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http://qawww.aetna.com/cpb/medical/data/200_299/0282_draft.html 04/22/2015

Clinical Policy Bulletin: Noninvasive Down Syndrome Screening

Revised February 2015

Number: 0282

Policy

Aetna considers the following noninvasive screening schemes for fetal aneuploidy

medically necessary:

First-trimester nuchal translucency (NT) testing alone (without serum

analyte screening) for multiple gestations; or

First-trimester NT measurements results combined with the results of first

trimester serum analyte tests that include pregnancy-associated plasma

protein A (PAPP-A) plus beta-human chorionic gonadotropin (hCG)*; or

Integrated, sequential, or contingent screening: First-trimester triple test

(NT, PAPP-A, and hCG*) plus second-trimester quadruple test (maternal

serum alfa-fetoprotein (MSAFP, unconjugated estriol, inhibin A, and hCG*)

screening; or

Second-trimester serum analyte screening (see CPB 0464 - Serum Marker

Screening for Down Syndrome); or

Serum integrated screening for pregnancies where NT measurement is not

available or can not be obtained: First-trimester (PAPP-A plus hCG*) plus

second-trimester quad (MSAFP, uncongugated estriol, inhibin A, and hCG*)

screening; or

Measurement of cell-free fetal nucleic acids in maternal blood when criteria

are met in CPB 0464 - Serum Marker Screening for Down Syndrome.

Aetna considers other noninvasive screening schemes for fetal aneuploidy to be

experimental and investigational, including the following becasue their

effectiveness has not been established:

First-trimester NT measurement alone (without first-trimester serum analyte

testing) in the absence of fetal cystic hygroma in singleton pregnancies.

First-trimester serum analyte testing (hCG* and PAPP-A) alone without NT

measurement.

First-trimester ultrasound assessment of the nasal bone.

http://qawww.aetna.com/cpb/medical/data/200_299/0282_draft.html



First-trimester maternal plasma levels of follistatin-related gene protein.

First-trimester maternal serum A disintegrin and metalloprotease 12

(ADAM12-S) level.

First-trimester maternal serum anti-Mullerian hormone level.

First-trimester maternal serum placental growth factor level.

Maternal plasma microRNA

*For purposes of this policy, these various forms of hCG are considered

interchangeable: free beta subunit of hCG, total hCG, or hyperglycosylated hCG

(also known as invasive trophoblast antigen [ITA]).

Note: All screening schemes that involve NT testing are considered medically

appropriate only when performed in a setting of demonstrated ultrasound

credentialing and ongoing quality monitoring.

See also CPB 0047 - Prenatal Care Provided by Primary Care Physicians, CPB

0106 - Fetal Echocardiograms, CPB 0140 – Genetic Testing, CPB 0189 - Genetic

Counseling, CPB 0199 - Ultrasound for Pregnancy, CPB 0348 - Recurrent

Pregnancy Loss, CPB 0358 - Invasive Prenatal Diagnosis of Genetic Diseases,

and CPB 0464 - Serum Marker Screening for Down Syndrome.

Background

Historically in the United States, risk assessment for Down syndrome (DS) and

other fetal chromosomal abnormalities had varied by maternal age. Invasive

genetic testing, either amniocentesis or chorionic villus sampling (CVS), were

offered to women who would be older than age 35 at the time of delivery with

singleton pregnancies. Second trimester maternal serum testing ("analyte

testing") was offered to women younger than 35 years at time of delivery with

singleton pregnancies, or those older than age 35 but who decline invasive

testing. The serum tests performed in the second trimester are either a "triple"

screen" (maternal age plus maternal serum alpha-fetal protein (MSAFP),

unconjugated estriol, and free or total beta-hCG) or a "quad" screen (maternal age

plus MSAFP, estriol, free or total beta-hCG, and dimeric inhibin A).

