NOTE: Carefully check the member’s benefit plan, summary plan description or contract for language specific to assisted reproductive technologies (ART) and related services. IF ART and its related services are determined to be eligible for member benefits then the following services that are listed as medically necessary should be considered for benefit coverage.
Blue Cross and Blue Shield of Montana (BCBSMT) may consider assisted reproductive technologies (ART) and related services medically necessary, including but not limited to the following:
- Evaluation and basic workup includes:
- fertility history and physical examination;
- routine semen analysis, including and limited to count, motility, volume and morphology;
- sperm penetration test, and/or Hyaluronan binding assay (see description section of this policy for an explanation of these tests);
- documentation of ovulation (basal body temperature, serum progesterone, or endometrial biopsy);
- postcoital test (sperm-cervical mucus interaction);
- evaluation of tubal patency (hysterosalpingography);
- urologic consultation for disorders such as hypospadias, cryptorchidism, varicocele, or genitourinary system infection; and
- diagnostic or surgical laparoscopy for diagnosis or treatment of endometriosis.
- Artificial insemination (AI) or intrauterine insemination (IUI).
- ART procedures, which include:
- in vitro fertilization (IVF);
- uterine embryo lavage;
- gamete intrafallopian tube transfer (GIFT), sperm;
- intracytoplasmic injection (ICSI);
- low tubal ovum transfer;
- embryo transfer (ET); and
- zygote intrafallopian tube transfer (ZIFT).
Therapeutic drugs (including but not limited to self-injectables), such as hormones, danazol, Parlodel, clomiphene citrate, Pergonal, Metrodin, etc., may be considered medically necessary and may be eligible for benefits IF ART, AI or IUI are covered benefits. (Check all appropriate pharmacy and medical contract provisions as some pharmacy or medical plans may exclude infertility drugs).
The following services are considered experimental, investigational and unproven:
- assisted hatching,
- co-culture of embryos,
- cryopreservation of ovarian tissue or oocytes,
- cryopreservation of testicular tissue of prepubertal boys as a method of preserving fertility.
NOTE: Cryopreservation of testicular tissue may be considered medically necessary in adult men with azoospermia as part of an ICSI procedure. (Check all contract benefits as cryopreservation may be a contract exclusion).
NOTE: Member contract benefits may vary. CHECK CONTRACTS FOR COVERAGE ELIGIBILITY of related services to ART, including but not limited to the following:
- Reversal of voluntary sterilization;
- Payment for medical services or supplies rendered to a surrogate for purposes of child birth;
- Costs associated with cryopreservation and storage of sperm, eggs, and embryos;
- Costs associated with the procurement of sperm, or harvesting of eggs and embryos from a donor; and
- Living and/or travel expenses.
Immunotherapy for recurrent fetal loss
Immunologic-based therapies to avoid recurrent spontaneous abortion are considered experimental, investigational and unproven. Such therapies include, but are not limited to:
- immunotherapy utilizing paternal leukocytes;
- immunotherapy utilizing seminal plasma;
- immunotherapy utilizing trophoblastic membranes; and/or
- therapy utilizing Intravenous Immune globulin (IVIg).
NOTE: Refer to the Medical Policy on Natural Killer (NK) Cells (MED207.140) for coverage when this testing is performed for a diagnosis of infertility.
The majority of procedure codes describing the various steps in assisted reproductive technology (ART) procedures are longstanding techniques. Only the relatively new ART techniques, i.e., intracytoplasmic sperm injection (ICSI), assisted hatching, co-culture of embryos, and cryopreservation of reproductive tissue (i.e., testicular, ovarian, or oocytes) will be discussed in this rationale.
Intracytoplasmic sperm injection (ICSI):
ICSI is performed in cases of male factor infertility when either insufficient numbers of sperm, abnormal morphology, or poor motility preclude unassisted in vitro fertilization. Using ICSI, fertilization rates of up to 76% have been reported, considerably better than the competing technique of sub-zonal insemination (up to 18%), in which sperm are injected into the perivitelline space (as opposed to into the oocyte itself), and by definition better than the negligible to absent fertilization rates seen in patients with male factor infertility. Fertilization rates represent an intermediate outcome; the final outcome is the number of pregnancies per initiated cycle or per embryo transfer, reported in the largest series as 44.7% and 49.6%, respectively. These rates are very competitive with standard IVF. In 1994, the American Society of Reproductive Medicine issued a policy statement that stated that ICSI could no longer be considered investigational in patients with male factor infertility.
