National Medical Policy

National Medical Policy Subject: Policy Number: Nuchal Translucency NMP219 Effective Date*: June 2005 Updated: September 2015 This National Medical Policy is subject to the terms in the IMPORTANT NOTICE at the end of this document For Medicaid Plans: Please refer to the appropriate Medicaid Manuals for coverage guidelines prior to applying Health Net Medical Policies The Centers for Medicare & Medicaid Services (CMS) For Medicare Advantage members please refer to the following for coverage guidelines first: Use Source Reference/Website Link National Coverage Determination (NCD) National Coverage Manual Citation Local Coverage Determination (LCD)* Article (Local)* Other X None Use Health Net Policy Instructions Medicare NCDs and National Coverage Manuals apply to ALL Medicare members in ALL regions. Medicare LCDs and Articles apply to members in specific regions. To access your specific region, select the link provided under Reference/Website and follow the search instructions. Enter the topic and your specific state to find the coverage determinations for your region. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare Administration Contractors (MACs) located outside their service area when those MACs have exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2) If more than one source is checked, you need to access all sources as, on occasion, an LCD or article contains additional coverage information than contained in the NCD or National Coverage Manual. If there is no NCD, National Coverage Manual or region specific LCD/Article, follow the Health Net Hierarchy of Medical Resources for guidance. Nuchal Translucency Sep 15 1

Current Policy Statement Health Net, Inc. considers first-trimester measurement of nuchal translucency (NT), combined serum levels of pregnancy-associated plasma protein A (PAPP-A) and beta human chorionic gonadotrophin (b-hcg) medically necessary for screening for chromosomal abnormalities. First-trimester screening, as noted above, is medically necessary when all of the following criteria is met: 1. Appropriate ultrasound training and ongoing quality monitoring programs are in place; and 2. There are sufficient information and resources to provide comprehensive counseling to women regarding the different screening options and limitations of these tests; and 3. Access to an appropriate diagnostic test is available when screening tests are positive. Note: First-trimester screening for detection of Down syndrome using measurement of NT alone is not considered medically necessary. Codes Related To This Policy NOTE: The codes listed in this policy are for reference purposes only. Listing of a code in this policy does not imply that the service described by this code is a covered or noncovered health service. Coverage is determined by the benefit documents and medical necessity criteria. This list of codes may not be all inclusive. On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and inpatient procedures will be replaced by ICD-10 code sets. Health Net National Medical Policies will now include the preliminary ICD-10 codes in preparation for this transition. Please note that these may not be the final versions of the codes and that will not be accepted for billing or payment purposes until the October 1, 2015 implementation date. ICD-9 Codes V28.3 Screening for malformation using ultrasonics V28.8 Other specified antenatal screening V28.9 Unspecified antenatal screening ICD-10 Codes Z36 Encounter for antenatal screening of mother CPT Codes 76813 Ultrasound, pregnant uterus, real time with image documentation, first trimester fetal nuchal translucency measurement, transabdominal or transvaginal approach, single or first gestation Nuchal Translucency Sep 15 2

76814 Ultrasound, pregnant uterus, real time with image documentation, first trimester fetal nuchal translucency measurement, transabdominal or transvaginal approach, each additional gestation (List separately in addition to code for primary procedure) 76817 Ultrasound, pregnant uterus, real time with image documentation, transvaginal 84163 Pregnancy-associated plasma protein-a (PAPP-A) 84702 Gonadotrophin, chorionic (hcg); quanatative HCPCS Codes N/A Scientific Rationale Update September 2013 Peuhkurinen et al (2013) compared the efficacy of fetal nuchal translucency (NT) screening, maternal serum screening and combined screening for Down syndrome in a prospective study in Northern Finland. A total of 35,314 women participated in the first-trimester screening for Down syndrome within the public healthcare system in 2002-08. There were 95 pregnancies involving Down syndrome. Serum samples were obtained from 35,314 women, NT was measured in 27,144 pregnancies and full combined screening was performed in those pregnancies, including 76 involving Down syndrome. The adjusted estimated risk for Down syndrome was calculated using the Perkin Elmer AutoDELFIA time-resolved fluoroimmunoassay kit for the measurement of pregnancy-associated plasma protein-a and free β-human chorionic gonadotropin. NT was measured by trained personnel in a university or district hospital. Risk cut-off figures 1:250 and 1:300 at term were used. Differences in detection rate, false-positive rate, positive and negative predictive values between nuchal translucency screening, serum screening