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MP 4.02.01 Laboratory Tests of Sperm Maturity, Function, and DNA Integrity (Archived)

Medical Policy
Section
OB/Gyn Reproduction
 
Original Policy Date
12/1/95
Last Review Status/Date
Archived/9:2009
 
Issue
4:2008
Return to Medical Policy Index

Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.


Description

This policy addresses the following 3 laboratory tests of sperm: the sperm penetration assay (i.e., sperm function), hyaluronan binding assay (i.e., sperm maturity), and DNA integrity (i.e., DNA fragmentation).

Sperm Penetration Assay (SPA)

The SPA is a multistep laboratory test that offers a biological assessment of human sperm fertilizing ability. Specifically, 4 distinct processes must occur for sperm-oocyte fertilization: capacitation, acrosome reaction, penetration of the ooplasm, and chromatin decondensation within the ooplasm. The SPA uses a zona-free hamster egg as an in vitro model for sperm-oocyte interaction. (The zona pellucida is a thick, glassy membrane surrounding the oocyte that maintains species specificity for fertilization. Removal of the zona pellucida from hamster ova permits their use as a model for sperm oocyte interaction.) The test is performed by incubating a number of zona-free hamster eggs with human sperm for several hours. According to the percentage of ova penetrated, the semen sample is rated as being in a potentially “fertile” or “infertile” range. Aspects of sperm function not assessed by the SPA include the capacity of sperm to penetrate the cervical barrier or their ability to bind to the zona pellucida of human ova.

The sperm penetration assay, alternatively referred to as the hamster oocyte penetration test or the zona-free hamster egg test, was initially developed in 1976. Although it has been used as a test for male infertility, the test has been controversial due to variability in procedures used by different laboratories, poor reproducibility of test outcomes, and uncertainty regarding the range of normal values.

Hyaluronan Binding Assay (HBA)

The HBA is a qualitative assay for the maturity of sperm in a fresh semen sample. The assay is based on the ability of mature, but not immature, sperm to bind hyaluronan, the main mucopolysaccharide of the cumulus oophorus matrix and a component of human follicular fluid. Research has shown that hyaluronan-binding capacity is acquired late in the sperm maturation process; immature sperm lack this ability. Therefore, a low level of sperm binding to hyaluronan suggests that there is a low proportion of mature sperm in the sample. Similar to the sperm penetration assay, it has been suggested that the HBA assay may be used to determine the need for an intracytoplasmic sperm injection procedure (ICSI) as part of an assisted reproductive technique. The HBA is a laboratory test that has received U.S. Food and Drug Administration (FDA) clearance through the 510(k) approval process. The FDA-labeled indications are as follows:

1. As a component of the standard analysis of semen in the diagnosis of suspected male infertility.

2. As a component of analyses for determining the proper course of in vitro fertilization treatment of infertility.

In 2006, a product containing hyaluronan (SpermSlow™) received 510(k) marketing clearance for the separation of mature from immature sperm prior to intracytoplasmic sperm injection (ICSI).

DNA Integrity and Fragmentation

In addition to the conventional parameters of sperm quality, such as concentration, motility, and morphology, sperm DNA integrity has emerged as a potential cause of idiopathic male infertility. For example, while sperm with fragmented DNA may be able to fertilize oocytes, subsequent embryo and fetal development may be impaired. Oocytes and embryos may be able to repair fragmented DNA, but there may be a point beyond which repair is possible. In addition, the ability of oocytes to repair DNA damage may decrease with age, while DNA fragmentation in sperm increases with age. Therefore, impaired DNA integrity may be an increasing infertility factor among older couples. A variety of etiologies have been proposed for impaired DNA integrity, including protamine deficiency, apoptosis, drugs, chemotherapy or radiation therapy, cigarette smoking, and varicoceles.

