BlueCross and BlueShield of Montana Medical Policy/Codes
Assisted Reproductive Technologies (ART) and Related Services
Chapter: Maternity/Gyn/Reproduction
Current Effective Date: November 26, 2013
Original Effective Date: November 26, 2013
Publish Date: August 26, 2013
Description

An assisted reproductive technology (ART) refers to an array of interventions designed to establish a viable pregnancy for couples who have been diagnosed with infertility, due either to:

  • female factors (i.e., pelvic adhesions, ovarian dysfunction, endometriosis, and prior tubal ligation),
  • male factors (i.e., abnormalities in sperm production, function, or transport, or prior vasectomy),
  • a combination of both male and female factors, or
  • unknown causes. 

In most instances, an ART will incorporate some type of IVF procedure in which oocytes harvested from the female are inseminated in vitro with sperm harvested from the male. Following the fertilization procedure, the zygote is cultured and ultimately transferred back into the female’s uterus or fallopian tubes.  (The latter procedure is also known as zygote intrafallopian transfer [ZIFT]).  In some instances, the oocyte and sperm are collected, but no IVF takes place, and the gametes are reintroduced into the fallopian tubes, a procedure known as gamete intrafallopian transfer (GIFT).

The various components of ART and implantation into the uterus can be broadly subdivided into:

  • oocyte harvesting procedures, which are performed on the female partner;
  • sperm collection procedures, which are performed on the male partner; and
  • the in vitro component, i.e., the laboratory procedures, which are performed on the collected oocyte and sperm.

The final step is the implantation procedure. 

NOTE:  Preimplantation genetic diagnosis (PGD), which may be performed as an adjunct to ART as a technique to deselect embryos that carry genetic abnormalities, is addressed separately in another medical policy. 

Procedures performed on the female

  • Ovarian follicle puncture for oocyte (unfertilized egg cell) removal.
  • Intrauterine transfer of an embryo (stage of reproductive development beginning in the first moments after fertilization).
  • Intrafallopian transfer of a gamete (mature male or female reproductive cell [sperm or ovum] with a haploid set of 23 chromosomes), zygote (product of the fusion of an egg and a sperm) or embryo. 
  • Intracervical or intrauterine artificial insemination performed where there is poor quality cervical mucus, anatomic factors, poor sperm quality or quantity, or poor postcoital tests.

Procedures performed on the male

  • Reversal of a prior vasectomy (vasovasectomy, vasovasorrhaphy).
  • Needle biopsy of epididymis - to aspirate sperm in men with obstructive or non-obstructive azoospermia (complete absence of sperm from the semen) or severe oligospermia (abnormally low number of sperm in the ejaculate).
  • Needle biopsy or fine needle aspiration of the testis to aspirate sperm.
  • Electroejaculation used in those patients unable to produce a normal ejaculate due to spinal cord or other nervous system disorder (e.g., diabetic neuropathy).

In Vitro laboratory procedures

  • Sperm washing for artificial insemination;
  • Culture of oocyte(s), less than four days, with or without co-culture of oocytes/embryos;
  • Assisted oocyte fertilization, microtechnique;
  • Assisted embryo hatching;
  • Oocyte identification from follicular fluid;
  • Preparation of embryo or cryopreserved embryos (includes thawing) for transfer;
  • Sperm identification from aspirate;
  • Cryopreservation of embryos or sperm.  Sperm are assessed for pre-freeze concentration and motility and viability;
  • Sperm isolation, simple or complex;
  • Sperm identification from testis tissue, fresh or cryopreserved.  This is typically done for a patient as part of as ICSI procedure;
  • Insemination of oocytes;
  • Extended culture of oocytes/embryos, four- to seven-days. Culturing beyond four-days allows the embryo to develop to the blastocyte stage;
  • Assisted oocyte fertilization, microtechnique.  This refers to ICSI procedure.
  • Biopsy of oocyte polar body or embryonic blastomere, microtechnique for PGD (addressed on medical policy – OB402.029);
  • Cryopreservation of testicular reproductive tissue.  In cases of azoospermia or where there is blockage of the epididymis, a testicular biopsy may be performed to harvest testicular tissue.  Spermatozoa isolated from testicular tissue may then be used in a subsequent IVF procedure, using ICSI;
  • Storage or thawing of embryo(s), sperm/semen, testicular/ovarian tissue, oocyte(s);
  • Cryopreservation of ovarian reproductive tissue.  The tissue is usually harvested either at the time of oophorectomy or during a laparoscopic procedure.  Cryopreservation of ovarian tissue has been investigated primarily as a technique of preserving fertility potential for prepubertal cancer patients or mature cancer patients, who do not have the luxury of the time required to undergo ovarian stimulation as a part of an in vitro fertilization procedure followed by embryo cryopreservation.  The cryopreserved tissue can be either autografted back into the host at a later date, or primordial follicles can be extracted from the ovarian tissue and then allowed to mature in vitro.  In contrast to the limited number of mature oocytes that can be harvested after ovarian stimulation, ovarian tissue typically contains an abundant number of primordial follicles;
  • Cryopreservation of oocytes.  Mature oocytes are difficult to cryopreserve due to their high water content and fragility of the meiotic apparatus.  Mature oocytes are extremely sensitive to temperature change and have little capacity for repairing cellular damage.  However, cryopreservation of oocytes has been investigated as a technique to preserve fertility options when a suitable male donor is not available.  In addition, cryopreservation of oocytes, compared to embryos, may present fewer ethical issues.

