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Obstetrics & Gynecology:
doi: 10.1097/AOG.0b013e3181a9479e
Original Research

Triple-Marker Prenatal Screening Program for Chromosomal Defects

Kazerouni, N Neely DrPH, MPH; Currier, Bob PhD; Malm, Linda; Riggle, Susan; Hodgkinson, Christina; Smith, Sylvia†; Tempelis, Corinna MPH; Lorey, Fred PhD; Davis, Amber MA; Jelliffe-Pawlowski, Laura PhD; Walton-Haynes, Lynn DDS, MPH; Roberson, Marie PhD

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Author Information

From the Genetic Disease Screening Program, California Department of Public Health, Richmond, California.

Supported by funding from the Genetic Disease Screening Program, California Department of Public Health.

Deceased.

From the California statewide registry for chromosomal defects.

Corresponding author: N. Neely Kazerouni, DrPH, MPH, Genetic Disease Screening Program, California Department of Public Health, 850 Marina Bay Parkway, F-175, MS-8200, Richmond, CA 94804; e-mail: neely.kazerouni@cdph.ca.gov.

Financial Disclosure The authors did not report any potential conflicts of interest.

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Abstract

OBJECTIVE: To examine screening performance of California's triple-marker screening program, using data from a statewide registry for chromosomal defects.

METHODS: This study included 752,686 women who received a screening risk and had an expected date of delivery between July 2005 and the end of June 2007. Follow-up diagnostic services for screen-positive women were performed at state-approved centers. Data on diagnostic outcomes from these visits were entered into the California Chromosomal Defect Registry (CCDR). Other CCDR sources include mandatory reporting by all cytogenetic laboratories and hospitals and outcome data forms submitted by prenatal care providers.

RESULTS: The observed detection rate for Down syndrome (N=1,217) was 77.4%. It varied significantly by gestational dating method and maternal age. The rates for women aged younger than 35 years and 35 years and older were 62.4% and 94.0%, respectively. The detection rates were 81.3% for ultrasound-dated pregnancies and 67.5% for last menstrual period–dated pregnancies. For Turner syndrome, trisomy 18, triploidy, and trisomy 13, the detection rates were 79.4%, 82.5%, 98.1%, and 36.0%, respectively. The positive rate for Down syndrome was 5.4%. Of women with a Down syndrome fetus who were screen positive, only 49.5% opted for amniocentesis. Of women who obtained results from amniocentesis indicating a Down syndrome fetus, 61.4% had an elective termination, 26.2% had a live birth, 4.5% had a death or miscarriage, and 7.9% had an unknown outcome.

CONCLUSION: The observed performance of this large triple-marker screening program exceeds generally predicted detection rates for Down syndrome. This study methodology will be used to measure the performance of subsequent screening enhancements.

LEVEL OF EVIDENCE: III

The California Expanded AFP Program is one of the largest, most comprehensive chromosomal disorder prenatal screening programs in the world.1 The large program size, centralized laboratory, and standardized patient follow-up systems allow for optimal laboratory quality control measures and for the use of optimal population characteristics for risk assessment. The Program also maintains the California Chromosomal Defect Registry (CCDR) of all chromosome disorders detected in the state that are diagnosed prenatally or before 1 year of age. This study attempts to validate the use of this CCDR data for evaluation of screening performance. The use of CCDR data eliminates the need to obtain outcome data for all women so that screening data from all women participating in the Program can be used.

The screening results of 752,686 women and 1,217 Down syndrome cases are included. There are limitations to directly comparing the reported detection rates of various studies of chromosomal disorder screening strategies that include different populations. These limitations include variable maternal age ranges among studies, low statistical power, and different cutoffs and screen-positive rates. The very large numbers in this study allow us to set a relatively precise baseline for screening detection rates for Down syndrome and other chromosomal disorders, using triple-marker screening in the second trimester. In addition, this study documents screening participant's choices with respect to use of diagnostic testing and pregnancy options in the context of second-trimester screening. The California program added inhibin in mid 2007 and will add first-trimester markers used in a coordinated step-wise protocol with the option of full integrated screening in early 2009. This study establishes Program baseline screening performance and a methodology to evaluate future protocol changes.

