fetal down syndrome screening: a cost effectiveness analysis of alternative screening programs
TRANSCRIPT
The Journal of Maternal-Fetal Medicine 8:243-248 (1999)
Fetal Down Syndrome Screening: A Cost Effectiveness Analysis of Alternative
Screening Programs
William Cusick’’ and Anthony M. Vintrileosz Division of Maternal-Fetal Medicine, Department of OB/GYN, The Stamford Hospital,
Stumbrd, Connecticut WMDNJ and St. Peter’s Medical Center, New Brunswick, New Jersey
Objectivw To compare the efficacy and cost effectiveness of different screening programs for fetal Down syndrome (DS). hhods: Screening tools evaluated included maternal age, triple screening (TS), and ultrasound (U/S) for fetal markers of DS. Sensitivities used were TS: 55% < 35 years, 80% 2 35 years; U/S: 70%. Average regional fees used were TS: $80, U/S: $200, amniocentesis (AM): $1,000. Five screening programs were evaluated: 1) <35 years, no screening; 2 3 5 years, AM; 2) <35 years, TS with AM for screen-positive subjects; 235 years, AM; 3) all patients, TS with AM for screen-positive subjects; 4) <35 years, TS followed by U/S for screen-positive women, AM for women with fetal markers of DS on U/S; 235 years TS with AM for screen-positive subjects; 5) all women, TS followed by U/S for screen-positive women, AM for women with fetal markers of DS on U/S. The sensitivity, total cost, cost/case DS detected (Cost/DS), AM losses, and residual risk (RR, undetected DS fetuseslwomen not receiving AM) were calculated for each screening program. Population analysis was performed using 1988 IL delivery statistics. Results: It was estimated that 260 cases of DS would occur in the population of 167,654 women (8.4% 2 35 years at delivery). Sensitivity for programs 1-5 was 30, 69, 62, 51, and 36 percent, respectively, and cost/DS was 181,000, 203,000, 162,000, 151,000, and 194,000 dollars, respectively. Conclusions: DS screening incorporating TS in all patients with program #4 and without program #3 selective U/S in women <35 years yield the best combination of sensitivity and cost effectiveness while minimizing the number of AM-related losses. J. Matern.-Fetal Med. 1999;8:243-248. o 1999 Wiley-Liss, Inc.
Key words: fetal Down syndrome; ultrasound; cost effectiveness analysis
INTRODUCTION Down syndrome occurs in 1/800 livebirths in the United
States and represents the most common chromosomal cause of mental retardation [l]. The birth of an infant with Down syndrome causes great emotional burden for affected fami- lies. Furthermore, the lifetime cost per case of Down syndrome has been estimated at $153,000-1,067,000 [2]. Accordingly, the prenatal identification of affected fetuses is a worthwhile endeavor. Initially, prenatal screening for fetal Down syndrome targeted women at risk secondary to advanced maternal age. Subsequently, maternal serum screening, first using alpha-fetoprotein ( AFP) alone and later in combination with beta human chorionic gonadotro-
pin (BhCG) and estriol (E3) allowed for screening of all women in combination with maternal age. Recently, several centers, in an effort to better identify individuals at greater risk, reported on the potential benefit of ultrasound (U/S) evaluation in patients at increased risk for fetal Down Syndrome [3-81. Presently, no single screening approach has
‘Correspondence to: William Cusick, Division of Maternal-Fetal Medi- cine, Department of OB/GYN, The Stamford Hospital, Shelburne Road at West Broad St., Stamford, CT 06904.
Received 18 November 1 998; revised 3 May 1999; accepted 17 May 1999
0 1999 wiley-Liss, Inc.
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been accepted; each is associated with definable risks and benefits.
Health care providers have long understood the impor- tance of reevaluating accepted clinical practice with the advent of new medical technologies. More recently, clini- cians have realized the importance of assessing the benefits of such practice in the context of economic and noneco- nomic costs. Such a reappraisal of prenatal Down syndrome screening programs is appropriate in light of the many screening options that are now available. The purpose of this study is to compare the efficacy and cost effectiveness of alternative prenatal screening programs for fetal Down syndrome.