and combined screening. Using the risk cut-off figure 1:250, the detection rates for serum screening, NT screening and combined screening were 64.2, 64.5 and 72.4%, respectively and the false-positive rates were 7.8, 4.4 and 4.0%, respectively. Investigators concluded combined screening is the method of choice for Down syndrome screening in Finland. Berktold et al (2013) analyzed the impact of the single parameters NT, pregnancyassociated plasma protein-a (PAPP-A) and free beta-human chorionic gonadotrophin (β-hcg) used in combined first trimester screening and to determine their contribution in the risk assessment. A retrospective risk assessment on the advanced first trimester screening (AFS) algorithm was made to determine the effect of a particular parameter while the remaining ones were fixed for calculation. Afterward data were recalculated by the AFS module. Test performance was measured by receiver operating characteristics (ROC) curves and their area under curve (AUC). Among the 14,862 cases are 14,748 healthy fetuses, 86 with trisomy 21, 22 with trisomy 18 and 6 with trisomy 13. Some settings obtain at default cut-off a very high sensitivity. However, a lack of specificity, as a high false-positive rate, too. The ROC analysis was best for NT, followed by PAPP-A. Free β-hcg showed the lowest AUC. Combining PAPP-A and free β-hcg offered a better AUC than each parameter alone. Best test performance was obtained by including all three parameters. Authors concluded a detection rate of 69 % for testing NT discretely is in order with present study data. PAPP-A is following and free β-hcg is not useful with a test positive rate of about a third. The detection rate of the biochemical parameters combined is higher than for NT alone, but results in a five times higher punctuation rate. All parameters together in the AFS provide the best test performance. The impact of each parameter NT, PAPP-A and free-β-hcg in a combined test strategy is nearly a third. Thus, every single parameter is needed to Nuchal Translucency Sep 15 3

provide a high detection rate for all of the trisomies and minimize the number of unnecessary invasive diagnostics. Karadzov-Orlić et al (2012) analyzed detection and false-positive rates of screening for aneuploidies in the first trimester by the combination of maternal age, fetal NT thickness and maternal serum free β-hcg and PAPP-A at 11-13+6 weeks of gestation, using the appropriate software developed by the Fetal Medicine Foundation. The screening study for aneuploidies analyzed 4172 singleton pregnancies from January 2006 to December 2010. The sensitivities and falsepositive rates using the combined aneuploidies determination for the risk cut-off of 1:275 were evaluated. In the trisomy 21 pregnancies, the fetal NT was higher than 95th centile, in 72.8%, serum free b-hcg concentration it was above the 95th centile in 55% and serum PAPP-A was below the 5th centile in 47% of the cases. In the trisomy 18 and 13, the fetal NT was above 95th centile in 66.6% and 44.4% of the cases, respectively. serum free b-hcg concentration was above the 95th centile in 0 and 10%, but serum PAPP-A was below 5th centile in 80.9% and 88.8% of pregnancies. In the trisomy 21 pregnancies the median free beta-hcg was 2.3 MoM and the median PAPP-A was 0.45 MoM. Chromosomal abnormalities were detected in 169 fetuses: trisomy 21 (97), Turner syndrome (19), trisomy 18 (28), trisomy 13 (11) and others (14). Detection rate of combined screening for aneuploides were 86.0% with false positive rate of 5.3% (mean age 33 +/- 4.9 years, > 35 years in 35% of pregnancies). Authors concluded the study suggests that the strategy of first-trimester combined screening of biochemical values and ultrasonographic parameters at 12 gestational weeks identifies higher percentage of aneuploidies with a lower false-positive rate than a single parameter strategy. Scholl et al (2012) sought to estimate the relationship between NT thickness and abnormal karyotype, major congenital anomaly, perinatal loss, and composite abnormal outcome in fetuses with first-trimester nuchal cystic hygroma. The authors performed a retrospective cohort study of first-trimester fetuses with ultrasounddiagnosed nuchal cystic hygroma collected over a 10-year period. There were 944 first-trimester fetuses with nuchal cystic hygroma. A karyotype abnormality occurred in 54.9% (400 of 729) of fetuses. A major congenital anomaly occurred in 28.8% (61 of 212) of fetuses with a normal karyotype. Perinatal loss occurred in 39% (115 of 295) of fetuses not electively terminated. Overall, an abnormal outcome occurred in 86.6% (543 of 627) of fetuses. After adjusting for potential confounders, every 1- mm increase in NT thickness increased the odds of an abnormal karyotype by 44% (adjusted odds ratio [OR] 1.44, 95% confidence interval [CI] 1.29-1.60, P<.001), the odds of major congenital anomaly by 26% (adjusted OR 1.26, 95% CI, 1.08-1.47, P=.003), the odds of perinatal loss by 47% (adjusted OR 1.47, 95% CI 1.07-2.02, P=.019), and the odds of a composite abnormal outcome by 77% (adjusted OR 1.77, 95% CI 1.15-2.74, P=.01). Authors concluded first-trimester nuchal cystic hygroma is associated with high rates of karyotype abnormality, major congenital anomaly, perinatal loss, and abnormal outcome. As the thickness of the NT increases, the odds of abnormal karyotype, major congenital anomaly, perinatal loss, and abnormal outcome increase. Prats et al (2012) described the performance of first-trimester combined risk assessment in twin pregnancies. Maternal serum free β-hcg and PAPP-A were determined at 8 to 12 weeks and fetal NT was measured at 11 to 13+6 weeks. The individual risk was estimated for each fetus using the combined test in dichorionic twins. In monochorionic twins, the mean risk assessment of the two fetuses was used. An invasive diagnostic procedure was offered when the risk was 1 : 270 in Nuchal Translucency Sep 15 4