Immunotherapy for recurrent fetal loss (RFL)

Recurrent fetal loss (RFL) is defined as three or more pregnancies resulting in a spontaneous abortion prior to 16–20 weeks of gestational age.  RSA may be caused by genetic, anatomic, endocrinologic, or autoimmune abnormalities.  Immunotherapy may consist of the following:

  • Paternal leukocytes:  Paternal whole blood is subjected to density gradient centrifugation. Mononuclear leukocytes are removed from the gradient, washed, and resuspended in normal saline.  Patients are immunized with the paternal leukocytes and then encouraged to conceive within a short time frame.
  • Seminal plasma:  Seminal plasmas and blood specimens from normal donors are capsulated and administered as vaginal suppositories on days 7, 14, and 21 of the monthly cycle and continued twice weekly after the first missed menses until 30 weeks into pregnancy.
  • Trophoblast membrane:  Extracts are prepared from placentas collected at delivery from healthy term pregnancies.  Villous tissue is separated from other placental components.  The sieved solution is centrifuged.  Membrane pellets are resuspended in sterile, pyrogen-free saline, then irradiated with ultraviolet light, washed, re-homogenized, and lyophilized for storage.  Membrane pellets are then reconstituted and administered with saline.
  • IVIg therapy:  Patients with RSA frequently have immunologic abnormalities, particularly antiphospholipid antibodies whose incidence may increase with each subsequent pregnancy loss.  Since these antibodies are associated with clotting abnormalities, treatment has included aspirin and heparin.  Other more subtle immune etiologies have also been investigated.  For example, a variety of cytokines and other mediators may be toxic to the conceptus.  These cytokines may be detected in an embryo cytotoxicity assay in which activated lymphocytes from women with RSA are shown to be toxic to placental cell lines. Elevated levels of natural killer cells, which may be associated with antiphospholipid antibodies, have also been implicated in RSA.  Another theory proposes that a lack of maternal blocking antibodies to prevent immunologic rejection of the fetus may be responsible.  IVIg has been explored as a treatment based on its ability to influence both T and B cell function. In fact, IVIg may be offered to those patients with antiphospholipid antibodies without a prior history of RSA who are currently pregnant or contemplating pregnancy.

Laboratory tests of sperm maturity and function

Sperm penetration assay (SPA):  The SPA is a multistep laboratory test that offers a biological assessment of human sperm fertilizing ability. Specifically, four distinct processes must occur for sperm-oocyte fertilization: capacitation, acrosome reaction, penetration of the ooplasm, and chromatin de-condensation within the ooplasm. The SPA uses a zona-free hamster egg as an in vitro model for sperm-oocyte interaction. (The zona pellucida is a thick, glassy membrane surrounding the oocyte that maintains species specificity for fertilization. Removal of the zona pellucida from hamster ova permits their use as a model for sperm oocyte interaction.) The test is performed by incubating a number of zona-free hamster eggs with human sperm for several hours. According to the percentage of ova penetrated, the semen sample is rated as being in a potentially “fertile” or “infertile” range. Aspects of sperm function not assessed by the SPA include the capacity of sperm to penetrate the cervical barrier or their ability to bind to the zona pellucida of human ova.  The sperm penetration assay, alternatively referred to as the hamster oocyte penetration test or the zona-free hamster egg test, was initially developed in 1976. Although it has been used as a test for male infertility, the test has been controversial due to variability in procedures used by different laboratories, poor reproducibility of test outcomes, and uncertainty regarding the range of normal values.

