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INFERTILITY - DIAGNOSIS & TREATMENT

Protocol: OBG013 Effective Date: March 21, 2011 Table of Contents Page

COMMERCIAL COVERAGE RATIONALE......................................................................................... 1 MEDICARE COVERAGE RATIONALE............................................................................................... 4 MEDICAID COVERAGE RATIONALE................................................................................................ 5 COMMERCIAL, MEDICARE & MEDICAID COVERAGE RATIONALE......................................... 5 BENEFIT CONSIDERATIONS .............................................................................................................. 6 BACKGROUND ...................................................................................................................................... 6 CLINICAL EVIDENCE........................................................................................................................... 7 U.S. FOOD AND DRUG ADMINISTRATION (FDA) ........................................................................ 16 APPLICABLE CODES .......................................................................................................................... 17 REFERENCES ....................................................................................................................................... 19 PROTOCOL HISTORY/REVISION INFORMATION ........................................................................ 25 INSTRUCTIONS FOR USE This protocol provides assistance in interpreting UnitedHealthcare benefit plans. When deciding coverage, the enrollee specific document must be referenced. The terms of an enrollee's document (e.g., Certificate of Coverage (COC) or Evidence of Coverage (EOC)) may differ greatly. In the event of a conflict, the enrollee's specific benefit document supersedes this protocol. All reviewers must first identify enrollee eligibility, any federal or state regulatory requirements and the plan benefit coverage prior to use of this Protocol. Other Protocols, Policies and Coverage Determination Guidelines may apply. UnitedHealthcare reserves the right, in its sole discretion, to modify its Protocols, Policies and Guidelines as necessary. This protocol is provided for informational purposes. It does not constitute medical advice.

COMMERCIAL COVERAGE RATIONALE Diagnostic Procedures The following procedures are medically necessary for use in diagnosing infertility in female patients: chromotubation of oviduct cultures (cervical, vaginal, uterine) endometrial biopsy hormone assay (luteinizing hormone (LH), follicle stimulating hormone (FSH), progesterone, prolactin, estradiol, thyroid, clomiphene citrate challenge test) hysterosalpingogram hysteroscopy laparoscopy

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pelvic ultrasound (abdominal or vaginal) sonohysterography or saline contrast hysterosonography The following procedures are medically necessary for use in diagnosing infertility in male patients: antisperm antibodies (semen only) cultures (genital) hormone assay (LH, FSH, prolactin, testosterone) leukocyte count in semen rectal ultrasound (indicated when ejaculatory duct obstruction is suspected) scrotal ultrasound semen analysis testicular biopsy vasography The following tests are not medically necessary for diagnosing infertility: computer-assisted sperm analysis (CASA) hemizona assay test hyaluronan binding assay (HBA) serum or cervical mucus antisperm antibodies (testing for antisperm antibodies in semen IS proven) sperm DNA integrity testing (e.g. Sperm Chromatin Structure Assay (SCSA), Comet assay, sperm DNA fragmentation assay, TUNEL assay, Sperm DNA DecondensationTM Test (SDD)) sperm penetration assay (SPA), zona-free hamster egg assay, or sperm acrosome reaction assay uterine/endometrial receptivity testing (e.g., E-tegrity® and Endometrial Function Test® (EFT)) There is insufficient evidence to permit conclusions regarding the use of these tests. More studies are needed to support improved outcomes (i.e., increased successful pregnancies with delivery of liveborn children) with use of these diagnostic tests. Therapeutic Procedures The following procedures are medically necessary for the treatment of infertility: ovulation induction insemination procedures (intrauterine insemination (IUI) and artificial insemination (AI) including sperm washing) assisted reproductive technologies (gamete intrafallopian transfer (GIFT), in vitro fertilization (IVF), and zygote intrafallopian transfer (ZIFT)) assisted embryo hatching intracytoplasmic sperm injection (ICSI) for treatment of male factor infertility sperm retrieval techniques (including microsurgical epididymal sperm aspiration (MESA), percutaneous epididymal sperm aspiration (PESA), and testicular sperm extraction (TESE), and electroejaculation)

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The following procedures to correct underlying disorders are medically necessary for the treatment of infertility: ablation or lysis of adhesions and/or surgical treatment of endometriosis, laparoscopic or open drainage of ovarian cyst fimbrioplasty salpingostomy* transurethral resection of ejaculatory ducts for treatment of ejaculatory duct obstruction tubotubal anastamosis* varicocele repair vasoepididymostomy* vasovasostomy* wedge resection of ovary or ovarian drilling in women with polycystic ovary syndrome *Note that interventions to reverse elective sterilization may not be covered health services. See the Benefit Considerations section for more information. The following procedures are not medically necessary for treating infertility: co-culture of embryos EmbryoGlue® partial zonal dissection (PZD) subzonal sperm insertion (SUZI) (also referred to as SCI) Wurn Technique (Clear Passage Therapies) Studies describe different techniques of co-culture of embryos, but no standardized method of coculturing has been defined. The use of co-cultures may improve blastocyst development but may not result in an improved pregnancy or delivery rate. There is inadequate published scientific data to permit conclusions regarding the use of EmbryoGlue. Intracytoplasmic sperm injection (ICSI) has largely replaced partial zonal dissection (PZD) and subzonal sperm insertion (SCI, SUZI) procedures. While results of one study are promising for the use of the Wurn Technique, there were no other studies to substantiate or replicate these results. There is no research to indicate that biomechanical dysfunction is a barrier to pregnancy. Cryopreservation of sperm, semen or embryos is medically necessary for individuals who are infertile or are planning to undergo therapies that threaten their reproductive health such as cancer chemotherapy. Cryopreservation of oocytes (eggs) is not medically necessary Although oocyte banking can be an option for women who have no partner at the time of cancer diagnosis, research indicates that unfertilized oocytes are more prone to damage during cryopreservation procedures than embryos, and as a result, the overall pregnancy rates may be lower than standard in vitro fertilization (IVF) procedures. New methods are developing rapidly; however, their use as a means to have a child after cancer treatment must be considered investigational and offered only with appropriate informed consent in a research setting and under the auspices of an institutional review board (IRB). Cryopreservation of ovarian or testicular tissue is not medically necessary.

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Ovarian tissue banking remains a promising clinical technique because it avoids ovarian stimulation and provides the opportunity for preserving gonadal function in prepubertal, as well as adult patients. However, this procedure has produced very few live births. Testicular tissue or testis xenografting are in the early phases of experimentation and have not yet been successfully tested in humans. Limited diagnostic and therapeutic infertility services determined to be Medically Necessary and Prior Authorized by HPN's Managed Care Program are available. Covered Services do not include those services specifically excluded, but do include limited: 1. Laboratory studies; 2. Diagnostic procedures; and 3. Artificial insemination services, up to six (6) cycles per Member per lifetime. The following infertility services and supplies are excluded, in addition to any other infertility services or supplies determined by HPN not to be Medically Necessary; 1. Advanced reproductive techniques such as; a. embryo transplants, b. in vitro fertilization, c. GIFT and ZIFT procedures, d. assisted hatching, e. intracytoplasmic sperm injection, f. egg retrieval via laparoscope or needle aspiration, g. sperm preparation, h. specialized sperm retrieval techniques, i. sperm washing except prior to artificial insemination if required. 2. Home pregnancy or ovulation tests; 3. Sonohysterography; 4. Monitoring of ovarian response to stimulants; 5. CT or MRI of sella turcica unless elevated prolactin level; 6. Evaluation for sterilization reversal; 7. Laparoscopy; 8. Ovarian wedge resection; 9. Removal of fibroids, uterine septae and polyps; 10. Open or laparoscopic resection, fulguration, or removal of endometrial implants; 11. Surgical lysis of adhesions; 12. Surgical tube reconstruction. 13. Reversal of surgically performed sterilization or subsequent resterilization; 14. Any services or supplies rendered in connection with Member acting as or utilizing the services of a surrogate mother. MEDICARE COVERAGE RATIONALE Medicare does not have a National Coverage Determination or a Local Coverage Determination for Nevada for Infertility, Treatment and Diagnosis. The Medicare Benefit Policy Manual, Chapter 15 ­ Covered Medical and Other Health Services addresses Infertility in §20.1 - Physician Expense for Surgery, Childbirth, and Treatment for Infertility as follows:

