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Free beta HCG subunit versus intact HCG in the multiple marker screening test for fetal down syndrome
S90 293
SPO Abstracts
J a n u a t 7 1997 Am J Obstet Gynecol
SECOND-TRIMESTER DETECTION OF TRISOMY 18 USING FREEBETA HCG AND AFP. D. Krantz 1~, T. Hallahan I, P. Buchanan2, j~ Larsen3, J~ Macril. 1NTD Laboratories, Inc. Huntington Station, NW, eGeneCare Medical Genetics Center, Chapel Hill, NC, 3George Washington Univ. Washington, DC. OBJECTIVE: To compare whether an atypicality index or a patient specific trisomy 18 risk calculation gives better screening efficiency" for trisomy 18. STUDY DESIGN: As part of routine prospective second-trimester Dovna Syndrome screening with free Beta hCG and AFP, 31 trisomy 18 cases were identified. A total of 3100 unaffected matched controls (100/T-18 ease) were evaluated. For each sample, an atypicality index based on the Mahalanobis Squared distance and a patient specific trisomy 18 risk were calculated. Modeling was based on age distribution of live births and observed likelihood ratios. RESULTS: Population parameters and weight adjusted screening results follow:
295
SIGNIFICANCE OF A FALSE POSITIVE TRISOMY 18 (T18) MULTIPLE MARKER SCREENING TEST (MMST). K.D. Wenstrom, j~ Owen, C.G. Brumfield, R.O. Davis, M. DuBardL Dept. of Ob/Gyn, University of Alabama at Birmingham, AL. OBJECTIVE: To determine if a l~alse [+] T18 MMST (Maternal serum alpha fetoprotein, [MSAFP] --< 0.75 MOM, estriol < 0.60 MOM, and human chorionic gonadotropin, [hCG] --< 0.55 MOM) indicates increased risk for obstetrical cmnplications or is related to maternal weight. STUDY DESIGN: We accessed our genetic data base, containing MMST results, fetal karyotypes, and pregnancy outcomes from patients seen in the prenatal diagnosis clinic from 1993 to 1996 in - 5376, mean maternal age = 32.5 4- 6.7). In the MMST, only MSAFP had been adjusted for nmternal weight. We selected all patients with a [+] T18 screening test (n = 119, 2.2%) and all patients with a normal MMST (n = 3933, 73%) and compared pregnancy outcomes. RESULTS: A [+] T18 screen identified 42% (5/12) of T18 fetuses. Compared to those with a normal MMST, women with a false [+] T18 screen were heavier (181 _+ 49 lbs. vs 161 + 38, p = 0.0002), and younger (30 4- 7 years vs 32 -+ 7 years, p = 0.0008). Weight adjusting estriol and hCG in addition to MSAFP reduced the screen [+] TI8 rate by 32% (from 2.2% to 1.5%) and reduced the number of amnios required per case detected (frmn 1/24 to 1/11), but did not change the T 18 detection rate. Compared to women with a normal MMST, women with a false [+] T18 screen were at no increased risk to have a preterm birth, low birth weight, spontaneous abortion, or neonatal demise. CONCLUSIONS: A false [+] T18 screening test does not indicate increased risk to develop pregnancy complications and may be related to higher maternal weight. Weight correction of all 3 analytes reduces the number of false [+] TI8 screening tests by one third.