One measure of sperm DNA integrity is the aperm chromatin structure assay (SCSA). Sperm DNA is exposed to an acid pH of 1.2, which will not affect normal DNA, but will denature fragmented DNA. Then the treated the DNA is stained with acridine orange, which emits green fluorescence in the presence of double-stranded, intact, DNA, and red fluorescence with single-stranded DNA. These patterns can be detected by flow cytometry. Therefore, flow cytometry can analyze thousands of sperm. Flow cytometry tests of DNA integrity that are commercially available include the sperm chromatin structure assay test (SCSA®) and the sperm DNA fragmentation assay (SDFA™) test, available at specialized reference laboratories. Another assay of sperm DNA integrity measures sperm chrmatin dispersion (SCD) following acid-induced decondensation (denaturation). A kit measure SCD is commercially available in Europe (Halosperm® kit, INDAS Laboratories). In the US, Repromedix® is marketing an 'advanced sperm panel' that includes a sperm DNA condensation test and a sperm DNA fragmentation assay. Other laboratory tests for sperm integrity, such as the TUNEL and COMET assays require microscopic analysis, and thus can only assess a limited number of sperm. These latter tests are not widely used clinically.

It has been proposed that sperm DNA testing may help to determine the most effective method of assisted reproduction [i.e., intrauterine insemination (IUI), in vitro fertilization (IVF), or intracytoplasmic sperm injection (ICSI)].

Other proposed clinical uses for tests of DNA integrity include:

  • Evaluation of failed pregnancy or spontaneous abortions, in unassisted pregnancy, and after failed in vitro fertilization (IVF) attempts.

Men with high levels of fragmented DNA could be advised that natural attempts at pregnancy or IVF attempts are unlikely to succeed, or that donor sperm should be used.

  • Selection of sperm sample for cryopreservation.

The level of DNA fragmentation from a given patient may vary. Therefore, multiple sperm samples could be tested over time, and the sample with the lowest level of fragmentation could be selected for storage.

Note: All of these tests are laboratory tests that are frequently performed as part of an assisted reproductive technique (ART). Other components of ART are considered separately in policy No. 4.02.04.


Policy

A sperm penetration assay may be considered medically necessary as a technique to determine whether intracytoplasmic sperm injection should be offered as part of an in vitro fertilization technique.

The sperm hyaluronan binding assay is considered investigational for determining sperm maturation.

Sperm selection with hyaluronan for intracytological injection (ICSI) is considered investigational.

Tests of sperm DNA integrity are considered investigational, including, but not limited to, sperm chromatin assays and sperm DNA fragmentation assays.


Policy Guidelines

In 2005, a category III CPT code is available that explicitly identifies the hyaluronan binding assay.

0087T Sperm evaluation, hyaluronan binding assay

The sperm penetration assay is identified by CPT code 89329: Sperm evaluation; hamster penetration test


Benefit Application

BlueCard/National Account Issues

The sperm penetration assay and hyaluronan binding assay may be considered a component of an assisted reproductive procedure. Benefits exclusions and restrictions for infertility treatment may apply.

State or federal mandates (e.g., FEP) may dictate that all devices approved by the FDA may not be considered investigational, and thus these devices may be assessed only on the basis of their medical necessity.


Rationale

Sperm Penetration Assay (SPA)

Originally, the SPA was used primarily as a diagnostic technique for male infertility. More recently, the advent of sperm micromanipulation techniques, specifically intracytoplasmic sperm injection (ICSI), has changed the role of in vitro fertilization (IVF) and changed the role of SPA. IVF was originally developed as a treatment option for women with irreversible tubal damage, but the development of sperm micromanipulation techniques as an adjunct to IVF has now expanded the indications for IVF to those with severe male factor infertility. Thus, SPA can be used to identify those normospermic patients who would benefit from ICSI or other adjuncts to IVF. In 2001, Freeman and colleagues reported on the diagnostic accuracy of sperm penetration assay in predicting success of in vitro fertilization. Among 216 couples, the sperm penetration assay predicted IVF with high negative (84%) and positive (98%) predictive value, with correct prediction in 88% of cycles. (1) While there is still concern regarding standardization of the procedure (2), these findings suggest that the results of the sperm penetration assay can be used to select patients for ICSI.