SUBJECTS AND METHODS This cost effectiveness analysis assumed that all pregnant
women underwent fetal Down syndrome screening and amniocentesis was performed in all women at increased risk. The following fetal Down syndrome screening tools were evaluated: advanced maternal age, second trimester triple screen, and second trimester U/S for fetal markers of Down syndrome. Maternal age 2 3 5 years of age at the time of delivery was considered advanced. A triple screen risk 21/270 was considered screen positive. A sensitivity of 55% and screen-positive rate of 7.1% (6.0% after recalculation for incorrect dates) was assumed for second trimester maternal serum triple screening (BhCG, E3, AFP) in women younger than 35 years of age [9]. In women 35 years and older, a sensitivity of 80% and screen-positive rate of 21% was used [9]. Several authors have described a “genetic sonogram” designed in an effort to detect fetuses with Down syndrome and other types of aneuploidy [3-81. The exams, although with some variations in technique, provide for a comprehensive evaluation of fetal structure designed to detect subtle structural and biometric dysmorphology pres- ent in many fetuses with Down syndrome (Table 1). For the purposes of this study, U/S was considered positive if one or fetal marker of Down Syndrome were detected. The U/S sensitivity for detecting fetal Down syndrome in the second trimester has been shown to be independent of maternal age [7] with a range of 50-93% [3-81. This sensitivity is achieved with a U/S screen-positive range of 7-13% [3-81, with 13% being the most common rate. Accordingly, individual cost analysis was performed using U/S sensitivi- ties of 5O%, 70%, and 90% and a U/S screen-positive rate of 13% (one or more fetal marker present) for screening programs incorporating U/S evaluation of at-risk patients.
Five different screening programs were evaluated (Table 2). Programs 1 and 2 offered amniocentesis to those women 235 years of age. In addition, Program 2 provided triple screening to women <35 years and offered amniocentesis to those who were screen positive. Program 2 represents the current standard of care for fetal Down Syndrome screening
TABLE 1. Sonographic Fetal Markers of Down Syndrome
Major structural anomaly Structural cardiac defect Nonimmune hydrops Duodenal atresia Choroid plexus cyst Renal pyelectasis Echogenic bowel Nuchal edema
Short ear Short humerus Short femur Hypoplasia Yh mid-phalynx Increased space 1sc-2nd toe Increased iliac wing angle Single umbilical artery Ventriculomegaly
TABLE 2. Screening Programs
Program <35 years 2 3 5 years
#1 No screening #2 Triple Screen
I @ Amniocentesis
I@
I @
I@ #5 Triple screen
I@ Genetic sono
I@ Amniocentesis
#3 Triple Screen
Amniocentesis #4 Triple screen
Genetic sono
Amniocentesis
Amniocentesis Amniocentesis
Triple screen
Amniocentesis Triple screen
Amniocentesis
I@
l @
Triple screen I@
Genetic sono I@
Amniocentesis
in many regions. Program 3 offered triple screening to women of all ages, providing amniocentesis to screen- positive patients. Program 4 provided triple screening to patients of all ages. In screen-positive women <35 years, genetic sonogram was performed and amniocentesis then performed on those with fetal markers of Down syndrome present. Women 235 years of age who were triple screen- positive went directly to amniocentesis. Program 5 provided triple screening followed by genetic sonogram for screen- positive women regardless of age. Those women with one or more fetal sonographic markers for Down syndrome under- went amniocentesis. U/S sensitivities of 50%, 70%, and 90% were utilized for those screening programs incorporat- ing U/S evaluation of at-risk patients.
The following 1996 regional cost averages (reflecting reimbursements) were used: maternal serum triple screen, $80.00; U/S exam, $200; amniocentesis, $1,000. A 1/250 procedural related loss rate due to amniocentesis was assumed. In 1988, 167,654 women delivered in the state of Illinois, 8.4% of whom were 235 years of age. For the purposes of this study, the different screening programs were applied to this real population . The expected number of Down syndrome fetuses in the second trimester was esti-
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FETAL DOWN SYNDROME SCREENING 245
mated using age-related risks for Down syndrome 1101 by multiplying the number of women in each age group by the age-specific risk. The sensitivity, screen-positive rate (FPR), cases of Down detected per amniocentesis (amnio/case DS), number of procedural losses, total program cost, cost per case of Down detected (cost/case DS) were determined for each screening program evaluated. In addition, the residual risk (RR) for fetal Down syndrome was determined by dividing the number of undetected cases of Down syndrome by the total number of women not undergoing amniocente- sis.
