Medical Policies - OBGYN


Reproductive Technologies or Techniques and Related Services

Number:OB402.023

Effective Date:10-01-2016

Coverage:

NOTE: Carefully check the member’s benefit plan, summary plan description or contract for language specific to reproductive technologies or techniques and related services. IF reproductive technologies or techniques, also known as reproductive technology(ies), 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.

This medical policy does NOT address Gender Reassignment Services (Transgender Services). This medical policy IS NOT TO BE USED for Gender Reassignment Services. Refer to SUR717.001, Gender Assignment Surgery and Gender Reassignment Surgery and Related Services

Reproductive technologies or techniques and related services may be considered 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 assay (SPA) testing, and/or hyaluronan binding assay (HBA) testing (see Description section of this policy for an explanation of these tests) for determination if intracytoplasmic injections (ICSI) should be a part of in vitro fertilization (IVF); determination of sperm maturation; and/or sperm selection;
  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).

Reproductive procedures, which include:

  1. In vitro fertilization (IVF);
  2. Uterine embryo lavage;
  3. Gamete intrafallopian tube transfer (GIFT), sperm;
  4. Intracytoplasmic injection (ICSI) (for male factor infertility);
  5. Low tubal ovum transfer;
  6. Embryo transfer (ET) or blastocyst transfer; 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 reproductive technologies or techniques, 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 reproductive techniques or services are considered experimental, investigational and/or unproven, including but not limited to the following:

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,

Intracytoplasmic sperm injections (ICSI) in the absence of male factor infertility, and/or

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

NOTE: Cryopreservation of testicular tissue may be considered medically necessary in adult men with azoospermia as a 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 reproductive technologies/techniques, including but not limited to the following; otherwise, these related services to reproductive technologies/techniques are considered not medically necessary:

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/or 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 cells (MED207.140) for coverage when this testing is performed for a diagnosis of infertility.

NOTE: Refer to the Medical Policy for use of intravenous immunoglobulin (RX504.003) as a treatment for recurrent fetal loss.

Description:

The policy addresses various techniques available to establish a viable pregnancy for an individual who has been suspected of and/or diagnosed with infertility due to a dysfunction of the reproductive system. Infertility may be 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.

Assisted reproductive technologies, as defined by the Centers for Disease Control (CDC) and other organizations, refers to fertility treatments in which both the eggs and sperm are handled. Generally, a reproductive technology does not include assisted insemination or reproductive artificial insemination (AI), but for the purposes of this policy, AI is included. In most instances, a reproductive technology will incorporate some type of in vitro fertilization (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). Additional examples of reproductive technologies include, but are not limited to, trans uterine fallopian transfer (TUFT), natural oocyte retrieval with intravaginal fertilization (NORIF), pronuclear state tubal transfer (PROST, tubal embryo transfer (TET), gamete and embryo cryopreservation, oocyte and embryo donation, and gestational surrogacy.

The various components of reproductive technologies 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;

The in vitro component, i.e., the laboratory procedures, which are performed on the collected oocyte and sperm; and

The final step is the implantation procedure.

NOTE: Preimplantation genetic diagnosis (PGD), which may be performed as an adjunct to reproductive technologies as a technique to deselect embryos that carry genetic abnormalities, is addressed separately in another medical policy (OB402.029).

Procedures Performed on the Female

Ovarian follicle punctures 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 reproductive AI 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 reproductive AI;

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 an 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 an IVF 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 assisted reproductive technology procedure.

Regulatory Status

There are no medical devices or diagnostic tests related to reproductive techniques that require U.S. Food and Drug Administration (FDA) approval or clearance.

Rationale:

This policy was originally created in 1999 and was updated with searches of the MedLine database. The most recent literature search was performed through May 2015. The majority of procedures and codes describing the various steps in assisted reproductive technologies or techniques are longstanding. Only the newer reproductive technology services, such as intracytoplasmic sperm injection (ICSI), blastocyst transfer, assisted hatching, co-cultures of embryos, and cryopreservation of reproductive tissues 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 (IVF). 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. (1-5) These rates are very competitive with standard IVF. A 2012 committee opinion of the American Society of Reproductive Medicine (ASRM) and Society for Assisted Reproductive Technology (SART) stated that ICSI is a safe and effective treatment for male factor infertility. (6) The document also stated that ICSI for unexplained fertility, low oocyte yield and advanced maternal age does not improve clinical outcomes. The opinion included a statement that ICSI may be beneficial for patients undergoing IVF with preimplantation genetic testing (PGT), in vitro matured oocytes and cryopreserved oocytes.