One key component of a successful attempt at IVF is implantation of the embryo in the uterus. Although the exact steps in implantation are poorly understood, one critical component is thought to be the normal rupture of the surrounding zona pellucida with escape of the developing embryo, termed hatching. It is hypothesized that during the in vitro component of the IVF, the zona pellucid becomes hardened, thus impairing the hatching process. Alternatively, some embryos may have some inherent inability to induce thinning of the zona pellucida before hatching. In either case, mechanical disruption of the zona pellucida (i.e., assisted hatching) has been proposed as a mechanism to improve implantation rates. Schoolcraft and colleagues reported that in patients over the age of 40 or who had failed prior attempts at implantation or when the embryos had a thick zona pellucida, assisted hatching was associated with a clinical pregnancy rate per transferred embryo of 33% compared to 6.5% in a control group. There is no evidence that assisted hatching should be routinely performed as part of IVF procedures.
In routine IVF procedures, the embryo is transferred to the uterus on day two or three of development, when it has between four and eight cells. However, with this approach the implantation rate is estimated to be between 5% and 30%, potentially related to the fact that under normal conditions the embryo reaches the uterus at a blastocyst stage of development. Embryo co-culture techniques, used successfully in domestic animals, represent an effort to improve the culture media for embryos such that a greater proportion of embryos will reach the blastocyst stage, thus hopefully improving the implantation and pregnancy rate. If the co-culture results in a higher implantation rate, then fewer embryos could be transferred at each cycle, thus resulting in a decreased incidence of multiple pregnancies. A variety of co-culture techniques have been investigated, involving the use of feeder cell layers derived from a range of tissues, including the use of human reproductive tissues (i.e., oviducts) to non-human cells (i.e., fetal bovine uterine or oviduct cells) to established cell lines (i.e., Vero cells or bovine kidney cells). However, no standardized method of co-culture has emerged and no controlled trials have evaluated an improved implantation or pregnancy rate associated with co-culture. For example, Wetzels and colleagues reported on a study that randomized IVF treatments to include co-culture with human fibroblasts or no culture. Patients in the two groups were stratified according to age (older or younger than 36 years) and prior IVF attempts (yes vs. no). The authors reported that fibroblast co-culture did not affect the implantation or the pregnancy rate. An updated literature review for the period of 2003 through November 2004 did not identify any additional published studies that would prompt reconsideration of the relevant policy statement.
Culture for greater than four days (i.e., extended culture into blastocyst stage)
The development of commercially available sequential media designed to reproduce the changes in nutrient requirements as the embryo develops has permitted the extended culture of embryos to the blastocyst stage, at which point the embryos are transferred. The rationale behind blastocyst transfer is that embryos progressing to the blastocyst stage have a much greater chance of implanting successfully in the uterus and resulting in an ongoing pregnancy. Due to the higher probability of implantation, it is thought that fewer blastocysts can be transferred, ultimately resulting in a decreased incidence of triplets and higher order pregnancies. It should be noted that embryos that progress to the blastocyst stage in vitro have demonstrated improved viability compared to earlier stage embryos, some of which inevitably fail to progress. In essence, blastocyst culture allows one to select the best quality embryos with the highest implantation potential. Therefore, due to this inherent selection bias, the pregnancy rate with blastocyst transfer is expected to be greater than that of day three embryo transfers. The major impact of blastocyst transfer is the anticipated decrease in incidence of multiple gestations. Gardner and colleagues reported on a trial that randomized IVF treatment to either embryo transfer after the eight-cell stage vs. blastocyst stage. While the clinical pregnancy rate was the same in the two groups (66% and 71%, respectively), the mean number of embryos transferred was lower in the blastocyst group (2.2 vs. 3.7, respectively). The authors concluded that the ability to transfer just two blastocysts while maintaining high pregnancy rates will help to eliminate high-order multiple gestations. Karaki and colleagues also reported on a randomized trial comparing day three transfers compared to blastocyst transfer. Significantly fewer embryos were required for transfer at the blastocyst state compared with day three embryos, and the higher order gestation rate was also significantly less with blastocyst transfer (4% vs. 19%). Other randomized studies and case series have also reported that blastocyst transfer is associated with an improved implantation rate and a reduction in the incidence of higher order gestations. It should be noted that not all women undergoing IVF would be considered candidates for blastocyst transfer. For example, if a woman responds poorly to ovarian stimulation therapy and few eggs are harvested (i.e., <3), there is a certain risk of opting for prolonged embryo culture to the blastocyst stage; in some cases, the embryos will die before reaching the blastocyst stage, and thus there will be no embryo to transfer.