Hyaluronan-Binding Assay (HBA)

The HBA has been proposed as a component of the standard analysis of semen in the diagnosis of suspected male infertility. In addition, it potentially represents a more convenient and reproducible laboratory test for identifying candidates for ICSI. However, published scientific data were inadequate to permit conclusions regarding either of these indications. A literature search identified 2 published articles that discussed the biologic basis of the HBA, but no articles were identified that established the diagnostic performance of the test (i.e., establishment of positive and negative cutoff values, sensitivity, specificity, positive and negative predictive values) or examined the clinical role of the test. (3, 4) The test information sheet also does not provide adequate data to evaluate the diagnostic performance of the test. (5)

Tests of Sperm DNA Integrity and Fragmentation (i.e., SCSA® and SDFA™)

Tests of DNA integrity and fragmentation have been an important research tool to further explore the etiologies of infertility. For example, as reviewed by O’Brien and Zini, several studies have reported that poor sperm DNA integrity is an independent risk factor for male infertility. (6) A threshold of 30% of abnormal DNA (referred to as the DNA fragmentation index or DFI) is frequently suggested as a cutoff to distinguish between a potentially fertile versus infertile semen sample. (7) However, this cutoff point has not been evaluated in large scale studies, and studies have reported variable results regarding the relation between DFI and reproductive outcomes. Payne and colleagues have published the largest case series, comparing the results of the SCSA test to outcomes of assisted reproductive techniques. (8) In the 100 couples included in the series, 19 had a DFI of >27%, suggesting a poor IVF outcome. However, 9 of these couples achieved a clinical pregnancy. In contrast, in 22 couples the DFI was less than 9%, suggesting a favorable outcome. Only 1 of these patients achieved a clinical pregnancy. These results are consistent with other reports (9, 10) and contrast with favorable results reported from smaller case series. (11-13).

In summary, there are inadequate published data to permit scientific conclusions about tests of DNA integrity of sperm as a diagnostic test used in the management of infertile couples.

2006-2007 Update

A search of the MEDLINE database was performed for the period of September 2005 through December 2006. Selection of mature sperm for ICSI using hyaluronan has been proposed as a promising method to reduce the risk of DNA abnormalities. (14) No studies were identified that assessed clinical outcomes following sperm selection with hyaluronic acid. This procedure is at an early stage of research and is considered investigational.

A meta-analysis of observational studies assessed the risk ratio (RR) for sperm DNA damage (assessed with either the TUNEL or SCSA assay) and fertilization or clinical pregnancy rates for IVF and ICSI. (15) The analysis found that sperm DNA damage as assessed by the SCSA assay was not predictive of fertilization or pregnancy rate after IVF or ICSI. Sperm DNA damage as assessed by the TUNEL assay was associated only with a decrease in clinical pregnancy for the IVF procedure (RR = 0.68). The impact of this information on clinical decision making is unknown.

The Practice Committee of the American Society for Reproductive Medicine concludes in their recent guidelines that although sperm DNA damage is more common in infertile men, there is no proven role for routine DNA integrity testing in the evaluation of infertility. (16) In the absence of any evidence that DNA integrity testing improves clinical outcomes, the policy statement remains unchanged.