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Reasonable and necessary services associated with treatment for infertility are covered under Medicare. Infertility is a condition sufficiently at variance with the usual state of health to make it appropriate for a person who normally is expected to be fertile to seek medical consultation and treatment. For Medicare and Medicaid Determinations Related to States Outside of Nevada: Please review Local Coverage Determinations that apply to other states outside of Nevada. http://www.cms.hhs.gov/mcd/search Important Note: Please also review local carrier Web sites in addition to the Medicare Coverage database on the Centers for Medicare and Medicaid Services' Website.

MEDICAID COVERAGE RATIONALE COVERAGE AND LIMITATIONS 1. Nevada Medicaid reimburses for covered medical services that are reasonable and medically necessary, ordered or performed by a physician or under the supervision of a physician, and that are within the scope of practice of their prognosis as defined by state law. 2. Infertility treatments are not a covered benefit, mostly because they are considered not medically necessary and Medicaid only pays for services that are medically necessary.

COMMERCIAL, MEDICARE & MEDICAID COVERAGE RATIONALE Cryopreservation of sperm, semen or embryos is medically necessary for individuals who are infertile or are planning to undergo therapies that threaten their reproductive health such as cancer chemotherapy. Cryopreservation of oocytes (eggs) is not medically necessary. Although oocyte banking can be an option for women who have no partner at the time of cancer diagnosis, research indicates that unfertilized oocytes are more prone to damage during cryopreservation procedures than embryos, and as a result, the overall pregnancy rates may be lower than standard in vitro fertilization (IVF) procedures. New methods are developing rapidly; however, their use as a means to have a child after cancer treatment must be considered investigational and offered only with appropriate informed consent in a research setting and under the auspices of an institutional review board (IRB). Cryopreservation of ovarian or testicular tissue is not medically necessary.

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Ovarian tissue banking remains a promising clinical technique because it avoids ovarian stimulation and provides the opportunity for preserving gonadal function in prepubertal, as well as adult patients. However, this procedure has produced very few live births. Testicular tissue or testis xenografting are in the early phases of experimentation and have not yet been successfully tested in humans. Medicare does not have a National Coverage Determination or a Local Coverage Determination for Nevada for Cyropreservation of Reproductive Tissue. (Accessed June 2010) For Medicare and Medicaid Determinations Related to States Outside of Nevada: Please review Local Coverage Determinations that apply to other states outside of Nevada. http://www.cms.hhs.gov/mcd/search Important Note: Please also review local carrier Web sites in addition to the Medicare Coverage database on the Centers for Medicare and Medicaid Services' Website.

BENEFIT CONSIDERATIONS Legislative mandates and the member-specific benefit document should be reviewed when determining benefit coverage for infertility services. Where legislative mandates exist, they supersede benefit plan design. Benefit coverage for testing and treatment of infertility are available only for the person(s) who are covered under the benefit document, and only when the member's specific plan provides benefits for infertility diagnosis and/or treatment. The member-specific document should be reviewed for applicable benefits, limitations, and/or exclusions. In vitro fertilization for the prevention of disease in offspring is not covered as an infertility benefit since this service is not a treatment for infertility. Cryopreservation services are subject to the limitations or exclusions of infertility benefits, if they exist, and if the individual has a diagnosis of infertility. In most Certificates of Coverage (COC) and Evidences of Coverage (EOC), storage after cryopreservation of sperm, oocytes (eggs), embryos or ovarian tissue is excluded, as it does not meet the definition of a covered health service. However, some states mandate benefit coverage for certain infertility services, including cryopreservation .

BACKGROUND Infertility is defined as a failure to achieve pregnancy after 12 months of unprotected sexual intercourse in opposite-sex partners. The cause of infertility can originate in either partner, or can be from unknown factors or a combination of factors. In some cases, environmental factors may contribute to infertility. In other cases, genetic conditions or other health problems are the main cause of infertility (NIH, 2006). Cryopreservation is the process of cooling and storing cells, tissues or organs at very low or freezing temperatures to save them for future use. It is used to preserve sperm, semen, oocytes (eggs), embryos, ovarian tissue or testicular tissue as an option for men and women who wish to or must delay

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reproduction for various reasons, including the need to undergo therapies that threaten their reproductive health such as cancer treatment. Cryopreservation is also used to preserve unused gametes or zygotes produced through various artificial reproductive techniques for use at a later time.

CLINICAL EVIDENCE Diagnostic Procedures Milingos et al. found that sonohysterography or saline contrast hysterosonography revealed the presence of intrauterine pathology with sensitivity of 94%, a specificity of 71%, a positive predictive value of 76%, and a negative predictive value of 95% in the abnormal uterine group (Milingos, 2005). In sub-fertile patients, hysterosonography revealed the presence of intrauterine pathology with a sensitivity of 96%, a specificity of 74%, a positive predictive value of 79%, and a negative predictive value of 95%. The authors found that hysterosonography is an extremely accurate modality for the diagnosis of focal endometrial pathology compared to diagnostic hysteroscopy. The efficacy of the following tests for evaluating infertility have not been demonstrated: Computer-Assisted Sperm Analysis (CASA) One clinical trial reported that the prognostic accuracy of computer-assisted sperm analysis was similar to manual techniques and that CASA system data was preferred by the laboratories (Irvine, 1994). More studies are needed to support improved outcomes (i.e., increased successful pregnancies) with use of CASA. The National Institute for Health and Clinical Excellence (NICE) states that unless there is azoospermia, the predictive value of subnormal semen variables is limited. No functional test has yet been established that can unequivocally predict the fertilizing capacity of spermatozoa. Sperm function tests such as computer-assisted semen analysis have not been found to be more predictive (NICE, 2004). Hemizona Assay (HZA) Test There is inadequate published scientific data to permit conclusions regarding the use of the hemizona assay test. A literature search identified one clinical trial that evaluated the value of HZA as a predictor of pregnancy in patients undergoing controlled ovarian hyperstimulation (COH) and intrauterine insemination (IUI). Semen analysis and HZA were performed within 3 months of starting COH/IUI therapy. Results of the study indicated that HZA predicted pregnancy in the IUI setting with high sensitivity and negative predictive value in couples with male factor infertility (Arslan, 2006). Hyaluronan Binding Assay (HBA) There is inadequate published scientific data to permit conclusions regarding the use of HBA. A literature search identified one study that investigated the relationship between HBA and fertilization rate in conventional IVF in 175 IVF patients. Both the standard semen analysis and the HBA were performed on the same ejaculated sperm samples used for IVF treatments. While both normal sperm morphology and HBA scores were statistically significantly related to fertilization rates, the HBA was less significant than normal sperm morphology. The investigators concluded that the clinical predictive value of HBA for sperm-fertilizing ability in vitro is limited (Ye, 2006).

