Pending Policies - OBGYN


Reproductive Technologies or Techniques and Related Services

Number:OB402.023

Effective Date:10-01-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, DrugDex (IIb level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.

NOTE 1: 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:

o Fertility history and physical examination;

o Routine semen analysis, including and limited to count, motility, volume and morphology;

o 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 sperm injections (ICSI) should be a part of in vitro fertilization (IVF); determination of sperm maturation; and/or sperm selection;

o Documentation of ovulation (basal body temperature, serum progesterone, or endometrial biopsy);

o Postcoital test (sperm-cervical mucus interaction);

o Evaluation of tubal patency (hysterosalpingography);

o Urologic consultation for disorders such as hypospadias, cryptorchidism, varicocele, or genitourinary system infection; and

o Diagnostic or surgical laparoscopy for diagnosis or treatment of endometriosis.

Artificial insemination (AI) or intrauterine insemination (IUI).

Reproductive procedures, which include:

o In vitro fertilization (IVF);

o Uterine embryo lavage;

o Gamete intrafallopian tube transfer (GIFT), sperm;

o Intracytoplasmic sperm injection (ICSI) (for male factor infertility);

o Low tubal ovum transfer;

o Embryo transfer (ET) or blastocyst transfer; and

o 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, are covered benefits. (Check all appropriate pharmacy and medical contract provisions as some pharmacy or medical plans may exclude infertility drugs).

The following reproductive techniques or services are considered experimental, investigational and/or unproven, including but not limited to:

Assisted hatching;

Co-culture of embryos;

Cryopreservation of ovarian tissue or oocytes;

Cryopreservation of testicular tissue;

Intracytoplasmic sperm injections (ICSI) in the absence of male factor infertility;

Tests of sperm DNA integrity, including but not limited to, sperm chromatin assays and sperm DNA fragmentation assays; and/or

Uterine transplant.

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 2: Refer to the Medical Policy on natural killer cells (MED207.140) for coverage when this testing is performed for a diagnosis of infertility.

NOTE 3: Refer to the Medical Policy for use of intravenous immunoglobulin (RX504.003) as a treatment for recurrent fetal loss.

NOTE 4: Refer to Medical Policy – eviCore Preimplantation Genetic Screening and Diagnosis for preimplantation genetic diagnosis (PGD), which may be performed as an adjunct to reproductive technologies as a technique to deselect embryos that carry genetic abnormalities.

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, prior tubal ligation, and absent or nonfunctioning uterus);

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 (ARTs), as defined by the Centers for Disease Control and Prevention and other organizations, refer 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, transuterine 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.

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;

Uterine transplantation for women with absolute uterine factor infertility (AUFI).

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.

Both SPA and HBA 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 has been updated with searches of the MedLine database. The most recent literature search was performed through March 2018. 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.

Assessment of efficacy for therapeutic intervention involves a determination of whether the intervention improves health outcomes. The optimal study design for this purpose is a randomized controlled trial (RCT) that includes clinically relevant measures of health outcomes. Intermediate outcome measures, also known as surrogate outcome measures, may also be adequate if there is an established link between the intermediate outcome and true health outcomes. Nonrandomized comparative studies and uncontrolled studies can sometimes provide useful information on health outcomes, but are prone to biases such as noncomparability of treatment groups, placebo effect, and variable natural history of the condition. The following is a summary of the key literature to date.

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. This outcome was reported in relatively large series published in the mid-1990s as between 45% and 50%. (1-5) At the time, those rates were very competitive with those of the standard IVF.

More recently, in 2015, Boulet et al. published a large retrospective analysis of the outcomes following ICSI versus standard IVF (data captured from the Centers for Disease Control and Preventions’s National Assisted Reproductive Technology Surveillance System from 2008 to 2012) (6) During that time, there were data on 494,907 fresh IVF cycles. A total of 74.6% of cycles used ICSI, with 92.9% of the cycles involving male factor infertility and 64.5% of the cycles not involving male factor infertility. Among couples with male factor infertility, there was a statistically significantly lower rate of implantation after ICSI (25.5%) than after standard IVF (25.6%) (p=0.02); however, 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.

Adverse Events

A 2015 systematic review and meta-analysis by Massaro et al. examined adverse events for ICSI and standard IVF without ICSI. (7) Twenty-two observational studies were included; no RCTs were identified. Meta-analysis of 12 studies found some significantly increased odds of congenital genitourinary malformations in children conceived using ICSI versus standard IVF (pooled odds ratio [OR]=1.27; 95% confidence interval [CI], 1.02 to 1.58; p=0.04; I2=0). Five studies in this analysis were considered at high risk of bias, and a pooled analysis of the 4 studies considered at low risk of bias did not find ICSI associated with statistically increased odds of genitourinary malformations.

Section Summary: Intracytoplasmic Sperm Injection

There is a lack of RCTs comparing ICSI with standard IVF. Observational studies have found similar rates of clinical pregnancy and live births after ICSI and standard IVF, but those observational studies are subject to limitations (e.g., selection bias). A 2015 meta-analysis of observational studies found a significantly higher rate of congenital genitourinary malformations in children born after ICSI versus IVF, but there was no significant difference when only studies with low risk of bias were included in the analysis. RCTs comparing health outcomes after ICSI for male factor infertility with standard IVF would strengthen the evidence base. Clinical input was obtained in 2012 by Blue Cross Blue Shield Association (BCBSA) and there was general agreement among reviewers that ICSI in men with male factor infertility was considered medically necessary.

Blastocyst Transfer

The most common days for embryo transfer in the clinical IVF setting are day 3 or day 5. Embryo transfer at the blastocyst-stage on day 5 continues to be less common than cleavage-stage transfer on day 3. First introduced in clinical practice in 2005, use of blastocyst transfer is increasing in clinical practice. The rationale and reported advantages for blastocyst transfer are: higher implantation and clinical pregnancy rates, a more viable option for limiting to single embryo transfer, more appropriate endometrium-embryo synchronicity, optimization of embryo selection due to embryo development progression, and decreased potential for embryo trauma with biopsy obtained for preimplantation genetic testing. Advances in cell culture techniques and embryology assessments have facilitated the increase in use of blastocyst transfer and research into the technique. Critics of blastocyst transfer have raised concerns about the limitation on the number of available embryos for transfer once the cleavage-stage is passed; critics also cite concern due to uncertainties about the effects of the culture microenvironment, as well as early indicators of a higher rate of adverse pregnancy outcomes.

Systemic Reviews

Several systematic reviews of studies comparing outcomes associated with blastocyst-stage transfer have been published. Only the 2012 Cochrane review included RCTs. (8) Cochrane reviewers identified 23 RCTs; 12 of which reported on the rates of live birth per couple. A pooled analysis of these trials found a significantly higher live birth rate with blastocyst transfer (292/751, [39%]) than with cleavage-stage transfer (237/759, [31%]). The odds for live birth was 1.40 (95% CI: 1.13 to 1.74). There was no significant difference in the rate of multiple pregnancies between the 2 treatment groups (16 RCTs; OR=0.92; 95% CI, 0.71 to 1.19). In addition, there was no significant difference in the miscarriage rate (14 RCTs; OR=1.14; 95% CI, 0.84 to 1.55).