Hyaluronan binding assay (HBA):  The HBA is a qualitative assay for the maturity of sperm in a fresh semen sample.  The assay is based on the ability of mature sperm to bind hyaluronan, the main mucopolysaccharide of the cumulus oophorus matrix and a component of human follicular fluid.  Research has shown that hyaluronan-binding capacity is acquired late in the sperm maturation process; immature sperm lack this ability.  Therefore, a low level of sperm binding to hyaluronan suggests that there is a low proportion of mature sperm in the sample. Similar to the sperm penetration assay, it has been suggested that the HBA assay may be used to determine the need for a procedure (ICSI) as part of an assisted reproductive technique. The HBA is a laboratory test that has received U.S. Food and Drug Administration (FDA) clearance through the 510(k) approval process.  The FDA-labeled indications are as follows:

  • As a component of the standard analysis of semen in the diagnosis of suspected male infertility; and
  • As a component of analyses for determining the proper course of in vitro fertilization treatment of infertility.

It is suggested that patients with poor binding capacity bypass intrauterine insemination and traditional IVF and proceed directly to ICSI.

NOTE: Both SPA and HPA are laboratory tests that are frequently performed as part of an ART procedure.

Policy

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions.  Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

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

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:
    1. fertility history and physical examination;
    2. routine semen analysis, including and limited to count, motility, volume and morphology;
    3. sperm penetration test, and/or Hyaluronan binding assay (see description section  of this policy for an explanation of these tests);
    4. documentation of ovulation (basal body temperature, serum progesterone, or endometrial biopsy);
    5. postcoital test (sperm-cervical mucus interaction);
    6. evaluation of tubal patency (hysterosalpingography);
    7. urologic consultation for disorders such as hypospadias, cryptorchidism, varicocele, or genitourinary system infection; and
    8. diagnostic or surgical laparoscopy for diagnosis or treatment of endometriosis.
  • Artificial insemination (AI) or intrauterine insemination (IUI).
  • ART procedures, which include:
    1. in vitro fertilization (IVF);
    2. uterine embryo lavage;
    3. gamete intrafallopian tube transfer (GIFT), sperm;
    4. intracytoplasmic injection (ICSI);
    5. low tubal ovum transfer;
    6. embryo transfer (ET); and
    7. 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.

Rationale

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.

Assisted hatching:

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.

Embryo co-culture

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.

2009 Update

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:

  1. administration of clomiphene citrate in women with polycystic ovarian syndrome;
  2. metformin plus clomiphene in women who fail to respond to clomiphene alone;
  3. ultrasound-guided embryo transfer, and transfer on day five post-fertilization, in couples with a good prognosis; and
  4. 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…”

Summary

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.

Coding

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. 

ICD-9 Codes

62.11, 62.91, 63.01, 63.09, 63.92, 65.91, 65.99, 68.12, 69.92, 87.92, 87.83, 87.84, 87.85, 87.89, 99.96, 99.99, 256.4, 606.0, 606.1, 606.8, 606.9, 614.5, 614.6, 617.0, 617.1, 617.2, 617.3, 617.4, 622.4, 628.0, 628.1, 628.2, 628.3, 628.4, 628.8, 628.9, V26.1, V26.21