either one of the fetuses. From February 2007 to June 2011, 447 twin pregnancies were enrolled in this study. There were 402 (89.9%) dichorionic and 45 (10.1%) monochorionic twins. In dichorionic twins, mean crown-rump length (CRL) was 63.9 mm; median NT multiples of the median (MoM) was 0.97; median Β-hCG was MoM 1.74; median PAPP-A was 1.72. In monochorionic twins, mean CRL was 61.9 mm; median NT MoM was 0. 98; median Β-hCG MoM was 1.44; and median PAPP-A was 1.51. Two pregnancies with Down syndrome were detected by first trimester screening, both in dichorionic twins. The false positive rate was 5.7% (95% confidence interval 4.1-7.3) and 4.4% (95% confidence interval 0.1-8.8%) in dichorionic and monochorionic twins, respectively. Authors concluded the combined test in twins appears to be a good method for Down syndrome screening with a high detection rate and an acceptable false-positive rate. Scientific Rationale Updated December 2010 According to an ACOG Practice Bulletin on Ultrasonography in Pregnancy (Feb 2009), For patients who desire an assessment of their individual risk of fetal aneuploidy, a standardized measurement of the nuchal translucency during a specific age interval is necessary. Nuchal translucency measurements should be used (in conjunction with serum biochemistry) to determine the risk of Down syndrome, trisomy 13, trisomy 18, or other anatomic abnormalities, such as heart defects. In this setting, it is important that the practitioner measure the nuchal translucency according to established guidelines for measurement. In addition, a quality assessment program is recommended to ensure accurate results. Organizations currently providing guidelines and ongoing quality assessment include the Nuchal Translucency Quality Review program of the Maternal Fetal Medicine Foundation and the program sponsored by the Fetal Medicine Foundation. The bulletin notes further, Ideally, all women should be offered aneuploidy screening before 20 weeks of gestation, regardless of maternal age. For women presenting before 14 weeks of gestation, the option for first-trimester screening is available, which may include ultrasonography for nuchal translucency measurement. Ultrasonography in the context of a nuchal translucency measurement provides accurate dating of pregnancy and a very effective screening test for Down syndrome and trisomy 18 when combined with maternal age and serum markers (pregnancy-associated plasma protein A and free or total b-hcg). However, a complete anatomic assessment is not possible before 14 weeks of gestation. Marchini et al (2010) evaluated the performance of the combined test (nuchal translucency, NT) and maternal serum free-beta human chorionic gonadotropin (free beta-hcg) and pregnancy-associated plasma protein-a (PAPP-A), compared to the NT measurement alone, in fetal aneuploidy screening in the general population and in pregnant women aged 35 years and over. In addition, the association between increased NT and presence of cardiac defects in fetuses with normal karyotype was evaluated. Screening at 11-14 weeks of gestation by NT measurement and combined test was carried out in 1521 pregnant women. The estimated risk for trisomy 21 and trisomy 13+18 was calculated (risk cut-off 1/300 and 1/750 respectively) and the outcomes was evaluated. Ten cases of trisomies (21 and 18) occurred, seven of which among the older group of pregnant women. The detection rate (DR) for the combined test was 80% in the general population and 85.7% in older pregnant women, which resulted higher rate than NT measurements alone. Detection rate of cardiac defects using NT measurements was 66.6%. The investigators concluded the combined test is an effective screening for aneuploidies and reduces at 14% the need of invasive testing in the older obstetric population, detecting all the trisomies occurred in this group. The association between increased Nuchal Translucency Sep 15 5

