Down syndrome risk assessment over the past decade has moved increasingly into the first trimester. The combined first-trimester screen is based on an ultrasonographic measurement of nuchal translucency and maternal serum analytes, β-human chorionic gonadotropin, and pregnancy-associated plasma protein A. Combined with maternal age, it provides a patient-specific risk of aneuploidy. Combined first-trimester screen has an 85–90% detection rate for aneuploidy at a false-positive rate of 5%.1,2 This implies that greater than 90% of invasive procedures yielded normal karyotypes. Noninvasive prenatal testing is a novel screening method involving quantifying cell-free fetal DNA fragments in maternal blood using massively parallel sequencing to screen for fetal aneuploidy with greater than 99% sensitivity with less than a 1% false-positive rate.3,4 Noninvasive prenatal testing can be performed after 10 weeks of gestation. In December 2012, a joint statement by the American College of Obstetricians and Gynecologists and the Society of Maternal-Fetal Medicine recognized noninvasive prenatal testing as a screening choice for women in a singleton pregnancy at high risk for aneuploidy. Although noninvasive prenatal testing offers a significant improvement, there is still a need for confirmatory diagnostic testing. However, because noninvasive prenatal testing has a higher sensitivity and lower false-positive rate, it is anticipated that there would be fewer diagnostic tests after noninvasive prenatal testing than combined first-trimester screen. Because diagnostic tests are invasive and may result in pregnancy loss, there is considerable interest in understanding how the introduction of combined first-trimester screen and noninvasive prenatal testing has affected use. In this study, we describe the changes in the number and rate of diagnostic testing after the introduction of a combined first-trimester screen and noninvasive prenatal testing over a 9-year period.
PATIENTS AND METHODS
We designed a retrospective study investigating prenatal testing over a 9-year period at a regional maternal-fetal medicine group practice. This was the only civilian perinatal program in our metropolitan area that performed the vast majority of screening and invasive diagnostic testing in the region. Monthly totals of four prenatal tests (combined first-trimester screen, noninvasive prenatal testing, chorionic villus sampling [CVS], and amniocentesis) between July 2004 and June 2013 were recorded from hospital billing records. Prenatal tests were compared over three time periods: 1) before a combined first-trimester screen was offered (July 2004 to February 2006, period A); 2) after a combined first-trimester screen was offered but before noninvasive prenatal testing (March 2006 to February 2012, period B); and 3) after introduction of noninvasive prenatal testing (March 2012 to June 2013, period C). Time intervals reflect academic years (ie, July 1 to June 30). To account for possible fluctuations in patient volume, the data were also compared by normalizing testing rates per 100 morphologic ultrasonograms (Current Procedural Terminology code 76811, which can only be billed once per pregnancy). These scans were performed by maternal-fetal medicine specialists only once per pregnancy and therefore accurately reflect the total number of patients seen during the course of the study. All amniocentesis procedures recorded in the data were performed for genetic indications; amniocenteses performed for other indications were excluded from our analysis.
The study design included all referred patients who presented to our perinatal practice and opted to undergo prenatal testing. Patients were initially counseled in a nondirective manner regarding the risks and benefits of prenatal testing by a certified genetic counselor or a specifically trained nurse and subsequently reinforced by the maternal-fetal medicine specialist. As such, patients made the final decision regarding their management choices. Chorionic villus sampling and amniocentesis were described as diagnostic procedures with greater than a 99.9% detection rate for Down syndrome and other chromosomal aneuploidies, but as an invasive test, it incurred a one in 200–300 risk of procedure-related pregnancy loss.5 Patients expressing interest in diagnostic testing were offered CVS or amniocentesis depending on their gestational age. Patients were instructed that diagnostic procedures were the only method that could definitively identify fetal karyotype. The combined first-trimester screen was introduced in March 2006 and was described as a noninvasive method with 85% sensitivity for Down syndrome and a 5% false-positive rate. Patients were informed that even if they declined a combined first-trimester screen, they were still offered first-trimester morphologic ultrasonograms. Noninvasive prenatal testing was introduced in March 2012 only to patients with a singleton pregnancy at high risk for aneuploidy, which included advanced maternal age, positive alternate screening test for aneuploidy, or previous pregnancy with aneuploidy. Noninvasive prenatal testing was described as a noninvasive prenatal screening method that uses cell-free fetal DNA fragments in maternal blood to obtain a greater than 99% detection rate for Down syndrome and a less than 1% false-positive rate. All previous screening methods were offered at these consultations in addition to noninvasive prenatal testing. It was also expressed that because noninvasive prenatal testing is a relatively new technology, some insurance companies may not fully reimburse patients, and interested parties were encouraged to explore financial concerns with their individual insurance programs.