Procedural Codes: 54500, 54800, 55400, 55870, 58321, 58322, 58323, 58345, 58350, 58970, 58974, 58976, 76857, 76948, 89250, 89251, 89253, 89254, 89255, 89257, 89258, 89259, 89260, 89261, 89264, 89268, 89272, 89280, 89281, 89300, 89310, 89320, 89321, 89322, 89325, 89329, 89330, 89331, 89335, 89342, 89343, 89344, 89346, 89352, 89353, 89354, 89356, 0058T, 0059T, S4011, S4013, S4014, S4015, S4016, S4017, S4018, S4020, S4021, S4022, S4023, S4025, S4026, S4027, S4028, S4030, S4031, S4035, S4040, S4042
References
  1. Infertility.  American College of Obstetricians and Gynecologists.   ACOG Technical Bulletin 125. (1989 February).
  2. New Reproductive Technology.   American College of Obstetricians and Gynecologists.  ACOG Technical Bulletin 140, (1990 March).  
  3. Male Infertility.  American College of Obstetricians and Gynecologists.  ACOG, Technical Bulletin 142 (1990 June). 
  4. Palermo, G., Joris, H., et al.  Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet (1992) 340(8810):17-8.
  5. Van Steirteghem, A.C., Liu, J., et al.  Higher success rate by intracytoplasmic sperm injection than by subzonal insemination. Report of a second series of 300 consecutive treatment cycles. Human Reproduction (1993) 8(7):1055-60.
  6. Van Steirteghem, A.C., Nagy, Z., et al.  High fertilization and implantation rates after intracytoplasmic sperm injection. Human Reproduction (1993) 8 (7):1061-6.
  7. Palermo, G. Jori. H., et al.   Sperm characteristics and outcome of human assisted fertilization by subzonal insemination and intracytoplasmic sperm injection. Fertility Sterility (1993) 59(4):826-35.
  8. Schoolcraft, W.B., Schlenker, T., et al.  Assisted hatching in the treatment of poor prognosis in vitro fertilization candidates. Fertility Sterility (1994) 62(3):551-4.
  9. Fishel, S., Timson, J., et al. Micro-assisted fertilization in patients who have failed subzonal insemination. Human Reproduction (1994) 9(3):501:5.
  10. Early Pregnancy Loss.  American College of Obstetricians and Gynecologists.  ACOG Technical Bulletin 212 (1995 September).
  11. Paternal or Fetal Antigen Immunotherapy for Recurrent Fetal Loss. C1998 TEC Assessments; Tab 14.hicago, Illinois: Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (1995 September) 10(18).
  12. Tucker, M.J., Morton, P.C., et al.  Enhancement of outcome from intracytoplasmic sperm injection: does co-culture or assisted hatching improve implantation rates? Human Reproduction (1996) 11(11):2434-7.
  13. Scholtes, M.C., and G.H  Zeilmaker.  A prospective, randomized study of embryo transfer results after 3 or 5 days of embryo culture in in vitro fertilization.  Fertility Sterility (1996) 65(6):1245-58.
  14. Hellebaut, S., De Sutter, P., et al.  Does assisted hatching improve implantation rates after in vitro fertilization or intracytoplasmic sperm injection in all patients?  A prospective randomized study. Journal of Assisted Reproductive Genetics (1996) 13(1):19-22.
  15. Bussel, J.B., Berkowitz, R.L., et al.  Antenatal management of alloimmune thrombocytopenia with intravenous gamma-globulin: a randomized trial of the addition of low-dose steroid to intravenous gamma-globulin.  American Journal of Obstetrics and Gynecology (1996 May) 174(5):1414-23.
  16. Kervancioglu, M.E., Saridogan, E., et al.  Human fallopian tube epithelial cell co-culture increases fertilization rates in male factor infertility but not in tubal or unexplained infertility. Human Reproduction (1997) 12(6):1253-8.
  17. Bider, D., Livshits, A., et al.  Assisted hatching by zona drilling of human embryos in women of advanced age. Human Reproduction (1997) 12(2):317-20.
  18. West’s Smith-Hurd Illinois Compiled Statutes Annotated, Chapter 215, Insurance Act 5, Illinois Insurance Code, Article XX,  Accident and Health Insurance, Corp. West Group 1998, Infertility Coverage.
  19. Intravenous Immune Globulin for Recurrent Spontaneous Abortion.  C1998 TEC Assessments; Tab 14.hicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program, (1998 August ) Tab 14.
  20. Gardner, D.K., Schoolcraft, W.B., et al.   A prospective randomized trial of blastocyst culture and transfer in in-vitro fertilization. Human Reproduction (1998) 13(12):3434-40.