NT and cardiac defects is confirmed but it seems too weak to consider NT as a single screening strategy for these abnormalities. Chelli et al (2009) sought to analyze the contribution of first trimester ultrasound in prenatal diagnosis of aneuploidy and early fetal malformations, and its impact on the strategy of prevention of disability in a prospective longitudinal descriptive study including all women who did a first trimester ultrasound during their pregnancy. The detection rate of malformations and chromosomal abnormalities of the morphological embryonary study and nuchal translucency were evaluated. These tests were then confronted with the results of fetal samples and the outcome of pregnancy. 593 ultrasound examinations were performed. The average age of pregnant women was 32.7 years. The mini-morphological ultrasound study revealed 26 abnormalities (3 major lethal malformations, 5 cystic hygroma and 18 increased nuchal translucency). Chromosomal abnormalities were found in six cases. The first trimester ultrasound has ensured the detection of 2/3 of total aneuploidies of the study. The investigators concluded the first trimester ultrasound allows early detection of a large number of aneuploidies and fetal malformations. Scientific Rationale Updated June 2007 In January 2007, the American College of Obstetricians and Gynecologist (ACOG) issued a practice bulletin, Screening for Fetal Chromosomal Abnormalities stating that all women should be offered aneuploidy screening before 20 weeks of gestation, regardless of maternal age. According to the ACOG practice bulletin, the following recommendations are based on good and consistent scientific evidence: First-trimester screening using both nuchal translucency measurement and biochemical markers is an effective screening test for Down syndrome in the general population. At the same false-positive rates, this screening strategy results in a higher Down syndrome detection rate than does the secondtrimester maternal serum triple screen [maternal serum alpha-fetoprotein (MSAFP), unconjugated estriol and human chorionic gonadotropin (hcg)] and is comparable to the quadruple screen (MSAFP, unconjugated estriol, hcg and inhibin-a) Measurement of nuchal translucency alone is less effective for first-trimester screening than is the combined test (nuchal translucency measurement and biochemical markers). Women found to have increased risk of aneuploidy with first-trimester screening should be offered genetic counseling and the option of CVS or second-trimester amniocentesis. Specific training, standardization, use of appropriate ultrasound equipment, and ongoing quality assessment are important to achieve optimal nuchal translucency measurement for Down syndrome risk assessment, and this procedure should be limited to centers and individuals meeting these criteria. Neural tube defect screening should be offered in the second trimester to women who elect only first-trimester screening for aneuploidy. Nuchal Translucency Sep 15 6

Scientific Rationale Initial A major goal of prenatal screening is antepartum detection of fetal aneuploidy (abnormal number of chromosomes). Sonographic examination is useful because fetuses with abnormal karyotypes often have structural changes or anomalies. The goal of first-trimester prenatal screening is to provide risk information early in pregnancy, thereby allowing for additional diagnostic testing such as chorionic villus sampling (CVS) or second-trimester amniocentesis, and optimal pregnancy management or early termination. Fetal nuchal translucency (NT) refers to the detection of subcutaneous edema in the fetal neck, and is measured as the maximal thickness of the sonolucent zone between the inner aspect of the fetal skin and the outer aspect of the soft tissue overlying the cervical spine or the occipital bone. The presence of increased fetal NT between 10 and 14 weeks gestation may be one of the best markers for the detection of fetal trisomies, especially trisomy 21 (Down syndrome.) Sonographic evaluation of NT must be very precise and is performed most accurately during a transvaginal ultrasound examination at 10 to 14 weeks gestation. NT changes with gestational age and values depend on the examiners ability to accurately determine gestational age based on crown-rump length (CRL). It is commonly believed that the larger the NT measurement, the greater the association with Down syndrome and other aneuploidy. Combined ultrasound and serum screening by measurement of pregnancy-associated plasma protein A (PAPPA or PAPP-A) and the free beta hcg (F[beta]hCG) in conjunction with the ultrasound NT measurement has greater specificity than NT measurement alone. Specific factors can complicate NT measurement, including contact or near contact between the fetus and the amnion, flexion or extension of the fetal neck, and wrapping of the umbilical cord around the fetal neck. According to the new ACOG Committee Opinion, sonographer training and ongoing quality assurance are essential if NT is used as a screening method. In June 2004, The American College of Obstetricians and Gynecologists (ACOG) issued a position on first-trimester screening methods stating that measuring NT has allowed for earlier, noninvasive screening for chromosomal abnormalities and, when combined with serum screening in the first trimester, have comparable detection rates as standard second-trimester screening. First-trimester screening can also help detect other chromosomal abnormalities such as trisomy 18 and may help detect pregnancies at risk for major heart defects in the fetus. First-trimester screening should not eliminate the need for second-trimester ultrasound currently used for detecting gross structural fetal anomalies. In addition, ACOG does not recommend first-trimester screening a screening test for spina bifida. A multicenter clinical trial, SURUSS (Serum Urine and Ultrasound Screening Study) was a prospective study that began in 1996 in the U.K. The study involved over 47,000 singleton pregnancies conducted in 25 maternity units. The goal of the study was to identify the most effective, safe and cost effective method of antenatal screening for Down syndrome. In various combinations, the study was performed using NT, maternal serum and urine markers in the first and second trimesters of pregnancy, and maternal age. Samples from each affected pregnancy and five matched controls were tested in both the first and second trimester, utilizing currently used Down syndrome markers as well as proposed Down syndrome markers and assessed the various combinations. Pregnancies were followed to determine the presence or absence of Down syndrome. The authors concluded that Nuchal Translucency Sep 15 7