More recently, guidelines from the American College of Obstetricians and

Gynecologists (ACOG, 2007) and the American College of Medical Genetics

(ACMG) (Palomaki et al, 2007) state that all women, regardless of age, should

have the option of invasive testing. Although invasive testing (amniocentesis or

CVS) detects 100 % of fetal chromosomal abnormalities, it is associated with an

increased risk of pregnancy loss compared to non-invasive testing. Maternal

serum testing with the quad screen in the second trimester is safe but only

maximally detects 79 % of DS cases.

First Trimester Noninvasive Screening

Recent advances in prenatal screening have been focused on first trimester non-

invasive screening. According to the American College of Obstetricians and

Gynecologists (ACOG), non-invasive first trimester screening for chromosomal

abnormalities, such as DS, offers several potential advantages over second




trimester screening. First trimester screening provides for earlier diagnosis of fetal

aneuploidy. For women with affected fetuses who elect termination of pregnancy,

the procedure is safer and results in fewer maternal complications when

performed early in pregnancy. Women who have negative test results may elect

to forego invasive testing thus avoiding the potential complication of unintended

fetal loss due to procedure-related complications.

Several population-based studies have evaluated the effectiveness of non-

invasive first trimester screening for the detection of DS using a combination of

first trimester serum markers with measurement of fetal nuchal translucency (NT)

(i.e., ultrasonographic measurement of the fluid accumulation behind the fetal

neck,). A large, National Institutes of Health (NIH)-sponsored, prospective, multi-

center study called the Blood, Ultrasound, and Nuchal Translucency (BUN) Trial

determined that an algorithm that combined the results an NT measurement in the

first trimester (between 11 weeks' and 1 day and 13 weeks' and 6 days' gestation)

with the results of maternal serum tests (free-beta hCG and PAPP-A) performed in

the first trimester detected about 79 % of all DS cases with a false-positive rate of

5 % (Wapner et al, 2003). A nested, case-controlled British trial called the Serum,

Urine and Ultrasound Screening Study (SURUSS) evaluated both first and second

trimester markers for DS in singleton pregnancies. Results for first trimester

screening found that NT in combination with free or total beta-hCG plus PAPP-A

detected 85 % of DS with a false-positive rate of 5 % (Wald et al, 2003). A United

States-based, NIH-funded First and Second Trimester Estimation of Risk

(FaSTER) Study was an intervention trial involving more than 38,000 pregnancies

that compared first and second trimester markers in the same women. Published

results of the first trimester analysis of NT combined with free beta-hCG plus

PAPP-A found DS detection rates of 85 % with a false-positive rate of 5 %

(Malone and D'Alton, 2003). The DS detection rates described in these studies

are comparable or better than those for second-trimester "quad" screening using

four serum markers (MSAFP, total or intact beta-hCG, unconjugated estradiol, and

serum inhibin A).

In fetuses with DS, NT measurements are increased, serum total and free beta-

hCG are increased and PAPP-A is decreased compared to fetuses without DS in

the gestational age window of 11 to 13 weeks (Canick and Kellner, 1999). The

performance of each of the markers, individually, varies as gestational age

progresses. For example, the performance of NT and PAPP-A declines and total

and free beta-hCG increases as gestational age proceeds through the end of the

first trimester and early second trimester. In order to achieve the detection rates

described in the 3 large trials described above, first trimester non-invasive

screening should involve all markers (NT, PAPP-A, and total or free beta-hCG)

and be performed in the time window of 11 to 13 weeks gestation.

Two analytes for hCG, "free" beta-hCG and "total" or "intact" beta-hCG, are

currently employed in first trimester risk assessment. The efficacy of the free beta-

hCG analyte has been more extensively studied. Both the BUN and FaSTER

trials support the efficacy of free beta-hCG. Support for the efficacy of the total or

intact beta-hCG analyte is provided by the SURUSS study. As individual markers,

NT is the most informative followed by PAPP-A (Wald et al, 2003). As an

individual marker, free beta-hCG outperforms total beta-hCG in detecting DS

affected pregnancies. Recent guidelines from the ACMG (Palomaki et al, 2007)




state that all screening schemes that involve measurement of hCG in first or first

and second trimester fetal aneuploidy screening should consider free beta subunit

of hCG, total hCG, or hyperglycosylated hCG (also known as invasive trophoglast

antigen (ITA)) interchangeable.