Cryopreservation of ovarian tissue
Cryopreservation of ovarian tissue with subsequent auto- or heterotopic transplant has been investigated as a technique to sustain the reproductive function of women or children who are faced with sterilizing procedures, such as chemotherapy, radiation therapy or surgery, frequently due to malignant diseases. A variety of articles have focused on the technical feasibility of such an option, and there are a few individual case reports of return of ovarian function using this technique. However, in general, the technique is not standardized, has been investigated more thoroughly in animal models, and has not been widely applied to humans. Kim and colleagues identify the following unresolved issues:
- optimization and standardization of a freeze-thaw method;
- metabolic injury;
- ischemia-reperfusion injury (i.e., after autotransplant);
- the optimal graft site;
- the quality of oocytes matured in a graft;
- the efficacy of frozen-thaw grafts for fertility restoration and hormonal function; and
- safety issues, particularly regarding the risk of reseeding residual cancer cells within a graft.
Cryopreservation of oocytes
Unlike cryopreservation of ovarian tissue, cryopreservation of oocytes is less commonly performed in the setting of malignancy due to the time constraints inherent in ovarian stimulation. Therefore, oocyte cryopreservation has been primarily investigated as an alternative to embryo cryopreservation due to ethical or religious reasons. The mature oocyte is very fragile due to its large size, high water content, and chromosomal arrangement. For example, the mature oocyte is arrested in meiosis, and as such the chromosomes are lined up in a meiotic spindle. This spindle apparatus is easily damaged both in freezing and thawing. Due to these factors, there is a poor survival of cryopreserved oocytes after thawing. Survival after thawing may also be associated with sub lethal damage, which may further impact the quality of the subsequent embryo. While several individual cases of successful pregnancies have been reported, the technique for cryopreservation and thawing of oocytes has not been standardized. It is estimated that the implantation rate of embryos derived from cryopreserved oocytes is about 4%.
Cryopreservation of testicular tissue
Testicular sperm extraction (TSE) refers to the collection of sperm from testicular tissue in men with azoospermia. TSE may be performed at the time of a diagnostic biopsy, or performed as a subsequent procedure, specifically for the collection of spermatozoa. The spermatozoa may be isolated immediately and a portion used for an ICSI procedure at the time of oocyte retrieval from the partner, with the remainder cryopreserved. Alternately, the entire tissue sample can be cryopreserved with a portion thawed and sperm isolation performed at subsequent ICSI cycles. This technique appears to be a well established component of the overall ICSI procedure; cryopreservation of either the isolated sperm of the tissue sample eliminates the need for multiple biopsies to obtain fresh tissue in the event of a failed initial ICSI cycle. However, a unique application of testicular tissue is its use to potentially preserve the reproductive capacity in a prepubertal boy undergoing cancer chemotherapy; the typical cryopreservation of an ejaculate is not an option in these patients. It is hoped that re-implantation of the frozen-thawed testicular stem cells will re-initiate spermatogenesis, or alternatively, spermatogenesis could be attempted in vitro, using frozen-thawed spermatogonia. While these strategies have been explored in animals, there are inadequate human studies.
Laboratory tests of sperm maturity and function
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 ICSI, has changed the role of 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. While there is still concern regarding standardization of the procedure, these results suggest that the results of the SPA 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 two 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 cut-off values, sensitivity, specificity, positive and negative predictive values) or examined the clinical role of the test. The package insert also does not provide adequate data to evaluate the diagnostic performance of the test.
