+2 1 47,+ 18 47,+ IS 47,+ 13 45, X 46,XX/47, + 20*
MuM 16 16 18 19.5 20.7 20.5 16 20 16 16 16
3 1.0 11 8.3 41.8 72.6 39.8 10.5 10.0 12.0 31.0 106.8 76.4
1.1 3 4.29 2.07 3.59 2.20 0.58 0.36 0.59 1.1 3 3.S9 2.78
MoM, Multiples of the median.
1.0
185
2505
310
93
Hispanic
White
Black
Oriental
Race Fig. 1. Weight-adjusted multiples of the median (mean :±: SEM) of different racial groups. Numbers within bars equal number of patients. One asterisk, Significance between white and Oriental women (p = 0.0 I); two asterisks, significance between white and black women (j) = 0.008).
women produces 9.8% more heG than the placenta of white women . Whether the increased amount of heG is due to increased placenta size or increased production cannot be determined from this study. It is worth noting that the heG levels recently reported for blacks by Simpson et al.,13 using the same assay system that was used in our study, are nearly the same as we report for whites. It appears that the median heG levels for whites in the study by Simpson et aI., are less than the levels we observed. Such geographic variation in heG levels in the pregnancies with normal outcomes of white women have previously been reported by Bartels et aLI I and most likely reflect differences in maternal weight rather than a true difference in heG production by the placenta. In this regard we observed a significantly lower weight in women enrolled in this study in Washington and a higher weight in women from Virginia. We believe that the use of weight-adjustment formulas is critical to accurate assessment of maternal heG levels and that the use of such formu las is appropriate both for comparative studies and for clinical evaluation of Down syndrome risk. Additional factors such as smoking ma y also affect heG levels"" IGand result in differences among subgroups wit hin the population. Although there is no documented difference in the incidence of fetal aneuploidy between different racial groups, screening programs that do not account for racial differences in weight, heG production, and perhaps smoking habits may result in different detection and false-positive rates.
*See article text.
Our results indicate no correlation between maternal age and heG levels; these results are consistent with previous reports'" and indicate that age and heG levels are independent factors useful in screening for fetal aneuploidy. Because of the increased placenta volume in twin as opposed to singleton pregnancies, the level of maternal serum heG has been reported to be higher in twin pregnancies. I' In our group of33 twin pregnancies with normal outcomes, weight-adjusted heG levels were significantly elevated (p = 0.001), with the median weight-adjusted heG level a pproximately 1.5 times the singleton median. In our study 6 of II pregnancies (54.5%) with fetal aneu ploidy had abnormal heG levels, including four of six pregnancies (66 .7 %) with Down syndrome (Table IV). These results are consistent with previous reports"']"; however, because of the limited number of cases of aneuploidy in this stud y, the statistical validity of the detection percentage is unreliable. To more accurately evaluate the relationship between h eG, AFP, age, and ane uploid y, we have evaluated 49 Down syndrome pregnancies between 15 and 20 weeks' gestation using a probability risk calculation similar to that of Petrocik et aU We observed a detection rate of 65.3%, with a false-positive rate of 7.85% (data not presented). This is quite similar to the findings of Petrocik et al. of approximately 68% detection at a 5 % false-positive rate. Our fa lse-positive rate is somewhat higher but is primarily based on gestational age estimation from the date of the mother's last menstrual period. It is wetl documented that approximately one third of women with abnormal maternal serum AFP levels have incorrect gestational age estimation when date of last menstrual period is compared with ultrasonographic evaluation. I" Assuming that there is a similar occurrence in our study of one third of the women with abnormal heG levels having incorrect ges-
Volume 165 Number 3
tational age estimates, our false-positive rate would drop to approximately 5.2% after ultrasonographic evaluation. Had this been an intervening study 7.8% of the women would have been referred for ultra sonographic evaluation, but only 5.2% would have had amniocentesis. Screening programs can be expected to lead to the detection of approximately 65% of fetal aneuploidy, including Down syndrome, within the approximately 5% to 7% of women offered amniocent~sis when calculation of combined-risk rates include evaluation of maternal age and hCG level. The findings of Wald et aI.' and Petrocik et al. 6 indicate that addition of maternal serum AFP evaluation to hCG and age only minimally increases detection of fetal aneuploidy; however, the