The Society for Maternal Fetal Medicine (SMFM) and ACMG have provided

guidance on follow-up of normal first trimester combination screening.

Specifically, women should not undergo independent sequential "triple" or "quad"

screening in the second trimester of pregnancy to further assess aneuploidy risk if

results of combined first trimester NT and serum analyte testing are negative

(normal) (Driscoll, 2004). Independent sequential testing of this sort is associated

with an unacceptably high false-positive rate (Hackshaw and Wald, 2001;

Malone and D'Alton, 2003). Instead, women who want a higher detection rate can

have an integrated or sequential screening test, which combines both first- and

second-trimester screening results (ACOG, 2007). An integrated approach to

screening uses both first-trimester and second-trimester markers to adjust a

woman's age-relatd risk of having a child with DS (ACOG, 2007). The results are

reported only after both first- and second-trimester screening tests are completed.

In the FASTER (First- and Second-Trimester Evaluation of Risk) trial, the detection

rate with "integrated screening" was 94 to 96 % at a 5 % screen-positive rate

(Malone et al, 2005). Although integrated screening has the highest sensitivity

and lowest false-positive rate of noninvasive screening methods, the main

disadvantage of integrated screening lies in the need to wait 3 to 4 weeks between

initiation and completion of the screening. This may result in patient anxiety and

the potential for patients to fail to complete the second-trimester portion of the

screening test after performing the first-trimester component. Another

disadvantage is that the patient loses the opportunity to consider CVS if the first-

trimester screening indicates a high risk of fetal aneuploidy.

Sequential screening approaches that obviate some of the disadvantages of

integrated screening have been developed (ACOG, 2007). With this strategy, the

patient is informed of the first-trimester screening result. Those at highest risk

might opt for an early diagnostic procedure, and those at lower risk can still take

advantage of the higher detection rate achieved with additional second-trimester

screening.

Guidelines from the ACMG have introduced the concept of contingent screening

(Palomaki et al, 2007). ACMG guidelines explain that contingent screening, like

sequential screening, incorporates aspects of first trimetser screening and

integrated screening. However, in contingent screening, the first trimester results

are divided into 3 outcomes: (i) screen positive, (ii) screen negative, and (iii)

intermediate/pending risk. Those patients at intermediate risk will then provide a

second trimester sample for testing in order to computed integrated risk. ACMG

guidelines explain that this strategy allows for early diagnosis of DS among a

small, high-risk group (screen positives) and early reassurance to a large, low-risk

group (screen negatives). It attempts to maintain high performance by having

those with intermediate/pending first trimester risks benefit from the integrated test

(Palomaki et al, 2007).

Integrated screening can be performed using only first-and second-trimester

serum markers ("serum integrated screening"), without incorporating an NT




measurement. In the FASTER trial, the serum integrated screen resulted in an 85

to 88 % detection rate (Malone et al, 2005). ACOG (2007) guidelines state that a

serum integrated screening approach is ideal for patients without access to NT

measurement or for whom reliable NT measurements can not be obtained.

First trimester NT testing alone is less sensitive than either first trimester combined

screening or second trimester “quad” screening and, thus, should not be used in

isolation for routine fetal aneuploidy screening in singleton pregnancies

(Malone and D’Alton, 2003). In multiple gestations, however, serum analyte

testing is unreliable and NT screening alone is medically appropriate. It should be

noted that the identification of a cystic hygroma during first trimester is a very

powerful predictor of fetal aneuploidy. In one large, prospective study, a septated

cystic hygroma was associated with a 51 % likelihood of DS (Malone et al, 2005).

This finding should immediately prompt counseling and consideration for

diagnostic testing and should not be delayed by serum analyte measurement and

further risk calculation.