Data were compared using one-way analysis of variance with Student-Newman-Keul's post hoc test on SigmaPlot 12.0. All data are represented as means±standard deviation. A value of P<.05 was considered statistically significant. The Office of Research Subjects' Protection at Eastern Virginia Medical School has reviewed the project and determined that it does not involve human subjects and therefore is not subject to institutional review board approval.
A total of 15,418 prenatal tests were recorded during the 9-year study period, consisting of 9,780 combined first-trimester screen, 1,265 noninvasive prenatal testing, 608 CVS, and 3,765 amniocenteses. Time intervals represent 20 months before combined first-trimester screen (July 2004 to February 2006, period A), 72 months after combined first-trimester screen introduction but before noninvasive prenatal testing (March 2006 to February 2012, period B), and 16 months when both noninvasive prenatal testing and combined first-trimester screen were available (March 2012 to June 2013, period C). Monthly averages for each test are listed in Table 1.
Combined first-trimester screen uptake was determined for an 88-month period after its introduction in March 2006, including after noninvasive prenatal testing introduction in March 2012. Combined first-trimester screen peaked at 1,836 in 2009–2010 (Fig. 1A). In the first full year after noninvasive prenatal testing was introduced in March 2012, only 952 combined first-trimester screen procedures were performed during the 2012–2013 academic year, reflecting a 48.1% decrease from peak numbers. The average number of combined first-trimester screen procedures per month decreased from 116.6 procedures per month before noninvasive prenatal testing (period B) to 86.8 procedures per month after noninvasive prenatal testing (period C), reflecting a 25.6% decrease in average combined first-trimester screen (Table 1). The monthly rate of combined first-trimester screen per 100 morphologic ultrasonograms was also assessed. The average number of monthly combined first-trimester screen procedures performed per 100 morphologic ultrasonograms significantly (P<.05) decreased after noninvasive prenatal testing introduction (period C), from 23.7 to 17.3 first-trimester screens per month per 100 morphologic scans (Fig. 1B). In sum, these results suggest that combined first-trimester screen was initially rapidly adopted by our patient population, but its use significantly decreased after introduction of noninvasive prenatal testing.
The change in the number and rate of CVS and amniocentesis procedures was assessed before and after introduction of a combined first-trimester screen and subsequently noninvasive prenatal testing. Yearly CVS rates are illustrated in Figure 2A, showing that a total of 55 CVS procedures were performed during the first year of the study (2004–2005). After combined first-trimester screen introduction in March 2006, CVS rates increased to a peak of 100 procedures in 2007–2008, representing an 81.8% increase from baseline levels. After noninvasive prenatal testing was introduced in March 2012, the CVS rate decreased to only 22 procedures during the 2012–2013 academic year, reflecting a 68.6% decrease from the previous year and a 78.0% decrease from peak numbers in 2007–2008. This is similarly indicated in Table 1, showing that CVS procedures per month increased by 26.0% after combined first-trimester screen introduction (period B) but subsequently decreased by 49.2% per month after introduction of noninvasive prenatal testing (period C). Furthermore, monthly CVS procedures per 100 morphologic ultrasonograms significantly (P<.05) increased after combined first-trimester screen (period B) but then significantly decreased after noninvasive prenatal testing (period C) to levels no different than before combined first-trimester screen (Fig. 2B). In sum, these results suggest that although combined first-trimester screen increased CVS testing, noninvasive prenatal testing subsequently decreased CVS testing.
The change in the number and rate of amniocentesis procedures performed over the same time intervals was also assessed. In comparison to CVS, amniocentesis rates declined every year of the study (Fig. 3A). A high of 755 amniocentesis procedures was performed during the first year of our study period (2004–2005) and decreased every year that the combined first-trimester screen was available. In the final year of combined first-trimester screen before noninvasive prenatal testing was introduced (2010–2011), amniocentesis had decreased to 300 procedures per year, reflecting a 60.3% decrease from peak numbers. After introduction of noninvasive prenatal testing in March 2012, amniocentesis further decreased to only 160 procedures in 2012–2013, representing a further 46.7% decrease from prenoninvasive prenatal testing levels. Over the course of the entire 9-year study period, the total number of amniocentesis procedures performed per year decreased by 78.8%. Similarly, amniocentesis decreased from 60.2 to 32.4 procedures (46.2% decrease) per month after combined first-trimester screen (period B) and decreased further to 14.1 (69.5% decrease) procedures per month after introduction of noninvasive prenatal testing (period C; Table 1). Monthly amniocentesis procedures per 100 morphologic ultrasonograms also significantly (P<.05) decreased after combined first-trimester screen introduction in 2006 (period B) and again after noninvasive prenatal testing introduction in 2012 (period C; Fig. 3B). In sum, these results suggest that the increased incidence of first-trimester screening resulting from the introduction of combined first-trimester screen and subsequently by noninvasive prenatal testing resulted in a significant decrease in amniocentesis.