  21. Wetzels, A.M., Bastiaans B.A., et al.  The effects of co-culture with human fibroblasts on human embryo development in vitro and implantation. Human Reproduction (1998) 13(5):1325-30.
  22. Menezo, Y.J., Hamamah, S., et al. Time to switch from co-culture to sequential defined media for transfer at the blastocyst stage. Human Reproduction (1998) 13(8):2043-4.
  23. Wiemer, K.E., Cohen, J., et al.  The application of co-culture in assisted reproduction: 10 years of experience with human embryos. Human Reproduction (1998) 13(supplement 4):226-38.
  24. Veiga, A., Torello, M.J., et al. Use of co-culture of human embryos on Vero cells to improve clinical implantation rate. Human Reproduction (1999) 14(supplement 2):112-20.
  25. Texas Insurance Code, Article 3:51-6, 3A, In Vitro Fertilization.
  26. Jablonowska, B., Selbing, A., et al. Prevention of recurrent spontaneous abortion by intravenous immunoglobulin: a double-blind placebo-controlled study.  Human Reproduction (1999) 14(3):838-41.
  27. Gook, D.A., and D.H. Edgar.  Cryopreservation of the human female gamete: current and future issues. Human Reproduction (1999) 14(12):2938-40.
  28. Marek, D., Langley, M., et al.   Introduction of blastocyst culture and transfer for all patients in an in vitro fertilization program. Fertility Sterility (1999) 72(6):1035-40.
  29. Schoolcraft, W.B., Gardner, D.K., et al. Blastocyst culture and transfer: analysis of results and parameters affecting outcome in two in vitro fertilization programs. Fertility Sterility (1999) 72(4):604-9.
  30. Rubio, C., Simon, C., et al.  Clinical experience employing co-culture of human embryos with autologous human endometrial epithelial cells. Human Reproduction (2000) 15 (supplement 6):31-8.
  31. Branch, D.W., Peaceman, A.M., et al.  A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy.   The Pregnancy Loss Study Group. American Journal of Obstetrics and Gynecology (2000) 182(1 pt 1):122-7.
  32. Porcu, E., Fabbri, R, et al.  Clinical experience and applications of oocyte cryopreservation. Molecular and Cellular Endocrinology (2000) 169(1-2):33-7.
  33. Huisman, G.J., Fauser, B.C., et al.  Implantation rates after in vitro fertilization and transfer of a maximum of two embryos that have undergone three to five days of culture. Fertility Sterility (2000) 73(1):117-22.
  34. Toledo, A.A., Wright, G., et al.  Blastocyst transfer: a useful tool for reduction of high-order multiple gestations in a human assisted reproduction program.  American Journal of Obstetrics and Gynecology (2000) 183(2):377-82.
  35. Oktay, K., and M.T. Kan.  Recent progress in oocyte and ovarian tissue cryopreservation and transplantation.  Current Opinions in Obstetrics and Gynecology (2001) 13(3):263-8.
  36. Kim, S.S., DE. Battaglia.  The future of human ovarian cryopreservation and transplantation: fertility and beyond. Fertility Sterility (2001) 75(6):1049-56.
  37. Intravenous Immunoglobulin (IVIG) and Recurrent Spontaneous Pregnancy Loss: A Practice Committee Report.  American Society of Reproductive Medicine. Intravenous Immunoglobulin (IVIG) and Recurrent Spontaneous Pregnancy Loss: A Practice Committee Report; A Committee Opinion. 1998. Available at http://www.asrm.org/Media/Practice/ivig.html . Accessed October 2002.
  38. American Society of Reproductive Medicine.   A Committee Opinion. (1998). Available at www.asrm.org (accessed on 2002 October 30).
  39. Wilson, M., Hartke, K., et al. Integration of blastocyst transfer for all patients. Fertility Sterility (2002) 77(4):693-6.
  40. Van de Auwera, I., Debrock. S., et al.  A prospective randomized study: day 2 versus day 5 embryo transfer. Human Reproduction (2002) 17(6):1507-12.
  41. Karaki, R.Z., Samarraie, S.S., et al.  Blastocyst culture and transfer: a step toward improved in vitro fertilization outcome. Fertility Sterility (2002) 77(1):114-8.
  42. Scott, J.R.  Immunotherapy for recurrent miscarriage (Cochrane Review).  In: The Cochrane Library, Issue 3 (2002). Oxford: Update Software.
  43. Christiansen, O.B., Pedersen, B., et al.  A randomized, double-blind, placebo-controlled trial of intravenous immunoglobulin in the prevention of recurrent miscarriage: evidence for a therapeutic effect in women with secondary recurrent miscarriage.  Human Reproduction (2002) 17(3):809-16.