First trimester serum analyte testing alone (with any combination of analytes) is

also not sufficiently sensitive to be used for routine fetal aneuploidy screening

(Wald et al, 2003; Malone and D’Alton, 2003; ACOG, 2004).

Rosen et al (2007), on behalf of the Nuchal Translucency Oversight

Committee/Maternal Fetal Medicine Foundation, stated that recent studies have

suggested that adding ultrasound assessment of the nasal bone to nuchal

translucency thickness and maternal serum analytes in the first-trimester will

improve performance. The authors evaluated the literature and discussed

practical issues that must be addressed before widespread implementation of

nasal bone screening in the United States. Furthermore, in a review on screening

for fetal abnormalities with ultrasound, Flood and Malone (2008) noted that the

limitations of first-trimester nasal bone measurement were reiterated while its

measurement has been shown to be beneficial in the second-trimester, especially

when calculated with multiples of the median. The authors concluded that

screening for fetal abnormalities continues to evolve with the introduction of novel

techniques and the further refinement of previously proposed screening tools.

How these modalities are implemented into routine clinical practice remains to be

seen.

Miron et al (2010) ascertained maternal plasma levels of follistatin-related gene

protein (FLRG) in the first trimester of pregnancy and assessed its potential role as

a marker for pre-natal screening of DS. Maternal plasma levels of FLRG were

determined in 100 pregnant women with normal fetuses in their first trimester of

pregnancy (i.e., 11th to 15th weeks). These results were compared with 20 cases

with DS fetuses, taking into consideration clinical and demographic variables, such

as maternal age, maternal weight, gestational age, smoking status and ethnicity.

Maternal plasma median of FLRG in the normal population was 1.41 ng/ml with 95

% confidence interval (CI) of 1.37 to 1.70 and inter-quartile range (IQR) of 0.88,

during the 11th to 15th weeks of pregnancy. Maternal age and weight were the

only variables significantly related to FLRG levels (p = 0.030 and 0.020,

respectively). Only maternal and gestational ages were related to DS (p = 0.039

and p = 0.006, respectively). Maternal plasma levels of FLRG were not

significantly different in the presence of DS fetuses compared to normal population




(p = 0.63). The authors concluded that FLRG can be successfully detected in

maternal plasma in the first trimester of pregnancy. However, its levels are not

significantly altered in the presence of DS fetuses.

Li and colleagues (2010) compared the difference in maternal serum anti-Mullerian

hormone (AMH) level between DS pregnancies and unaffected pregnancies, and

evaluated its performance as a screening marker for DS pregnancy. A total of 145

pregnancies affected by fetal DS and 290 unaffected controls matched with

maternal age and gestational age were selected, and their archived first or second

trimester serum retrieved for AMH assay. There was no significant difference in

maternal serum AMH level between pregnancies affected and unaffected by fetal

DS. The first trimester serum samples had higher AMH concentration compared

to second trimester samples. The authors concluded that maternal serum AMH

level, as a marker of ovarian age, is not superior to chronological age in predicting

DS pregnancies. Despite the cross-sectional nature of this study, the variation of

maternal serum AMH concentration with gestational age warrants further

investigation.

A disintegrin and metalloprotease 12 (ADAM12-S) has previously been reported to

be significantly reduced in maternal serum from women with fetal aneuploidy early

in the first trimester and to significantly improve the quality of risk assessment for

fetal trisomy 21 in prenatal screening. Torring and colleagues (2010) examined if

ADAM12-S is a useful serum marker for fetal trisomy 21 using the mixture model.

In this case control study, ADAM12-S was measured by KRYPTOR ADAM12-S

immunoassay in maternal serum from gestational weeks 8 to 11 in 46 samples of

fetal trisomy 21 and in 645 controls. Comparison of sensitivity and specificity of

first trimester screening for fetal trisomy 21 with or without ADAM12-S included in

the risk assessment using the mixture model. The concentration of ADAM12-S

increased from week 8 to 11 and was negatively correlated with maternal weight.