Paternal or fetal antigen immunotherapy for recurrent fetal loss
This policy was originally based on a 1995 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment that concluded that paternal or fetal antigen immunotherapy did not meet the TEC criteria as a treatment of recurrent spontaneous abortion. A search of literature was completed through the MedLine database for the period of 1995 through November 2003. The search did not identify any randomized controlled trials published during this period. Therefore the policy statement is unchanged.
IVIg as a treatment of recurrent fetal loss (RFL)
The policy on IVIg as a treatment of RFL is based on a 1998 TEC Assessment, which offered the following conclusions:
- The scientific evidence is not sufficient to support the conclusion that IVIg reduces spontaneous abortion (fetal loss) in women with antiphospholipid antibodies who have a history of recurrent spontaneous abortion.
- The scientific evidence is not sufficient to support the conclusion that IVIg therapy is superior to no treatment in women without antiphospholipid antibodies who have a history of recurrent spontaneous abortion (fetal loss).
Four blinded randomized controlled trials (RCTs) of IVIg have focused on this patient population. Only one of these trials showed a significant treatment effect. The treatment effect of the four trials was summarized by meta-analysis; the overall relative risk and odds ratio values and their confidence intervals indicate no significant treatment effect. Two subsequent meta-analyses of five and six trials concluded that IVIg provides no significant beneficial effect over placebo in preventing further miscarriages. A blinded RCT of 41 women treated with IVIg or saline placebo found no differences in live birth rates. A multicenter RCT comparing heparin and low-dose aspirin with versus without IVIg in women with lupus anticoagulant, anticardiolipin antibody, or both, found no significant differences. More recently, an RCT of 58 women with at least four unexplained miscarriages tested IVIg versus placebo and analyzed results by intention to treat. The live birth rate was the same for both groups; also, there was no difference in neonatal data. Other non-randomized but controlled trials also report no benefit for IVIg treatment. There is insufficient evidence RCTs or other trials to support benefit in secondary (live birth followed by consecutive spontaneous abortions) versus primary (no prior live births) spontaneous pregnancy loss. A variety of immunologic tests may precede the initiation of IVIg therapy. These tests, including various subsets of lymphocytes, human leukocyte antigen (HLA) (markers that identify cells as "self" and prevent the immune system from attacking) testing, and lymphocyte functional testing (i.e., natural killer cell assays and the embryo cytotoxicity test), are research tools that explore subtle immunologic disorders that may contribute to maternal immunologic tolerance of the fetus. However, there are no clinical data that indicate the results of these tests can be used in the management of patients to reduce the incidence of RFL particularly since IVIg therapy has not been shown to be an effective therapy.
Active research to improve oocyte cryopreservation methods revealed a meta-analysis that reported outcomes from 26 reports of IVF with cryopreserved oocytes, during 1997 through 2005, in 354 patients, and compared them with outcomes from IVF with unfrozen oocytes during a similar time period. Live birth rates were reported to be 3% per injected cryopreserved oocyte (vs. 7% for unfrozen oocytes) and 22% (vs. 60%) per embryo transfer. The authors concluded that pregnancy rates appear to have improved, but further studies will be needed to determine the efficiency and safety of this technique.
Technology Assessments and Systematic Reviews
In May 2008, Agency for Healthcare Research and Quality (AHRQ) published the evidence report or technology assessment, “Effectiveness of Assisted Reproductive Technology.” The report reviewed the evidence regarding the outcomes of interventions used in ovulation induction, superovulation, and IVF for the treatment of infertility. Short-term outcomes included pregnancy, live birth, multiple gestation, and complications. Long-term outcomes included pregnancy, and post-pregnancy complications for both mothers and infants. Approximately 80% of the included studies were performed outside the United States.
The limitations of the AHRQ review included:
- the majority of randomized trials comparing techniques were not designed to detect differences in pregnancy and live birth rates; and
- most trials did not have sufficient power to detect clinically meaningful differences in live birth rates, and had still lower power to detect differences in less frequent outcomes such as multiple births and complications.