296
ELEVATED SECOND TRIMESTER DIMERIC INHIBIN A LEVELS IDENTIFY DOWN SYNDROME PREGNANCIES. KD. Wenstrom~~ Owen, D.C. Chux, L. Boots'. Dept. of Ob/Gyn., The University of Alabama at Birmingham, ~L. OBJECTIVE: To determine if second trimester dimeric inhibin A (IH-A) levels distinguish Down syndrome (DS) from euploid pregnancies. STUDY DESIGN: We utilized second trimester maternal serum samples obtained prior to genetic anmioeentesis, subjected to the multiple marker screening test for DS (MMST, maternal sermn alphafetoprotein, unconjugated estriol, hCG, and maternal age), and then stored at - 7 0 ~ for -<2 years. We randomly selected 313 samples fi-om euploid pregnancies evenly distributed from 14 to 20 weeks (mean maternal age = 35.6 + 5.2 years), and also analyzed 33 samples from DS pregnancies. IH-A levels were measured by ELISA (Serotec, Oxford) and converted to week specific MOMs. The screen positive rate (DS risk > 1:190), DS detection rate, and IH-A's performance in the MMST were determined. RF~ULTS: The mean IH-A MOM was significantly higher in the DS group than in the euploid group (2.8 -+ 2.0 vs 1.2 -+ 1.0, p - 0.0001). An IH-A level -> 2.0 MOM identified 55% of all DS pregnancies at a screen positive rate of 16.5%. (The relatively high screen positive rate reflects the high maternal age of the study population.) IH-A correlated better with hCG (r = 065) than with MSAFP (r = 0.29) or estriol (r = -0.10). Replacing estriol with IH-A in the MMST resulted in a higher DS detection rate (91% vs 85%) at a lower screen positive rate (23% vs 28%). At a cut-off chosen to produce the same DS detection rate (1:150, 85%), the screen positive rate with IH-A was even lower (20% vs 28%). CONCLUSIONS: Elevated second trimester maternal serum IH-A levels identify DS pregnancies; replacing estriol with IH-A in the MMST results in a lower screen positive (amniocentesis) rate while maintaining a high DS detection rate.
Mean Sample
Age
GA
AFP Mom Median, SD
FB MoM Median, SD
r
Controls Cases
27.4 33.1
16.6 16.2
0.99(0.370) 0.68(0.513)
1.01(0.661) 0.20(0.740)
0.044 -.246
The calculated false positive and detection rates are as follows:
ded DE Atypicality: 9.21 TI8 risk: 1/lfi0 T18 Risk: 1/150 T18 Risk: 1/200
0.7% 0.3% 0.4% 0.6%
45% 55% 61% 65%
0.7% 0.3% 0.4% 0.6%
45% 50% 54% 58%
CONCLUSION: Using the free Beta/AFP protocol, patient specific risk estimation gives better detection of trisomy 18 than an atypicality index.
294
FREE BETA HCG SUBUNIT VERSUS INTACT HCG IN THE MULTIPLE MARKER SCREENING TEST FOR FETAL DOWN SYNDROME. K.D. Wenstrom,~ Owen, D.C. Chux, L. BootsL Dept. of Ob/Gyn, Univ. of Alabama at Birmingham, AL. OBJECTIVE: To compare second trimester maternal serum Free [3 human chorionic gonadotropin (F[ghCG) to intact hCG (IhCG) in the muhiple marker screening test (MMST) for fetal Down Syndrome (DS). STUDY DESIGN: From our bank of second trimester maternal sera obtained prior to genetic anmioeentesis, subjected to the MMST for DS (maternal serum alphafetoprotein, unconjugated estriol, human ehorionic gonadotropin, and maternal age) and stored at - 7 0 ~ C for -<2 years, we randmnly selected 312 samples from euploid pregnancies evenly distributed from 14 to 20 weeks' gestation, (mean maternal age = 35.6 4- 5.2 years) and 33 samples from DS pregnancies. F[3hCG was analyzed by ELISA (CIS-US, Bedford MA), and week-specific muhiples of the median (MOM) were derived. The N3hCG DS screen positive and detection rates were determined, and F[3hCG was then substituted for IhCG in the MMST. RESULTS: The mean FI3hCG MOM in the DS group was significantly higher than in the euploid group (2.4 • 1.1 vs 1.2 • 1.0, p - 0.0001). A F[3hCG >2.0 MOM identified 55% ofDS pregancies at a screen positive rate of 17%. Replacing IhCG with FI3hCG in the MMST resulted in the following:
RISK CUTOFFI :190
RISK CUTOFF 1:300
SERUM ANAL YTES
5"1?%
D S Det %
SP%
DS Det %
MSAFP, Est, IhCG MSAFP, Est, F[3hCG MSAFP, FI3hCG
28 23 22
85 84 84
35 28 28
88 97 87
SP% = Screen positive rate Det% - Detection rate CONCLUSIONS: Replacing IhCG and estriol with F~hCG in the MMST results in a similm- DS detection rate at a lower screen positive (amniocentesis) rate. Alternatively, if the screen positive rate is held constant, MSAFP, Est, and FI3hCG result in the highest DS detection rate.