Log multiples of median (MoM) ADAM12-S was positively correlated with log MoM

PAPP-A (r = 0.39, p < 0.001), and with log MoM free beta hCG (r = 0.21, p <

0.001). The median ADAM12-S MoM in cases of fetal trisomy 21 in gestational

week 8 was 0.66 increasing to approximately 0.9 MoM in week 9 and 10. The use

of ADAM12-S along with biochemical markers from the combined test (PAPP-A,

free beta-hCG) with or without nuchal translucency measurement did not affect the

detection rate or false positive rate of fetal aneuploidy as compared to routine

screening using PAPP-A and free beta-hCG with or without nuchal translucency.

The authors concluded that these findings show moderately decreased levels of

ADAM12-S in cases of fetal aneuploidy in gestational weeks 8 to 11. However,

including ADAM12-S in the routine risk does not improve the performance of first

trimester screening for fetal trisomy 21.

Liao et al (2010) evaluated the potential of maternal serum using ADAM12 as a

marker for trisomy 21 in Chinese pregnant women. Serum samples were

collected and stored from women having a viable singleton pregnancy undergoing

first trimester screening for trisomy 21 between 2006 and 2007. Serum

concentration of ADAM12 was measured using an automated time-solved immuno

-fluorometric assay from 608 stored serum samples (601 euploidy and 7 trisomy

21). Regression analysis was used to determine the expected median in euploidy

pregnancies after adjusting for pregnancy characteristics. The level of ADAM12

MoM was compared between trisomy 21 and euploidy pregnancies. Expected




median levels in Chinese were compared to that published for Caucasians and

Afro-Caribbeans. In euploidy pregnancies, the concentration of ADAM12

increased with crown-rump length and decreased with maternal weight. The

expected median level of ADAM12 in Chinese was significantly lower than

Caucasian and Afro-Caribbeans (F = 14.2, p < 0.0001). There was a significant

correlation between log10 ADAM12 MoM both log10 PAPP-A MoMs (r = 0.46; p <

0.001) and log10 free beta-hCG MoMs (r = 0.08; p = 0.048). The median

ADAM12 MoM in trisomy 21 pregnancies was not significantly different from that in

euploidy pregnancies (z = 0.18; p = 0.88). The authors concluded that ADAM12

concentrations in Chinese are lower than those of Caucasians and Afro-

Carribeans; that ADAM12 MoM levels in euploidy and trisomy 21 pregnancies

were not statistically different.

Valinen et al (2010) examined the correlation between ADAM12 and PAPP-A and

free beta-hCG during the first trimester of pregnancy. ADAM12, PAPP-A and free

beta-hCG were measured in 225 serum samples of randomly chosen pregnancies

with completely normal outcome. The samples were taken between pregnancy

weeks 9+0 and 12+6. The ADAM12 levels tended to increase with advanced

gestational age and the highest levels were detected at pregnancy week 12. The

ADAM12 levels correlated with PAPP-A levels. After weight correction and

logarithmic transformation the MoM of ADAM12 still correlated with the MoMs of

PAPP-A and also with the MoMs of free beta-hCG. Smokers had lower ADAM12

levels than non-smokers. The authors concluded that secretion of ADAM12

seems to resemble the secretion of PAPP-A in the end of the first trimester.

Accordingly ADAM12 appears not to be a separate marker independent of PAPP-

A. They stated that it remains to be assessed whether adding ADAM12 in DS

screening risk calculation will reduce the false positive rate during the first

trimester of pregnancy.

Cowans et al (2010) examined placental growth factor (PlGF) levels in first

trimester maternal serum in trisomy 21 pregnancies and investigated the potential

value of PlGF in a first trimester screening test. First trimester maternal serum

from 70 trisomy 21 cases and 375 euploid controls were retrospectively analyzed

for PlGF using a DELFIA Xpress immunoassay platform. Results were expressed

as MoM for comparison. PlGF levels were significantly decreased in pregnancies

with trisomy 21, 0.76 MoM versus 0.98 MoM in controls. Inclusion of PlGF into the

first trimester combined test (maternal age, PAPP-A, free beta-hCG) and nuchal

translucency would increase the detection rate by 0.5 % at a 5 % false-positive

rate. The authors concluded that PlGF at 11 weeks to 13 weeks 6 days has the

potential to be included as a marker for the detection of pregnancies with trisomy

21.