RESULTS It was estimated that 260 cases of fetal Down syndrome
occurred in 167,654 women delivered in Illinois in 1988, 8.4% of whom were 235 years of age. Amniocentesis in all women 235 years of age (Program 1) would identify 30% (78/260) of fetuses with Down syndrome in the total population (Table 3). The identification of these fetuses would be achieved at a cost of $181,000 per case and would be expected to result in the procedural-related loss of 56 normal pregnancies. A maximum number of Down syn- drome fetuses 178/260 (68.5%) are identified when women 235 years and women <35 years with abnormal triple screen undergo amniocentesis (Program 2). Such superior sensitivity is, however, associated with significant costs. This screening approach possesses the highest screen- positive rate (14.9%), highest total cost, and cost per case detected among the various screening programs evaluated. Furthermore, such an approach is expected to result in the amniocentesis procedural-related loss of 100 normal pregnan- cies (Table 3).
Performing maternal serum triple screening on all pa- tients and reserving amniocentesis for those who are screen-positive (Program 3) offers several significant advan- tages (Table 3). The number of screen-positive women is 44% lower (screen-positive rate: 8.3%), with only a 9% reduction in screening sensitivity (62.3%) compared to Program 2. In addition, this program is associated with a lesser cost in comparison to the universal triple screen approach (Program 2), with $41,000 saved per case detected and a total screening cost savings of 10 million dollars. Although 16 fewer fetuses with Down syndrome would be identified using this approach, fewer women are exposed to the risks of amniocentesis, which translates into 45 fewer procedural-related losses.
The use of U/S greatly reduces the screen-positive rate when selectively used as an adjunct to triple screen testing in women <35 years (Program 4) or in all age groups (Program 5). Using U/S prior to amniocentesis allows one to better target women at greatest risk for fetal Down syndrome. As a result, the number of amniocentesis per case detected is greatly reduced and the number of amniocentesis-
related losses minimized. Overall, the efficacy of U/S in the evaluation of patients at increased risk for fetal Down syndrome is largely dependent on the U/S sensitivity (Tables 4,5). With increasing U/S sensitivity for fetal Down syndrome, more fetuses are identified at a lesser cost. With a U/S sensitivity of 50%, there are no cost savings and only 43.1% and 21.5% of fetuses with Down syndrome are identified in Programs 4 and 5, respectively. Better detec- tion rates are obtained with a U/S sensitivity of 70% for fetal Down syndrome: 50.7% for Program 4 and 35.8% for Program 5. In addition to minimizing the number of procedural losses, the use of U/S in triple screen-positive women <35 years of age prior to amniocentesis results in a total savings compared to those programs not incorporating this exam (Programs 2 and 3). With a U/S sensitivity of 90% for fetal Down syndrome, 58.5% and 52.7% of fetuses are identified in Programs 4 and 5, receptively. These detection rates are achieved with a low screen-positive rate (2.7%, 1.2%), low amniocentesis per case Down detected rate (29:1, 13:1), and low cost/case detected ($131,000, $131,000), while at the same time minimizing the number of procedural losses ( 17, 7).
DISCUSSION When evaluating alternative screening programs for
Down syndrome, one must consider more than just the overall sensitivity associated with each approach. The screen-positive rate, or the number of women with normal fetuses who nevertheless are identified as being at increased risk for Fetal Down syndrome, is important for several reasons. First, screening programs provoke considerable anxiety in those women with positive results. Second, such women require counseling and additional interventions, both of which involve considerable resources and expense. Third, a higher screen-positive rate will expose more women with normal fetuses to amniocentesis, resulting in a greater number of procedural-related losses. For these rea- sons, a low screen-positive rate is desirable. In addition, the number of amniocenteses performed per case of Down syndrome identified is an important measure of the screen- ing program’s ability to identify those patients at greatest risk. The lower the number, the fewer the number of normal pregnancies subjected to the risks of amniocentesis. Finally, the economic costs need be considered, particularly when evaluating regional screening programs. This is best re- flected in the cost per case Down syndrome detected, which is a measure of the cost efficiency of each approach.