More recently, in 2015, Boulet et al. published a large retrospective analysis of 2008 to 2012 data from the U.S. National Assisted Reproductive Technology (ART) Surveillance System on outcomes after ICSI versus standard IVF. (67) During this time period, there were data on 494,907 fresh IVF cycles. A total of 74.6% of cycles used ICSI, 92.9% of the cycles with male factor infertility and 64.5% of the cycles without male factor infertility. Among couples with male factor infertility, there was a statistically significantly lower rate of implantation after ICSI (25.5%) versus standard IVF (25.6%) (p=0.02), but the degree of difference between groups may not be clinically significant. Rates of clinical intrauterine pregnancy and live birth did not differ significantly between ICSI and standard IVF. In couples without male factor infertility, implantation, clinical pregnancy and live birth rates were all significantly higher with standard IVF than with ICSI. Data continue to support the conclusion that ICSI is not useful in the absence of male factor infertility and are less supportive than previous data for ICSI use with male factor infertility.

Section Summary: There are data indicating that ICSI for male factor infertility has a relatively high rate of successful pregnancy, although recent data are less supportive. The available data suggest that ICSI is not useful in the absence of male factor infertility. In 2012 Blue Cross Blue Shield Association (BCBSA) received positive clinical input support for considering ICSI for male factor infertility and cryopreservation of testicular tissue in adult men with azoospermia as part of an ICSI injection procedure when used in assisted reproductive technology.

Blastocyst Transfer

This refers to the extended culture of oocytes/embryos, i.e., for greater than 4 days. 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.

Several systematic reviews of studies comparing outcomes associated with blastocyst stage transfer compared to earlier stage transfer have been published. Only Cochrane review, published in 2012, included randomized clinical trials (RCTs). (7) The Cochrane review identified a total of 23 RCTs; 12 of these reported on the on the rate of live birth per couple. A pooled analysis of these trials found a significantly higher live birth rate with blastocyst transfer (292/751, 39%) compared to cleavage-stage transfer (237/759, 31%). The odds ratio (OR) for live birth was 1.40 (95% CI [confidence interval]: 1.13 to 1.74). There was not a significant difference in the rate of multiple pregnancies in the 2 treatment groups (16 RCTs, OR: 0.92; 95% CI: 0.71 to 1.19). In addition, there was not a significant difference in the miscarriage rate (14 RCTs, OR: 1.14, 95% CI: 0.84 to 1.55).

A 2013 systematic review identified 8 observational studies analyzing singleton births following embryo transfer at the blastocyst- or cleavage-stage and reporting obstetric and/or perinatal outcomes. (8) A meta-analysis of 6 studies found a significantly higher rate of preterm delivery <37 weeks after blastocyst stage transfer compared to cleavage-stage transfer (RR [relative risk]: 1.27, 95% CI: 1.22 to 1.31); the absolute increase in risk was 2% (95% CI: 1 to 4%). Other pooled analysis of 2 to 3 studies each did not find significantly increased rates of low birth weight <1500g, congenital anomies or perinatal mortality following blastocyst-stage versus cleavage-stage embryo transfer.

A 2010 retrospective cohort study reported on risks associated with blastocyst transfer. Data were taken from the Swedish Medical Birth Register. (9) There were 1,311 infants born after blastocyst transfer and 12,562 born after cleavage-stage transfer. There were no significant differences in the rates of multiple births, which were 10% after blastocyst transfer and 8.9% after cleavage-stage transfer. Among singleton births, the rate of pre-term birth (less than 32 weeks) was 18/1,071 (1.7%) in the blastocyst transfer group and 142/10,513 (1.35%) in the cleavage-stage transfer. In a multivariate analysis controlling for year of birth, maternal age, parity, smoking habits, and body mass index, the adjusted OR was 1.44 (95% CI: 0.87-2.40). The rate of low birthweight singletons (less than 1,500 grams or less than 2,500 grams) did not differ significantly in the blastocyst transfer compared to the cleavage-stage transfer groups. There was a significantly higher rate of relatively severe congenital malformation (e.g., spina bifida, cardiovascular defects, cleft palate, etc.) after blastocyst transfer (61/1,311, 4.7%) than cleavage-stage transfer (509/12,562, 4.1%, adjusted OR: 1.33, 95% CI: 1.01-1.75). The 2 groups did not differ significantly in their rates of low APGAR scores, intracranial hemorrhage, respiratory diagnoses, or cardiovascular malformations. Respiratory diagnoses were given to 94/1,311 (7.2%) infants born after blastocyst transfer and 774/12,562 (6.2%) after cleavage-stage transfer (OR: 1.15, 95% CI: 0.90-1.47). The study was not randomized and, although the investigators adjusted for some potential confounders e.g., age and parity, there may have been other differences in the 2 groups that affected outcomes.