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Serum or Cervical Mucus Antisperm Antibodies (ASA) Much of the literature regarding antisperm antibodies consists of review articles focusing on whether these antibodies exist and if current tests can distinguish ASA that may inhibit fertility from those that do not. Most of the research involves small numbers of patients either from case series or convenience samples. The methodology is variable among the studies published and makes comparison of study findings difficult (Hayes, 2008b). A study compared the prevalence of ASA in semen, peripheral blood, and follicular fluid and determined total immunoglobulin concentration in the serum and follicular fluid. IVF related outcomes were measured. Fifty-two married couples were enrolled and semen MAR test IgG was less than 20% in 38 couples, and more than 20% in 14 couples. Fertilization and pregnancy rates were not significantly different between the groups. The results of direct and indirect MAR testing were not associated with fertilization and improved pregnancy rates. The study concluded that the presence of ASA on sperm or in the serum and follicular fluid was not associated with IVF outcome in the couples with good quality semen characteristic (Vujisic, 2005). Another study estimated the presence of antisperm antibodies in 17 infertile women after IVF failure and 10 women with a history of successful IVF pregnancies and concluded that immunological alterations may be involved in the cause of unexplained fertility; however, more study is needed for further clarification (Putowski, 2004). There is currently insufficient evidence to determine the accuracy and clinical utility of ASA serum or cervical mucous testing for the diagnosis of infertility. While it is known that some ASA interfere with fertility, not all ASA cause infertility. At present the antigenic specificity of antibodies that cause infertility are not known and no test currently exists that differentiates between ASA that interfere with fertility and those that do not. This limits the usefulness of current tests that detect all ASA. In addition, the diagnostic performance of the detection of overall ASA levels has not been sufficiently investigated (Hayes, 2008b). Sperm DNA Integrity Testing (Sperm Chromatin Structure Assay (SCSA), Comet Assay, Sperm DNA Fragmentation Assay, TUNEL assay) A meta-analysis performed by Li et al. (2006) concluded that sperm DNA damage as assessed by SCSA had no significant effect on the chance of clinical pregnancy after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment. Another meta-analysis concluded that SCSA was significantly predictive for reduced pregnancy success using in-vivo, intrauterine insemination (IUI) and routine IVF (Evenson, 2006). A study conducted by Gandini et al. (2004) found no differences in SCSA parameter values between patients initiating pregnancies and not doing so in ICSI or IVF. Pregnancy was obtained even with high levels of DNA fragmentation index. A cross-sectional prospective study concluded that there is a moderate correlation between sperm motility and SCSA parameters and supported the assumption that motility and SCSA can be relatively independent predictors of infertility (Giwercman, 2003).

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Sperm Penetration Assay (SPA) or Zona-Free Hamster Egg Assay A limited number of relevant articles were identified in a literature search and there was a paucity of recent studies. Most of the studies involved relatively small numbers of patients, most of whom were potential candidates for in vivo fertilization (IVF). The majority of the studies evaluated the SPA as a predictor of success of IVF or as a way to select suitable candidates. Methodology appeared to be variable among the studies and hampered comparison of study findings (Hayes, 2008a). Aoki et al. (2005) evaluated the relationship between SPA scores and polyspermy rates during conventional IVF cycles in 1350 consecutive IVF patients. A significant positive relationship was observed between SPA score and polyspermy rate. Clinical pregnancy and implantation rates improved slightly as SPA score increased and there was a decrease in the rate of spontaneous abortion as SPA score increased. A prospective study by Freeman et al. (2001) evaluated the diagnostic accuracy of the sperm penetration assay (SPA) and standard semen parameters for subsequent fertilization in 216 couples undergoing IVF. The SPA predicted IVF fertilization with 84% negative predictive value and 98% positive predictive value, with overall correct prediction in 88% of cycles. In contrast, sperm concentration, motility, morphology, and complete sperm analysis showed poor predictive accuracy. Results suggest that SPA can predict which couples are likely to have success with normal fertilization in IVF and which might benefit from intracytoplasmic sperm injection. A meta-analysis by Oehninger et al. (2000) used data from 2906 patients in 34 prospective, controlled studies to evaluate the predictive value of four categories of sperm functional assays, including SPA, for IVF outcome. In this analysis, the sperm-zona pellucida binding assay and the induced-acrosome reaction assay had a high predictive value for fertilization outcome. SPA had a relatively high positive predictive value (more than 70%), but the negative predictive value was variable, ranging from 11% to 100%, with most studies reporting NPV less than 75%. The authors noted that this assay was limited by the need for standardization. There is weak to moderate evidence that the sperm penetration assay can be used to evaluate sperm function and predict success of fertilization during IVF procedures, and may be useful in reducing the use of intracytoplasmic sperm injection (Hayes, 2008a). Uterine Receptivity Testing Several studies of uterine receptivity testing indicate that even though integrins may be important markers of endometrial receptivity and provide additional information, more study is needed before uterine receptivity testing can be considered a clinically useful test (Thomas, 2003; Lessey, 2000). Creus et al. (2002) found a clear dissociation in the temporal expression of the most cited markers of endometrial receptivity believed to define the window of implantation. Professional Societies American Society for Reproductive Medicine (ASRM) ASRM states that sperm DNA damage may contribute to poor reproductive performance. However, current methods for evaluating sperm DNA integrity do not reliably predict treatment outcomes and no

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treatment for sperm DNA damage has proven value (ASRM, 2008a). Royal College of Obstetricians and Gynecologists It has been presumed that screening for immunological abnormalities will lead to the development of therapeutic strategies to prevent reproductive failure. However, with the exception of the aPL syndrome in recurrent miscarriage, there is a paucity of good data to support this hypothesis (RCOG, 2008). Therapeutic Procedures Assisted Embryo Hatching A review of the published literature for assisted hatching (AH) demonstrated inconsistent success rates. Several randomized controlled trials concluded that AH improves the outcome of embryo transfer (Balaban, 2006; Ma, 2006; Petersen, 2005; Gabrielsen, 2004). A randomized controlled trial (RCT) of 199 good prognosis (i.e., patient 39 years of age or younger, no more than one previous unsuccessful cycle of in vitro fertilization (IVF) embryo transfer, and good embryo quality) patients undergoing IVF-embryo transfer concluded that assisted hatching does not improve clinical outcomes in good prognosis patients (Sagoskin, 2007). Another RCT concluded that AH does not improve embryo transfer outcome in women 37 years of age or older (Frydman, 2006). In a randomized double-blinded controlled trial, Ng et al. did not find that AH improved the implantation rate and recommended that AH should not be performed routinely (Ng, 2005). A multicenter prospective randomized study of 426 patients concluded that absence of implantation after several transfers of good quality embryos are the strongest patient selection criteria for AH (Primi, 2004). A meta analysis completed by Cochrane involved 2668 women in 23 RCTs. Women undergoing AH were significantly more likely to achieve clinical pregnancy. However, there were no significant differences in the effect of AH on live birth rates. The investigators concluded that there is insufficient evidence to recommend assisted hatching (Seif, 2006). A meta-analysis of 13 randomized controlled trials concluded that AH increases the pregnancy and implantation rates significantly in poor prognosis patients, particularly those with repeated IVF or ICSI failures (Sallam, 2003). A systematic review of 23 trials concluded that AH probably enhances clinical pregnancy; however, trials were of poor quality (Edi-Osagie, 2003). According to ASRM, the published evidence does not support the routine or universal application of assisted hatching in all IVF cycles. However, assisted hatching may be useful in patients with a poor prognosis (i.e., patients who have failed 2 or more IVF cycles, patients who have poor embryo quality or women 38 years of age or older) (ASRM, 2008b). Co-Culturing of Embryos Studies describe different techniques of co-culture, but no standardized method of co-culturing has been defined. In a meta-analysis of 17 prospective, randomized trials, Kattal et al. (2008) evaluated the role of coculture in human IVF. Primary outcomes measured were implantation rates and pregnancy rates (clinical and ongoing). Secondary outcomes included evaluation of pre-embryo development based on average number of blastomeres per embryo. The pooled data of human trials on coculture demonstrate a statistically significant improvement in blastomere number, implantation rates and clinical and