2008 Update
As indicated above, the Practice Committee of the American Society for Reproductive Medicine concluded in 2006 that the clinical utility of sperm DNA testing was unknown. (16) At issue was the limited data on the relationship between abnormal DNA integrity and reproductive outcomes. In particular, studies had indicated that “the results of sperm DNA integrity testing alone do not predict pregnancy rates achieved with intercourse, IUI, or IVF and ICSI.” Therefore, an updated search of the MEDLINE database, performed for the period of January 2007 through February 2008, focused on this issue.
Recent studies indicate that DNA integrity does not affect pregnancy rates for IVF and ICSI, although it may alter fertilization rate, embryo quality, and miscarriage rate. (17-19) A prospective study with 322 couples (88 IVF cycles and 234 ICSI cycles) found that a DNA fragmentation index (DFI) of 15% or greater was associated with lower fertilization rate and embryo quality (ICSI only), but pregnancy rates (either ICSI or IVF) were not altered. (17) Miscarriage rates were found to be higher (38% vs. 9%) when the DFI was 15% or greater. DFI was weakly correlated (r = -0.2) with standard sperm parameters (count, motility, morphology). Similar results were obtained in 2 additional studies with a combined total of 850 couples (18, 19). Lin et al. note that, “The selection of morphologically normal sperm for ICSI and good quality embryos for transfer at IVF/ICSI may reduce the potential adverse effects of sperm DNA damage on outcome of ART.” (19)
Another multicenter study from Europe examined the relation between sperm DNA integrity and pregnancy outcomes in 637 consecutive couples with either unexplained infertility (387 IUI cycles), female factor infertility (388 IVF cycles) or male infertility factor (223 ICSI cycles). (20) A high DFI (> 30% by SCSA) was observed in 17% of IUI, 16% of IVF, and 32% of ICSI cases. Pregnancy rates were not affected by the percentage of DNA fragmentation in IVF and ICSI groups, and early pregnancy loss was not significantly different in these groups. For the group referred to IUI due to unexplained infertility, the pregnancy rate for a DFI > 30% was 2/66 (3%) compared to 76/321 (24%) cycles when the DFI was 30% or less. In another study, sperm DNA integrity (measured by SCD) was assessed in 100 couples undergoing IUI; female infertility was unexplained in 79 (79%) of the couples. (21) There were 23 (23%) pregnancies with 25 newborns from the first cycle. Weak correlations ('r = -0.22 to -0.29) were observed between DNA dispersion and standard sperm parameters; no differences in SCD were found between couples that did or did not achieve a pregnancy.
Reports from the Practice Committee of the American Society for Reproductive Medicine indicate that up to 30% of couples who are unable to conceive are determined to have unexplained infertility, and up to 8% of infertile men will have abnormal DNA integrity despite normal semen parameters. (16, 22) Current literature indicates that sperm DNA integrity does not affect pregnancy rates in couples who undergo IVF or ICSI. One study suggests that sperm DNA integrity testing with a chromatin structure assay may improve decision making for couples with infertility unexplained by standard panels; however, another study indicates no relation between sperm chromatin dispersion and pregnancy outcomes following IUI. The evidence is insufficient to permit conclusions concerning the effect of sperm DNA integrity tests on health outcomes. Therefore, the policy statements are unchanged.

References:

  1. Freeman MR, Archibong AE, Mrotek JJ et al. Male partner screening before in vitro fertilization: preselecting patients who require intracytoplasmic sperm injection with the sperm penetration assay. Fertil Steril 2001; 76(6):1113-9.
  2. Oehninger S, Franken DR, Sayed E et al. Sperm function assays and their predictive value for fertilization outcome in IVF therapy: a meta-analysis. Hum Reprod Update 2000; 6(2):160-8.
  3. Huszar G, Ozenci CC, Cayli S et al. Hyaluronic acid binding by human sperm indicates cellular maturity, viability and unreacted acrosomal status. Fertile Steril 2003; 79(suppl 3):1616-24.
  4. Cayli S, Jakab A, Ovari L et al. Biochemical markers of sperm function: male fertility and sperm selection for ICSI. Reprod Biomed Online 2003; 7(4):462-8.
  5. Midatlantic Diagnostics, Inc. HBA Sperm Hyaluronan Binding Assay information sheet. http://www.midatlanticdiagnostics.com/products/sperm/hba.htm
  6. O’Brien J, Zini A. Sperm DNA integrity and male infertility. Urology 2005; 65(1):16-22.
  7. Evenson DP, Larson KL, Jost LK. Sperm chromatin structure assay: its clinical use for detecting sperm DNA fragmentation in male infertility and comparisons with other techniques. J Androl 2002; 23(1):23-43.
  8. Payne JF, Raburn DJ, Couchman GM et al. Redefining the relationship between sperm deoxyribonucleic acid fragmentation as measured by the sperm chromatin structure assays and outcomes of assisted reproductive techniques. Fertil Steril 2005;84(2):356-64.
  9. Bungum M, Humaidan P, Spano M et al. The predictive value of sperm chromatin structure assay parameters for the outcome of intrauterine insemination. Hum Reprod 2004; 19(6):1401-8.
  10. Gandini L, Lombardo F, Paoli D et al. Full term pregnancies achieved with ICSI despite high levels of sperm chromatin damage. Hum Reprod 2004; 19(6):1409-17.
  11. Larson KL, DeJonge CJ, Barnes AM et al. Sperm chromatin structure assay parameters as predictors of failed pregnancy following assisted reproductive techniques. Hum Reprod 2000; 15(8):1717-22.
  12. Larson-Cook KL, Brannian JD, Hansen KA et al. Relationships between the outcomes of assisted reproductive techniques and sperm DNA fragmentation as measured by the sperm chromatin structure assay. Fertil Steril 2003; 80(4):895-202.
  13. Virro MR, Larson-Cook KL, Evenson DP. Sperm chromatin structure assay (SCSA) parameters are related to fertilization, blastocyst development, and ongoing pregnancy in in vitro fertilization and intracytoplasmic sperm injection cycles. Fertil Steril 2004; 81(5):1289-95.
  14. Huszar G, Ozkavukcu S, Jakab A et al. Hyaluronic acid binding ability of human sperm reflects cellular maturity and fertilizing potential: selection of sperm for intracytoplasmic sperm injection. Curr Opin Obstet Gynecol 2006; 18(3):260-7.
  15. Li Z, Wang L, Cai J et al. Correlation of sperm DNA damage with IVF and ICSI outcomes: a systematic review and meta-analysis. J Assist Reprod Genet 2006; 23(9-10):367-76.
  16. The Practice Committee of the American Society for Reproductive Medicine. The clinical utility of sperm DNA integrity testing. Fertil Steril 2006; 86(suppl 5):S35-7.
  17. Benchaib M, Lornage J, Mazoyer C et al. Sperm deoxyribonucleic acid fragmentation as a prognostic indicator of assisted reproductive technology outcome. Fertil Steril 2007; 87(1):93-100.
  18. Velez de la Calle JF, Muller A, Walschaerts M et al. Sperm deoxyribonucleic acid fragmentation as assessed by the sperm chromatin dispersion test in assisted reproductive technology programs: results of a large prospective multicenter study. Fertil Steril 2007; [Epub ahead of print].
  19. Lin MH, Kuo-Kuang Lee R, Li SH et al. Sperm chromatin structure assay parameters are not related to fertilization rates, embryo quality, and pregnancy rates in in vitro fertilization and intracytoplasmic sperm injection, but might be related to spontaneous abortion rates. Fertil Steril 2007 Sep 26; [Epub ahead of print]
  20. Bungum M, Humaidan P, Axmon A et al. Sperm DNA integrity assessment in prediction of assisted reproduction technology outcome. Hum Reprod 2007; 22(1):174-9.
  21. Muriel L, Meseguer M, Fernández JL et al. Value of the sperm chromatin dispersion test in predicting pregnancy outcome in intrauterine insemination: a blind prospective study. Hum Reprod 2006; 21(3):738-44.
  22. Practice Committee of the American Society for Reproductive Medicine. Effectiveness and treatment for unexplained infertility. Fertil Steril 2006; 86(5 Suppl):S111-4.

 

Codes

Number

Description

CPT 

89329 

Sperm evaluation; hamster penetration test 

 

0087T 

Sperm evaluation, hyaluronan binding assay 

ICD-9 Procedures 

No code 

 

ICD-9 Diagnosis 

V26.21

Fertility testing

HCPCS 

No code 

 

Type of Service 

Fertility 

Place of Service 

Outpatient
 
Physician’s Office
 


Index

Hamster Egg Penetration Test
Hyaluronan Binding Assay, Sperm
SCSA test
Sperm DNA Integrity
Sperm Penetration Assay
Zona-Free Hamster Egg Test


Policy History

Date Action Reason
12/01/95 Add to OB/Gyn Reproduction section New policy
09/23/98 Replace policy Policy reviewed, no changes in policy
07/12/02 Replace policy Policy revised: sperm penetration assay considered medically necessary to determine need for ICSI as part of an IVF procedure
07/17/03 Replace policy Policy no longer scheduled for review
11/09/04 Replace policy Policy revised, retitled, and put back on review schedule with addition of second test; the hyaluronan binding assay, considered investigational
12/14/05 Replace policy Policy revised with addition of tests of sperm DNA integrity, considered investigational. Reference numbers 6-13 added
02/15/07 Replace policy Policy updated with literature review; reference numbers 14-16 added; policy statement added on use of hyaluronan binding for sperm selection, considered investigational
04/09/08 Replace policy  Policy updated with literature review; references 17-22 added; policy statements unchanged 
09/2009 Policy Archived  


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