The Practice Committees of the SART and the ASRM issued a Committee Opinion on blastocyst transfer in 2008. (10) They stated that, in trials with good prognosis patients, blastocyst transfer has been found to result in a higher live birth rate compared to transfer of equal numbers of cleavage stage transfer. However, cumulative live birth rates may not differ when frozen and fresh embryos from a given cycle are considered because extended culture yields fewer surplus embryos, and the post-thaw survival rate is lower for blastocysts than for cleavage stage embryos that have been frozen.

Section Summary: According to evidence from RCTs, observational studies and meta-analyses of published studies, blastocyst transfer results in higher live birth rates compared to cleavage stage transfer. One meta-analysis found a significantly higher rate of preterm birth after blastocyst-stage versus cleavage-stage transfer, but not increased risks of other outcomes including low birth rate and perinatal mortality. In 2012 BCBSA received clinical input support for considering blastocyst transfer as a method to decrease multiple gestations when used in reproductive technologies.

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 IVF. 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. (11) While there is still concern regarding standardization of the procedure, (12) 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. (13, 14) The package insert also does not provide adequate data to evaluate the diagnostic performance of the test. (15) In the mid-2000’s, selection of mature sperm for ICSI using hyaluronan had been proposed as a promising method to reduce the risk of DNA abnormalities. (16)

Tests of Sperm DNA Integrity and Fragmentation (i.e., SCSA® and SDFA™): Tests of DNA integrity and fragmentation has been an important research tool to further explore the etiologies of infertility. For example, as reviewed by O’Brien and Zini, several studies have reported that poor sperm DNA integrity is an independent risk factor for male infertility. (17) A threshold of 30% of abnormal DNA (referred to as the DNA fragmentation index or DFI) is frequently suggested as a cutoff to distinguish between a potentially fertile versus infertile semen sample. (18) However, this cutoff point has not been evaluated in large scale studies, and studies have reported variable results regarding the relation between DFI and reproductive outcomes. Payne and colleagues have published the largest case series, comparing the results of the SCSA test to outcomes of assisted reproductive techniques. (19) In the 100 couples included in the series, 19 had a DFI of >27%, suggesting a poor IVF outcome. However, 9 of these couples achieved a clinical pregnancy. In contrast, in 22 couples the DFI was less than 9%, suggesting a favorable outcome. Only 1 of these patients achieved a clinical pregnancy. These results are consistent with other reports (20, 21) and contrast with favorable results reported from smaller case series. (22-24).

A meta-analysis of observational studies assessed the risk ratio for sperm DNA damage (assessed with either the TUNEL or SCSA assay) and fertilization or clinical pregnancy rates for IVF and ICSI. (25) The analysis found that sperm DNA damage as assessed by the SCSA assay was not predictive of fertilization or pregnancy rate after IVF or ICSI. Sperm DNA damage as assessed by the TUNEL assay was associated only with a decrease in clinical pregnancy for the IVF procedure (risk ratio = 0.68). The impact of this information on clinical decision making is unknown.

The Practice Committee of the American Society for Reproductive Medicine concludes in their recent guidelines that although sperm DNA damage is more common in infertile men, there is no proven role for routine DNA integrity testing in the evaluation of infertility. (26) At issue was the limited data on the relationship between abnormal DNA integrity and reproductive outcomes. In particular, studies had indicated that “the results of sperm DNA integrity testing alone do not predict pregnancy rates achieved with intercourse, IUI [intrauterine insemination], or IVF and ICSI.”