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MATERIALS AND METHODS

This study was found to be exempt by the Committee for the Protection of Human Subjects, from the State of California Health and Human Services Agency. The California Expanded AFP Program is a statewide program authorized by the state legislature and implemented by state regulations.2 These regulations require that all women seen by prenatal care providers by the 140th day of gestation be provided with a booklet prepared by the Department. This booklet describes the prenatal birth defect screening program. Prenatal care providers are required to offer the women an opportunity to participate in the program. Follow-up diagnostic services of genetic counseling, ultrasonography, and amniocentesis are offered at state-approved prenatal diagnosis centers, and the cost of these services is covered by the Expanded AFP Program. The operation of this Program has been described in detail previously.1

In July of 1995, the Program implemented triple-marker screening for birth defects, including chromosomal abnormalities, using an automated analytical system, (AutoDELFIA, PerkinElmer, Waltham, MA), which measures intact human chorionic gonadotropin (hCG), unconjugated estriol (uE3) and alpha-fetoprotein (AFP). Software for the risk analysis was created specifically for the California program, and risk calculations for Down syndrome are based on the standard multivariable Gaussian algorithm.3 The test request form did not ask for information on the egg donor's age. Therefore this risk was calculated using the maternal age. Because the proportion of in vitro fertilization cases using donor eggs is expected to be very small, we did not expect risk based on maternal age to affect the overall study results. Risks for trisomy 18 are calculated using a published algorithm.4 Marker medians are based on California population measures. Medians are continuously monitored and adjusted as necessary for kit lot variation. Changes in kit lots are preceded by a variance evaluation before acceptance to limit major changes in medians. The large volume of samples tested allows for detection of small but statistically significant changes in medians, which can be adjusted to improve screening performance. Adjustments to multiples of the medians (MoMs) for weight and race are also based on California population measures. Adjustments also occur for type 1 diabetes. There are seven regional screening laboratories which use the same kit lots for the same time period. Analytical results are transmitted to the central site in Richmond, CA, for a secondary quality control review and for calculation of risk and transmittal of results to follow-up coordinators and prenatal care providers.

The CCDR has been in existence since 1985 when the California legislature passed regulations that mandate reporting of all chromosome abnormalities detected prenatally or before 1 year of age.2 In mid 2005, a major restructuring of the CCDR database and screen interfaces occurred, along with a restructuring of the clinical screening information system. The restructuring allowed the integration of CCDR data with that of the prenatal screening program and newborn screening program data. All data are stored in linked tables in a large structured query language relational database.

The CCDR receives data from a variety of sources. Diagnostic reports are received for all screen-positive patients who receive follow-up services from the program. These reports are tied to payment for services, and compliance with filing the reports is virtually complete. Outcome of pregnancy forms are sent to prenatal care providers of the screen-positive women when a karyotype has not been obtained from a Prenatal Diagnosis Center. The program coordinators also receive reports of chromosomal abnormalities from prenatal care providers and are able to enter this information into screening information system for CCDR monitor review and confirmation. Reporting by all cytogenic laboratories is mandatory, so compliance is very good for laboratories within the state. Reporting by laboratories located in other states is not complete, but cases not reported by laboratories in other states can be captured through other sources. The CCDR also receives reports from hospitals on live births with known chromosomal abnormalities. Therefore, the majority of cases have been reported from multiple sources. The software allows for the input of all the records and links the records to the woman's demographic profile. The demographic profile links to both the CCDR and the screening information. Although all original reports from multiple sources are maintained in the system, a single consolidated record is created by a CCDR monitor for analytic purposes.

The expected liveborn prevalence for each of the maternal ages in the screening program was calculated using the individual year rates ascertained by Morris et al.5 California Chromosomal Defect Registry cases were counted if the live birth occurred between July 1, 2005, and June 30, 2007. If the live birth date was not available, we used the estimated date of delivery within this time period. Because a portion of the pregnancies detected at mid trimester would have aborted spontaneously or resulted in a stillbirth if continued, all elective terminations, fetal demises, and those with unknown outcomes were adjusted by a factor of 0.77.6 This adjustment was necessary to make comparisons with liveborn prevalence rates. The estimated ascertainment rate of the CCDR was determined by comparing the expected number of liveborn cases with the adjusted number of registry cases.