SPO Abstracts
J a n u a t 7 1997 Am J Obstet Gynecol
SECOND-TRIMESTER DETECTION OF TRISOMY 18 USING FREEBETA HCG AND AFP. D. Krantz 1~, T. Hallahan I, P. Buchanan2, j~ Larsen3, J~ Macril. 1NTD Laboratories, Inc. Huntington Station, NW, eGeneCare Medical Genetics Center, Chapel Hill, NC, 3George Washington Univ. Washington, DC. OBJECTIVE: To compare whether an atypicality index or a patient specific trisomy 18 risk calculation gives better screening efficiency" for trisomy 18. STUDY DESIGN: As part of routine prospective second-trimester Dovna Syndrome screening with free Beta hCG and AFP, 31 trisomy 18 cases were identified. A total of 3100 unaffected matched controls (100/T-18 ease) were evaluated. For each sample, an atypicality index based on the Mahalanobis Squared distance and a patient specific trisomy 18 risk were calculated. Modeling was based on age distribution of live births and observed likelihood ratios. RESULTS: Population parameters and weight adjusted screening results follow:
295
SIGNIFICANCE OF A FALSE POSITIVE TRISOMY 18 (T18) MULTIPLE MARKER SCREENING TEST (MMST). K.D. Wenstrom, j~ Owen, C.G. Brumfield, R.O. Davis, M. DuBardL Dept. of Ob/Gyn, University of Alabama at Birmingham, AL. OBJECTIVE: To determine if a l~alse [+] T18 MMST (Maternal serum alpha fetoprotein, [MSAFP] --< 0.75 MOM, estriol < 0.60 MOM, and human chorionic gonadotropin, [hCG] --< 0.55 MOM) indicates increased risk for obstetrical cmnplications or is related to maternal weight. STUDY DESIGN: We accessed our genetic data base, containing MMST results, fetal karyotypes, and pregnancy outcomes from patients seen in the prenatal diagnosis clinic from 1993 to 1996 in - 5376, mean maternal age = 32.5 4- 6.7). In the MMST, only MSAFP had been adjusted for nmternal weight. We selected all patients with a [+] T18 screening test (n = 119, 2.2%) and all patients with a normal MMST (n = 3933, 73%) and compared pregnancy outcomes. RESULTS: A [+] T18 screen identified 42% (5/12) of T18 fetuses. Compared to those with a normal MMST, women with a false [+] T18 screen were heavier (181 _+ 49 lbs. vs 161 + 38, p = 0.0002), and younger (30 4- 7 years vs 32 -+ 7 years, p = 0.0008). Weight adjusting estriol and hCG in addition to MSAFP reduced the screen [+] TI8 rate by 32% (from 2.2% to 1.5%) and reduced the number of amnios required per case detected (frmn 1/24 to 1/11), but did not change the T 18 detection rate. Compared to women with a normal MMST, women with a false [+] T18 screen were at no increased risk to have a preterm birth, low birth weight, spontaneous abortion, or neonatal demise. CONCLUSIONS: A false [+] T18 screening test does not indicate increased risk to develop pregnancy complications and may be related to higher maternal weight. Weight correction of all 3 analytes reduces the number of false [+] TI8 screening tests by one third.