Recent studies indicate that DNA integrity does not affect pregnancy rates for IVF and ICSI, although it may alter fertilization rate, embryo quality, and miscarriage rate. (27-29) A prospective study with 322 couples (88 IVF cycles and 234 ICSI cycles) found that a DFI of 15% or greater was associated with lower fertilization rate and embryo quality (ICSI only), but pregnancy rates (either ICSI or IVF) were not altered. (27) Miscarriage rates were found to be higher (38% vs. 9%) when the DFI was 15% or greater. DFI was weakly correlated (r = -0.2) with standard sperm parameters (count, motility, morphology). Similar results were obtained in 2 additional studies with a combined total of 850 couples (28, 29). Lin et al. note that, “The selection of morphologically normal sperm for ICSI and good quality embryos for transfer at IVF/ICSI may reduce the potential adverse effects of sperm DNA damage on outcome of ART [assisted reproductive technology{ies}].” (29)

Another multicenter study from Europe examined the relation between sperm DNA integrity and pregnancy outcomes in 637 consecutive couples with either unexplained infertility (387 IUI cycles), female factor infertility (388 IVF cycles), or male infertility factor (223 ICSI cycles). (30) A high DFI (>30% by SCSA) was observed in 17% of IUI, 16% of IVF, and 32% of ICSI cases. Pregnancy rates were not affected by the percentage of DNA fragmentation in IVF and ICSI groups, and early pregnancy loss was not significantly different in these groups. For the group referred to IUI due to unexplained infertility, the pregnancy rate for a DFI >30% was 2/66 (3%) compared to 76/321 (24%) cycles when the DFI was 30% or less. In another study, sperm DNA integrity (measured by SCD [sperm chromatin dispersion] testing) was assessed in 100 couples undergoing IUI; female infertility was unexplained in 79 (79%) of the couples. (31) There were 23 (23%) pregnancies with 25 newborns from the first cycle. Weak correlations (r = -0.22 to -0.29) were observed between DNA dispersion and standard sperm parameters; no differences in SCD were found between couples that did or did not achieve a pregnancy.

Reports from the Practice Committee of the ASRM indicate that up to 30% of couples who are unable to conceive are determined to have unexplained infertility, and up to 8% of infertile men will have abnormal DNA integrity despite normal semen parameters. (26, 32) Current literature indicates that sperm DNA integrity does not affect pregnancy rates in couples who undergo IVF or ICSI. One study suggests that sperm DNA integrity testing with a chromatin structure assay may improve decision making for couples with infertility unexplained by standard panels; however, another study indicates no relation between sperm chromatin dispersion and pregnancy outcomes following IUI.

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.

A 2012 systematic review and meta-analysis from the Cochrane collaboration identified 31 RCTs on assisted hatching with a total of 5,728 individuals. (33) Twelve studies included women with a poor prognosis, 12 studies included women with a good prognosis, and the remaining 7 studies did not report this factor. Fifteen studies used laser for assisted hatching, 11 used chemical means, and 5 used mechanical means. Live birth rate was reported in 9 studies with 1,921 women. A pooled analysis of data from the 9 studies did not find a statistically significant difference between the groups receiving assisted hatching or a control condition, OR: 1.03, 95% CI: 0.85 to 1.26. The rate of live birth was 313/995 (31%) in the assisted hatching group and 282/926 (30%) in the control group. All 31 trials reported clinical pregnancy rates. In a meta-analysis of all of these trials, assisted hatching improved the pregnancy rate, but the OR just reached statistically significance, OR: 1.13 (95% CI: 1.01 to 1.27).

In 2014, Kissin et al. published a retrospective review of data on assisted hatching in the United States from 2000 to 2010. (34) Data were taken from the Centers for Disease Control and Prevention National ART Surveillance System. The analysis on outcomes was limited to fresh autologous IVF cycles for which a transfer was performed on either day 3 or 5. For the total patient population (N=536,852), rates of implantation, clinical pregnancy, and live birth rates were significantly lower when assisted hatching was used. For example, the live birth rate was 28.3% with assisted hatching and 36.5% without assisted hatching (adjusted OR=0.75; 95% CI, 0.70 to 0.81). Moreover, the rate of miscarriage was significantly higher when assisted hatching was used (18.0% vs 13.5%; adjusted OR=1.43; 95% CI, 1.34 to 1.52).