A second method of estimating CCDR ascertainment used birth certificate data available for infants delivered in 2006. An attempt was made to match the mothers listed on the birth certificate files with the women who participated in the Expanded AFP screening program. We conducted a record linkage, matching birth certificate information on the mother and neonate with that of women participating in the screening program with expected delivery in 2006. The rate of CCDR ascertainment was estimated as the percentage of total cases listed on the birth certificate data that had been previously reported to the registry in 2006.

The screen-positive rate was calculated as the percentage of women offered diagnostic services from the Expanded AFP Program. Interpretation factors such as maternal age, gestational age, race, weight, and diabetic status are verbally confirmed with the prenatal care provider before referral to a prenatal diagnostic center. Gestational age was determined by ultrasound measurements of the biparietal diameter (as per American College of Medical Genetics Standards and Guidelines7) before the woman was offered the option of amniocentesis. The midtrimester risk cutoff used for Down syndrome is 1:190 and for trisomy 18 is 1:100. The detection rate was defined as the percentage of total registry cases that received a screen-positive result and were offered amniocentesis via the Program. Ninety-five percent confidence intervals (95% CIs) and χ2P values were calculated using SAS (SAS Institute, Inc., Cary, NC).8

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RESULTS

A total of 752,686 women were successfully screened (Table 1) by the Expanded AFP screening program and had an expected date of delivery or a live birth between July 1, 2005, and June 30, 2007. The screen-positive rate for Down syndrome for this group was 5.4%. The overall screen-positive rate for all screened disorders (Down syndrome, trisomy 18, neural tube defects, and Smith-Lemli-Opitz syndrome) was 6.6%. Using the Morris et al5 Down syndrome prevalence rates by single year of maternal age, we estimated the expected number of liveborn cases, in the absence of termination, to be 1,326 in this 2-year group (Table 1). The number of live birth cases reported to the registry was 711. In addition, 506 electively terminated, miscarried, or prenatally diagnosed and lost to follow-up cases were reported to the registry. These 506 cases were adjusted for an estimated 23% that would have been lost before term,6 yielding an adjusted registry ascertainment of 1,100 liveborn equivalent cases. Comparison of the expected number of liveborn Down syndrome cases with the adjusted registry case ascertainment yielded an overall estimated registry case ascertainment rate of 83% for the 2-year period. The rate of ascertainment for the women aged younger than 35 years was calculated to be 91% (95% CI 88.9–93.3%) and was 75% (95% CI 72.1–78.6%) for women aged 35 years and older (Table 1). Currently, many women in the 35 years and older group have first-trimester screening and only participate in the Expanded AFP Program if they have screen-negative first-trimester screening results. Thus, the actual number of expected Down syndrome cases in the 35 years and older group could be less than the number estimated by using the Morris et al5 prevalence rates. Therefore, the registry ascertainment rate of 91% in the women aged younger than 35 years may be the most accurate estimate.

Table 1
Table 1
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Table. No caption av...
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The registry ascertainment rate was also estimated using birth certificate data in 2006. Among successfully screened Expanded AFP participants who could be matched to the mothers on birth certificate files (72.3% match rate), only 100 were actually coded as Down syndrome, and 27 of those cases were clearly erroneously coded upon investigation. All but 15 of the 73 cases coded correctly as Down syndrome (n=58) had already been reported to the CCDR. This would indicate a 79.5% (95% CI 70.2–88.7%) CCDR ascertainment rate. But, with a 72.3% match rate, it would be expected that a total of 267 cases, based on 369 live births reported to the registry in 2006, would be listed on the birth certificate files.