In 2016, an update to the 2012 Cochrane review placed further focus on whether blastocyst-stage (day 5-6) embryo transfers improved the live birth rates, and other associated outcomes, compared with cleavage-stage (day 2-3) embryo transfers. (9) Data from four new studies, three of which were published papers and resulted in a total of 27 parallel-design RCTs that included 4031 couples or women. (10-12) The data from a fourth study was only available in abstract form and reported on outcomes from a multicenter trial comparing blastocyst with day 2-3 transfer in ICSI cycles for male factor infertility. There were no exclusions from the 2012 review. The live birth rate following fresh transfer was higher in the blastocyst transfer group (OR=1.48; 95% CI, 1.20 to 1.82; 13 RCTs, 1630 women, I2=45%, low-quality evidence). There was no evidence of a difference between groups in rates of cumulative pregnancy per couple following fresh and frozen-thawed transfer after 1 oocyte retrieval (OR=0.89; 95% CI, 0.64 to 1.22; 5 RCTs, 632 women, I2=71%, very low-quality evidence). The clinical pregnancy rate was also higher in the blastocyst transfer group, following fresh transfer (OR=1.30; 95% CI, 1.14 to 1.47; 27 RCTs, 4031 women, I2=56%, moderate-quality evidence). Embryo freezing rates were lower in the blastocyst transfer group (OR=0.48; 95% CI, 0.40 to 0.57; 14 RCTs, 2292 women, I2=84%, low-quality evidence). Failure to transfer any embryos was higher in the blastocyst transfer group (OR=2.50; 95% CI, 1.76 to 3.55; 17 RCTs, 2577 women, I2=36%, moderate-quality evidence).

The data for rates of multiple pregnancy and miscarriage were incomplete in 70% of the trials and limit conclusions concerning the following findings. There was no evidence of a difference between the groups in rates of multiple pregnancy (OR=1.05, 95% CI, 0.83 to 1.33; 19 RCTs, 3019 women, I2=30%, low-quality evidence) or miscarriage (OR=1.15, 95% CI, 0.88 to 1.50; 18 RCTs, 2917 women, I2=0%, low- quality evidence).

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. (13) Meta-analysis of 6 studies found a significantly higher rate of preterm delivery less than 37 weeks after blastocyst-stage transfer compared with 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 analyses of 2 to 3 studies each did not find significantly increased rates of low birth weight less than 1500 grams, congenital anomalies, or perinatal mortality following blastocyst-stage versus cleavage-stage embryo transfer.

Observational Studies

A 2010 retrospective cohort study reported on risks associated with blastocyst transfer. Data were taken from the Swedish Medical Birth Register. (14) 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 (10% after blastocyst transfer versus 8.9% after cleavage-stage transfer). Among singleton births, the rate of pre-term birth (less than 32 weeks) was 18 (1.7%) of 1071 in the blastocyst transfer group and 142 (1.35%) of 10,513 in the cleavage-stage transfer group. In a multivariate analysis controlling for year of birth, maternal age, parity, smoking habits, and body mass index, the adjusted odds ratio (AOR) was 1.44 (95% CI, 0.87 to 2.40). The rate of low birthweight singletons (less than 1,500 grams or less than 2,500 grams) did not differ significantly between the blastocyst transfer group and the cleavage-stage transfer group. There was a significantly higher rate of relatively severe congenital malformation (e.g., spina bifida, cardiovascular defects, cleft palate) after blastocyst transfer (61/1,311 [4.7%]) than after cleavage-stage transfer (509/12,562 [4.1%]; AOR=1.33; 95% CI, 1.01 to 1.75). The groups did not differ significantly in their rates of low APGAR scores, intracranial hemorrhage rates, respiratory diagnoses, or cardiovascular malformations. Respiratory diagnoses were given to 94 (7.2%) of 1,311 infants born after blastocyst transfer and 774 (6.2%) of 12,562 after cleavage-stage transfer (OR=1.15; 95% CI, 0.90 to 1.47). The study was not randomized and, although the investigators adjusted for some potential confounders (e.g., age and parity), there might have been other differences between groups that affected outcomes.

In 2016, Ginström Ernstad et al. published another retrospective registry cohort study using data crosslinked between the Swedish Medical Birth Register, the Register of Birth Defects, and the National Patient Register. (15) All singleton deliveries after blastocyst transfer in Sweden from 2002 through 2013 were compared with deliveries after cleavage-stage transfer and deliveries after spontaneous conception. There were 4819 singletons born after blastocyst transfer, 25,747 after cleavage-stage transfer, and 1,196,394 after spontaneous conception. Singletons born after blastocyst transfer had no increased risk of birth defects compared with singletons born after cleavage-stage transfer (AOR=0.94; 95% CI, 0.79 to 1.13) or spontaneous conception (AOR=1.09; 95% CI, 0.92 to 1.28). Perinatal mortality was higher in the blastocyst group vs the cleavage-stage group (AOR=1.61; 95% CI, 1.14 to 2.29). When comparing singletons born after blastocyst transfer to singletons born after spontaneous conception, a higher risk of preterm birth (<37 weeks) was seen (AOR=1.17; 95% CI, 1.05 to 1.31). Singletons born after blastocyst transfer had a lower rate of low birthweight (AOR=0.83; 95% CI, 0.71 to 0.97) than singletons born after cleavage-stage transfer. The rate of being small for gestational age was also lower in singletons born after blastocyst transfer than after both cleavage-stage conception (AOR=0.71; 95% CI, 0.56 to 0.88) and spontaneous conception (AOR=0.70; 95% CI, 0.57 to 0.87). The risks of placenta previa and placental abruption were higher in pregnancies after blastocyst transfer than in pregnancies after cleavage-stage (AOR=2.08; 95% CI, 1.70 to 2.55 and AOR=1.62; 95% CI, 1.15 to 2.29, respectively) and after spontaneous conception (AOR=6.38; 95% CI, 5.31 to 7.66 and AOR=2.31; 95% CI, 1.70 to 3.13, respectively).