  44. Hovatta, O.  Cryobiology of ovarian and testicular tissue.  Best Practice and Research Clinical Obstetrics and Gynaecology (2003 April) 17(2):331-42.
  45. Tryde Schmidt, K.L., Andersen, C., et al. Orthoptic auotransplantation of cyropreserved ovarian tissue to a woman cured of cancer – follicular growth, steroid production and oocyte retrieval. Reproductive Biomedicine Online (2004) 8:448-53.
  46. Oktay, K, Buyuk, E., et al. Embryo development after heterotopic transplantation of cryopreserved ovarian tissue. Lancet (2004) 363:837-40.
  47. Paternal or Fetal Antigen Immunotherapy for Recurrent Fetal Loss.  Chicago. Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2004 January) OB/GYN Reproduction 4.02.02.
  48. Laboratory Tests of Sperm Maturity and Function.  Chicago. Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2004 April) OB/GYN Reproduction 4.02.01.
  49. Anonymous.  Ovarian tissue and oocyte cryopreservation.  Fertility and Sterility (2004 October) 82(4):993-8.
  50. Donnez, J., Dolmans, M.M., et al.  Livebirth after orthotopic transplantation of cryopreserved ovarian tissue.  Lancet (2004 October) 364(9443):1405-10.
  51. Tournaye, H., Goossens, E., et al.  Preserving the reproductive potential of men and boys with cancer: current concepts and future prospects.  Human Reproduction Update (2004 November-December) 10(6):525-32.
  52. Assisted Reproductive Technologies.  Chicago. Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2005 January) OB/GYN Reproduction 4.02.04.
  53. Intravenous Immune Globulin Therapy.  Chicago. Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2005 February) Therapy 8.01.05.
  54. Dafopoulos, K., Griesinger, G., et al.  Cumulative pregnancy rate after ICSI with cryopreserved testicular tissue in non-obstructive azoospermia.  Reproduction BioMedicine Online (2005 April) 10(4):461-6.
  55. The Ethics Committee of the American Society for Reproductive Medicine.  Fertility preservation and reproduction in cancer patients.  Fertility and Sterility 83(6); (2005 June):1622-8.
  56. Levi, Setti, P.E., Albani, E., et al.  Cryopreservation of supernumerary oocytes in IVF/ICSI cycles.  Human Reproduction (2006 February) 21(2):370-5.
  57. Borini, A., Sciajoo, R., et al.  Clinical outcome of oocyte cryopreservation after slow cooling with a protocol utilizing a high sucrose concentration.  Human Reproduction (2006 February) 21(2):512-7.
  58. Oktay, K., Cil, A.P., et al.  Efficiency of oocyte cryopreservation: a meta-analysis.  Fertility and Sterility (2006 July) 86(1):70-80.
  59. Anonymous.  Ovarian tissue and oocyte cryopressurization.  Fertility and Sterility (2006 November) 86(5 Supplement 1):S142-7.
  60. Myers, E.R., McCrory, D.C., et al.  Effectiveness of assised reproductive technology (ART).  Evidence Report – Technology Assessment (Full Report) (2008 May) (167):1-195.
  61. Anonymous.  The role of assisted hatching in in vitro fertilization: a review of the literature.  A Committee opinion.  Fertility and Sterility (2008 November) 90(5 Supplement):S196-8.
  62. Immune Globulin Therapy.  Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2008 December) Therapy 8.01.05.
  63. Reproductive Techniques.  Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2009 April) OB/GYN Reproduction 4.02.04.
  64. State of Illinois, Illinois Department of Insurance.  Notice of Adopted Amendment – Infertility Coverage.  50 Ill. Adm. Code 2015, Implementing Section 356m of the Illinois Insurance Code [215 ILCS 5/356m].  Chicago, Illinois:(2010 February 11).
History
August 2013  New 2013 BCBSMT medical policy.
BCBSMT Home
®Registered marks of the Blue Cross and Blue Shield Association, an association of independent Blue Cross and Blue Shield Plans. ®LIVE SMART. LIVE HEALTHY. is a registered mark of BCBSMT, an independent licensee of the Blue Cross and Blue Shield Association, serving the residents and businesses of Montana.
CPT codes, descriptions and material only are copyrighted by the American Medical Association. All Rights Reserved. No fee schedules, basic units, relative values or related listings are included in CPT. The AMA assumes no liability for the data contained herein. Applicable FARS/DFARS Restrictions Apply to Government Use. CPT only © American Medical Association.
Assisted Reproductive Technologies (ART) and Related Services