The low percentage, 22% (58 of 267), of the expected cases determined by the CCDR data in 2006, which appear correctly coded on the birth certificate data, limits the validity of this approach. In addition, 27% of the cases coded on the birth certificate files as Down syndrome were erroneously coded. Considering these limitations and extensive efforts in using the birth certificate data and a relatively high CCDR ascertainment rate, we chose not to use this case finding approach for the study's entire time period and instead focused our efforts on the completeness of the CCDR reports.

The age distribution of the screened population was similar to that of the 2006 pregnant population in the United States, as determined by 2006 data from the National Center for Health Statistics.9 The mean age of the California screening population was 27.8 years and the U.S. mean was 27.5 years. The U.S. data indicated that 14.3% of the women were aged 35 years or older, and 13.7% of the women in this California screening population were aged older than 35 years (Table 2). California has a diverse racial composition. The majority of the screened women are Hispanic, 54.9%, primarily originating from Mexico and Central America. Whites represent 23.6%, Asians 9.1%, African Americans 5.1%, and other races 7.3% of the population (Table 2).

Table 2
Table 2
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The observed detection rate for Down syndrome for the 2-year period was 77.4% (95% CI 75.0–79.7%). This assumes that any underascertainment of cases would be proportionally split in a similar ratio to the cases that were reported to the CCDR (Table 3). The detection rates varied considerably by maternal age (Table 1) and by gestational dating method (Table 4). The observed detection rate was 62.4% (95% CI 58.6–66.1%) for women aged younger than 35 years and 94.0% (95% CI 92.0–95.9%) for women aged older than 35 years. If the pregnancy was dated by ultrasonography, the detection rate was 81.3% (95% CI 78.8–83.8%), but it was reduced to 67.5% (95% CI 62.0–72.9%) for last menstrual period (LMP)-dated pregnancies.

Table 3
Table 3
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Table 4
Table 4
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As shown in Table 3, for trisomy 18, triploidy, and trisomy 13, the detection rates were 82.5%, 98.1%, and 36.0%, respectively (note the 95% CI in the table). The detection rate for Turner syndrome was calculated as 79.4%, and the detection rate for Klinefelter syndrome was calculated at 36.6%. However, these two disorders often are not diagnosed in the first year of life. These detection rates do not reflect cases diagnosed subsequent to the first year of life. The detection rate for all other chromosome abnormalities was 51.4%. This includes all reported abnormalities, except balanced translocations and Robertsonian balanced translocations.

Although more than 90% of the screen-positive patients received follow-up services at the state-approved prenatal diagnosis centers,1 not all screen-positive women chose to have amniocentesis. The rate of acceptance of diagnostic services is not significantly different among groups other than trisomy 21 (Table 5).

Table 5
Table 5
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Table 6 lists the pregnancy outcomes by disorder for the women who chose to have amniocentesis through the State Expanded AFP Program. The elective termination rate for trisomy 21 was 61% and the fetal demise/spontaneous abortion rate was 4.5% (Table 6). However, because of the link of CCDR data to the state's newborn screening data, we expect that most of the 7.9% of cases that were lost to follow-up represent either elective terminations or pregnancy losses.

Table 6
Table 6
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DISCUSSION

Previous detection rates for Down syndrome using triple-marker screening have been estimated to be approximately 60% at a 5% false-positive rate,3,10 and 69% if the pregnancy is dated by ultrasonography.11 The Serum, Urine and Ultrasound Screening Study, which used ultrasound dating, estimated a 74% detection rate at a 5% false-positive rate.12 If inhibin is added (quadruple screening), the estimated detection rate increases to 81%.12 The results from the California program are higher than previously reported for triple-marker screening. The results indicate an overall Program detection rate for Down syndrome of 77.4% at a 5.4% screen-positive rate. For women aged younger than 35 years, the detection rate was 62.4% at a 3.1% screen-positive rate. Women aged 35 years and older had a detection rate of 94.0% at a screen-positive rate of 19.3%. If gestational age is determined by ultrasonography, the overall detection rate is 81.3%, which approaches that of reported rates for both quadruple screening and combined first-trimester screening, especially when the higher first-trimester loss rate is considered.13–15 Clinicians should note that the detection rate is only 67.5% when LMP is used to determine gestational age. Combined first-trimester screening uses nuchal translucency combined with maternal age, serum markers pregnancy-associated plasma protein A, and either total hCG or free β-hCG. Four major studies have reported detection rates of 79%, 85%, 83%, and 90% at a 5% false-positive rate for combined first-trimester screening.12,16–18 Although there are significant advantages to first-trimester screening, it is reassuring that nearly equivalent detection rates at similar screen-positive rates can be obtained in the second trimester, with just triple-marker screening. Many women are not able to meet the strict timelines necessary for first-trimester screening, and there are not enough practitioners properly trained to make the nuchal translucency measurements necessary for the calculation of a first-trimester risk.