Section Summary: Blastocyst Transfer

An updated 2016 Cochrane review of 27 RCTs compared the effectiveness of blastocyst transfers with cleavage-stage transfers. The primary outcomes of live birth and cumulative clinical pregnancy rates were higher with fresh blastocyst transfer. There were no differences between groups in multiple pregnancies or early pregnancy loss (miscarriage). The main limitation of the RCTs was serious risk of bias, associated with failure to describe acceptable methods of randomization and unclear or high risk of attrition bias. Differences in outcomes with the use of cryopreserved blastocysts and use of cleavage-stage embryos have been reported, and the mechanisms are not well-understood. There are conflicting reports from retrospective studies on the incidence of pregnancy and neonatal adverse outcomes, including low birth weight and increased congenital anomalies. 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. (16) While there is still concern regarding standardization of the procedure, (17) 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. (18, 19) The package insert also does not provide adequate data to evaluate the diagnostic performance of the test. (20) 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. (21)

In 2013, Worrilow et al. published a prospective, multicenter, double-blinded, randomized Institutional Review Board (IRB)-approved study involving 802 consented couples receiving ICSI as a component of their assisted reproductive therapy (ART). This study asked the question, Does the selection of sperm for ICSI based on their ability to bind to hyaluronan improve the clinical pregnancy rate (CPR) (primary end-point), implantation (IR) and pregnancy loss rates (PLR)? In this study the summary answer stated that in couples where <65% of sperm bound hyaluronan, the selection of hyaluronan-bound (HB) sperm for ICSI led to a statistically significant reduction in PLR. (83)

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. (22) 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. (23) 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. (24) 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 (25, 26) and contrast with favorable results reported from smaller case series. (27-29).

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. (30) 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. (31) 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. (34-36) 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. (34) 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 (35, 36). 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}].” (36)

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). (37) 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. (38) 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. (31, 39) 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

Implantation of the embryo in the uterus is a key component of success with in vitro fertilization (IVF). Although the exact steps in implantation are poorly understood, normal rupture of the surrounding zona pellucida with escape of the developing embryo (termed hatching) is crucial. Mechanical disruption of the zona pellucida (i.e., assisted hatching) has been proposed as a mechanism to improve implantation rates.

Systemic Reviews

A 2012 Cochrane review and meta-analysis identified 31 RCTs on assisted hatching (total N=5,728 individuals). (40) Twelve studies included women with a poor fertility prognosis, 12 studies included women with a good fertility 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 rates were reported in 9 studies (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 and a control condition (OR, 1.03; 95% CI, 0.85 to 1.26). The rate of live birth was 313 (31%) of 995 in the assisted hatching group and 282 (30%) of 926 in the control group. All 31 trials reported clinical pregnancy rates. In a meta-analysis of all trials, assisted hatching improved the pregnancy rate, but the estimate for the OR was marginally statistically significance (OR=1.13; (95% CI, 1.01 to 1.27).

In 2014, Kissin et al. retrospectively reviewed data on assisted hatching in the United States from 2000 to 2010. (41) Data were taken from the Centers for Disease Control and Prevention’s National ART Surveillance System. The analysis of 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 were significantly lower when assisted hatching was used. For example, the live birth rate was 28.3% with assisted hatching and 36.5% without (AOR, 0.75; 95% CI, 0.70 to 0.81). Moreover, the rate of miscarriage was significantly higher when assisted hatching was used (18.0% versus 13.5%; AOR=1.43; 95% CI, 1.34 to 1.52).

Randomized Controlled Trials

Two additional RCTs comparing laser-assisted hatching with standard of care were published in 2016. Shi et al. included 178 patients of advanced maternal age (age range, 35-42 years). (42) There were no statistically significant differences in implantation rates (32.5% in the assisted hatching group vs 39.3% in the control group) or in clinical pregnancy rates (48.8% in the assisted hatching group vs 50.4% in the control group; p-values not reported). Kanyo et al. assessed 413 women (mean age, 33 years). (43) In the overall study population, there was no statistically significant difference in the clinical pregnancy rate between the assisted hatching group (33.3%) and the control group (27.4%; p=0.08). However, in the subgroup of patients ages 38 or older, the clinical pregnancy rate was significantly higher in the assisted hatching group (18.4%) than in the control group (11.4%; p=0.03). There was no significant between- group difference in clinical pregnancy rate among women younger than 38 years old. The age groupings (i.e., <38 years vs ≥38 years) were not specifically discussed as a prespecified subgroup analysis. Neither trial reported live birth rates.

Section Summary: Assisted Hatching

The available literature has generally not found better outcomes with assisted hatching than with standard of care. A 2012 Cochrane review of heterogenous RCTs found that clinical pregnancy rates but not the live birth rates improved with assisted hatching. In subsequent RCTs, laser-assisted hatching did not improve the clinical pregnancy rate but, in 1 study, there was a higher rate of clinical pregnancy in the subgroup of women 38 years or older. In addition, analysis of a large national database found better outcomes (e.g., clinical pregnancy and live birth rates) when assisted hatching was not used.

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. 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, in an attempt to improve the implantation and pregnancy rates. 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 clinical trials have generally not found that co-culture is associated with an improved implantation or pregnancy rates. (44-49) For example, Wetzels et al. (1988) reported on a RCT that assigned IVF treatments to co-culture with human fibroblasts or no culture. (49) Patients in the two groups were stratified by age (older or younger than 36 years) and prior IVF attempts (yes versus. no). The authors reported that fibroblast co-culture did not affect the implantation or pregnancy rates. In 2015, Ohl et al. reported on a novel co-culture technique involving autologous endometrial cell co-culture. (50) In an interim analysis of 320 patients, the clinical pregnancy rate per embryo transfer was significantly higher in the co- culture group (53.4%) than in the control group (37.3%; p=0.025).

Section Summary: Embryo Co-Culture

There is no standardized method of co-culture, and few clinical trials have evaluated outcomes. Most studies have not found improved implantation or pregnancy rates after co-culture. One 2015 RCT reported on a novel co-culture method and an interim analysis of the trial found a higher clinical pregnancy rate with co-culture than with standard practice control group. Additional studies are needed to evaluate this novel co-culture technique. No studies have reported on the impact of co-culture on live birth rates.

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. There are a few case reports assessing the return of ovarian function using this technique. (51, 52) There are also case series describing live births using cryopreserved ovarian tissue. (53-55) However, in general, the technique is not standardized and not sufficiently studied to determine the success rate. (56-57) 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. (58) 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: Cryopreservation of Ovarian Tissue

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

Cryopreservation of Oocytes

Cryopreservation of oocytes has been examined as a fertility preservation option for reproductive-age women undergoing cancer treatment. 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 aligned in a meiotic spindle. This spindle is easily damaged 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. There are 2 primary approaches to cryopreservation: a controlled-rate slow-cooling method, and a flash-freezing process known as vitrification. Vitrification, the newer method is faster and requires a higher concentration of cryoprotectants.

In 2013, the American Society for Reproductive Medicine (ASRM) and Society for Assisted Reproductive Technology (SART) updated their joint guidelines on mature oocyte cryopreservation. (59) 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 trials were conducted in Europe and none among patients who desired to preserve fertility after medical treatment (e.g., chemotherapy). 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 et al. in Spain in 2010. (60) This trial included oocyte recipients between 18 and 49 years of age who had 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 to 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. The guidelines noted that the available data might not be generalizable to the United States, to clinics with less experience with these techniques or to other populations (e.g., older women, 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.

Also published in 2013, after the ASRM/SART guidelines was an observational study by Levi Setti et al. in Italy. (61) This study compared outcomes in pregnancies achieved with fresh or frozen oocytes. The investigators identified 855 patients in an Italian database who had become pregnant using fresh and/or cryopreserved and thawed oocytes. The authors did not state the reasons for a desire for fertility preservation. 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% (134/197) from frozen and thawed oocytes and 77.2% (584 /757) fresh oocyte cycles. The live birth rate was significantly higher after fresh cycle oocytes (p=0.008).

