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Evaluation of the significance of a positive serum screen for Trisomy 18
S162 SMFM Abstracts 567 MOM VERSUS DELTA NT: TRISOMY-21 RISK ASSESSMENT USING NUCHAL TRANSLUCENCY (NT) SONOGRAPHY FERGAL D. MALONE1, HOWARD CUCKLE2, ROBERT H. BALL3, DAVID A. NYBERG4, CHRISTINE H. COMSTOCK5, RADEK BUKOWSKI6, KEITH EDDLEMAN7, SUSAN J. GROSS8, LORRAINE DUGOFF9, SABRINA D. CRAIGO10, ILAN E. TIMOR11, STEPHEN R. CARR12, HONOR M. WOLFE13, KIMBERLY A. DUKES14, MARY E. D’ALTON15, 1Royal College of Surgeons in Ireland, Dublin, Ireland, 2University of Leeds, Leeds, United Kingdom, 3University of Utah, Salt Lake City, Utah, 4Swedish Medical Center, Seattle, Washington, 5 William Beaumont Hospital, Royal Oak, Michigan, 6University of Texas Medical Branch at Galveston, Galveston, Texas, 7Mount Sinai School of Medicine, New York, New York, 8Albert Einstein College of Medicine, Bronx, New York, 9University of Colorado Health Sciences Center, Denver, Colorado, 10Tufts University, Boston, Massachusetts, 11NYU Medical Center, New York, New York, 12Brown University, Providence, Rhode Island, 13University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 14DMSTAT, Boston, Massachusetts, 15Columbia University, New York, New York OBJECTIVE: To compare the two most commonly used approaches for interpretation of nuchal translucency (NT) sonography for Trisomy-21 risk assessment: multiples of the median (MoM) and Delta NT (NT). STUDY DESIGN: 35,087 patients had NT at 11-13 wks, including 116 cases of Trisomy-21. NT measurements were converted to both MoM and NT. NT MoMs were used with Gaussian likelihood ratios (LRs), and NTs were used with empirical LRs from a large prospective study (Spencer et al, Ultrasound Obstet Gynecol, 2003;22:142), to generate individualized patient risk estimates for Trisomy-21. A 1:270 mid-trimester risk cut-off was used to define screen positivity. RESULTS: NT distribution in unaffected pregnancies was not constant, with inter-tertile ranges of 0.67, 0.75 and 0.83 mm at 11, 12 and 13 wks respectively. The sensitivity of NT with maternal age using NT and empirical LRs was 66% (3.1% FPR), compared with 78% (8.2% FPR) when using NT MoM and Gaussian LRs. At a fixed 5% FPR, detection rates were 71% and 72% respectively. The observed prevalence of Trisomy-21 was closer to that expected from NT MoM-based risks than with the NT approach (see Table). CONCLUSION: Calculating individualized patient risk for Trisomy-21 using NT MoMs is superior to use of NT, with more cases detected, and more accurate risk estimates. (NIH-RO1-HD-38652) Risk (1 in)
N
MoM Expected (%) Observed (%) N
Delta NT Expected (%) Observed (%)
O25 25-50 51-100 101-200 201-400 401-800 !800 All
449 228 347 746 1,605 3,124 28,588 35,087
15.0 2.9 1.4 0.7 0.3 0.2 0.04 0.30
13.2 2.9 1.4 0.7 0.3 0.2 0.01 0.12
12.0 4.8 2.6 1.2 0.6 0.3 0.06 0.21
179 148 173 306 442 874 32,965 35,087
22.4 7.4 5.8 2.6 2.0 0.8 0.09 0.21
568 D331(GOA) POLYMORPHISM IN PROGESTERONE RECEPTOR GENE IS NOT ASSOCIATED WITH SPONTANEOUS PRETERM BIRTH ERROL NORWITZ1, THOMAS MORGAN2, VICTORIA SNEGOVSKIKH1, JESSICA ILLUZZI1, CATALIN BUHIMSCHI1, EDMUND FUNAI1, EDWARD KUCZYNSKI1, CHARLES IRINA BUHIMSCHI1, LOCKWOOD1, 1Yale University, Obstetrics & Gynecology, New Haven, Connecticut, 2Yale University, Genetics, New Haven, Connecticut OBJECTIVE: Progesterone supplementation can prevent preterm birth in some high-risk women. Progesterone acts by binding to progesterone receptors (PR) and modulating the expression of target genes. Single nucleotide polymorphisms (SNPs) in the single-copy human PR gene have been associated with recurrent miscarriage and reproductive tract malignancies. This study investigates for the first time the association between C331(GOA) SNP in the PR gene and preterm birth. This SNP alters the ratio of PR-A to PR-B isoforms in myometrium, which has been shown to change prior to the onset of labor. STUDY DESIGN: Consecutive patients with spontaneous (non-iatrogenic) preterm birth were identified from the March of Dimes Perinatal Emphasis Research Initiative project (MOD # 20-FY03-30) at New York University, NY and Yale-New Haven Hospital, CT, Jan 1989-June 2005. Cases were matched (1:3) with uncomplicated term deliveries (controls). DNA was extracted from stored buffy coats and genotyped for C331 (GOA) SNP using established primers. All specimens were linked with demographic and medical data abstrated from maternal/neonatal records. Chi-squares and logistic regression were used to evaluate the relationship between race/ethnicity, genotype, and preterm birth. RESULTS: 72/77 (94%) of cases and 230/234 (98%) of controls were successfully genotyped. The rate of C331 (GOA) SNP