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ongoing pregnancy rates. However, the authors acknowledged that confounding factors such as heterogeneity of cell lines and variability in culture media used limit the conclusions. A comparative study evaluated 517 women undergoing cumulus co-culture and cumulus-aided embryo transfer with those who underwent cumulus co-culture but did not undergo cumulus-aided embryo transfer. The study results demonstrated a significant increase in the implantation rate in the study group of 25.6% versus 14.5% in the control group and a significant increase in the pregnancy rate in the study group of 47.6% versus 34% in the control group (Parikh, 2006). Another study evaluated the effectiveness of autologous endometrial co-culture (AECC) in 1,030 consecutive cycles of in vitro fertilization-embryo transfer. Embryos were randomly grown on endometrial co-culture or conventional media if more than 6 oocytes were normally fertilized. Otherwise, all embryos were grown on AECC. The study results demonstrated a significant improvement in embryo quality with endometrial co-culture (Spandorfer, 2004). Johnson et al. (2007) evaluated whether culture of immature human oocytes with and without autologous cumulus cells (CCs) in standard culture medium would provide additional oocytes for use in IVF procedure in 61 women. This study demonstrated good maturation of metaphase I (MI) oocytes but poor maturation of germinal vesicle (GV) oocytes in standard culture medium. The investigators concluded that these extended culturing techniques were inefficient in maturing and providing additional oocytes/embryos for patient use. Ebner et al. (2006) evaluated the influence of adhering CCs on further preimplantation development and concluded that co-culture of oocytes with attached CCs may enhance preimplantation development. Electroejaculation Several studies have demonstrated that electroejaculation is effective in treating anejaculatory infertility (Ohl, 2001; Hovav, 2005). Electroejaculation can be attempted if penile vibratory stimulation is unsuccessful (Brackett, 1997; Nehra, 1996). EmbryoGlue In a single center, prospective randomized study (n=224), Hazlett et al. (2008) found that routine use of EmbryoGlue did not significantly improve pregnancy or implantation rates in nonselected patients receiving either a day 3 or day 5 embryo transfer compared with standard culture media. Future prospective randomized studies are needed to determine whether EmbryoGlue is beneficial in a selected patient population. In a prospective randomized clinical trial, Valojerdi et al. (2006) evaluated the efficacy of EmbryoGlue. A total of 815 patients were randomly allocated to the test group (embryos were treated with EmbryGlue prior to intrauterine transfer) (n=417) and the control group (embryos were not treated with EmbryoGlue) (n=398). The clinical pregnancy and implantation rate increased significantly in the test group compared to the control group. More studies are needed to evaluate the effectiveness and safety of EmbryoGlue.

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Intracytoplasmic Sperm Injection (ICSI) ASRM considers intracytoplasmic sperm injection (ICSI) to be a standard clinical technique and no longer considers this technique to be experimental (ASRM, 2008c). Ovarian Drilling Several studies have shown that ovarian drilling is an effective procedure in women with polycystic ovarian syndrome (PCOS) (Api, 2005; Al-Ojaimi, 2004; Malkawi, 2003). A 2007 Cochrane review of 9 RCTs was done to determine the effectiveness and safety of laparoscopic ovarian drilling (LOD) compared with medical ovarian induction for subfertile women with PCOS (Farquhar, 2007). The investigators concluded that there was no evidence of a difference in the live birth rate and miscarriage rate in women with clomiphene resistant PCOS undergoing LOD compared to gonadotrophin treatment. Multiple pregnancy rates were lower with ovarian drilling. However, there are concerns about long term effects of LOD on ovarian function. Sperm Retrieval Techniques [including Microsurgical Epididymal Sperm Aspiration (MESA), Percutaneous Epididymal Sperm Aspiration (PESA), and Testicular Sperm Extraction (TESE)] A Cochrane review of 2 trials involving 98 men concluded that there is not enough evidence to recommend any specific sperm retrieval technique for azoospermic men undergoing ICSI (Van Peperstraten, 2006). A study compared pregnancy outcomes between electroejaculation, TESE, and prostatic massage and found that these techniques resulted in similar pregnancy outcomes (Engin-Uml, 2006). Transurethral Resection of Ejaculatory Ducts Results from several studies have shown that transurethral resection of the ejaculatory ducts for treatment of ejaculatory duct obstruction has resulted in improvement in semen parameters and pregnancy rates (Yurdakul, 2007; Johnson, 2005; Kadioglu, 2001; Paick, 2000). Wurn Technique (Clear Passage Therapies) Wurn et al. (2004) evaluated 53 infertile patients who received a 10- to 20-hour series of site-specific manual physical therapy treatments. Seventeen patients hoped to achieve a natural pregnancy; 36 planned to undergo IVF within 15 months. Of the 14 patients (in the natural pregnancy group) available for follow-up, 10 (71.4%) became pregnant within 1 year, and 9 (64.3%) reported full-term deliveries. Of the 25 patients (in the pre-IVF group) available for follow-up, clinical pregnancies were documented in 22 of 33 embryo transfers vs. the US Centers for Disease Control and Prevention 2001 age-adjusted expected number of 12.7. While these results are promising, there were no other studies to substantiate or replicate these results. There is no research to indicate that biomechanical dysfunction is a barrier to pregnancy. Cryopreservation In a meta-analysis, Oktay, et al. (2006) studied the efficiency of oocyte cryopreservation relative to in vitro fertilization (IVF) with unfrozen oocytes. Compared to women who underwent IVF after slow freezing (SF), IVF with unfrozen oocytes resulted in significantly better rates of fertilization. Although oocyte cryopreservation with the SF method appears to be justified for preserving fertility when a medical indication exists, its value for elective applications remains to be determined. Pregnancy rates using a vitrification (VF) method appear to have improved, but further studies are needed to determine