296
ELEVATED SECOND TRIMESTER DIMERIC INHIBIN A LEVELS IDENTIFY DOWN SYNDROME PREGNANCIES. KD. Wenstrom~~ Owen, D.C. Chux, L. Boots'. Dept. of Ob/Gyn., The University of Alabama at Birmingham, ~L. OBJECTIVE: To determine if second trimester dimeric inhibin A (IH-A) levels distinguish Down syndrome (DS) from euploid pregnancies. STUDY DESIGN: We utilized second trimester maternal serum samples obtained prior to genetic anmioeentesis, subjected to the multiple marker screening test for DS (MMST, maternal sermn alphafetoprotein, unconjugated estriol, hCG, and maternal age), and then stored at - 7 0 ~ for -<2 years. We randomly selected 313 samples fi-om euploid pregnancies evenly distributed from 14 to 20 weeks (mean maternal age = 35.6 + 5.2 years), and also analyzed 33 samples from DS pregnancies. IH-A levels were measured by ELISA (Serotec, Oxford) and converted to week specific MOMs. The screen positive rate (DS risk > 1:190), DS detection rate, and IH-A's performance in the MMST were determined. RF~ULTS: The mean IH-A MOM was significantly higher in the DS group than in the euploid group (2.8 -+ 2.0 vs 1.2 -+ 1.0, p - 0.0001). An IH-A level -> 2.0 MOM identified 55% of all DS pregnancies at a screen positive rate of 16.5%. (The relatively high screen positive rate reflects the high maternal age of the study population.) IH-A correlated better with hCG (r = 065) than with MSAFP (r = 0.29) or estriol (r = -0.10). Replacing estriol with IH-A in the MMST resulted in a higher DS detection rate (91% vs 85%) at a lower screen positive rate (23% vs 28%). At a cut-off chosen to produce the same DS detection rate (1:150, 85%), the screen positive rate with IH-A was even lower (20% vs 28%). CONCLUSIONS: Elevated second trimester maternal serum IH-A levels identify DS pregnancies; replacing estriol with IH-A in the MMST results in a lower screen positive (amniocentesis) rate while maintaining a high DS detection rate.
Mean Sample
Age
GA
AFP Mom Median, SD
FB MoM Median, SD
r
Controls Cases
27.4 33.1
16.6 16.2
0.99(0.370) 0.68(0.513)
1.01(0.661) 0.20(0.740)
0.044 -.246
The calculated false positive and detection rates are as follows:
ded DE Atypicality: 9.21 TI8 risk: 1/lfi0 T18 Risk: 1/150 T18 Risk: 1/200
0.7% 0.3% 0.4% 0.6%
45% 55% 61% 65%
0.7% 0.3% 0.4% 0.6%
45% 50% 54% 58%
CONCLUSION: Using the free Beta/AFP protocol, patient specific risk estimation gives better detection of trisomy 18 than an atypicality index.
294
FREE BETA HCG SUBUNIT VERSUS INTACT HCG IN THE MULTIPLE MARKER SCREENING TEST FOR FETAL DOWN SYNDROME. K.D. Wenstrom,~ Owen, D.C. Chux, L. BootsL Dept. of Ob/Gyn, Univ. of Alabama at Birmingham, AL. OBJECTIVE: To compare second trimester maternal serum Free [3 human chorionic gonadotropin (F[ghCG) to intact hCG (IhCG) in the muhiple marker screening test (MMST) for fetal Down Syndrome (DS). STUDY DESIGN: From our bank of second trimester maternal sera obtained prior to genetic anmioeentesis, subjected to the MMST for DS (maternal serum alphafetoprotein, unconjugated estriol, human ehorionic gonadotropin, and maternal age) and stored at - 7 0 ~ C for -<2 years, we randmnly selected 312 samples from euploid pregnancies evenly distributed from 14 to 20 weeks' gestation, (mean maternal age = 35.6 4- 5.2 years) and 33 samples from DS pregnancies. F[3hCG was analyzed by ELISA (CIS-US, Bedford MA), and week-specific muhiples of the median (MOM) were derived. The N3hCG DS screen positive and detection rates were determined, and F[3hCG was then substituted for IhCG in the MMST. RESULTS: The mean FI3hCG MOM in the DS group was significantly higher than in the euploid group (2.4 • 1.1 vs 1.2 • 1.0, p - 0.0001). A F[3hCG >2.0 MOM identified 55% ofDS pregancies at a screen positive rate of 17%. Replacing IhCG with FI3hCG in the MMST resulted in the following:
RISK CUTOFFI :190
RISK CUTOFF 1:300
SERUM ANAL YTES
5"1?%
D S Det %
SP%
DS Det %
MSAFP, Est, IhCG MSAFP, Est, F[3hCG MSAFP, FI3hCG
28 23 22
85 84 84
35 28 28
88 97 87
SP% = Screen positive rate Det% - Detection rate CONCLUSIONS: Replacing IhCG and estriol with F~hCG in the MMST results in a similm- DS detection rate at a lower screen positive (amniocentesis) rate. Alternatively, if the screen positive rate is held constant, MSAFP, Est, and FI3hCG result in the highest DS detection rate.