the integrated test (NT and PAPP-A measurements in the first-trimester in addition to the quadruple test [AFP, unconjugated estriol, free b-hcg or total HCG, and inhibin- A, together with maternal age early in the second trimester]) proved to be the most effective screen overall with a detection rate of 85% and a false positive rate of 0.9%. For those women opting for a screening result and diagnosis at 11 weeks, the combined test (NT measurement and screening for a low maternal serum level of PAPP-A with a high level of b-hcg in the first trimester) was optimal with an 85% detection rate for Down syndrome and a false positive rate of 4.3%. Another prospective, multicenter trial, reported similar results to SURESS. The First and Second Trimester Evaluation of Risk (FASTER) Trial, analyzed outcomes of over 34,000 women with singleton pregnancies at 15 centers in the United States who underwent both first and second trimester Down syndrome screening. First trimester screening included measurement of NT as well as serum screening with PAPP-A and free b-hcg (combined test.) Results were only communicated to the participants after they had completed second trimester quadruple screening, which consisted of alpha fetoprotein (AFP), hcg, estriol, and inhibin. Genetic counseling and amniocentesis were offered to those participants with a positive screen. The pregnancy outcomes were followed. The authors reported first-trimester screening had an 83% sensitivity for detecting Down syndrome when the false-positive rate was 5%. This was similar to the sensitivity of the quad test, which was 79%, with a similar false-positive rate of 5%, and superior to the triple screen (AFP, hcg, and estriol). The studies also showed that integrating first- and second-trimester screening yields the highest detection rate for Down syndrome, with a sensitivity of 90% and a false positive rate of 5%. Another published study reviewed the performance of first-trimester screening by fetal NT along with maternal serum free beta-hcg) and PAPP-A. The study concluded that using a combination of NT and the double test was superior to that using either NT or the double test alone due to a very low false positive results and a higher detection rates. NT could be measured in 97.5% of cases. The detection rate for Downs Syndrome with NT screening alone was 75% with a false positive rate of 1.8%. The detection rate for the combined test was 91%, with a false positive rate of 2.1%. Published evidence suggests that increased first trimester NT measurement was also associated with an increased risk of major congenital heart defect in chromosomally normal pregnancies. A first trimester (10 weeks 4 days of gestation to 13 weeks 6 days of gestation) study restricted to singleton pregnancies, was conducted between May 1998 and December 2000. Gestational age was determined by crown rump length measurements. There were 8167 chromosomally normal pregnancies, of which 21 cases of major congenital heart defect were identified at follow-up examination (incidence, 2.6/1000 pregnancies). The risk of congenital heart defect rose with increasing NT measurements. With a NT measurement of <2.0 mm, the incidence of congenital heart defect was 13 of 6757 pregnancies (1.9 of every 1000 pregnancies). At > 3.5 mm, the incidence was 1 of 43 pregnancies (23 of every 1000 pregnancies. This study suggests that NT was associated significantly with congenital heart defect. The practical implications of the findings are that patients with unexplained elevations of NT may need referral for a fetal echocardiogram. Review History June 28, 2005 June 2007 Medical Advisory Council initial approval No change to coverage position Nuchal Translucency Sep 15 8

December 2010 September 2011 August 2012 September 2013 September 2014 September 2015 2007 CPT codes added Update no revisions Update no revisions Update no revisions Update no revisons. Code updates Update no revisions. Code updates Update - no revisions. Code updates This policy is based on the following evidence-based guidelines: 1. Kirkham C, Harris S, Grzybowski S. Evidence-based prenatal care: Part I. General prenatal care and counseling issues. Am Fam Physician. 2005 Apr 1;71(7):1307-16. http://www.aafp.org/afp/20050401/1307.html 2. ACOG Practice Bulletin. Clinical Management Guidelines For Obstetrician- Gynecologist. Screening for Fetal Chromosomal Abnormalities. Number 77, January 2007. Reaffirmed in 2011. Reaffirmed in 2013. 3. ACOG Practice Bulletin. Clinical Management Guidelines For Obstetrician- Gynecologist. Ultrasonography in Pregnancy. Number 101, February 2009, Reaffirmed in 2011. Reaffirmed 2014. 