Section Summary: RCTs and meta-analyses of these trials have not found that assisted hatching significantly improves the live birth rate compared to a control intervention. Meta-analyses of heterogenous studies have found that the clinical pregnancy rate is improved with assisted hatching.

Embryo Co-Culture

In routine IVF procedures, the embryo is transferred to the uterus on day 2 or 3 of development, when it has between 4 and 8 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. In addition, if co-culture results in a higher implantation rate, fewer embryos could be transferred at each cycle, 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. (35-40) For example, Wetzels and colleagues reported on a study that randomized IVF treatments to include co-culture with human fibroblasts or no culture. (40) 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.

Section Summary: There is a lack of controlled trials demonstrating improved outcomes with co-culture, and no standardized method of co-culture has emerged in the literature.

Cryopreservation of Ovarian Tissue

Cryopreservation of ovarian tissue or an entire ovary 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, also known as “oncofertility” services. 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. (41-42) There are also several case series describing live births using cryopreserved ovarian tissue. (43-45) However, in general, the technique is not standardized, has not been sufficiently studied to determine the success rate. (46-47) In 2011, Johnson and Patrizio commented on whole ovary freezing as a technique of fertility preservation in women with disease or disease treatment that threaten their reproductive tract function. (48) They concluded, “Although theoretically optimal from the point of view of maximal follicle protection and preservation, the risks and difficulties involved in whole ovary freezing limit this technique to experimental situations.”

Section Summary: This technique has not been standardized, and there is insufficient published data that cryopreservation of ovarian tissue is an effective and safe reproductive technique.

Cryopreservation of Oocytes

Cryopreservation of oocytes was originally investigated primarily as an alternative to embryo cryopreservation due to ethical or religious reasons. More recently, it has been examined as a fertility preservation option for reproductive-age women undergoing cancer treatment both single women and those who do not want the option of embryo cryopreservation. 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. Survival after thawing may also be associated with sublethal damage, which may further impact on the quality of the subsequent embryo. Moreover, due to the large amount of water, when the oocyte is frozen, ice crystals can form that can damage the integrity of the cell. To reduce or prevent ice crystals, oocytes are dehydrated using cryoprotectants, which replace the water in the cell. The most common method of freezing oocytes is a controlled-rate slow-cooling method. There are 2 primary approaches to cryopreservation, a controlled-rate slow-cooling method, and a flash-freezing process known as vitrification. This technique is faster, yet requires a higher concentration of cryoprotectants.

No studies were identified that compared outcomes after embryo cryopreservation versus oocyte cryopreservation.

In 2013, the Practice Committees of the ASRM and the SART published an updated guideline on mature oocyte cryopreservation. (49) A systematic review of the literature, conducted as part of guideline development, identified 4 RCTs comparing outcomes of assisted reproduction with cryopreserved and fresh oocytes. All of the trials were conducted in Europe. In these studies, fertilization rates ranged from 71% to 79% and the clinical pregnancy rates per transfer ranged from 36% to 61%. The largest RCT cited in the guideline (n=600) was published by Cobo and colleagues in Spain in 2010. (50) This study included oocyte recipients who were between 18 and 49 years old and who failed fewer than 3 previous IVF attempts. The primary outcome was the ongoing pregnancy rate; this was defined as the presence of at least 1 viable fetus 10-11 weeks after embryo transfer. In an intention to treat analysis, the ongoing pregnancy rate was 43.7% in the vitrification group and 41.7% in the fresh oocyte group. Vitrification was considered non-inferior to fresh oocyte transfer according to a pre-specified margin of difference. Cobo et al. did not discuss whether any of the percipients had cancer or were undergoing chemotherapy. The guideline noted that the data may not be generalizable to the United States, to clinics with less experience with these techniques or to other populations, e.g. older women or cancer patients. The authors stated that data from the United States are available only from a few clinics and report on young highly selected populations. Pregnancy outcomes and rates of congenital anomalies were not discussed in the publication.