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the efficiency and safety of this technique. Cryopreservation of oocytes and ovarian tissue represent uncertain efficacy at present. Access to such innovative techniques should be limited to carefully designed research settings where efficacy and outcomes can be assessed (FIGO, 2006). In an evidence-based report, the National Institute for Health and Clinical Excellence (NICE) makes the following recommendations (NICE, 2004): · Men and adolescent boys preparing for medical treatment that is likely to make them infertile should be offered semen cryostorage because the effectiveness of this procedure has been established. · Women preparing for medical treatment that is likely to make them infertile should be offered oocyte or embryo cryostorage as appropriate if they are well enough to undergo ovarian stimulation and egg collection, provided that this will not worsen their condition and that sufficient time is available. · Women preparing for medical treatment that is likely to make them infertile should be informed that oocyte cryostorage has very limited success, and that cryopreservation of ovarian tissue is still in an early stage of development. Bedaiwy et al. (2008) performed a systematic review of reproductive function after ovarian tissue transplantation (OTT) for fertility preservation in women at high risk of premature ovarian failure (POF). Women with follicle-stimulating hormone (FSH) >30 IU/l at the time of OTT were included in a meta-analysis to evaluate the time to re-establishment of ovarian function (ROF). Secondary outcomes included short-term (<12 months) and long-term (>12 months) ovarian function (OVF) and pregnancy after OTT. Transplantation of ovarian tissue can re-establish OVF after POF; however, the efficacy of OTT using cryopreserved tissues is not yet equivalent to that of fresh grafts. A prospective, controlled multicenter trial with sufficient follow-up is needed to provide valid evidence of the potential benefit of this procedure. Borini et al. (2004) studied the pregnancies and births in 68 women after undergoing assisted reproduction procedures for infertility problems using cryopreserved oocytes. Fifteen of the women became pregnant, there were 3 spontaneous abortions, and 13 healthy babies (one set of twins) were delivered. Quintans (2002) reported on a series of in vitro fertilizations in twelve women using oocytes that had been cryopreserved in an alternative freezing medium. Six clinical pregnancies resulted, one of these was ectopic and three aborted spontaneously. Two healthy babies were born. Radiation therapy and chemotherapy treatments may cause temporary or permanent infertility. These side effects are related to a number of factors including the patient's sex, age at time of treatment, the specific type and dose of radiation therapy and/or chemotherapy, the use of single therapy or many therapies and length of time since treatment. Patients who are concerned about the effects of cancer treatment on their ability to have children should discuss this with their doctor before treatment. The doctor can recommend a counselor or fertility specialist who can discuss available options and help patients and their partners through the decision-making process. Options may include freezing sperm,

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eggs or ovarian tissue before cancer treatment (NCI, 2006). Professional Societies American Cancer Society (ACS) Preserving Fertility in Women Embryo freezing is the most common and successful method of preserving fertility today. Mature eggs are removed from the woman's ovaries and fertilized in the lab via in vitro fertilization (IVF). The embryos are then frozen for future use after successful cancer treatment. However, some women who have fast-growing cancers cannot wait 2 to 3 weeks to begin treatment. Successful pregnancy rates vary from center to center. Centers with the most experience usually have better success rates. Egg freezing involves removing mature eggs with the same procedure used for embryo freezing, but the eggs are frozen without being fertilized. Few babies have been born (only around 150 worldwide) as a result of egg freezing, and the procedure remains investigational. This may be an option for women who have no partner at the time of cancer diagnosis, but egg freezing is not very reliable in producing pregnancy. The methods are improving, but the results are not as good as those with embryo freezing. Ovarian tissue freezing involves surgically removing all or part of one ovary. The ovarian tissue is usually divided into small strips, frozen and stored to be transplanted back into the woman's body after treatment. Usually the eggs produced by the tissue would need to be collected and fertilized in the laboratory. In a few cases, the whole ovary has been frozen with the idea of transplanting it back. This procedure is experimental and has produced very few live births (ACS, 2009). Preserving Fertility in Men Sperm banking is an effective way for men who have gone through puberty to store sperm for future use. In sperm banking, one or more samples of semen are collected, tested, frozen and stored. The success rates of infertility treatments using frozen sperm vary and depend on the quality of the sperm after it is thawed. In general, sperm collected before cancer treatment is just as likely to start a pregnancy as sperm from men without cancer. Sperm banking has resulted in thousands of pregnancies, without unusual rates of birth defects or health problems in the children. Once sperm is stored, it remains good for many years (ACS, 2009). American College of Obstetricians and Gynecologists (ACOG) A number of techniques have been used to protect the ovaries and preserve fertility in women at risk of losing ovarian function prematurely as a consequence of cancer therapy. In vitro fertilization (IVF) with cryopreservation of embryos is a proven method and is the most successful approach. Ovarian tissue cryopreservation and oocyte cryopreservation are two options with the potential to preserve fertility. Although these methods are developing rapidly, their use as a means to have a child after cancer treatment must be considered investigational and offered only with appropriate informed consent in a research setting and under the auspices of an institutional review board (ACOG, 2008). American Society for Reproductive Medicine (ASRM)/Society for Assisted Reproductive Technology (SART) Semen samples may be frozen at a sperm bank or fertility center before starting chemotherapy or radiation therapy. Samples can be stored for years and used later for insemination. Cryopreservation of

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eggs is investigational, expensive, invasive and may delay cancer treatment. If used, eggs are collected as for in vitro fertilization (IVF) but are frozen before they are fertilized. Theoretically, frozen eggs may be stored, thawed, fertilized and used for embryo transfer. Actual success with this method is very limited, and few babies have been born with this technique (ASRM, 2004). Embryo banking is a proven method but requires both available sperm and several weeks of preparation. Oocyte banking avoids some of the disadvantages of embryo banking, although investigations of the application of this technology have been hampered historically by poor oocyte survival, fertilization and resulting pregnancy rates. Ovarian tissue banking remains a promising clinical technique because it avoids ovarian stimulation and provides the opportunity for preserving gonadal function in prepubertal, as well as adult patients. In the case of patients who are facing infertility due to chemotherapy, oocyte cryopreservation may be one of the few options available. It might therefore be acceptable under these circumstances with appropriate informed consent in an investigational protocol under the auspices of an IRB. Although currently investigational, ovarian tissue cryopreservation and oocyte cryopreservation hold promise for future female fertility preservation, particularly following aggressive chemotherapy and/or radiotherapy treatment protocols (ASRM, 2008d). At this time, oocyte and ovarian tissue cryopreservation can only be recommended as experimental protocols in carefully selected patients (ASRM, 2008d). American Society of Clinical Oncology (ASCO) Preservation of Fertility in Males The available evidence suggests that sperm cryopreservation is an effective method of fertility preservation in males treated for cancer. In contrast, testicular tissue or spermatogonial cryopreservation and transplantation or testis xenografting are in the early phases of experimentation and have not yet been successfully tested in humans. Sperm cryopreservation is the most established technique for fertility preservation in men. Due to recent advances in in-vitro fertilization (IVF) technology and sperm banking procedures, even men with extremely reduced sperm count and motility are candidates for sperm cryopreservation (Lee, 2006). Preservation of Fertility in Females Fertility preservation options in females depend on the patient's age, type of treatment, diagnosis, whether she has a partner, the time available and the potential that cancer has metastasized to her ovaries. Embryo cryopreservation is considered an established fertility preservation method as it has routinely been used for storing surplus embryos after in vitro fertilization for infertility treatment. This approach typically requires approximately two weeks and may entail a delay in cancer treatment. Cryopreservation of unfertilized oocytes is another option for fertility preservation, particularly in patients for whom a partner is unavailable, or who have religious or ethical objections to embryo freezing. The oocytes are thawed later and fertilized in vitro. Research indicates that unfertilized oocytes are more prone to damage during cryopreservation procedures than embryos, and as a result, the overall pregnancy rates may be lower than standard IVF procedures. Further research is needed to delineate the current success rates and safety, as well as to improve the efficiency of this procedure. Ovarian tissue cryopreservation is an investigational method of fertility preservation but has the

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advantage of requiring neither a sperm donor nor ovarian stimulation. Ovarian cryopreservation and transplantation procedures should only be performed in centers with the necessary expertise under IRB approved protocols that include follow-up for recurrent cancer (Lee, 2006).