Nuchal Translucency Measurement

Correct performance of the NT measurement is critical to the accuracy, safety, and

effectiveness of the new non-invasive screening schemes. First trimester NT

screening involves the ultrasound measurement of the echo-free area of the back

of the fetal neck measured between 10 and 14 weeks gestation. The NT

measurement is highly dependent on experience of the ultrasonographer, Small

differences -- less than 1/10 of 1 mm -- in NT measurements can characterize the

difference between a screen negative or “normal” and screen positive or




“abnormal” test result. The increased detection rates seen with non-invasive first

and second trimester screening compared to older screening schemes is mostly

due to the contribution of the NT measurement. All the published trials that have

demonstrated superior detection rates of the new screening strategies the

incorporate NT measurements have relied on NT measurements performed by

highly trained and credentialed ultrasonographers.

Recognizing the potential magnitude of the problem that would result from the

performance of NT measurement by untrained ultrasonographers, the SMFM has

recommended that first trimester screening not be made widely available until a

national program of quality review and oversight is established for the United

States. Similarly, ACOG, the ACMG, the American Institute for Ultrasound in

Medicine, and the National Institute of Child Health and Development (NICHD) of

the NIH have cautioned that screening based on NT measurements should only

be made available in the setting of quality credentialing and oversight monitoring

(ACOG, 2004). Specifically, ACOG concluded that, in order for first-trimester

screening for DS and trisomy 18 to be an option, it should be offered only if the

following criteria are met (ACOG, 2004):

1. Access to an appropriate diagnostic test is available where screening test

results are positive; and

2. Appropriate ultrasound training and ongoing quality monitoring programs

are in place; and

3. Sufficient information and resources are available to provide

comprehensive counseling to women regarding the different screening

options and limitations of these tests.

Nuchal translucency credentialing and quality oversight review process have been

established in the NT Oversight Committee (NTOC) of the Maternal Fetal Medicine

Foundation (MFMF). A wide range of national, regional, and local genetics

laboratory providers will only provide risk assessment using the components of NT

measurement and serum analyte values if the sonographers demonstrate

evidence of NT credentialing. Non-invasive first trimester nuchal translucency

testing for fetal aneuploidy is considered medically appropriate only under such a

credentialing program.

Maternal Plasma MicroRNA for Down Syndrome Screening

Kamhieh-Milz et al (2014) hypothesized that different fetal developmental

processes might be reflected by extra-cellular microRNAs (miRNAs) in maternal

plasma and may be utilized as biomarkers for the non-invasive pre-natal diagnosis

of chromosomal aneuploidies. In this proof-of-concept study, these investigators

reported on the identification of extra-cellular miRNAs in maternal plasma of DS

pregnancies. Using high-throughput quantitative PCR (HT-qPCR), a total of 1,043

miRNAs were investigated in maternal plasma via comparison of 7 DS

pregnancies with age- and fetal sex-matched controls. A total of 695 miRNAs

were identified; 36 significantly differentially expressed mature miRNAs were

identified as potential biomarkers. Hierarchical cluster analysis of these miRNAs

resulted in the clear discrimination of DS from euploid pregnancies. Gene targets

of the differentially expressed miRNAs were enriched in signaling pathways such

as mucin type-O-glycans, ECM-receptor interactions, TGF-beta, and endocytosis,

which have been previously associated with DS. The authors concluded that




miRNAs are promising and stable biomarkers for a broad range of diseases and

may allow a reliable, cost-efficient diagnostic tool for the non-invasive prenatal

diagnosis of DS.