4. Hayes. Medical Technology Directory. First-Trimester Prenatal Screening Using Nuchal Translucency Combined with Maternal PAPP-A and Free β-hcg Levels. December 12, 2005. Updated February 23, 2009. Archived January 12, 2011. References Update September 2015 1. Kamhieh-Milz J, Moftah RF, Bal G, et al. Differentially expressed micrornas in maternal plasma for the noninvasive prenatal diagnosis of Down syndrome (trisomy 21). Biomed Res Int. 2014;2014:402475. 2. Lutgendorf MA, Stoll KA, Knutzen DM, et al. Noninvasive prenatal testing: Limitations and unanswered questions. Genet Med. 2014;16(4):281-285. References Update September 2014 1. Hermann M, Fries N, Mangione R, et al. Nuchal translucency measurement: are qualitative and quantitative quality control processes related? Prenat Diagn 2013; 33:770. 2. Messerlian GM. Farina A, Palomaki GE. First trimester combined test and integrated tests for screening for Down syndrome and trisomy 18. UpToDate. September 19, 2013. References Update September 2013 1. Barone C, Bianca S. Further evidence of no association between spinal muscular atrophy and increased nuchal translucency. Fetal Diagn Ther. 2013;33(1):65-8. 2. Berktold L, V Kaisenberg C, Hillemanns P, et al. Analysis of the impact of PAPP- A, free β-hcg and nuchal translucency thickness on the advanced first trimester screening. Arch Gynecol Obstet. 2013 Mar;287(3):413-20. 3. Bijok J, Ziora-Jakutowicz K, Ilnicka A, et al. Increased nuchal translucency in chromosomally normal fetuses and pregnancy outcomes--a retrospective study Ginekol Pol. 2013 Mar;84(3):172-9 4. Gabriel CC, Echevarria M, Rodríguez I, Serra B. Analysis of quality of nuchal translucency measurements: its role in prenatal diagnosis. ScientificWorldJournal. 2012;2012:482832 5. Karadzov-Orlić N, Egić A, Filimonović D, et al. Screening for aneuploidies by maternal age, fetal nuchal translucency and maternal serum biochemistry at 11-13+6 gestational weeks. Srp Arh Celok Lek. 2012 Sep-Oct;140(9-10):606-11. Nuchal Translucency Sep 15 9

6. Kozarov G, Milosević TM, Vuksić B. Nuchal translucency measurement--the effect of 3D/4D ultrasound. Med Pregl. 2013 Mar-Apr;66(3-4):145-8. 7. Lichtenbelt KD, Schuring-Blom GH, van der Burg N, et al. Factors determining uptake of invasive testing following first-trimester combined testing. Prenat Diagn. 2013 Apr;33(4):328-33. 8. Peuhkurinen S, Laitinen P, Honkasalo T, et al. Comparison of combined, biochemical and nuchal translucency screening for Down syndrome in first trimester in Northern Finland. Acta Obstet Gynecol Scand. 2013 Jul;92(7):769-74. 9. Prats P, Rodríguez I, Comas C, Puerto B. First trimester risk assessment for trisomy 21 in twin pregnancies combining nuchal translucency and first trimester biochemical markers. Prenat Diagn. 2012 Oct;32(10):927-32. 10. Scholl J, Durfee SM, Russell MA, et al. First-trimester cystic hygroma: relationship of nuchal translucency thickness and outcomes. Obstet Gynecol. 2012 Sep;120(3):551-9. 11. Torella M, Tormettino B, Zurzolo V, et al. Screening for trisomy 21 by maternal age fetal nuchal translucency thickness and maternal serum sample. Minerva Ginecol. 2013 Jul 23. 12. Van Keirsbilck J, Dewulf V, Van Calsteren K, De Catte L. Comparison and Reproducibility of Nuchal Translucency Measurements Using Two-Dimensional and Volume Nuchal Translucency Ultrasound: A Prospective Study. Fetal Diagn Ther. 2013 Jul 31:103-109. References Update August 2012 1. Antsaklis A, Daskalakis G, Theodora M, et al. Assessment of nuchal translucency thickness and the fetal anatomy in the first trimester of pregnancy by two- and three-dimensional ultrasonography: A pilot study. J Perinat Med. 2011;39(2):185-193. 2. Pergament E, Alamillo C, Sak K, Fiddler M. Genetic assessment following increased nuchal translucency and normal karyotype. Prenat Diagn 2011; 31:307. 3. Simpson LL. First trimester cystic hygroma and increased nuchal translucency. UpToDate. May 28, 2012. Update January 17, 2014. 4. Sotiriadis A, Papatheodorou S, Makrydimas G. Neurodevelopmental outcome of fetuses with increased nuchal translucency and apparently normal prenatal and/or postnatal assessment: a systematic review. Ultrasound Obstet Gynecol 2012; 39:10. References Update September 2011 1. Ghaffari SR, Tahmasebpour AR, Jamal A, et al. First Trimester Screening for Chromosomal Abnormalities by Integrated Application of Nuchal Translucency, Nasal Bone, Tricuspid Regurgitation, Ductus Venosus Flow Combined with Maternal Serum Free β-hcg and PAPP-A: A 5-Year Prospective Study. Ultrasound Obstet Gynecol. 2011 Jul 26:132. doi: 10.1002/uog.10051. 2. Guanciali-Franchi P, Iezzi I, Palka C, et al. Comparison of combined, stepwise sequential, contingent, and integrated screening in 7292 high-risk pregnant women. Prenat Diagn. 2011 Jul 29. doi: 10.1002/pd.2836. 3. Jakobsen TR, Søgaard K, Tabor A. Implications of a first trimester Down syndrome screening program on timing of malformation detection. Acta Obstet Gynecol Scand. 2011 Jul;90(7):728-36. doi: 10.1111/j.1600-0412.2011.01156.x. 4. Loncar D. Predictive value of fetal nuchal translucency. Med Glas Ljek komore Zenicko-doboj kantona. 2011 Feb;8(1):19-23. Nuchal Translucency Sep 15 10