Section Summary: Cryopreservation of Oocytes

There are insufficient published data on the safety and efficacy of cryopreservation of oocytes; and data are only available from select clinical settings, generally outside of the United States. Moreover, there is a lack of published data on success rates with cryopreserved oocytes in women who froze oocytes because they are undergoing chemotherapy. Data on health outcomes (e.g., clinical pregnancy rate, live birth rate) in the population of interest are needed.

Cryopreservation of Testicular Tissue in Adult Men with Azoospermia

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 as a subsequent procedure, specifically for the collection of spermatozoa. 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. (62) However, clinical trials evaluating health outcomes after cryopreservation of testicular tisuue in adult men with azoospermia were not identified.

Section Summary: Cryopreservation of Testicular Tissue

While cryopreservation of testicular tissue in adult men with azoospermia is a well-established component of the ICSI procedure, there is a lack of clinical trials to support this treatment.

Cryopreservation of Testicular Tissue in Prepubertal Boys Undergoing Cancer Therapy

A potential application of cryopreservation of testicular tissue is its potential to preserve the reproductive capacity in prepubertal boys undergoing cancer chemotherapy; the typical cryopreservation of an ejaculate is not an option in these patients. It is hypothesized that reimplantation of the frozen-thawed testicular stem cells will reinitiate spermatogenesis or, alternatively, spermatogenesis could be attempted in vitro, using frozen-thaw spermatogonia. While these strategies have been explored in animals, there are inadequate human studies. (63, 64)

Section Summary: Cryopreservation of Testicular Tissue in Prepubertal Boys Undergoing Cancer Therapy

No clinical trials were identified evaluating the safety and efficacy of cryopreservation of testicular tissue in prepubertal boys undergoing cancer therapy.

Uterine Transplant

In 2017, ECRI published a technology assessment that concluded that there is very limited evidence from several case reports that indicate that uterine transplantation is a safe long-term (up to 3 years) therapeutic option for live donors and recipient women with absolute uterine factor infertility (AUFI) who wish to bear children. One ongoing clinical trial is evaluating uterine transplantation using uteri from deceased donors. The current evidence indicates that this procedure results in very few births. Ongoing clinical trials may provide additional data on the safety of the uterine transplant in donors and recipients and the effectiveness in terms of conceiving and delivering a child. It is a short-term transplantation, as the transplanted uterus from the donor is removed from the recipient shortly after the birth of one or two children to prevent the need for long-term immunosuppression. (84)

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 reviews have addressed risk of birth defects. (65-67) The review with the most data was published by Hansen et al. (2013). (66) They examined 45 cohort studies with outcomes in 92,671 infants born following assisted reproduction 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 conducted in the United States or Canada (RR=1.38; 95% CI, 1.16 to 1.64). Another review published by Davies et al. (2012), included data on 308,974 live births in Australia, 6,163 of which followed use of ART. (67) There was a higher rate of birth defects after assisted conception (8.3%) compared with births to fertile women who did not need assisted reproduction (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, 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) Reviewers included controlled studies reporting at least 1 postnatal morbidity outcome in children who were and were not conceived using assisted reproductive. Twenty 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 studies), and allergic disease (5 studies). Findings were mixed on the risk of infectious and parasitic diseases. In the 8 studies examining this outcome, ORs varied between 1.37 and 5.7, and most results were not statistically significant. Rates of asthma or obstructive bronchitis were examined in 8 studies; three found significantly increased risk in children conceived by ART versus conceived spontaneously.

A Danish registry published in 2013 addressed the risk of childhood and adolescent mental disorders following assisted reproduction. (69) The study included 524 children born after IVF or ICSI and 22,009 children born after spontaneous conception. In an analysis adjusted for potential confounders, compared with spontaneously conceived children, there were no statistically significant increases in mental retardation, disorders of psychological development (e.g., autism spectrum disorders, speech and language disorders, 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 (70) 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.

Immune globulin (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, (71) 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).

A 2006 Cochrane review of various immunotherapies for treating recurrent miscarriage concluded that IVIG therapy provides no significant beneficial effect over placebo in preventing further miscarriages. (72) Meta-analyses published in 2015 and 2016 that included 11 RCTs also found no significant difference in the frequency of the number of live birth with IVIG vs placebo or treatment as usual. (73, 74) A 1999 blinded RCT of 41 women treated with IVIG or saline placebo also found no differences in live birth rates. (75) Likewise, a 2000 multicenter RCT comparing heparin plus low-dose aspirin with or without IVIG in women with lupus anticoagulant, anticardiolipin antibody, or both, found no significant differences. (76) In addition, a 2002 RCT of 58 women with at least 4 unexplained miscarriages compared IVIG with placebo and analyzed results by intention to treat. (77) The live birth rate was similar for both groups; also, there were no differences in neonatal data (e.g., birth weight, gestational age at delivery). Other nonrandomized but controlled trials have also reported no benefit for IVIG treatment.

In 2017, ECRI completed a health technology assessment focusing on immunotherapy for recurrent pregnancy loss. (78) The evidence review included 6 systemic reviews, 1 RCT, 2 non-RCTs, 4 case series, and 3 retrospective cohorts. ECRI concluded that immunotherapy provides no benefit for women who have experienced recurrent pregnancy loss and wish to become pregnant and carry a pregnancy to viability.

Section Summary: IVIg as a Treatment of Recurrent Fetal Loss

The evidence for IVIG treatment of recurrent fetal loss consists of multiple RCTs summarized in a Cochrane review, BCBSA TEC Assessment and ECRI health technology assessment that concluded that IVIG therapy provides no significant beneficial effect over placebo in preventing further miscarriages.

Practice Guidelines and Position Statements

American Society for Reproductive Medicine (ASRM) and Society for Assisted Reproductive Technology (SART)

In 2014, the ASRM and the SART published joint guidelines on assisted hatching in IVF. (79) The single recommendation in these guidelines stated 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. (59) The guidelines stated, “evidence indicates that oocyte vitrification and warming should no longer be considered experimental” and it included the following 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”.

American College of Obstetricians and Gynecologists (ACOG)

In 2014, the ACOG endorsed the 2013 ASRM/SART joint guidelines on mature oocyte cryopreservation. (80) The endorsement was affirmed in 2016.

American Society of Clinical Oncology (ASCO)

In 2013, the ASCO published guidelines on fertility preservation for patients with cancer. (81) The guidelines included the following recommendations for males and females, respectively.

“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...”.

“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 to patients who do not have a male partner, do not wish to use donor sperm, or have religious or ethical objections to embryo freezing”.