heterozygous state in preterm birth cases was 4.2% (3/72) vs 4.8% (11/230) in controls (OR, 0.87; 95% CI, 0.24-3.19); no homozygotes were identified. The heterozygous state was found in 9.5% (2/21) of Caucasians, 5.4% (9/167) of Hispanics, and 5% (3/60) of others; no carriers were found among Asian (0/34) or AfricanAmerican (0/20) women (P=0.407). Logistic regression analysis failed to show any interaction between race/ethnicity and C331 (GOA) SNP genotype in predicting preterm birth (P=0.974). CONCLUSION: The C331 (GOA) SNP in human PR gene does not appear to be associated with spontaneous preterm birth. Further studies are required to define the mechanism by which progesterone supplementation prevents preterm birth.
569 EVALUATION OF THE SIGNIFICANCE OF A POSITIVE SERUM SCREEN FOR TRISOMY 18 YINKA OYELESE (F)1, LUIS TOBON1, JOSEPH CANTERINO2, CANDE ANANTH1, MARTIN CHAVEZ1, LAMI YEO1, JOHN SMULIAN1, ANTHONY VINTZILEOS1, 1 UMDNJ-Robert Wood Johnson Medical School/Robert Wood Johnson University Hospital, Obstetrics, Gynecology, and Reproductive Sciences, New Brunswick, New Jersey, 2Perinatal Institute, Jersey Shore Medical Center, Obstetrics & Gynecology, Neptune, New Jersey OBJECTIVE: 1. To evaluate the proportion of false positive (FP) serum screens (SS) for Trisomy 18 (T18). 2. To determine the proportion of false negative (FN) serum screens for T18. 3. To evaluate the sensitivity of ultrasound for diagnosing T18. 4. To determine if FP SS for T18 were associated with other pregnancy complications. STUDY DESIGN: This was a retrospective cohort study of women with a positive SS for T18 at our institutions. Cases were ascertained through the ultrasound database using the diagnoses ‘‘positive SS for T18’’ and ‘‘T18’’. We calculated the proportions of FP SS and the positive predictive value (PPV) of SS for T18. We also evaluated the proportion of FN SS in women who had pregnancies with T18. We evaluated the sensitivity of ultrasound for diagnosing T18. Finally, we recorded whether pregnancies associated with a FP SS for T18 had any other pregnancy complications. RESULTS: There were 93 women with positive SS for T18 with a range of reported risks for T18 ranging from 1:2 to 1:100. There were 8 cases of T18. Only 3 women with a positive SS for T18 had fetuses with T18. The proportion of FP SS was 97%, while the PPV of the T18 SS was 3.2%. There were 3/6 cases of T18 with a negative SS, giving a proportion of FN of 50%. Two cases of T18 had no SS. In all cases of T18, ultrasound demonstrated multiple major structural anomalies (Miminum of 4). Thus ultrasound had a 100% sensitivity for T18. Ten pregnancies (11%) with FP SS for T18 had other fetal anomalies. CONCLUSION: Patients with positive SS for T18 have a low likelihood of having fetuses with T18. In the absence of structural anomalies on ultrasound in experienced hands, a diagnosis of T18 is very unlikely. Thus women with a positive SS for T18 who have a normal ultrasound should be counseled that the risk of losing a normal fetus from the amniocentesis exceeds the likelihood of detecting a T18 fetus. This strategy will reduce costs and unnecessary pregnancy losses associated with amniocentesis. However, the high rate of other anomalies justifies a thorough sonographic anatomic survey in these women. 570 TRENDS IN AMNIOCENTESIS UTILIZATION FROM 1990 TO 2002 HENRY ROQUE1, BRUCE MORRIS1, MARY BETH JANICKI1, JAMES EGAN1, 1University of Connecticut, Obstetrics and Gynecology, Farmington, Connecticut OBJECTIVE: To assess trends in amniocentesis utilization and its relation to the incidence of Down Syndrome (DS) livebirths in the United States from 1990 to 2002. STUDY DESIGN: Non-diabetic patients from the Natality Data Set from the years 1990 to 2002 were evaluated for documentation of amniocentesis and stratified by maternal age . Diabetic patients were excluded to decrease a source of non-genetic amniocentesis. We modeled the Natality data for the estimates of expected Down syndrome (DS) births and recorded maternal age specific prevalence of DS livebirths. RESULTS: A total of 49,483,175 non-diabetic pregnancies were analyzed. In the study interval a 47.6% & 45% reduction in the percent of pregnancies with a recorded amniocentesis was observed in women O35 yrs and !35 yrs respectively. During this interval there was an increase in the prevalence of livebirths to women O35 yrs from 9.2% to 14.9%. Modeling the Natality data on estimates of expected Down syndrome (DS) births there is an anticipated increase of 540% in the incidence of DS for women !35 yrs, and a 359% increase for women O35 yrs. Yet during this time there was no change in the total number of reported DS livebirths (1863 in 1990 vs 1738 in 2002).