U.S. FOOD AND DRUG ADMINISTRATION (FDA) Sperm DNA integrity testing (Sperm Chromatin Structure Assay (SCSA)), Comet assay, sperm DNA fragmentation assay, TUNEL assay, Sperm DNA Decondensation Test and E-tegrity uterine receptivity testing is regulated under the Clinical Laboratory Improvement Amendments (CLIA) of 1988. Premarket approval from the FDA is therefore not required for this laboratory testing. In November 2003, the FDA approved the use of Sperm-Hyaluronan Binding Assay for the following indications: 1) as a component of the standard analysis of semen in the diagnosis of suspected male infertility and 2) as a component of analyses for determining the proper course of in vitro fertilization (IVF) treatment of infertility. Additional information is available at: http://www.accessdata.fda.gov/cdrh_docs/reviews/K032874.pdf. Accessed March 12, 2010. The FDA has developed a document titled, Information and Recommendations for Physicians Involved in the Co-Culture of Human Embryos with NonHuman Animal Cells. Last updated April 2009. Additional information is available at: http://www.fda.gov/BiologicsBloodVaccines/Xenotransplantation/ucm136532.htm. Accessed March 12, 2010. Products and media used for cryopreservation of reproductive tissue are too numerous to list. See the following web site for more information (use product code MQL). Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/pmn.cfm. Accessed March 12, 2010.

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APPLICABLE CODES The codes listed in this policy are for reference purposes only. Listing of a service or device code in this policy does not imply that the service described by this code is a covered or non-covered health service. Coverage is determined by the benefit document. This list of codes may not be all inclusive. CPT® Code Description Diagnostic (Medically Necessary ) 54500 Biopsy of testis, needle (separate procedure) 54505 Biopsy of testis, incisional (separate procedure) Vasotomy for vasograms, seminal vesiculograms, or epididymograms, 55300 unilateral or bilateral 55899 Unlisted procedure, male genital system Endometrial sampling (biopsy) with or without endocervical sampling 58100 (biopsy), without cervical dilation, any method (separate procedure) Endometrial sampling (biopsy) performed in conjunction with colposcopy 58110 (List separately in addition to code for primary procedure) Catheterization and introduction of saline or contrast material for saline 58340 infusion sonohysterography (SIS) or hysterosalpingography Transcervical introduction of fallopian tube catheter for diagnosis and/or re58345 establishing patency (any method), with or without hysterosalpingography 58350 Chromotubation of oviduct, including materials 58555 Hysteroscopy, diagnostic (separate procedure) Vasography, vesiculography, or epididymography, radiological supervision 74440 and interpretation 74740 Hysterosalpingography, radiological supervision and interpretation Transcervical catheterization of fallopian tube, radiological supervision and 74742 interpretation Ultrasound, pelvic (nonobstetric), real time with image documentation; 76856 complete Chorionic gonadotropin stimulation panel; estradiol response This panel must 80415 include the following: Estradiol (82670 x 2 on three pooled blood samples) 82670 Estradiol 83001 Gonadotropin; follicle stimulating hormone (FSH) 83002 Gonadotropin; luteinizing hormone (LH) 84144 Progesterone Semen analysis; presence and/or motility of sperm including Huhner test 89300 (post coital) 89325 Sperm antibodies Diagnostic (Not medically necessary) 89329 Sperm evaluation; hamster penetration test Sperm evaluation; cervical mucus penetration test, with or without 89330 spinnbarkeit test

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Treatment (Medically Necessary) 55870 Electroejaculation 58321 Artificial insemination; intra-cervical 58322 Artificial insemination; intra-uterine 58323 Sperm washing for artificial insemination Transcervical introduction of fallopian tube catheter for diagnosis and/or re58345 establishing patency (any method), with or without hysterosalpingography 58672 Laparoscopy, surgical; with fimbrioplasty 58673 Laparoscopy, surgical; with salpingostomy (salpingoneostomy) 58740 Lysis of adhesions (salpingolysis, ovariolysis) 58750 Tubotubal anastomosis 58760 Fimbrioplasty 58770 Salpingostomy (salpingoneostomy) 58970 Follicle puncture for oocyte retrieval, any method 58974 Embryo transfer, intrauterine 58976 Gamete, zygote, or embryo intrafallopian transfer, any method Transcervical catheterization of fallopian tube, radiological supervision and 74742 interpretation Saline infusion sonohysterography (SIS), including color flow Doppler, when 76831 performed Ultrasound, pelvic (nonobstetric), real time with image documentation; 76857 limited or follow-up (eg, for follicles) Ultrasonic guidance for aspiration of ova, imaging supervision and 76948 interpretation Ovulation tests, by visual color comparison methods for human luteinizing 84830 hormone 89250 Culture of oocyte(s)/embryo(s), less than 4 days; 89253 Assisted embryo hatching, microtechniques (any method) 89254 Oocyte identification from follicular fluid 89255 Preparation of embryo for transfer (any method) 89257 Sperm identification from aspiration (other than seminal fluid) Sperm isolation; simple prep (eg, sperm wash and swim-up) for insemination 89260 or diagnosis with semen analysis Sperm isolation; complex prep (eg, Percoll gradient, albumin gradient) for 89261 insemination or diagnosis with semen analysis 89264 Sperm identification from testis tissue, fresh or cryopreserved 89268 Insemination of oocytes 89272 Extended culture of oocyte(s)/embryo(s), 4-7 days 89280 Assisted oocyte fertilization, microtechnique; less than or equal to 10 oocytes 89281 Assisted oocyte fertilization, microtechnique; greater than 10 oocytes 89310 Semen analysis; motility and count (not including Huhner test) 89320 Semen analysis; volume, count, motility, and differential

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Treatment (Not medically necessary) 55400 Vasovasostomy, vasovasorrhaphy Culture of oocyte(s)/embryo(s), less than 4 days; with co-culture of 89251 oocyte(s)/embryos Cryopreservation 89258 Cryopreservation; embryo 89259 Cryopreservation; sperm 89335 Cryopreservation, reproductive tissue, testicular 89342 Storage, (per year); embryo(s) 89343 Storage, (per year); sperm/semen 89344 Storage, (per year); reproductive tissue, testicular/ovarian 89346 Storage, (per year); oocyte(s) 89352 Thawing of cryopreserved; embryo(s) 89353 Thawing of cryopreserved; sperm/semen, each aliquot 89354 Thawing of cryopreserved; reproductive tissue, testicular/ovarian 89356 Thawing of cryopreserved; oocytes, each aliquot

CPT® is a registered trademark of the American Medical Association.

HCPCS Code S0126 S0128 S3655 S4013 S4014 S4028 S4030 S4031 S4040

Description Injection, follitropin alfa, 75 IU Injection, follitropin beta, 75 IU Antisperm antibodies test (immunobead) Complete cycle, gamete intrafallopian transfer (GIFT), case rate Complete cycle, zygote intrafallopian transfer (ZIFT), case rate Microsurgical epididymal sperm aspiration (mesa) Sperm procurement and cryopreservation services; initial visit Sperm procurement and cryopreservation services; subsequent visit Monitoring and storage of cryopreserved embryos, per 30 days

Coding Clarification Cryopreservation may be done to preserve reproductive tissue for use at a later time. Some treatments for cancer and other conditions may impact an individual's fertility. For example, the diagnosis code range for cancer is 140 - 239.8.

REFERENCES Al-Ojaimi EH. Endocrine changes after laparoscopic ovarian drilling in clomiphene citrate-resistant women with polycystic ovarian syndrome. Saudi Med J. 2004 Aug;25(8):1032-9. Erratum in: Saudi Med J. 2004 Dec;25(12):2063. American Cancer Society (ACS). Fertility and cancer: what are my options? Available at: http://www.cancer.org/docroot/MBC/MBC_2x_Fertility_and_Cancer.asp?sitearea=&level=. Accessed February 4, 2010.