5. Miao ZY, Liu X, Shi TK, Ge JM, Xu Y. First trimester and second-trimester integrated screening for Down's syndrome. Zhonghua Yi Xue Za Zhi. 2011 Jan 18;91(3):185-8. References Update December 2010 1. Abu-Rustum RS, Daou L, Abu-Rustum SE. Role of first-trimester sonography in the diagnosis of aneuploidy and structural fetal anomalies. J Ultrasound Med. 2010 Oct;29(10):1445-52 2. Alexioy E, Alexioy E, Trakakis E, et al. Predictive value of increased nuchal translucency as a screening test for the detection of fetal chromosomal abnormalities. J Matern Fetal Neonatal Med. 2009 Oct;22(10):857-62 3. Chelli D, Gaddour I, Najar I, et al. First trimester ultrasound: an early screening tool for fetal structural and chromosomal abnormalities. Tunis Med. 2009 Dec;87(12):857-62 4. Marchini G, Rosati A, Ribiani E, et al. Nuchal translucency and combined test: what are the implications in clinical practice? Minerva Ginecol. 2010 Jun;62(3):187-93. 5. Nadel AS, Likhite ML. Impact of first-trimester aneuploidy screening in a highrisk population. Fetal Diagn Ther. 2009;26(1):29-34 6. Scott F, Evans J, McLennan A. Perinatal outcome in fetuses with extremely large nuchal translucency measurement. Aust N Z J Obstet Gynaecol. 2009 Jun;49(3):254-7. References 1. Up to date: The sonographic diagnosis of fetal aneuploidy, accessed May 2005. 2. Bahado-Singh RO, Wapner R, Thom E, et al. Elevated first-trimester nuchal translucency increases the risk of congenital heart defects. Am J Obstet Gynecol. 2005 May;192(5):1357-61. 3. Wojdemann KR, Shalmi AC, Christiansen M, et al. Improved first-trimester Down syndrome screening performance by lowering the false-positive rate: a prospective study of 9941 low-risk women. Ultrasound Obstet Gynecol. 2005 Mar;25(3):227-33. 4. Liao SX, Huang FF, Yang YL, et al. Screening for chromosomal abnormalities using nuchal translucency measurement with materal serum biochemistry markers in first trimester. Beijing Da Xue Xue Bao. 2005 Feb 18;37(1):39-41. 5. Wald NJ, Rodeck C, Hackshaw AK, Rudnicka A. SURUSS in perspective. BJOG. 2004 Jun;111(6):521-31. BJOG. 2004 Jun;111(6):521-31. 6. Benn PA. Advances in prenatal screening for Down syndrome: II first trimester testing, integrated testing, and future directions. Clin Chim Acta. 2002 Oct;324(1-2):1-11. 7. Benn PA, Kaminsky LM, Ying J, et al. Combined second-trimester biochemical and ultrasound screening for Down syndrome. Obstet Gynecol. 2002 Dec;100(6):1168-76. 8. Up to Date: First trimester screening for Down syndrome and trisomy 18, accessed May 2005 9. Bernstein PS. Highlights from the Society of Maternal-Fetal Medicine 24th Annual Clinical Meeting. Medscape Ob/Gyn & Women s Health 9(1). 2004 Mar. 10. Benn PA, Fang M, Egan JF. Trends in the use of second trimester maternal serum screening from 1991 to 2003. Genet Med. 2005 May-Jun;7(5):328-31. 11. Grant SS. Options for Down syndrome screening: what will women choose? J Midwifery Womens Health. 2005 May-Jun;50(3):211-8. Nuchal Translucency Sep 15 11

12. Van den Berg M, Timmermans DR, Ten Kate LP, et al. Are pregnant women making informed choices about prenatal screening? Genet Med. 2005 May- Jun;7(5):332-8. 13. Saltvedt S, Almstrom H, Kublickas M, et al. Screening for Down syndrome based on maternal age or fetal nuchal translucency: a randomized controlled trial in 39 572 pregnancies. Ultrasound Obstet Gynecol. 2005 May 23;25(6):537-545 14. Zoppi MA, Ibba RM, Floris M, et al. Nuchal translucency measurement at different crown-rump lengths along the 10- to 14-week period for Down syndrome screening. Prenat Diagn. 2005 May;25(5):411-6. 15. Cheng PJ, Chang SD, Shaw SW, et al. Nuchal translucency thickness in fetuses with chromosomal translocation at 11-12 weeks of gestation. Obstet Gynecol. 2005 May;105(5):1058-62. Important Notice General Purpose. Health Net's National Medical Policies (the "Policies") are developed to assist Health Net in administering plan benefits and determining whether a particular procedure, drug, service or supply is medically necessary. The Policies are based upon a review of the available clinical information including clinical outcome studies in the peer-reviewed published medical literature, regulatory status of the drug or device, evidence-based guidelines of governmental bodies, and evidence-based guidelines and positions of select national health professional organizations. Coverage determinations are made on a case-by-case basis and are subject to all of the terms, conditions, limitations, and exclusions of the member's contract, including medical necessity requirements. Health Net may use the Policies to determine whether under the facts and circumstances of a particular case, the proposed procedure, drug, service or supply is medically necessary. The conclusion that a procedure, drug, service or supply is medically necessary does not constitute coverage. The member's contract defines which procedure, drug, service or supply is covered, excluded, limited, or subject to dollar caps. The policy provides for clearly written, reasonable and current criteria that have been approved by Health Net s National Medical Advisory Council (MAC). The clinical criteria and medical policies provide guidelines for determining the medical necessity criteria for specific procedures, equipment, and services. In order to be eligible, all services must be medically necessary and otherwise defined in the member's benefits contract as described this "Important Notice" disclaimer. In all cases, final benefit determinations are based on the applicable contract language. To the extent there