Percent of pregnancies with a recorded amniocentesis CONCLUSION: Despite the observed decrease in amniocentesis there was a decrease in the observed/expected DS livebirths. These findings taken together suggest wide acceptance of non-invasive DS screening strategies, or an increased acceptance of Chorionic villus sampling.
N
MoM Expected (%) Observed (%) N
Delta NT Expected (%) Observed (%)
O25 25-50 51-100 101-200 201-400 401-800 !800 All
449 228 347 746 1,605 3,124 28,588 35,087
15.0 2.9 1.4 0.7 0.3 0.2 0.04 0.30
13.2 2.9 1.4 0.7 0.3 0.2 0.01 0.12
12.0 4.8 2.6 1.2 0.6 0.3 0.06 0.21
179 148 173 306 442 874 32,965 35,087
22.4 7.4 5.8 2.6 2.0 0.8 0.09 0.21
568 D331(GOA) POLYMORPHISM IN PROGESTERONE RECEPTOR GENE IS NOT ASSOCIATED WITH SPONTANEOUS PRETERM BIRTH ERROL NORWITZ1, THOMAS MORGAN2, VICTORIA SNEGOVSKIKH1, JESSICA ILLUZZI1, CATALIN BUHIMSCHI1, EDMUND FUNAI1, EDWARD KUCZYNSKI1, CHARLES IRINA BUHIMSCHI1, LOCKWOOD1, 1Yale University, Obstetrics & Gynecology, New Haven, Connecticut, 2Yale University, Genetics, New Haven, Connecticut OBJECTIVE: Progesterone supplementation can prevent preterm birth in some high-risk women. Progesterone acts by binding to progesterone receptors (PR) and modulating the expression of target genes. Single nucleotide polymorphisms (SNPs) in the single-copy human PR gene have been associated with recurrent miscarriage and reproductive tract malignancies. This study investigates for the first time the association between C331(GOA) SNP in the PR gene and preterm birth. This SNP alters the ratio of PR-A to PR-B isoforms in myometrium, which has been shown to change prior to the onset of labor. STUDY DESIGN: Consecutive patients with spontaneous (non-iatrogenic) preterm birth were identified from the March of Dimes Perinatal Emphasis Research Initiative project (MOD # 20-FY03-30) at New York University, NY and Yale-New Haven Hospital, CT, Jan 1989-June 2005. Cases were matched (1:3) with uncomplicated term deliveries (controls). DNA was extracted from stored buffy coats and genotyped for C331 (GOA) SNP using established primers. All specimens were linked with demographic and medical data abstrated from maternal/neonatal records. Chi-squares and logistic regression were used to evaluate the relationship between race/ethnicity, genotype, and preterm birth. RESULTS: 72/77 (94%) of cases and 230/234 (98%) of controls were successfully genotyped. The rate of C331 (GOA) SNP heterozygous state in preterm birth cases was 4.2% (3/72) vs 4.8% (11/230) in controls (OR, 0.87; 95% CI, 0.24-3.19); no homozygotes were identified. The heterozygous state was found in 9.5% (2/21) of Caucasians, 5.4% (9/167) of Hispanics, and 5% (3/60) of others; no carriers were found among Asian (0/34) or AfricanAmerican (0/20) women (P=0.407). Logistic regression analysis failed to show any interaction between race/ethnicity and C331 (GOA) SNP genotype in predicting preterm birth (P=0.974). CONCLUSION: The C331 (GOA) SNP in human PR gene does not appear to be associated with spontaneous preterm birth. Further studies are required to define the mechanism by which progesterone supplementation prevents preterm birth.