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American College of Obstetricians and Gynecologists (ACOG). Committee Opinion #405. Ovarian tissue and oocyte cryopreservation. Obstet Gynecol. 2008 May;111(5):1255-6. American Society for Reproductive Medicine (ASRM). The clinical utility of sperm DNA integrity testing. Fertil Steril. 2008a Nov;90(5 Suppl):S178-80. American Society for Reproductive Medicine (ASRM). The role of assisted hatching in in-vitro fertilization: a review of the literature. A Committee opinion. Fertil Steril. 2008b Nov;90(5 Suppl):S196-8. American Society for Reproductive Medicine (ASRM). Intracytoplasmic sperm injection (ICSI). Fertil Steril. 2008c Nov;90(5 Suppl):S187. American Society for Reproductive Medicine (ASRM). Ovarian tissue and oocyte cryopreservation. Fertil Steril. 2008d Nov;90(5 Suppl):S241-6. American Society for Reproductive Medicine (ASRM). Fertility preservation and reproduction in cancer patients. Fertil Steril. 2005 Jun;83(6):1622-8. American Society for Reproductive Medicine (ASRM). Patient Factsheet. Cancer and fertility preservation. 2004. Available at: http://www.asrm.org/uploadedFiles/ASRM_Content/Resources/Patient_Resources/Fact_Sheets_and_I nfo_Booklets/cancer.pdf. Accessed February 4, 2010. Aoki V.W. Peterson C.M. Parker-Jones K. Hatasaka H.H. Gibson M. Huang I. Carrell D.T. Correlation of sperm penetration assay score with polyspermy rate in in-vitro fertilization. Journal of Experimental and Clinical Assisted Reproduction. 2005;2(1):3. Api M, GH, Cetin A. Laparoscopic ovarian drilling in polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 2005 Mar 1;119(1):76-81. Arslan M, Morshedi M, Arslan EO et al. Predictive value of the hemizona assay for pregnancy outcome in patients undergoing controlled ovarian hyperstimulation with intrauterine insemination. Fertil Steril. 2006 Jun;85(6):1697-707. Balaban B, Urman B, Yakin K, Isiklar A. Laser-assisted hatching increases pregnancy and implantation rates in cryopreserved embryos that were allowed to cleave in vitro after thawing: a prospective randomized study. Hum Reprod. 2006 Aug;21(8):2136-40. Bedaiwy MA, El-Nashar SA, El Saman AM, et al. Reproductive outcome after transplantation of ovarian tissue: a systematic review. Hum Reprod. 2008 Dec;23(12):2709-17. Borini A, Bonu MA, Coticchio G, et al. Pregnancies and births after oocyte cryopreservation. Fertil Steril 2004;82(3):601-5.

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Brackett NL, Padron OF, Lynne CM. Semen quality of spinal cord injured men is better when obtained by vibratory stimulation versus electroejaculation. J Urol. 1997 Jan;157(1):151-7. Creus M, Ordi J, FF et al. alphavbeta3 integrin expression and pinopod formation in normal and outof-phase endometria of fertile and infertile women. Hum Reprod. 2002 Sep;17(9):2279-86. Ebner T, Moser M, Sommergruber M, Shebl O, Tews G. Incomplete denudation of oocytes prior to ICSI enhances embryo quality and blastocyst development. Hum Reprod. 2006 Nov;21(11):2972-7. ECRI Institute. Hotline Response. Cryopreservation of Reproductive Tissue. December 2009. ECRI Institute. Hotline Response. Co-culture to improve embryo quality and implantation in infertility patients. February 2008. ECRI Institute. Hotline Response. Sperm-Hyaluronan-Binding Assay (HBA) [HYDAK®] for Assessment of Sperm Quality. November 2004. Edi-Osagie E, Hooper L, Seif MW. The impact of assisted hatching on live birth rates and outcomes of assisted conception: a systematic review. Hum Reprod. 2003 Sep;18(9):1828-35. Engin-Uml Stun, Korkmaz C, Duru NK, BaI. Comparison of three sperm retrieval techniques in spinal cord-injured men: pregnancy outcome. Gynecol Endocrinol. 2006 May;22(5):252-5. Evenson D, Wixon R. Meta-analysis of sperm DNA fragmentation using the sperm chromatin structure assay. Reprod Biomed Online. 2006 Apr;12(4):466-72. Farquhar C, Lilford RJ, Marjoribanks J, Vandekerckhove P. Laparoscopic 'drilling' by diathermy or laser for ovulation induction in anovulatory polycystic ovary syndrome. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD001122. FIGO Committee for the Ethical Aspects of Human Reproduction and Women's Health. Ethical considerations and recommendations on oocyte and ovarian cryopreservation. Int J Gynaecol Obstet. 2006 Mar;92(3):335-6. Freeman MR. Archibong AE. Mrotek JJ. Whitworth CM. Weitzman GA. Hill GA. Male partner screening before in vitro fertilization: preselecting patients who require intracytoplasmic sperm injection with the sperm penetration assay. Fertility & Sterility. 2001;76(6):1113-1118 Frydman N, Madoux S, Hesters L, et al. A randomized double-blind controlled study on the efficacy of laser zona pellucida thinning on live birth rates in cases of advanced female age. Hum Reprod. 2006 Aug;21(8):2131-5. Gabrielsen A, Agerholm I, Toft B, et al. Assisted hatching improves implantation rates on cryopreserved-thawed embryos. A randomized prospective study. Hum Reprod. 2004 Oct;19(10):2258-62.

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Gandini L, Lombardo F, Paoli D, et al. Full-term pregnancies achieved with ICSI despite high levels of sperm chromatin damage. Hum Reprod. 2004 Jun;19(6):1409-17. Giwercman A, Richthoff J, HjH, et al. Correlation between sperm motility and sperm chromatin structure assay parameters. Fertil Steril. 2003 Dec;80(6):1404-12. Hayes Inc. Research Highlights. Serum or Cervical Mucous Antisperm Antibodies. February 2008b. Hayes Inc. Research Highlights. Sperm Penetration Assay and Zona-Free Hamster Egg Assay. January 2008a. Hazlett WD, Meyer LR, Nasta TE, et al. Impact of EmbryoGlue as the embryo transfer medium. Fertil Steril. 2008 Jul;90(1):214-6. Hovav Y, Sibirsky O, Pollack RN, Kafka I, Elgavish G, Yaffe H. Comparison between the first and the second electroejaculate qualities obtained from neurologically intact men suffering from anejaculation. Hum Reprod. 2005 Sep;20(9):2620-2. Irvine DS, Macleod IC, Templeton AA, Masterton A, Taylor A. A prospective clinical study of the relationship between the computer-assisted assessment of human semen quality and the achievement of pregnancy in vivo. Hum Reprod. 1994 Dec;9(12):2324-34. Johnson CW, Bingham JB, Goluboff ET, Fisch H. Transurethral resection of the ejaculatory ducts for treating ejaculatory symptoms. BJU Int. 2005 Jan;95(1):117-9. Johnson JE, Higdon Iii HL, Boone WR. Effect of human granulosa cell co-culture using standard culture media on the maturation and fertilization potential of immature human oocytes. Fertil Steril. 2007 Oct 20; Kadioglu A, Cayan S, Tefekli A, Orhan I, Engin G, Turek PJ. Does response to treatment of ejaculatory duct obstruction in infertile men vary with pathology? Fertil Steril. 2001 Jul;76(1):138-42. Kattal N, Cohen J, Barmat LI. Role of coculture in human in vitro fertilization: a meta-analysis. Fertil Steril. 2008 Oct;90(4):1069-76. Lee SJ, Schover LR, Partridge AH, et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol. 2006 Jun 20;24(18):2917-31. Lessey BA, Castelbaum AJ, Wolf L, et al. Use of integrins to date the endometrium. Fertil Steril. 2000 Apr;73(4):779-87. Li Z, Wang L, Cai J, Huang H. Correlation of sperm DNA damage with IVF and ICSI outcomes: a systematic review and meta-analysis. J Assist Reprod Genet. 2006 Sep-Oct;23(9-10):367-76. Ma S, Rowe T, Yuen BH. Impact of assisted hatching on the outcome of intracytoplasmic sperm injection: a prospective, randomized clinical trial and pregnancy follow-up. Fertil Steril. 2006