A screening program incorporating maternal serum triple screening in all pregnant women, regardless of maternal age (Program 3), yields an excellent fetal Down syndrome detection rate and is associated with an acceptably low false-positive rate. The number of amniocenteses required to detect each case of Down syndrome and the cost per case
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TABLE 3. Efficacy of Alternative Screening Programs (U/S sensitivity = 70%, U/S positive rate = 13%)
Screening program #l #2 #3 #4 #5 Screen-positive rate 8.4% 14.9% 8.3% 2.7% 1.2% Sensitivity (n) 30.0% (78) 68.5% (178) 62.3% (162) 50.7% (132) 35.8% (93) Amniolcase DS 181 132 77 33 19 Costlcase DS $181k $203k $162k $151k $194k Total cost $ 14.lm $ 36.1111 $ 26.lm $ 20.01~1 $ 18.0m Amnio losses 56 100 55 17 7 RR <35 years 0.12% 0.06% 0.06% 0.07% 0.09% RR 235 years 0% 0% 0.14% 0.14% 0.25%
TABLE 4. Analysis of Screening Program #4 Using Alternative U/S Sensitivities for Fetal Down Svndrome*
TABLE 5.
U/S Down syndrome sensitivity Screen positive rate Sensitivity (n) Amnio/case DS Costlcase DS Amnio losses RR <35 years RR 235 vears
50% 70% 90%
43.1% (112) 50.7% (132) 58.5% (152) 39 33 29
$178k $151k $131k 17 17 17
2.7% 2.7% 2.7%
0.09% 0.07% 0.06% 0.14% 0.14% 0.14%
*All women received maternal serum triple screen; genetic sonogram for screen-positive individuals <35 years, amniocentesis for women with fetal markers of Down syndrome and amniocentesis for screen-positive individuals 2 3 5 years.
Analysis of Screening Promam #5 * Using I
Alternative U/S Sensitivities for Fetal Down Syndrome
U/S Down syndrome sensitivity 50% 70% 90%
Screen-positive rate 1.2% 1.2% 1.2% Sensitivity (n) 32 19 13 Cost/case DS $320k $194k $131k Amnio losses 7 7 7 RR <35 years 0.10% 0.09% 0.07% RR 235 years 0.34% 0.25% 0.16% *All women receive maternal serum triple screen followed by genetic sonogram for screen-positive patients.
detected are reduced in comparison to Programs 1 and 2, respectively. Some may question the wisdom of providing triple screening to women 235 years of age who, in the past, were offered amniocentesis on the basis of age risk alone. Although it is true that 16 fewer fetuses with Down syndrome would be identified in women 235 years of age if universal maternal serum triple screening was performed, 45 fewer amniocentesis-related losses would occur with screen- ing cost savings. Furthermore, the residual risk for fetal Down syndrome in triple screen negative women 235 years of age is small, 0.14%. The hypothetical advantages of providing triple screening to women 235 years of age has been validated in two recent studies by Kellner [9] and Haddow [ 1 I].
Recently, the use of U/S in the evaluation of patients at increased risk for fetal Down syndrome either due to
advanced maternal age or abnormal triple screening has been reported by a number of authors [3-81. These compre- hensive fetal exams, incorporating a detailed fetal biometric and structural survey for markers of fetal Down syndrome, require special expertise and are only available at a small number of referral ultrasound centers. The specifics of the U/S examination and the overall Down syndrome detection rate differ among centers, with sensitivities of 50-93% being reported [3-81. Incorporating U/S in the evaluation of patients at risk for fetal Down syndrome would theoretically allow one to better identify those fetuses at greatest risk. This, then, leads to a further reduction in the screen- positive rate, fewer amniocentesis per case of Down Syn- drome detected, and minimizes the number of amniocentesis- related losses.