569 EVALUATION OF THE SIGNIFICANCE OF A POSITIVE SERUM SCREEN FOR TRISOMY 18 YINKA OYELESE (F)1, LUIS TOBON1, JOSEPH CANTERINO2, CANDE ANANTH1, MARTIN CHAVEZ1, LAMI YEO1, JOHN SMULIAN1, ANTHONY VINTZILEOS1, 1 UMDNJ-Robert Wood Johnson Medical School/Robert Wood Johnson University Hospital, Obstetrics, Gynecology, and Reproductive Sciences, New Brunswick, New Jersey, 2Perinatal Institute, Jersey Shore Medical Center, Obstetrics & Gynecology, Neptune, New Jersey OBJECTIVE: 1. To evaluate the proportion of false positive (FP) serum screens (SS) for Trisomy 18 (T18). 2. To determine the proportion of false negative (FN) serum screens for T18. 3. To evaluate the sensitivity of ultrasound for diagnosing T18. 4. To determine if FP SS for T18 were associated with other pregnancy complications. STUDY DESIGN: This was a retrospective cohort study of women with a positive SS for T18 at our institutions. Cases were ascertained through the ultrasound database using the diagnoses ‘‘positive SS for T18’’ and ‘‘T18’’. We calculated the proportions of FP SS and the positive predictive value (PPV) of SS for T18. We also evaluated the proportion of FN SS in women who had pregnancies with T18. We evaluated the sensitivity of ultrasound for diagnosing T18. Finally, we recorded whether pregnancies associated with a FP SS for T18 had any other pregnancy complications. RESULTS: There were 93 women with positive SS for T18 with a range of reported risks for T18 ranging from 1:2 to 1:100. There were 8 cases of T18. Only 3 women with a positive SS for T18 had fetuses with T18. The proportion of FP SS was 97%, while the PPV of the T18 SS was 3.2%. There were 3/6 cases of T18 with a negative SS, giving a proportion of FN of 50%. Two cases of T18 had no SS. In all cases of T18, ultrasound demonstrated multiple major structural anomalies (Miminum of 4). Thus ultrasound had a 100% sensitivity for T18. Ten pregnancies (11%) with FP SS for T18 had other fetal anomalies. CONCLUSION: Patients with positive SS for T18 have a low likelihood of having fetuses with T18. In the absence of structural anomalies on ultrasound in experienced hands, a diagnosis of T18 is very unlikely. Thus women with a positive SS for T18 who have a normal ultrasound should be counseled that the risk of losing a normal fetus from the amniocentesis exceeds the likelihood of detecting a T18 fetus. This strategy will reduce costs and unnecessary pregnancy losses associated with amniocentesis. However, the high rate of other anomalies justifies a thorough sonographic anatomic survey in these women. 570 TRENDS IN AMNIOCENTESIS UTILIZATION FROM 1990 TO 2002 HENRY ROQUE1, BRUCE MORRIS1, MARY BETH JANICKI1, JAMES EGAN1, 1University of Connecticut, Obstetrics and Gynecology, Farmington, Connecticut OBJECTIVE: To assess trends in amniocentesis utilization and its relation to the incidence of Down Syndrome (DS) livebirths in the United States from 1990 to 2002. STUDY DESIGN: Non-diabetic patients from the Natality Data Set from the years 1990 to 2002 were evaluated for documentation of amniocentesis and stratified by maternal age . Diabetic patients were excluded to decrease a source of non-genetic amniocentesis. We modeled the Natality data for the estimates of expected Down syndrome (DS) births and recorded maternal age specific prevalence of DS livebirths. RESULTS: A total of 49,483,175 non-diabetic pregnancies were analyzed. In the study interval a 47.6% & 45% reduction in the percent of pregnancies with a recorded amniocentesis was observed in women O35 yrs and !35 yrs respectively. During this interval there was an increase in the prevalence of livebirths to women O35 yrs from 9.2% to 14.9%. Modeling the Natality data on estimates of expected Down syndrome (DS) births there is an anticipated increase of 540% in the incidence of DS for women !35 yrs, and a 359% increase for women O35 yrs. Yet during this time there was no change in the total number of reported DS livebirths (1863 in 1990 vs 1738 in 2002).
Percent of pregnancies with a recorded amniocentesis CONCLUSION: Despite the observed decrease in amniocentesis there was a decrease in the observed/expected DS livebirths. These findings taken together suggest wide acceptance of non-invasive DS screening strategies, or an increased acceptance of Chorionic villus sampling.