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Apr;85(4):895-900. Malkawi HY, Qublan HS, Hamaideh AH. Medical vs. surgical treatment for clomiphene citrateresistant women with polycystic ovary syndrome. J Obstet Gynaecol. 2003 May;23(3):289-93. Milingos S, Kallipolitis G, Stefanidis K, et al. Saline contrast hysterosonography in infertile patients and in women with abnormal uterine bleeding. Eur J Gynaecol Oncol. 2005;26(5):564-7. National Cancer Institute (NCI). Sexuality and reproductive issues PDQ. October 2009. Available at: http://www.cancer.gov/cancertopics/pdq/supportivecare/sexuality/patient/allpages. Accessed March 12, 2010. National Institute for Clinical Excellence (NICE). Fertility: assessment and treatment for people with fertility problems. February 2004. Available at: http://www.nice.org.uk/nicemedia/pdf/CG011niceguideline.pdf. Accessed March 12, 2010. National Institutes of Health (NIH). Infertility/Fertility. October 2006. Available at: http://www.nichd.nih.gov/health/topics/infertility_fertility.cfm. Accessed March 12, 2010. Nehra A, Werner MA, Bastuba M, Title C, Oates RD. Vibratory stimulation and rectal probe electroejaculation as therapy for patients with spinal cord injury: semen parameters and pregnancy rates. J Urol. 1996 Feb;155(2):554-9. Ng EH, Naveed F, Lau EY, et al. A randomized double-blind controlled study of the efficacy of laserassisted hatching on implantation and pregnancy rates of frozen-thawed embryo transfer at the cleavage stage. Hum Reprod. 2005 Apr;20(4):979-85. Oehninger S. Franken DR. Sayed E. Barroso G. Kolm P. Sperm function assays and their predictive value for fertilization outcome in IVF therapy: a meta-analysis. Human Reproduction Update. 2000;6(2):160-168. Ohl DA, Wolf LJ, Menge AC, et al. Electroejaculation and assisted reproductive technologies in the treatment of anejaculatory infertility. Fertil Steril. 2001 Dec;76(6):1249-55. Oktay K, Cil AP, Bang H. Efficiency of oocyte cryopreservation: a meta-analysis. Fertil Steril. 2006 Jul;86(1):70-80. Paick J, Kim SH, Kim SW. Ejaculatory duct obstruction in infertile men. BJU Int. 2000 Apr;85(6):720-4. Parikh FR, Nadkarni SG, Naik NJ, et al. Cumulus coculture and cumulus-aided embryo transfer increases pregnancy rates in patients undergoing in vitro fertilization. Fertil Steril. 2006 Oct;86(4):83947. Petersen CG, Mauri AL, Baruffi RL, et al. Implantation failures: success of assisted hatching with quarter-laser zona thinning. Reprod Biomed Online. 2005 Feb;10(2):224-9.

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Primi MP, Senn A, Montag M, et al. A European multicentre prospective randomized study to assess the use of assisted hatching with a diode laser and the benefit of an immunosuppressive/antibiotic treatment in different patient populations. Hum Reprod. 2004 Oct;19(10):2325-33. Putowski L, Darmochwal-Kolarz D, Rolinski J, Oleszczuk J, Jakowicki J. The immunological profile of infertile women after repeated IVF failure (preliminary study). Eur J Obstet Gynecol Reprod Biol. 2004 Feb 10;112(2):192-6. Quintans CJ, Donaldson MJ, Bertolino MV, et al. Birth of two babies using oocytes that were cryopreserved in a choline-based freezing medium. Human Reproduction. 2002;17(12):3149-3152. Royal College of Obstetricians and Gynaecologists (RCOG). Scientific Advisory Committee. Opinion Paper 5. Immunological testing and interventions for reproductive failure. June 2008. Available at: http://www.rcog.org.uk/files/rcog-corp/uploaded-files/SACI5mmunologicalTesting2008.pdf. Accessed March 12, 2010. Sagoskin AW, Levy MJ, Tucker MJ, et al. Laser assisted hatching in good prognosis patients undergoing in vitro fertilization-embryo transfer: a randomized controlled trial. Fertil Steril. 2007 Feb;87(2):283-7. Sallam HN, Sadek SS, Agameya AF. Assisted hatching--a meta-analysis of randomized controlled trials. J Assist Reprod Genet. 2003 Aug;20(8):332-42. Seif MM, Edi-Osagie EC, Farquhar C, et al. Assisted hatching on assisted conception (IVF & ICSI). Cochrane Database Syst Rev. 2006 Jan 25;(1):CD001894. Spandorfer SD, Pascal P, Parks J, et al. Autologous endometrial coculture in patients with IVF failure: outcome of the first 1,030 cases. J Reprod Med. 2004 Jun;49(6):463-7. Thomas K, Thomson A, Wood S, et al. Endometrial integrin expression in women undergoing in vitro fertilization and the association with subsequent treatment outcome. Fertil Steril. 2003 Sep;80(3):5027. Valojerdi MR, Karimian L, Yazdi PE, et al. Efficacy of a human embryo transfer medium: a prospective, randomized clinical trial study. J Assist Reprod Genet. 2006 May;23(5):207-12. Vujisic S, Lepej SZ, JerkoviL, Emedi I, SokoliB. Antisperm antibodies in semen, sera and follicular fluids of infertile patients: relation to reproductive outcome after in vitro fertilization. Am J Reprod Immunol. 2005 Jul;54(1):13-20. Wurn BF, Wurn LJ, King CR, Heuer MA, Roscow AS, Scharf ES, Shuster JJ. Treating female infertility and improving IVF pregnancy rates with a manual physical therapy technique. MedGenMed. 2004 Jun 18;6(2):51. Ye H, Huang GN, Gao Y, Liu de Y. Relationship between human sperm-hyaluronan binding assay and

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fertilization rate in conventional in vitro fertilization. Hum Reprod. 2006 Jun;21(6):1545-50. Yurdakul T, Gokce G, Kilic O, Piskin MM. Transurethral resection of ejaculatory ducts in the treatment of complete ejaculatory duct obstruction. Int Urol Nephrol. 2007 Sep 26.

PROTOCOL HISTORY/REVISION INFORMATION Date 01/28/2011 09/23/2010 09/25/2009 06/26/2009 Action/Description Corporate Medical Affairs Committee

The foregoing Health Plan of Nevada/Sierra Health & Life Health Operations protocol has been adopted from an existing UnitedHealthcare coverage determination guideline that was researched, developed and approved by the UnitedHealthcare Coverage Determination Committee.

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