are any conflicts between medical policy guidelines and applicable contract language, the contract language prevails. Medical policy is not intended to override the policy that defines the member s benefits, nor is it intended to dictate to providers how to practice medicine. Policy Effective Date and Defined Terms. The date of posting is not the effective date of the Policy. The Policy is effective as of the date determined by Health Net. All policies are subject to applicable legal and regulatory mandates and requirements for prior notification. If there is a discrepancy between the policy effective date and legal mandates and regulatory requirements, the requirements of law and regulation shall govern. * In some states, prior notice or posting on the website is required before a policy is deemed effective. For information regarding the effective dates of Policies, contact your provider representative. The Policies do not include definitions. All terms are defined by Health Net. For information regarding the definitions of terms used in the Policies, contact your provider representative. Policy Amendment without Notice. Health Net reserves the right to amend the Policies without notice to providers or Members. In some states, prior notice or website posting is required before an amendment is deemed effective. No Medical Advice. The Policies do not constitute medical advice. Health Net does not provide or recommend treatment to members. Members should consult with their treating physician in connection with diagnosis and treatment decisions. No Authorization or Guarantee of Coverage. The Policies do not constitute authorization or guarantee of coverage of particular procedure, drug, service or supply. Members and providers should refer to the Member contract to determine if exclusions, limitations, and dollar caps apply to a particular procedure, drug, service or supply. Policy Limitation: Member s Contract Controls Coverage Determinations. Statutory Notice to Members: The materials provided to you are guidelines used by this plan to authorize, modify, or deny care for persons with similar illnesses or conditions. Specific care and treatment may vary Nuchal Translucency Sep 15 12

depending on individual need and the benefits covered under your contract. The determination of coverage for a particular procedure, drug, service or supply is not based upon the Policies, but rather is subject to the facts of the individual clinical case, terms and conditions of the member s contract, and requirements of applicable laws and regulations. The contract language contains specific terms and conditions, including pre-existing conditions, limitations, exclusions, benefit maximums, eligibility, and other relevant terms and conditions of coverage. In the event the Member s contract (also known as the benefit contract, coverage document, or evidence of coverage) conflicts with the Policies, the Member s contract shall govern. The Policies do not replace or amend the Member s contract. Policy Limitation: Legal and Regulatory Mandates and Requirements The determinations of coverage for a particular procedure, drug, service or supply is subject to applicable legal and regulatory mandates and requirements. If there is a discrepancy between the Policies and legal mandates and regulatory requirements, the requirements of law and regulation shall govern. Reconstructive Surgery CA Health and Safety Code 1367.63 requires health care service plans to cover reconstructive surgery. Reconstructive surgery means surgery performed to correct or repair abnormal structures of the body caused by congenital defects, developmental abnormalities, trauma, infection, tumors, or disease to do either of the following: (1) To improve function or (2) To create a normal appearance, to the extent possible. Reconstructive surgery does not mean cosmetic surgery," which is surgery performed to alter or reshape normal structures of the body in order to improve appearance. Requests for reconstructive surgery may be denied, if the proposed procedure offers only a minimal improvement in the appearance of the enrollee, in accordance with the standard of care as practiced by physicians specializing in reconstructive surgery. Reconstructive Surgery after Mastectomy California Health and Safety Code 1367.6 requires treatment for breast cancer to cover prosthetic devices or reconstructive surgery to restore and achieve symmetry for the patient incident to a mastectomy. Coverage for prosthetic devices and reconstructive surgery shall be subject to the co-payment, or deductible and coinsurance conditions, that are applicable to the mastectomy and all other terms and conditions applicable to other benefits. "Mastectomy" means the removal of all or part of the breast for medically necessary reasons, as determined by a licensed physician and surgeon. Policy Limitations: Medicare and Medicaid Policies specifically developed to assist Health Net in administering Medicare or Medicaid plan benefits and determining coverage for a particular procedure, drug, service or supply for Medicare or Medicaid members shall not be construed to apply to any other Health Net plans and members. The Policies shall not be interpreted to limit the benefits afforded Medicare and Medicaid members by law and regulation. Nuchal Translucency Sep 15 13