Also published in 2013, after the ASRM/SART guideline, was an observational study by Levi Setti and colleagues in Italy. (51) This study compared outcomes in pregnancies achieved with fresh or frozen oocytes in the same patient population. The investigators identified 855 patients in an Italian database who had become pregnant using fresh and/or cryopreserved and thawed oocytes. The 855 patients had a total of 954 clinical pregnancies, 197 were obtained with frozen oocytes and 757 with fresh oocytes. There were 687 pregnancies from fresh cycle oocytes only, 129 pregnancies with frozen oocytes only and 138 pregnancies from both fresh and frozen oocyte cycles. The live birth rate was 68% (134 of 197) from frozen/thawed oocytes and 77.2% (584 of 757) fresh oocyte cycles. The live birth rate was significantly higher after fresh cycle oocytes, p=0.008.

In addition to the above literature, several meta-analyses have compared the 2 main approaches to cryopreservation; slow-cooling cryopreservation and vitrification. A 2013 study by Cil and colleagues analyzed individual patient data from 10 studies with a total of 1805 patients. (52) There were 328 clinical pregnancies that resulted in 224 live births, 163 after slow-freeze cryopreservation and 61 after vitrification. Oocyte survival rates and fertilization rates were lower after slow-freeze cryopreservation (65% and 74%, respectively) than with vitrification (85% and 79%, respectively), p<0.001. Moreover, after vitiation, implantation rates were higher (p=0.002) and miscarriage rates were lower (p=0.005) compared with slow-freeze cryopreservation. The authors created models to estimate the probability of live birth as a function of age and the number of oocytes frozen and thawed. For example, the probability of a live birth for a 30-year-old woman with 2 to 6 oocytes thawed was 9.1 to 10.5% after slow-freeze cryopreservation and 21.4% to 24.1% after vitrification. In general, the likelihood of successful live birth declined with maternal age, and, when controlling for the number of thawed and injected oocytes and for the number of embryos transferred, the probability of live birth was higher after vitrification than slow freeze cryopreservation regardless of age group.

A 2014 Cochrane review identified 2 RCTs with 106 participants that compared these techniques. (53) Neither study reported live birth rates. A meta-analysis of data from the 2 trials found a significantly higher clinical pregnancy rate with vitrification than with slow cooling (risk ratio [RR], 3.86; 95% CI, 1.63 to 9.11).

Also in 2009, Noyes identified published reports of 609 live births after oocyte cryopreservation. (54) An additional 327 births were identified from communications with fertility centers, for a total of 936 live births. Of these, 532 resulted from slow frozen oocytes, 392 from vitrified oocytes and 12 from a combination of the 2 techniques. There were a total of 12 congenital anomalies, 8 major and 4 minor, for an overall incidence of 1.3%. The incidence in the births from slow frozen oocytes was 6 of 532 (1.1%) and from vitrification births 6/392 (1.5%). The author stated that this compared favorably with the 3% rate of congenital anomalies in the general U.S. population, according to the Centers for Disease Control. The incidence of ventricular septal defects was 0.3% (3 of 936) on the oocyte cryopreservation population and 1 of 125 (0.8%) naturally conceived newborns. The author acknowledges that not all reports were from peer-reviewed publications and limited outcome data were available.

Section Summary: There are insufficient published data on the safety and efficacy of cryopreservation of oocytes; data are only available from select clinical settings and select populations. There is a lack of published data on success rates with cryopreserved oocytes in women who froze oocytes because they are undergoing chemotherapy.

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. (55) However, a unique application of cryopreservation 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. (56-57)

Section Summary: Cryopreservation of testicular tissue in adult men with azoospermia is a well-established component of the ICSI procedure.

Potential Adverse Effects to Offspring Associated with Reproductive Techniques

A number of systematic reviews and registry studies have evaluated potential adverse effects in offspring after assisted reproduction. Several of these reviews addressed risk of birth defects. (58-60) The review with the largest amount of data was published by Hansen and colleagues. (59) They examined 45 cohort studies with outcomes in 92,671 infants born following reproductive techniques and 3,870,760 naturally conceived infants. In a pooled analysis of the data, there was a higher risk of birth defects in infants born using reproductive techniques (RR: 1.32, 95% CI: 1.24 to 1.42). The risk of birth defects was also elevated when the analysis was limited to the 6 studies that were conducted in the United States or Canada (RR: 1.38, 95% CI: 1.16 to 1.64). A review by Davies and colleagues included data on 308,974 live births in Australia, 6,163 of which followed use of reproductive techniques. (59) There was a higher rate of birth defects after assisted conception (8.3%) compared to births to fertile women that did not involve assisted conception (5.8%). (Unadjusted OR: 1.47, 95% CI: 1.33 to 1.62). The risk of birth defects was still significantly elevated but was lower in an analysis that adjusted for other factors that might increase risk e.g., maternal age, parity, maternal ethnicity, maternal smoking during pregnancy and socioeconomic status (OR: 1.28: 95% CI: 1.16 to 1.41).