No specific screening algorithms or cutoffs are employed for the detection of chromosomal disorders other than Down syndrome and trisomy 18. Cases detected were screen positive for trisomy 21, trisomy18, or neural tube defects. Despite this, 70.8% (235 of 332) of the other most common aneuploidies (trisomy 13, Turner syndrome, and triploidy) are detected by the California program. The First and Second Trimester Evaluation of Risk trial reported a 44% detection rate for these same aneuploidies with second-trimester quadruple screening based on a total of 16 cases with an overall screen-positive rate of 8.9%.19

The higher-than-expected detection rate for Down syndrome through the California Program is likely a reflection of multiple factors. The centralized, large-volume screening program allows for quality control measures not possible with small-volume laboratories. The California population-specific measures are used for risk analysis. Separate medians for pregnancies dated by ultrasonography, LMP, and physical examination are used to improve the screening performance.7 Coordinated follow-up of screen-positive cases improves ascertainment of MoM adjustment factors. All test request forms with missing information, such as weight and race, elicit follow-up calls to the provider to obtain missing information before a risk is calculated. Provider education on the benefits of ultrasound dating has resulted in 74.8% of the Down syndrome–affected pregnancies being dated by ultrasonography. Follow-up of screen-positive cases occurs only at state-approved prenatal diagnostic centers where standardized protocol is used. Prenatal diagnostic centers must redate and recalculate the risk of a Down syndrome screen-positive pregnancy if a prenatal diagnostic center ultrasonogram indicates a dating change of 14 days or more. This eliminates many false-positive cases resulting from incorrect gestational dating.

Tables 5 and 6 reflect the range of choices made by women participating in the Program. Even though the screening program designates women at high risk of having a pregnancy affected with Down syndrome status, 50.5% of those actually affected will decline amniocentesis. Of those women with a definite diagnosis of a Down syndrome pregnancy, at least 26.2% continue the pregnancy. Because our CCDR database is linked to the state's newborn screening database, when we were unable to locate a liveborn for the unknown category in Table 6, we assumed the majority of these cases were either fetal demises or elective terminations. However, the women could have moved out of state or changed names and other identifiers to the extent that locating records in the newborn screening database was not possible.

The California Expanded AFP Program added inhibin as a fourth marker in July 2007. The program also expects to add first-trimester markers (nuchal translucency, pregnancy-associated plasma protein A, and total hCG) in early 2009. The California program will be one of coordinated step-wise testing in accordance with the current guidelines issued by the American College of Obstetricians and Gynecologists and the Society for Maternal–Fetal Medicine.20 Women who obtain a nuchal translucency measurement and have a first-trimester blood sample sent to the program will receive a risk calculation. Those at highest risk will be offered diagnostic services through the Program. For women who choose not to receive diagnostic services based on their first-trimester risk, a second-trimester sample will be obtained and a revised risk will be calculated using both the first- and second-trimester markers. For women who are unable to obtain a first-trimester sample, the existing quadruple marker program still will be available. Modeled projections indicate that for the women able to get a nuchal translucency measurement and a first-trimester sample, approximately 75% of Down syndrome fetuses can be detected in the first trimester by the step-wise protocol at a 2.5% screen-positive rate. This study establishes baseline screening performance and methodology to evaluate these improvements to California's prenatal screening program.

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REFERENCES

1. Cunningham GC, Tompkinison DG. Cost and effectiveness of the California triple marker prenatal screening program. Genet Med 1999;1:199–206.