Agency for Healthcare Research and Quality (AHRQ)

In May 2008, the AHRQ published an evidence report on the effectiveness of assisted reproductive technology. (82) The report reviewed evidence on the outcomes of interventions used in ovulation induction, superovulation, and IVF for the treatment of infertility. Reviewers concluded that interventions for which there was sufficient evidence to demonstrate improved pregnancy or live birth rates included:

Administration of clomiphene citrate in women with polycystic ovarian syndrome;

Metformin plus clomiphene in women who fail to respond to clomiphene alone;

Ultrasound-guided embryo transfer, and transfer on day five post-fertilization, in couples with a good prognosis; and

Assisted hatching in couples with previous IVF failure.

The limitations of the AHRQ report 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.

There was insufficient evidence on other interventions. Infertility itself is associated with most of the adverse longer term outcomes. Reviewers concluded that despite the large emotional and economic burden resulting from infertility, there was relatively little high-quality evidence to support the choice of specific interventions. The AHRQs conclusion was based primarily on studies that had pregnancy rates as the primary end point, not live births. In addition, studies used multiple assisted hatching techniques.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 1.

Table 1. Summary of Key Trials

NCT No.

Trial Name

Planned Enrollment

Completion Date

Ongoing

Ovarian tissue cryopreservation

NCT02646384

Ovarian Tissue Freezing For Fertility Preservation In Girls Facing A Fertility Threatening Medical Diagnosis Or Treatment Regimen: A Study By The Naitonal Physicians Cooperative of the Oncofertility Consortium At Northwestern University

100

Jan 2020

NCT02900625

Validation of Method to Search Residual Disease in Auto-cryopreserved Ovarian Tissues

240

May 2020

NCT02846064

Development of Ovarina Tissue Autograft in Order to Restore Ovarian Function

50

Oct 2020

NCT02678910

Ovarian Tissue Freezing For Fertility Preservation in Women Facing A Fertility Threatening Medical Diagnosis/Treatment

24

Jan 2021

NCT01993732

Ovarian Tissue Cryopreservation in Females Undergoing Procedures That Will Potentially Lead to Loss of Ovarian Function

15

Dec 2041

Testicular tissue cryopreservation

NCT02872532

Testicular Tissue Cryopreservation for Fertility Preservation in Males Facing Fertility-causing Diseases or Treatment Regimens

100

Aug 2020

NCT02972801

Testicular Tissue Cryopreservation for Fertility Preservation in Patients Facing Infertility-causing Diseases or Treatment Regimens

250

Jan 2021

Blastocyst transfer

NCT02712840

Pregnancy Outcomes in Good Prognosis Patients Utilizing Fresh Single Blastocyst Transfer versus ‘Freeze-All’ and Delayed Frozen Single Blastocyst Transfer

118

Jun 2017

NCT02148393

Implantation Enhancement by Elective Cryopreservation of All Viable Embryos

212

Dec 2017

NCT02999958a

Adding Antioxidants Into Human Sequential Culture Media System

128

Mar 2018

NCT02746562

A Multicentre Randomized Controlled Trial of A “Freeze-All and Transfer Later” Versus a Conventional “Fresh Embryo Transfer” Strategy for Assisted Reproductive Technology (ART) in Women With A Regular Menstrual Cycle

424

Feb 2020

NCT03173885

An RCT Evaluating the Implantation Potential of Vitrified Embryos Screened by Next Generation Sequencing Following Trophectoderm biopsy, Versus Vitrified Unscreened Embryos In Good Prognosis Patients Undergoing IVF

276

Jan 2022

NCT: national clinical trial.

a Denotes industry-sponsored or cosponsored trial.

Summary of Evidence

For individuals who have male factor infertility who receive in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI), the evidence includes observational studies and a systematic review. Relevant outcomes are health status measures and treatment-related morbidity. No randomized controlled trials (RCTs) are available. Observational studies, which are subject to design limitations (e.g., selection bias), have found similar rates of clinical pregnancy and live birth after ICSI and standard IVF, and a meta-analysis of observational studies found a higher rate of genitourinary malformations in children born after ICSI (but only when lower quality studies were included in the analysis). Multiple RCTs are needed to compare health outcomes after ICSI for male factor infertility and standard IVF. The evidence is insufficient to determine the effects of the technology on health outcomes however, clinical input was obtained in 2012 by Blue Cross Blue Shield Association (BCBSA) and there was general agreement among reviewers that ICSI in men with male factor infertility was considered medically necessary.

For individuals who have infertility who receive IVF with blastocyst transfer, the evidence includes RCTs and meta-analyses. Relevant outcomes are health status measures and treatment-related morbidity. RCTs and meta-analyses have found that blastocyst transfer is associated with higher live birth rates than cleavage-stage transfer. One retrospective cohort study has reported a significantly higher rate of preterm birth after blastocyst-stage vs cleavage-stage transfer, but did not find increased risks of other outcomes such as low birth rate or perinatal mortality. A retrospective registry review of a similar population reported different findings. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have infertility sperm penetration assay (SPA) and hyaluronan binding assay (HBA) testing for determination if ICSI should be a part of IVF; determination of sperm maturation; and/or sperm selection the evidence identified is limited that assessed clinical outcomes. 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. A prospective RCT reported that the selection of hyaluronan-bound sperm for ICSI led to statistically significant reduction in pregnancy loss rates.

For individuals who have infertility who receive IVF with assisted hatching, the evidence includes RCTs, a systematic review, and a large observational study. Relevant outcomes are health status measures and treatment-related morbidity. RCTs have not shown that assisted hatching improves the live birth rate compared with standard care. Findings on clinical pregnancy rates after assisted hatching were mixed, but RCTs generally did not find improvements with assisted hatching vs standard care. A large observational study found that assisted hatching was associated with worse outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have infertility who receive IVF with embryo co-culture, the evidence includes RCTs and case series. Relevant outcomes are health status measures and treatment-related morbidity. Most clinical trials have not found improved implantation or pregnancy rates after co-culture, and studies have not reported live birth rates. Moreover, co-culture techniques have not been standardized. One RCT did report a higher clinical pregnancy rate with co-culture than with a standard practice control group, however, this process used a novel technique that has not yet been fully evaluated. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have cancer who will undergo treatment that may lead to infertility who receive cryopreservation of ovarian tissue, the evidence includes case series that have reported technique as well as pregnancies and live births after transplantation. Relevant outcomes are health status measures and treatment-related morbidity. The technique has not been standardized, and there is a lack of controlled studies on health outcomes following cryopreservation of ovarian tissue. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have cancer who will undergo treatment that may lead to infertility who receive cryopreservation of oocytes, the evidence includes RCTs and a systematic review on the technique in related populations. Relevant outcomes are health status measures and treatment-related morbidity. The systematic review found that fertilization rates ranged from 71% to 79%, and the clinical pregnancy rates per transfer ranged from 36% to 61%. The available studies have been conducted in highly selected populations and may not be generalizable to the population of interest, women with cancer. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have azoospermia who receive cryopreservation of testicular tissue as part of ICSI, the evidence includes no clinical trials. Relevant outcomes are health status measures and treatment-related morbidity. Although an established component of the ICSI procedure, there is a lack of clinical trials on cryopreservation of testicular tissue in adult men with azoospermia. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who are prepubertal boys with cancer who receive cryopreservation of testicular tissue, the evidence includes no clinical trials. Relevant outcomes are health status measures and treatment-related morbidity. No clinical trials were identified evaluating the safety and efficacy of cryopreservation of testicular tissue in prepubertal boys undergoing cancer therapy. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals in need of sperm DNA integrity testing the evidence identified no studies that assessed clinical outcomes. 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.