A 2015 systematic review by Kettner et al. considered potential adverse events in children of various ages. (68) The review included controlled studies reporting at least 1 postnatal morbidity outcome in children who were and were not conceived using reproductive techniques. A total of 22 studies met the eligibility criteria; 30 were cohort studies and 8 were case control studies. There were no strong consistent associations between use of reproductive techniques and childhood disease. For example, no statistically significant differences were found in rates of the following in children conceived spontaneously or with ART: chronic diseases (2 studies), cancer (3), and allergic disease (5). Findings were mixed on risk of infectious and parasitic diseases. In the 8 studies examining this outcome, ORs varied between 0.37 and 5.7, and most results were not statistically significant. Rates of asthma or obstructive bronchitis were examined in 8 studies; 3 found significantly increased risk in children conceived by ART versus conceived spontaneously.

Another systematic review published in 2013 addressed risk of childhood and adolescent mental disorders following assisted reproduction. (61) Data from a Danish birth registry, which included 524 children born after IVF or ICSI and 22,009 children born after spontaneous conception, were used for the analysis. In an analysis adjusted for potential confounders, compared to spontaneously conceived children, there was not a statistically significant increase in mental retardation, disorders of psychological development (including autism spectrum disorders, speech and language disorders and others), attention deficit hyperactivity disorder (ADHD) or conduct, emotional or social disorders.

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 (62) that concluded that paternal or fetal antigen immunotherapy did not meet the TEC criteria as a treatment of recurrent spontaneous abortion. A literature search did not identify any RCTs that had been published.

IVIg as a Treatment of Recurrent Fetal Loss

The policy on IVIg as a treatment of recurrent fetal loss is based on a 1998 BCBSA TEC Assessment, (63) 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 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 recurrent fetal loss 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.

Practice Guidelines and Position Statements

In 2014, the American Society for Reproductive Medicine (ASRM) and the Society for Assisted Reproductive Technology (SART) published a guideline on assisted hatching in IVF. (69) The single recommendation in this guideline states that assisted hatching should not be used routinely for all patients undergoing IVF.

In 2013, the ASRM and the SART published a joint guideline on mature oocyte cryopreservation. (49) The guideline stated “evidence indicates that oocyte vitrification and warming should no longer be considered experimental” and it included the following 4 recommendations:

• “In patients facing infertility due to chemotherapy or other gonadotoxic therapies, oocyte cryopreservation is recommended with appropriate counseling”;

• “More widespread clinic-specific data on the safety and efficacy of oocyte cryopreservation in donor populations are needed before universal donor oocyte banking can be recommended”;

• “There are not yet sufficient data to recommend oocyte cryopreservation for the sole purpose of circumventing reproductive aging in healthy women”;

• “More data are needed before this technology should be used routinely in lieu of embryo cryopreservation”.

In 2014, The American College of Obstetricians and Gynecologists (ACOG) issued a Committee Opinion endorsing the ASRM/SART joint guideline on mature oocyte cryopreservation. (64)

In 2013, the American Society of Clinical Oncology updated a guideline on fertility preservation for patients with cancer. (65) The guideline included the following recommendations:

Males:

• “Recommendation 2.1. Sperm cryopreservation: Sperm cryopreservation is effective, and health care providers should discuss sperm banking with postpubertal males receiving cancer treatment”;

• “Recommendation 2.2. Hormonal gonad-protection: Hormonal therapy in men is not successful in preserving fertility. It is not recommended”;

• “Recommendation 2.3. Other methods to preserve male fertility: Other methods, such as testicular tissue cryopreservation and reimplantation or grafting of human testicular tissue, should be performed only as part of clinical trials or approved experimental protocols...”.