The utility of U/S in the evaluation of patients at increased risk for fetal Down syndrome is significantly influenced by the U/S sensitivity for fetal Down syndrome. With a U/S sensitivity of 50%, the overall Down syndrome detection rate is poor and there is no clear cost advantage associated with the use of ultrasound in triple screen- positive women of any age (Programs 4 and 5). With a U/S sensitivity of 70%, however, there are some advantages to the use of U/S in triple screen-positive women <35 years of age prior to amniocentesis. The slightly reduced sensitivity compared to Program 3, in which triple screen-positive women <35 years proceed directly to amniocentesis, is offset by a marked reduction in the screen-positive rate to
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TABLE 6. Down Syndrome Screening Costs per 100,000 Pregnancies (8.4% 2 35 Years of Age)
Screening program #1 #2 #3 #4 #5 Total cost $8.4m $21.6m $15.6m $11.9m $10.7m Costlcase DS $181k $203k $162k $151k $194k Amnio losses 34 60 33 11 5 Using U/S sensitivity of 70% for fetal Down syndrome.
2.7%. The number of amniocentesis performed per case of Downs detected is reduced by 57% and the number of procedural-related losses is reduced by 69%. The residual risk for women <35 years of age not undergoing amniocen- tesis is 0.07%. The benefits in triple screen-positive women 35 years and older is less apparent at this level of U/S sensitivity. There is, however, a significant advantage to offering U/S prior to amniocentesis to triple screen-positive women of all ages (Program 5 ) when U/S sensitivities for fetal Down syndrome of 90% are achievable. Such a screening program appears superior to all others evaluated and would detect 52.7% of all Down syndrome fetuses in 1.2% of the population. Thirteen amniocentesis would be performed for each case of Down syndrome detected and only seven procedural losses would be expected. This could be accomplished with considerable cost savings, requiring the expenditure of $131,000 per case of detected Down syndrome. Furthermore, the residual risk for fetal Down syndrome in women not undergoing amniocentesis would be small (0.07% and 0.16% for women <35 and 235 years of age, respectively.)
In this hypothetical analysis, we attempted to evaluate alternative screening programs for fetal Down syndrome. Cost analysis was restricted to screening costs. We did not intend to perform a lifetime cost analysis for neonates with Down syndrome that went undetected or to estimate the economic and social costs associated with the loss of normal fetuses secondary to amniocentesis. Since the primary purpose of Down syndrome screening programs is the identification of fetuses with Trisomy 21, we did not attempt to estimate the detection rates for other chromosomal abnormalities. The calculated screening sensitivities are best estimates since not all women can be expected to undergo screening. Furthermore, a significant proportion of women at risk for fetal Down syndrome decline amniocente- sis. It is important to remember that, although a high detection rate for fetal Down syndrome is the goal of any screening program, the identification of an affected fetus alone may have no impact on patient care and may not prevent birth of the affected fetus. In the absence of major structural abnormalities of the affected fetus, no additional antepartum interventions are then required. Since a signifi- cant percentage of couples are opposed to elective termina- tion for fetal Down Syndrome, they would be disinterested
in risking a loss of pregnancy for the sake of prenatal diagnosis.
Prenatal screening programs for Down syndrome are associated with significant social and economic costs (Table 6 ) . When evaluating the merits of alternative fetal Down syndrome screening methodologies, all costs need to be considered. The cost analysis presented here was intended to estimate the associated costs and benefits of Down Syndrome screening strategies applied to a statewide popula- tion. Although this provides important insight into the overall sensitivities and economic costs associated with these different programs, such an approach fails in elucidat- ing the noneconomic costs to the patient. Much patient anxiety is associated with the reporting of an abnormal screening test in pregnancy. This is further compounded when she is faced with the difficult decision of undergoing amniocentesis, an invasive, physically and emotionally painful procedure that is associated with a real risk for pregnancy loss. Whereas some patients may be unaffected by the birth of a Down syndrome infant, all would be devastated by the amniocentesis-related loss of a normal pregnancy. Therefore, a screening approach with a low screen-positive rate and requiring fewer amniocenteses per case Down syndrome detected is preferable.
The physician is instrumental in providing pertinent information to all pregnant patients about the risks and benefits of available Down syndrome screening tools. Pa- tients at risk should be provided with Down syndrome counseling and informed of the availability of ultrasound evaluation, if regionally available and with acceptable sensitivity. Amniocentesis should be performed only after a patient has considered all of her available options and has demonstrated a sound understanding of the procedure and its associated risks. In the final analysis, the decision to proceed with amniocentesis rests solely with the well- informed patient.
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