For individuals who have uterine factor infertility and are considering uterine transplantation the evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who with a history of recurrent spontaneous abortion the evidence for immunologic-based therapies to avoid recurrent spontaneous abortion consists of multiple RCTs summarized in a Cochrane review, BCBSA Technology Evaluation Center Assessment and an ECRI health technology assessment that concluded that immunotherapy provides no significant beneficial effect in preventing further miscarriages.

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, 89398, 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:

1. Van Steirteghem AC, Liu J, Joris H, et al. Higher success rate by intracytoplasmic sperm injection than by subzonal insemination. Report of a second series of 300 consecutive treatment cycles. Hum Reprod. Jul 1993; 8(7):1055-1060. PMID 8408486

2. Palermo G, Joris H, Devroey P, et al. Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet. Jul 4 1992; 340(8810):17-18. PMID 1351601

3. Palermo G, Joris H, Derde MP, et al. Sperm characteristics and outcome of human assisted fertilization by subzonal insemination and intracytoplasmic sperm injection. Fertil Steril. Apr 1993; 59(4):826-835. PMID 8458504

4. Van Steirteghem AC, Nagy Z, Joris H, et al. High fertilization and implantation rates after intracytoplasmic sperm injection. Hum Reprod. Jul 1993; 8(7):1061-1066. PMID 8408487

5. Fishel S, Timson J, Lisi F, et al. Micro-assisted fertilization in patients who have failed subzonal insemination. Hum Reprod. Mar 1994; 9(3):501-505. PMID 8006142

6. Boulet SL, Mehta A, Kissin DM, et al. Trends in use of and reproductive outcomes associated with intracytoplasmic sperm injection. JAMA. Jan 20 2015; 313(3):255-263. PMID 25602996

7. Massaro PA, MacLellan DL, Anderson PA, et al. Does intracytoplasmic sperm injection pose an increased risk of genitourinary congenital malformations in offspring compared to in vitro fertilization? A systematic review and meta-analysis. J Urol. May 2015; 193(5 Suppl):1837-1842. PMID 25813561

8. Glujovsky D, Blake D, Farquhar C, et al. Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology. Cochrane Database Syst Rev. Jul 11 2012; 7(7):CD002118. PMID 22786480

9. Glujovsky D, Farquhar C, Quinteiro Retamar AM, et al. Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology. Cochrane Database Syst Rev. Jun 30 2016; (6):Cd002118. PMID 27357126

10. Aziminekoo E, Mohseni Salehi MS, Kalantari V, et al. Pregnancy outcome after blastocyst stage transfer comparing to early cleavage stage embryo transfer. Gynecol Endocrinol. 2015; 31(11):880-884. PMID 26437606

11. Fernandez-Shaw S, Cercas R, Brana C, et al. Ongoing and cumulative pregnancy rate after cleavage-stage versus blastocyst-stage embryo transfer using vitrification for cryopreservation: impact of age on the results. J Assist Reprod Genet. Feb 2015; 32(2):177-184. PMID 25403438

12. Kaur P, Swarankar ML, Maheshwari M, et al. A comparative study between cleavage stage embryo transfer at day 3 and blastocyst stage transfer at day 5 in in-vitro fertilization/intra-cytoplasmic sperm injection on clinical pregnancy rates. J Hum Reprod Sci. Jul 2014; 7(3):194-197. PMID 25395745

13. Maheshwari A, Kalampokas T, Davidson J, et al. Obstetric and perinatal outcomes in singleton pregnancies resulting from the transfer of blastocyst-stage versus cleavage-stage embryos generated through in vitro fertilization treatment: a systematic review and meta-analysis. Fertil Steril. Dec 2013; 100(6):1615-1621, e1-10. PMID 24083875

14. Kallen B, Finnstrom O, Lindam A, et al. Blastocyst versus cleavage stage transfer in in vitro fertilization: differences in neonatal outcome? Fertil Steril. Oct 2010; 94(5):1680-1683. PMID 20137785

15. Ginström Ernstad E, Bergh C, Khatibi A, et al. Neonatal and maternal outcome after blastocyst transfer: a population-based registry study. Am J Obstet Gynecol. Mar 2016; 214(3):378, e371-378, e310. PMID 26928152

16. Freeman MR, Archibong AE, Mrotek JJ, et al. Male partner screening before in vitro fertilization: preselecting patients who require intracytoplasmic sperm injection with the sperm penetration assay. Fertil Steril. 2001; 76(6):1113-9. PMID 11730736

17. Oehninger S, Franken DR, Sayed E, et al. Sperm function assays and their predictive value for fertilization outcome in IVF therapy: a meta-analysis. Hum Reprod Update. 2000; 6(2):160-8. PMID 10782574

18. Huszar G, Ozenci CC, Cayli S, et al. Hyaluronic acid binding by human sperm indicates cellular maturity, viability and unreacted acrosomal status. Fertil Steril. 2003; 79(supplement3):1616-24. PMID 12801568

19. Cayli S, Jakab A, Ovari L, et al. Biochemical markers of sperm function: male fertility and sperm selection for ICSI. Reprod Biomed Online. 2003; 7(4):462-8. PMID 14656409

20. Origio, Inc. HBA Sperm Hyaluronan Binding Assay information sheet. Available at http://www.origio.com (accessed on 2013 November 18).

21. O’Brien J, Zini A. Sperm DNA integrity and male infertility. Urol. 2005; 65(1):16-22. PMID 15667855

22. Evenson DP, Larson KL, Jost LK. Sperm chromatin structure assay: its clinical use for detecting sperm DNA fragmentation in male infertility and comparisons with other techniques. J Androl. 2002; 23(1):23-43. PMID 11780920

23. Payne JF, Raburn DJ, Couchman GM, et al. Redefining the relationship between sperm deoxyribonucleic acid fragmentation as measured by the sperm chromatin structure assays and outcomes of assisted reproductive techniques. Fertil Steril. 2005; 84(2):356-64. PMID 16084876

24. Bungum M, Humaidan P, Spano M, et al. The predictive value of sperm chromatin structure assay parameters for the outcome of intrauterine insemination. Hum Reprod. 2004; 19(6):1401-8. PMID 15117894

25. Gandini L, Lombardo F, Paoli D, et al. Full term pregnancies achieved with ICSI despite high levels of sperm chromatin damage. Hum Reprod. 2004; 19(6):1409-17. PMID 15117904

26. Larson KL, DeJonge CJ, Barnes AM, et al. Sperm chromatin structure assay parameters as predictors of failed pregnancy following assisted reproductive techniques. Hum Reprod. 2000; 15(8):1717-22. PMID 10920092