2. California Code of Regulations, Title 17, Section 6532. Current as of January 09, 2009. Available at: http://ccr.oal.ca.gov/linkedslice/default.asp?SP=CCR-1000&Action=Welcome. Retrieved January 09, 2009.

3. Wald NJ, Cuckle HS, Densem JW, Nanchahal K, Royston P, Chard T, et al. Maternal serum screening for Down's syndrome in early pregnancy [published erratum appears in BMJ 1988;297:1029]. BMJ 1988;297:883–7.

4. Palomaki GE, Haddow JE, Knight GJ, Wald NJ, Kennard A, Canick JA, et al. Risk-based prenatal screening for trisomy 18 using alpha-fetoprotein, unconjugated oestriol and human chorionic gonadotropin. Prenat Diagn 1995;15:713–23.

5. Morris JK, Mutton DE, Alberman E. Revised estimates of the maternal age specific live birth prevalence of Down's syndrome. J Med Screen 2002;9:2–6.

6. Morris JK, Wald NJ, Watt HC. Fetal loss in Down syndrome pregnancies. Prenat Diagn 1999;19:142–5.

7. Palomaki GE, Bradley LA, McDowell GA, Down syndrome working group, ACMG Laboratory Quality Assurance Committee. Technical standards and guidelines: prenatal screening for Down syndrome. Genet Med 2005;7:344–54.

8. SAS Institute, Inc. SAS software of statistical analysis. Version 9.1.3. Cary (NC): SAS Institute, Inc.; 2005.

9. National Center for Health Statistics. 2006 birth tables. National Vital Statistics System. Hyattsville, MD: US Department of Health and Human Services, CDC, National Center for Health Statistics. Available at: http://205.207.175.93/VitalStats/TableViewer/tableView.aspx?ReportId=15095.

10. ACOG educational bulletin. Maternal serum screening. Number 228, September 1996 (replaces no. 154, April 1991). Committee on Educational Bulletins of the American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 1996;55:299–308.

11. Wald NJ, Kennard A, Hackshaw A, McGuire A. Antenatal screening for Down's syndrome [published erratum appears in J Med Screen 1998;5:110. J Med Screen 1998;5:166]. J Med Screen 1997;4:181–246.

12. Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM. First and second trimester antenatal screening for Down's syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS). J Med Screen 2003;10:56–104.

13. Bray IC, Wright DE. Estimating the spontaneous loss of Down syndrome fetuses between the times of chorionic villus sampling, amniocentesis and livebirth. Prenat Diagn 1998;18:1045–54.

14. Cuckle H. Down syndrome fetal loss rate in early pregnancy. Prenat Diagn 1999;19:1177–9.

15. Halliday JL, Watson LF, Lumley J, Danks DM, Sheffield LJ. New estimates of Down syndrome risks at chorionic villus sampling, amniocentesis, and livebirth in women of advanced maternal age from a uniquely defined population. Prenat Diagn 1995;15:455–65.

16. Malone FD, Canick JA, Ball RH, Nyberg DA, Comstock CH, Bukowski R, et al. First-trimester or second-trimester screening, or both, for Down's syndrome. N Engl J Med 2005;353:2001–11.

17. Wapner R, Thom E, Simpson JL, Pergament E, Silver R, Filkins K, et al. First-trimester screening for trisomies 21 and 18. N Engl J Med 2003;349:1405–13.

18. Nicolaides KH, Spencer K, Avgidou K, Faiola S, Falcon O. Multicenter study of first-trimester screening for trisomy 21 in 75 821 pregnancies: results and estimation of the potential impact of individual risk-orientated two-stage first-trimester screening. Ultrasound Obstet Gynecol 2005;25:221–6.

19. Breathnach FM, Malone FD, Lambert-Messerlian G, Cuckle HS, Porter TF, Nyberg DA. First- and second trimester screening: detection of aneuploidies other than Down syndrome. Obstet Gynecol 2007;110:651–7.

20. ACOG Committee on Practice Bulletins. ACOG Practice Bulletin No. 77: screening for fetal chromosomal abnormalities. Obstet Gynecol 2007;109:217–27.

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