Females:

• “Recommendation 3.1. Embryo cryopreservation: Embryo cryopreservation is an established fertility preservation method, and it has routinely been used for storing surplus embryos after in vitro fertilization”;

• “Recommendation 3.2. Cryopreservation of unfertilized oocytes: Cryopreservation of unfertilized oocytes is an option, particularly for patients who do not have a male partner, do not wish to use donor sperm, or have religious or ethical objections to embryo freezing”.

In May 2008, Agency for Healthcare Research and Quality (AHRQ) published the evidence report or technology assessment, “Effectiveness of Assisted Reproductive Technology.” (66) 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.

Summary

ICSI has a relatively high rate of successful live births for treatment of male factor infertility due to low sperm count and/or impaired sperm motility. BCBSA received positive clinical input on ICSI for male factor infertility and cryopreservation of testicular tissue in adult men with azoospermia as part of an ICSI injection procedure. The positive clinical provider support was also true of blastocyst transfer and the evidence from RCTs of a higher live birth rate than the cleavage-stage embryo transfer. These techniques may be considered medically necessary.

The changing role of utilization of SPA in IVF has not changed the results confirming the use of SPA in select patients with ICSI. Therefore, SPA is considered medically necessary when used as a part of the IVF technique. No studies were identified that assessed clinical outcomes following sperm selection with hyaluronic acid. This procedure is at an early stage of research and considered experimental, investigational, and/or unproven. The evidence is insufficient to permit conclusions concerning the effect of sperm DNA integrity tests on health outcomes used in the management of infertile individuals. Thus sperm DNA integrity testing is considered experimental, investigational, and/or unproven.

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; ICSI in the absence of male factor infertility, and storage and thawing of ovarian tissue, oocytes, or testicular tissue on health outcomes. For these procedures, there is a lack of published data on live birth rates, the incidence of multiples and neonatal and child outcomes, compared to established reproductive techniques. Cryopreservation of oocytes has been endorsed by several national guidelines, especially by women facing infertility due to chemotherapy. There are limited data on cryopreservation of oocytes and a lack of studies in this population. Therefore, the coverage position of this medical policy remains experimental, investigational and/or unproven for those services.

No new clinical trial publications or any additional information concerning the effectiveness of immunotherapy on recurrent fetal loss that would change the experimental, investigational, and/or proven coverage position of this medical policy.

Contract:

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.

Coding:

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.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT 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, 89337, 89342, 89343, 89344, 89346, 89352, 89353, 89354, 89356, 0058T, 0357T

HCPCS Codes

S4011, S4013, S4014, S4015, S4016, S4017, S4018, S4020, S4021, S4022, S4023, S4025, S4026, S4027, S4028, S4030, S4031, S4035, S4037, S4040, S4042

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

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Policy History:

Date Reason
10/1/2016 Reviewed. No changes.
11/1/2015 Document updated with literature review. The following was added to the reproductive techniques or services experimental, investigational and/or unproven coverage statement, “Intracytoplasmic sperm injections (ICSI) in the absence of male factor infertility.”
7/1/2014 Document updated with literature review. The following changes were made: 1.) For determination if intracytoplasmic injections (ICSI) should be a part of in vitro fertilization (IVF); determination of sperm maturation; and/or sperm selection as added to sperm penetration assay testing and/or hyaluronan binding assay testing medically necessary criteria; 2.) “for male factor infertility” was added to the medically necessary intracytoplasmic injection criteria; 3.) “blastocyst transfer was added to the medically necessary embryo transfer criteria; and, 4.) Tests of sperm DNA integrity, including but not limited to, sperm chromatin assays and sperm DNA fragmentation assays were added to the experimental, investigational and/or unproven coverage listing. Clarification made to the definition of infertility within the Description section, changing from couples with infertility, to an individual who has been suspected of and/or diagnosed with infertility due to a dysfunction of the reproductive system. The remainder of the infertility definition remains unchanged. Title changed from Assisted Reproductive Technologies and Related Services. Rationale substantially revised.
5/15/2010 Revised/updated entire document. Coverage remains conditional when benefit contract does not exclude assisted reproductive technology and/or related therapy services. Added recent Illinois Insurance Code mandate amendment information. This policy is no longer scheduled for routine literature review and update.
1/1/2007 Revised/updated entire document
1/1/2005 New CPT/HCPCS code(s) added (with bit changes)
7/1/1999 New medical document

Archived Document(s):

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