27. Larson-Cook KL, Brannian JD, Hansen KA, et al. Relationships between the outcomes of assisted reproductive techniques and sperm DNA fragmentation as measured by the sperm chromatin structure assay. Fertil Steril. 2003; 80(4):895-202. PMID 14556809

28. Virro MR, Larson-Cook KL, Evenson DP. Sperm chromatin structure assay (SCSA) parameters are related to fertilization, blastocyst development, and ongoing pregnancy in in vitro fertilization and intracytoplasmic sperm injection cycles. Fertil Steril. 2004; 81(5):1289-95. PMID 15136092

29. Huszar G, Ozkavukcu S, Jakab A, et al. Hyaluronic acid binding ability of human sperm reflects cellular maturity and fertilizing potential: selection of sperm for intracytoplasmic sperm injection. Curr Opin Obstet Gynecol. 2006; 18(3):260-7. PMID 16735824

30. Li Z, Wang L, Cai J, et al. Correlation of sperm DNA damage with IVF and ICSI outcomes: a systematic review and meta-analysis. J Assist Reprod Genet. 2006; 23(9-10):367-76. PMID 17019633

31. The Practice Committee of the American Society for Reproductive Medicine. The clinical utility of sperm DNA integrity testing. Fertil Steril. 2006; 86(supplement 5):S35-7. PMID 17055843

32. The Practice Committee of American Society for Reproductive Medicine and Society for Assisted Reproductive Technology. Intracytoplasmic sperm injection (ICSI) for non-male factor infertility. Available at: <http://www.sreproductive tecnologies.org> (accessed on 2015 February 27).

33. The Practice Committee of Society for Assisted Reproductive Technology, Practice Committee of American Society for Reproductive Medicine. Blastocyst culture transfer in clinical-assisted reproduction: A Committee Opinion. Fertil Steril. 2008; 90(supplement 5):S174-7.

34. Benchaib M, Lornage J, Mazoyer C, et al. Sperm deoxyribonucleic acid fragmentation as a prognostic indicator of assisted reproductive technology outcome. Fertil Steril. 2007; 87(1):93-100. PMID 17074327

35. Eles de la Calle JF, Muller A, Walschaerts M, et al. Sperm deoxyribonucleic acid fragmentation as assessed by the sperm chromatin dispersion test in assisted reproductive technology programs: results of a large prospective multicenter study. Fertil Steril. 2007; [Epub ahead of print]. PMID 18166175

36. Lin MH, Kuo-Kuang Lee R, Li SH, et al. Sperm chromatin structure assay parameters are not related to fertilization rates, embryo quality, and pregnancy rates in in vitro fertilization and intracytoplasmic sperm injection, but might be related to spontaneous abortion rates. Fertil Steril. 2007 Sep 26; [Epub ahead of print] PMID 17904130

37. Bungum M, Humaidan P, Axmon A, et al. Sperm DNA integrity assessment in prediction of assisted reproduction technology outcome. Hum Reprod. 2007; 22(1):174-9. PMID 16921163

38. Muriel L, Meseguer M, Fernández JL, et al. Value of the sperm chromatin dispersion test in predicting pregnancy outcome in intrauterine insemination: a blind prospective study. Hum Reprod. 2006; 21(3):738-44. PMID 16311292

39. The Practice Committee of the American Society for Reproductive Medicine. Effectiveness and treatment for unexplained infertility. Fertil Steril. 2006; 86(5 supplement):S111-4. PMID 17055802

40. Carney SK, Das S, Blake D, et al. Assisted hatching on assisted conception (in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Cochrane Database Syst Rev. 2012; 12:CD001894. PMID 23235584

41. Kissin DM, Kawwass JF, Monsour M, et al. Assisted hatching: trends and pregnancy outcomes, United States, 2000-2010. Fertil Steril. Sep 2014; 102(3):795-801. PMID 25044084

42. Shi W, Hongwei T, Zhang W, et al. A prospective randomized controlled study of laser-assisted hatching on the outcome of first fresh IVF-ET cycle in advanced age women. Reprod Sci. Oct 2016; 23(10):1397-1401. PMID 27071963

43. Kanyo K, Zeke J, Kriston R, et al. The impact of laser-assisted hatching on the outcome of frozen human embryo transfer cycles. Zygote. Oct 2016; 24(5):742-747. PMID 26957232

44. Kervancioglu ME, 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. Hum Reprod. 1997; 12(6):1253-8. PMID 9222012

45. Tucker MJ, Morton PC, et al. Enhancement of outcome from intracytoplasmic sperm injection: does co-culture or assisted hatching improve implantation rates? Hum Reprod. 1996; 11(11):2434-7. PMID 8981127

46. Veiga A, Torello MJ, et al. Use of co-culture of human embryos on Vero cells to improve clinical implantation rate. Hum Reprod. 1999; 14(supplement 2):112-20. PMID 10690807

47. Wiemer KE, Cohen J, et al. The application of co-culture in assisted reproduction: 10 years of experience with human embryos. Hum Reprod. 1998; 13(supplement 4):226-38. PMID 10091073

48. Rubio C, Simon C, et al. Clinical experience employing co-culture of human embryos with autologous human endometrial epithelial cells. Hum Reprod. 2000; 15 (supplement 6):31-8. PMID 11261481

49. Wetzels AM, Bastiaans BA, et al. The effects of co-culture with human fibroblasts on human embryo development in vitro and implantation. Hum Reprod. 1998; 13(5):1325-30. PMID 9647567

50. Ohl J, de Mouzon J, Nicollet B, et al. Increased pregnancy rate using standardized coculture on autologous endometrial cells and single blastocyst transfer: a multicentre randomized controlled trial. Cell Mol Biol (Noisy-le- grand). 2015; 61(8):79-88. PMID 26718434

51. Tryde SKL, Yding AC, Starup J, et al. Orthotopic autotransplantation of cryopreserved ovarian tissue to a woman cured of cancer – follicular growth, steroid production and oocyte retrieval. Reprod BioMed Online. 2004; 8(4):448-53. PMID 15149569

52. Oktay K, Buyuk E, et al. Embryo development after heterotopic transplantation of cryopreserved ovarian tissue. Lancet. (2004) 363:837-40. PMID 15031026

53. Meirow D, Levron J, Eldar-Geva T, et al. Pregnancy after transplantation of cryopreserved ovarian tissue in a patient with ovarian failure after chemotherapy. N Engl J Med. Jan 3 2005; 353:318-21. PMID 15983020

54. Siegel-Itzkovich J. Woman gives birth after receiving transplant of her own ovarian tissue. BMJ. 2005; 331(7508):70. PMID 16002876

55. Donnez J, Dolmans MM, Demylle D, et al. Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet. 2004; 364(9443):1405-10. PMID 15488215

56. Kim SS, Battaglia DE, Soules MR. The future of human ovarian cryopreservation and transplantation: fertility and beyond. Fertil Steril. 2001; 75(6):1049-56. PMID 11384626