Furthermore, an UpToDate review on “Down syndrome: Prenatal screening

overview” (Messerlian and Palomaki, 2014) does not mention microRNA as a tool

for non-invasive prenatal diagnosis of DS.

Credentialing Process for NT Measurements in the U.S.

In December 2004, NICHD, SMFM, ACOG, and the March of Dimes co-sponsored

a "State of the Science" workshop where all extant data were reviewed by national

and international experts. Shortly thereafter, the MFMF was founded. Functioning

under the auspices of the MFMF, the NT Oversight Committee developed an

educational, training, and quality review program that was initiated in February

2005. This program, known as the Nuchal Translucency Quality Review Program

(NTQR), is one rof two recognized credentialing systems for the United States.

Information about the MFMF credentialing process and on-line registration can be

found at the NTQR website at http://www.NTQR.org.

The Fetal Medicine Foundation - United States (FMS-US) offers another

recognized credentialing system for the United States for screening for aneuploidy

with nuchal translucency measurements. FMF-US has been offering an

education, training, credentialing, and ongoing quality review program that was

initiated in the United States more than 5 years ago. The FMF-US is affiliated with

its European counterpart, the Fetal Medicine Foundation - United Kingdom (FMF-

UK). Information about the FMF-US credentialing process and on-line registration

can be found at the FMF-US website at http://fetalmedicine.com/usa/.

CPT Codes / HCPCS Codes / ICD-9 Codes

CPT codes covered if selection criteria is met:

76813 Ultrasound, pregnant uterus, real time with image

documentation, first trimester fetal nuchal translucency

measurement, transabdominal or transvaginal approach; single

or first gestation

+ 76814 each additional gestation (List separately in addition to code

for primary procedure)

81509 Fetal congenital abnormalities, biochemical assays of three

proteins (PAPP-A, hCG [any form], DIA), utilizing maternal

serum, algorithm reported as a risk score

81510 Fetal congenital abnormalities, biochemical assays of three

analytes (AFP, uE3, hCG [any form]), utilizing maternal serum,

algorithm reported as a risk score

81511 Fetal congenital abnormalities, biochemical assays of four

analytes (AFP, uE3, hCG [any form], DIA) utilizing maternal


http://www.ntqr.org/

http://fetalmedicine.com/usa/



serum, algorithm reported as a risk score (may include

additional results from previous biochemical testing)

81512 Fetal congenital abnormalities, biochemical assays of five

analytes (AFP, uE3, total hCG, hyperglycosylated hCG, DIA)

utilizing maternal serum, algorithm reported as a risk score

84704 Gonadotropin, chorionic (hCG); free beta chain

CPT codes not covered for indications listed in the CPB:

83520 Immunoassay, analyte quantitative; not otherwise specified

[first-trimester maternal serum anti-Mullerian hormone level]

[first trimester serum A disintegrin and metalloprotease 12

(ADAM 12-S)] [first trimester maternal serum placental growth

factor]

Other CPT codes related to the CPB:

59000 Amniocentesis; diagnostic

59015 Chorionic villus sampling, any method

82105 Alpha-fetoprotein (AFP); serum

82106 amniotic fluid

82397 Chemiluminescent assay

82677 Estriol

84163 Pregnancy-associated plasma protein-A (PAPP-A)

84702 Gonadotropin, chorionic (hCG); quantitative

86336 Inhibin A

ICD-9 codes covered if selection criteria are met:

758.0 - 758.9 Chromosomal anomalies

V28.81 -

V28.89

Other specified antenatal screening

Other ICD-9 codes related to the CPB:

V28.3 Encounter for routine screening for malformation using

ultrasonics

V82.79 Other genetic screening

The above policy is based on the following references:




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14.

15.

16.

17.

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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in

administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy

Bulletin contains only a partial, general description of plan or program benefits and does not constitute a

contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or

outcomes. Participating providers are independent contractors in private practice and are neither

employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice

and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.

CPT only copyright 2008 American Medical Association. All Rights Reserved.


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