The AHRQ authors concluded that interventions for which there was sufficient evidence to demonstrate improved pregnancy or live birth rates included:
- administration of clomiphene citrate in women with polycystic ovarian syndrome;
- metformin plus clomiphene in women who fail to respond to clomiphene alone;
- ultrasound-guided embryo transfer, and transfer on day five post-fertilization, in couples with a good prognosis; and
- assisted hatching in couples with previous IVF failure.
There was insufficient evidence regarding other interventions. Infertility itself is associated with most of the adverse longer term outcomes. Consistently, infants born after infertility treatments are at risk for complications associated with abnormal implantation or placentation; the degree, to which this is due to the underlying infertility, treatment, or both, is unclear. Infertility, but not infertility treatment, is associated with an increased risk of breast and ovarian cancer. The authors concluded that despite the large emotional and economic burden resulting from infertility, there is relatively little high-quality evidence to support the choice of specific interventions. AHRQ’s conclusion was based primarily on studies that had pregnancy rates as the primary endpoint not live births. In addition, studies used multiple assisted hatching techniques.
In November 2008, the Practice Committee of the Society for Assisted Reproductive Technology and the Society for Reproductive Medicine released a Committee Opinion titled “The role of assisted hatching in in vitro fertilization.” The Committee conducted a comprehensive review and meta-analysis that identified 23 RCTs (n=2,572) with women undergoing assisted hatching during ART. Only six studies included (n=523) reported live birth rates with and without assisted hatching. Overall, live birth rates in the two groups were not different. Assuming a delivery rate of 30% in the control group overall, a total of 720 patients would be required to detect a 10% difference in delivery rates between the two groups. The Committee concluded; “the number of live births reported in studies thus far do not allow a confident conclusion regarding the clinical efficacy of assisted hatching procedures.” The available published evidence does not support the use of assisted hatching in all IVF cycles at this time due to lack of data related to impact on live birth rates.
In 2004, the Practice Committee of the American Society for Reproductive Medicine issued a statement that described ovarian tissue cryopreservation as an experimental procedure as follows,
“Given the uncertain and un-established state of this procedure, it is essential that it be offered only as part of an internal review board (IRB) approved protocol, with full disclosure of risks and uncertainly of benefits to the patient. Later efforts to thaw and transplant the removed ovarian tissue should also be subject to IRB review until the safety and efficacy of transplantation or other use of the tissue have been established.”
A 2006 report of the Practice Committee of the American Reproductive Medicine Society considers cryopreservation of oocytes or ovarian tissue investigational but promising for future female fertility preservation. “Although based on a limited number of established pregnancies and deliveries resulting from cryopreserved oocytes, no increase in chromosomal abnormalities, birth defects, or developmental deficits have been noted in children born from cryopreserved oocytes to date.” The committee recommends that these procedures “be considered an experimental technique only to be performed under investigational protocol under the auspices of an IRB.”
In November 2008, the Practice Committee of Society for Assisted Reproductive Technology; Practice Committee of American Society for Reproductive Medicine issued an opinion regarding the role of assisted hatching in IVF. This Committee Opinion reviewed the published literature regarding appropriate use of assisted hatching as a part of IVF. The Committee concluded; “the number of live births reported in studies thus far do not allow a confident conclusion regarding the clinical efficacy of assisted hatching procedures.”
Research is beginning to emerge in a new field called oncofertility, which is exploring various options for oncologists that wish to preserve the reproductive health of women, men, and children who are diagnosed with cancer. The review article authored by a leading oncofertility researcher and breast surgical oncologist provides strategies based on type of cancer and age and gender of the patient. The article stated that the cryopreservation “of mature oocytes is considered experimental…”
A search of peer-reviewed literature through November 2009 identified:
- The evidence is insufficient to permit conclusions concerning the effectiveness of the following reproductive techniques: assisted hatching; co-culture of embryos; cryopreservation of ovarian tissue or oocytes; cryopreservation of testicular tissue in prepubertal boys; and storage and thawing of ovarian tissue, oocytes, or testicular tissue on health outcomes. Therefore, the coverage position of this medical policy remains unchanged; AND
- No new clinical trial publications or any additional information concerning the effectiveness of immunotherapy on recurrent fetal loss that would change the coverage position of this medical policy.
Disclaimer for coding information on Medical Policies
Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.
The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.
Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.