57. Lobo RA. Potential options for preservation of fertility in women. N Engl J Med. 2005; 353(1):64-73. PMID 16000356

58. Johnson J, Patrizio P. Ovarian cryopreservation strategies and the fine control of ovarian follicle development in vitro. Ann N Y Acad Sci. 2011; 1221:40-6. PMID 21401628

59. The Practice Committees of American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. Mature oocyte cryopreservation: a guideline. Fertil Steril. 2013; 99(1):37-43. PMID 23083924

60. Cobo A, Meseguer M, Remohi J, et al. Use of cryo-banked oocytes in an ovum donation programme: a prospective, randomized, controlled, clinical trial. Hum Reprod. 2010; 25(9):2239-46. PMID 20591872

61. Levi Setti PE, Albani E, Morenghi E, et al. Comparative analysis of fetal and neonatal outcomes of pregnancies from fresh and cryopreserved/thawed oocytes in the same group of patients. Fertil Steril. 2013; 100(2):396-401. PMID 23608156

62. Dafopoulos K, Griesinge G, Schultze-Mosgau A, et al. Cumulative pregnancy rate after ICSI with cryopreserved testicular tissue in non-obstructive azoospermia. Reprod BioMed Online. Apr 2005; 10(4):461-6. PMID 15901452

63. Hovatta O. Cryobiology of ovarian and testicular tissue. Best Pract Res Clin Obstet Gynaecol. Apr 2003; 17(2):331-42. PMID 12758103

64. Tournaye H, Goossens E, et al. Preserving the reproductive potential of men and boys with cancer: current concepts and future prospects. Hum Reprod Update. Nov-Dec 2004; 10(6):525-32. PMID 15319377

65. Farhi A, Reichman B, Boyko V, et al. Congenital malformations in infants conceived following Assisted Reproductive Technology in comparison with spontaneously conceived infants. J Matern Fetal Neonatal Med. Mar 4 2013. PMID 23451839

66. Hansen M, Kurinczuk JJ, Milne E, et al. Assisted reproductive technology and birth defects: a systematic review and meta-analysis. Hum Reprod Update. 2013. PMID 23449641

67. Davies MJ, Moore VM, Willson KJ, et al. ART and the risk of birth defects. N Engl J Med. May 10 2012; 366(19):1803-13. PMID 22559061

68. Kettner LO, Henriksen TB, Bay B, et al. Assisted reproductive technology and somatic morbidity in childhood: a systematic review. Fertil Steril. Mar 2015; 103(3):707-719. PMID 25624193

69. Bay B, Mortensen EL, Hvidtjorn D, et al. Fertility treatment and risk of childhood and adolescent mental disorders: register based cohort study. BMJ. 2013; 347:f3978. PMID 23833075

70. Paternal or Fetal Antigen Immunotherapy for Recurrent Fetal Loss. 1998 TEC Assessments; Tab 14. Chicago, Illinois: Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (1995 September) 10(18).

71. Intravenous Immune Globulin for Recurrent Spontaneous Abortion. 1998 TEC Assessments; Tab 14. Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program, (1998 August) Tab 14.

72. Porter TF, LaCoursiere Y, Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database Syst Rev. Apr 19 2006; (2):CD000112. PMID 16625529

73. Egerup P, Lindschou J, Gluud C, et al. The effects of intravenous immunoglobulins in women with recurrent miscarriages: a systematic review of randomised trials with meta-analyses and trial sequential analyses including individual patient data. PLoS One. Oct 2015; 10(10):e0141588. PMID 26517123

74. Wang SW, Zhong SY, Lou LJ, et al. The effect of intravenous immunoglobulin passive immunotherapy on unexplained recurrent spontaneous abortion: a meta-analysis. Reprod Biomed Online. Dec 2016; 33(6):720-736. PMID 27720163

75. Jablonowska B, Selbing A, Palfi M, et al. Prevention of recurrent spontaneous abortion by intravenous immunoglobulin: a double-blind placebo-controlled study. Hum Reprod. Mar 1999; 14(3):838-841. PMID 10221723

76. Branch DW, Peaceman AM, Druzin M, et al. A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy. The Pregnancy Loss Study Group. Am J Obstet Gynecol. Jan 2000; 182(1 Pt 1):122-127. PMID 10649166

77. Christiansen OB, Pedersen B, Rosgaard A, 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. Hum Reprod. Mar 2002; 17(3):809-816. PMID 11870141

78. ECRI Institute. Immunotherapy for Recurrent Pregnancy Loss. Plymouth Meeting (PA): ECRI Institute; 2017 June. 9 p. (Hotline Response)

79. Practice Committee of the American Society for Reproductive Medicine, Practice Committee of the Society for Assisted Reproductive Technology. Role of assisted hatching in in vitro fertilization: a guideline. Fertil Steril. Aug 2014; 102(2):348-351. PMID 24951365

80. American College of Obstetricians and Gynecologists (ACOG). Committee Opinion No. 584: Oocyte Cryopreservation (January 2014, Reaffirmed 2016). Available at <https://www.acog.org> (accessed – 2018 March 19).

81. Loren AW, Mangu PB, Beck LN, et al. Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. Jul 1 2013; 31(19):2500-10. PMID 23715580

82. Myers ER, McCrory DC, Mills AA, et al. Effectiveness of assisted reproductive technology (Evidence Report/Technology Assessment No. 167). Rockville, MD: Agency for Healthcare Research and Quality; May 2008.

83. Worrilow KC, Eid S, Woodhouse D, et al. Use of hyaluronan in the selection of sperm for intracytoplasmic sperm injection (ICSI): significant improvement in clinical outcomes—multicenter, double-blinded and randomized controlled trial. Hum Reprod. Feb 2013; 28(2):306-14. PMID 23203216

84. ECRI Institute. Uterine Transplantation for Treating Absolute Uterine Factor Infertility. Plymouth Meeting (PA): ECRI Institute; 2017 May. 8 p. (Hotline Response)

85. Paternal or Fetal Antigen Immunotherapy for Recurrent Fetal Loss. (Archived) Chicago. Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2009 November) OB/GYN Reproduction 4.02.02.

86. Immunoglobulin Therapy. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2017 October) Therapy 8.01.05.

87. Laboratory Tests of Sperm Maturity and Function. (Archived) Chicago. Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2009 September) OB/GYN Reproduction 4.02.01.

88. Reproductive Techniques. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2017 August) OB/Gyn Reproduction 4.02.04.

Policy History:

Date Reason
10/1/2018 Document updated with literature review. The following changes were made to Coverage Section: 1) Removed 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 ); 2) removed AI or IUI from Therapeutic drugs coverage statement; 3) removed “of prepubertal boys as a method of preserving fertility” from EIU reproductive techniques stating Cryopreservation of testicular tissue of prepubertal boys as a method of preserving fertility; and 4) added uterine transplant to the list of EIU reproductive techniques. References 7, 9-13, 15, 42-43, 50, 72-78, 83-84 added.
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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