Our results indicate that although combined first-trimester screen and noninvasive prenatal testing are both considered first-trimester screening methods, they have resulted in differing effects on the number of diagnostic procedures performed. The introduction of combined first-trimester screen in March 2006 resulted in an increase in yearly CVS, CVS per month, and average CVS per 100 morphologic ultrasonograms. However, noninvasive prenatal testing introduction in March 2012 resulted in a decrease in these rates of CVS testing. In contrast, amniocentesis decreased after the introduction of both combined first-trimester screen and noninvasive prenatal testing. The number of combined first-trimester screens also significantly decreased after noninvasive prenatal testing introduction, suggesting a shift in patient screening preference. These changes were likely driven both by patient desire for noninvasive procedures as well as physician desire to provide patients with the most efficient risk assessment for aneuploidies at the earliest gestational age. It is important to note that although noninvasive prenatal testing is a safe and efficient screening method for aneuploidy, abnormal results should be confirmed with either amniocentesis or CVS.
Increased nuchal translucency between the 10th and 14th week of gestation is known to be an early marker for fetal aneuploidy.6 Combined with maternal age and serum analytes, the “combined first-trimester screen” increases the sensitivity for detection of Down syndrome to 80–85% but with a 5% false-positive rate.7,8 In a trial on 1,280 patients with advanced maternal age, Wray et al9 report that after the combined first-trimester screen was introduced, patients were less likely to elect for diagnostic testing. Other groups report a more modest decrease in diagnostic testing or even an increase in the number of amniocentesis performed.10 A gradual decline in the rate of diagnostic procedures has been reported to occur despite an increase in the number of advanced maternal age pregnancies.11 Our analysis over 9 years also reports extensive patient acceptance, but although amniocenteses did decrease after combined first-trimester screen, the number of CVS procedures actually increased. This increase is likely the result of a combined first-trimester screen being performed earlier in the pregnancy, allowing patients to have more access to first-trimester CVS. This finding is surprising considering the greater risk of complications for CVS over amniocentesis, which has been reported to be four times greater.12 This may imply that some patients prioritize learning the karyotype of the fetus over waiting several more weeks for the safer amniocentesis.
We report decreased CVS and amniocentesis after the introduction of noninvasive prenatal testing, which is in agreement with a previous study by Chetty et al13 who reported decreased invasive prenatal test postnoninvasive prenatal testing. Our study focuses on testing rates from all patients referred to our practice, which was designed to emphasize more global trends in diagnostic testing observable at an institutional level. Our data also exclude nongenetic amniocentesis and reflect procedures with strictly genetic indications. However, in both the Chetty study and our report, invasive diagnostic testing was still being frequently performed. Preference for CVS or amniocentesis over noninvasive prenatal testing has also been previously reported in certain ethnic groups.14 This phenomenon is likely the result of the relative novelty of noninvasive prenatal testing, suggesting that more work should be done to better educate patients regarding the benefits of noninvasive prenatal testing.
Strengths of this report include the scope of the study encompassing a 9-year period involving the complete combined first-trimester screen experience in our clinic and consisting of 15,418 prenatal tests overall. Our institution was also one of the first to offer noninvasive prenatal testing in our region, and as more clinics begin to include this technology, our report provides an early analysis of the effects on diagnostic testing that can be expected postnoninvasive prenatal testing. Limitations include a retrospective design precluding an ability to determine the precise factors contributing to patient decisions and the inability to determine whether patients were at high or low risk for aneuploidy. Also, an analysis of other screening methods such as second-trimester serum analyte testing was not included in this study. Because these tests are offered in the second trimester, patients have missed the opportunity for combined first-trimester screen or CVS testing, and their decision regarding antenatal screening may be biased and therefore not included in our report.
In conclusion, this study reveals that CVS increased while amniocentesis procedures decreased after the introduction of combined first-trimester screen. In comparison, noninvasive prenatal testing resulted in a decrease in both amniocentesis and CVS. Overall, with the introduction of more effective risk assessment, the annual rate of genetic amniocentesis has decreased by 78.8%, and the annual rate of CVS has decreased by 60.0% over the 9-year study period. With increasing physician and public awareness of the availability of noninvasive prenatal testing, we expect similar trends to be experienced at other institutions.
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