value of maternal serum AFP in detecting other types of abnormalities is well known. The addition of other biochemical parameters such as the gonadotropin a-subunit,3,4 unconjugated estriol,"19 and pregnancyspecific 131-g1ycoprotein (SPl)20 for increasing detection of fetal aneuploidy have been proposed. There are conflicting claims regarding the value of unconjugated estriol'9 21 and SP 1,14,20,22 and the findings of Bogart et al. 3 ,4 on the free a-subunit have not been independently verified. Thus the value of these biochemical tests in addition to or as a replacement for maternal serum AFP in age-hCG-AFP risk evaluation for fetal aneuploidy remains to be proved. Decisions regarding the incorporation of one or more of the alternative biochemical tests depend on judgment of cost, accuracy, consistency, available assay systems, and ease of use. At this time there is insufficient evidence to determine which protocol is most efficacious. Regardless of conflicting claims regarding the addition of alternative biochemical tests, all screening protocols primarily depend on hCG evaluation. Thus it is important to establish baseline data on race differences, to establish weightadjustment formulas, and to begin recognizing other pregnancy complications that are associated with elevated levels of hCG. We acknowledge the assistance ofJai Dev, Pam King, Peggy Grau, MD, and Effrain Valladolid. REFERENCES 1. Palomaki GE, Knight G], Holman MS. Haddow]E, Maternal serum a-fetoprotein screening for fetal Down syndrome in the United States: results of a survey. AM] OBSTET GVNECOL 1990;162:317-21. 2, Cuckle HS, Wald N], Lindenbaum RH, et al. Maternal serum alpha-fetoprotein measurement: a screening test for Down syndrome. Lancet 1984; 1:926-9,
Prospective hCG evaluation
667
3. Bogart MH, Pan dian MR,]ones OW, Abnormal maternal serum chorionic gonadotropin levels in pregnancies with fetal chromosome abnormalities. Pre nat Diagn 1987; 7:623-30, 4. Bogart MH, Golbus MS, Sorg ND, Jones OW. Human chorionic gonadotropin levels in pregnancies with aneuploid fetuses, Pre nat Diagn 1989;9:379-84. 5. Wald N], Cuckle HS, Densem ]W, et al. Maternal serum screening for Down's syndrome in early pregnancy. BM] 1988;297:833-7, 6, Petrocik E, Wassman ER, Kelly]C. Prenatal screening for Down syndrome with maternal serum human chorionic gonadotropin levels, AM ] OBSTET GV;\IECOL 1989; 161:1168-73, 7. Osathanondh R, Canick ]A, Abell KB, et al. Second trimester screening for trisomy 21. Lancet 1989;2:52, 8. White I, Papiha SS, Magnay D. Improving methods of screening for Down's syndrome, N Engl ] Med 1989;320:401-2. 9, Norgaard-Pedersen B, Larsen SO, Arends .I, et al. Maternal serum markers in screening for Down syndrome. Clin Genet 1990;37:35-43. 10. Suchy SF, Yeager MT. Down syndrome screening in women under 35 with maternal serum hCG. Obstet Gynecol 1990;76:20-4, 11. Knight G], Palomaki GE, Haddow .IE. Use of alphafetoprotein measurements to screen for Down's syndrome. Clin Obstet Gynecol 1988;31:306-27, 12, Grimes DA, Epidemiology of gestational trophoblastic disease. AM] OBSTET GVNECOL 1984;150:309-18. 13, Simpson ]L, Elisa S, Morgan CD, et al. Second trimester maternal serum human chorionic gonadotropin and unconjugated oestriol levels in blacks and whites. Lancet 1990;335: 1459-60. 14, Bartels I, Thiele M, Bogart MH. Maternal serum hCG and SPI in pregnancies with fetal aneuploidy, Am] Med Genet 1990;37:261-4. 15. Bernstein L, Pike MC, Lobo RA, et al. Cigarette smoking in pregnancy results in marked decrease in maternal hCG and oestradiol levels. Br ] Obstet Gynaecol 1989;96: 92-6, 16. Cuckle HS, Wals N], Densem ]W, et al. The effect of smoking in pregnancy on maternal serum alpha-fetoprotein, unconjugated oestriol, human chorionic gonadotropin, progesterone and dihydroepiandrosterone sulphate levels, Br] Obstet Gynaecol 1990;97:272-6. 17. Reuter AM, Gaspard U], Deville ]L, et al. Serum concentrations of human chorionic gonadotropin and its alpha and beta subunits. 1, During normal singleton and twin pregnancies, Clin Endocrinol (Oxf) 1980;13:305-18, 18, Lustig L, Clarke S, Cunningham G, et al. California's experience with low MS-AFP results, Am .I Med Genet 1988;31 :211-22. 19. Canick .lA, Knight G], Palomaki GE, et aL Low second trimester maternal serum unconjugated oestriol in pregnancies with Down's syndrome, Br .I Obstet Gynaecol 1988;95:334-41. 20, Bartels I, Lindemann A. Maternal levels of pregnancyspecific J3 1-glycoprotein (SP-l) are elevated in pregnancies affected by Down's syndrome, Hum Genet 1988;80:46-8. 21. Macri ]N, Kasturi RV, Krantz DA, et al. Maternal serum Down syndrome screening: lInconjugated estriol is not useful. AM] OBSTET GV;\IECOL 1990; 162:672-3, 22, Wald N, Clickle H, Densem J. Maternal serum specific beta I-glycoprotein in pregnancies associated with Down's syndrome, Lancet 1989;2:450.
