Infertility

Infertility can be due either to female factors (ie, pelvic adhesions, ovarian dysfunction, endometriosis, prior tubal ligation), male factors (ie, abnormalities in sperm production, function, or transport or prior vasectomy), a combination of male and female factors, or unknown causes.

Treatment

Various reproductive techniques are available to establish a viable pregnancy; different techniques are used depending on the reason for infertility. 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. Not included in assisted reproduction is assisted insemination (artificial insemination) using sperm from either a woman's partner or a sperm donor. In most instances, assisted reproduction will involve in vitro fertilization, a 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. In some instances, the oocyte and sperm are collected but no in vitro fertilization takes place, and the gametes are reintroduced into the fallopian tubes. Examples of ARTs include, but are not limited to, gamete intrafallopian transfer, transuterine fallopian transfer, natural oocyte retrieval with intravaginal fertilization, pronuclear stage tubal transfer, tubal embryo transfer, zygote intrafallopian transfer, gamete, and embryo cryopreservation, oocyte, and embryo donation, and gestational surrogacy.

The various components of ART and implantation into the uterus can be broadly subdivided into oocyte harvesting procedures, which are performed on the female partner; sperm collection procedures, which are performed on the male partner; and the in vitro component (ie, the laboratory procedures), which are performed on the collected oocyte and sperm. The final step is the implantation procedure.

Most CPT codes describing the various steps in ART procedures are longstanding. They include codes for oocyte retrieval, sperm isolation, culture and fertilization of the oocyte, and embryo; zygote; or gamete transfer into the uterus or fallopian tubes. Only the relatively new reproductive techniques (ie, intracytoplasmic sperm injection, assisted hatching, co-culture of embryos) and cryopreservation of reproductive tissue (ie, testicular, ovarian, oocytes) will be considered within this evidence summary.

Regulatory Status

There are no medical devices or diagnostic tests related to assisted reproductive technologies that require U.S. Food and Drug Administration approval or clearance.

Related Policies

• Preimplantation Genetic Testing (Policy #005 in the Obstetrics Section)

(NOTE: The mandate excludes certain procedures/services including, but not limited to, cryopreservation and storage of sperm, eggs and embryos. Thus, cryopreservation services under the mandate will be subject to the eligibility criteria as defined below under policy statements III.B. and III.D.)

A. Eligible procedures/services that are routinely performed in all ART procedures involving in vitro fertilization (IVF):
• oocyte retrieval;
• either culture of oocyte(s)/embryo(s). less than 4 days, or extended culture and fertilization of oocyte(s)/embryo(s), 4-7 days;
• either insemination of oocytes, or assisted oocyte fertilization, microtechnique, either less than or greater than 10 oocytes;
• sperm isolation, simple or complex prep;
• preparation of embryo for transfer;
• embryo, zygote, or gamete transfer, intrauterine or intrafallopian.
B. Eligible procedures/services not routinely performed in all ART procedures involving IVF:
• sperm identification from aspiration (only performed in members with oligospermia, or low number of sperm in the semen, who have undergone a prior testicular or epididymal aspiration; typically performed as a part of intracytoplasmic sperm injection procedure);
• sperm identification from testicular tissue, fresh or cryopreserved (only performed in members with oligospermia who have undergone a prior testicular biopsy; typically performed as a part of an intracytoplasmic sperm injection procedure);
• intracytoplasmic sperm injection (only in members with male factor infertility);
• assisted embryo hatching, microtechniques (only performed in women over the age of 40, or in cases in which prior ART attempts resulted in failed implantation);
• cryopreservation of oocytes (only in members facing infertility due to chemotherapy or other gonadotoxic therapies);
• cryopreservation of embryos;
• cryopreservation of testicular tissue (only in adult men with azoospermia or absence of sperm in the semen, as part of an intracytoplasmic sperm injection procedure);
• cryopreservation of sperm;
• thawing of various cryopreserved components (only for eligible cryopreserved components);
• blastocyst transfer

C. [Please note that artificial insemination (assisted insemination) is NOT considered as an ART procedure.]
Although artificial insemination is not included in ART, procedures/services that are routinely performed as part of an intrauterine or intracervical artificial insemination include the following:
• intracervical artificial insemination;
• intrauterine artificial insemination;
• sperm washing for artificial insemination.

D. Procedures/services considered investigational:
• co-culture of embryos;
• intracytoplasmic sperm injection in the absence of male factor infertility;
• cryopreservation of ovarian tissue;
• cryopreservation of oocytes (other than for members facing infertility due to chemotherapy or other gonadotoxic therapies);
• cryopreservation of testicular tissue in prepubertal boys (but cryopreservation of testicular tissue is considered eligible in adult men with azoospermia, or absence of sperm in the semen, as part of an intracytoplasmic injection procedure);
• storage and thawing of ovarian tissue and other investigational cryopreserved components.

For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.

FIDE SNP:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[RATIONALE: This policy was created in 2009 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was conducted through June 10, 2019.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Assisted Hatching

Clinical Context and Therapy Purpose

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 (ie, assisted hatching) has been proposed as a mechanism to improve implantation rates.

The purpose of IVF with assisted hatching in patients with infertility is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does IVF with assisted hatching treat infertility and improve the net health outcome?

The following PICOs were used to select literature to inform this review.

Patients

The relevant population of interest are patients who are infertile.

Interventions

The therapy being considered is IVF with assisted hatching.

IVF with assisted hatching is performed by gynecologists in an outpatient setting.

Comparators

The following practice is currently being used to make decisions about infertility: IVF without assisted hatching.

Patients who do not receive IVF with assisted hatching are also managed by gynecologists and primary care providers in an outpatient setting.

Outcomes

The general outcomes of interest are live birth rates and infant abnormalities.

Follow-up is measured in weeks to confirm a successful pregnancy and months to confirm a successful birth.

Systematic Reviews

A Cochrane review and meta-analysis by Carney et al (2012) identified 31 RCTs evaluating assisted hatching (total n=5728 individuals).^1, 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 a laser for assisted hatching, 11 used chemical means, and 5 used mechanical means. Live birth rates were reported in 9 studies (n=1921 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 (odds ratio [OR], 1.03; 95% confidence interval [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 odds was marginally statistically significant (OR=1.13; 95% CI, 1.01 to 1.27).

Randomized Controlled Trials

Two RCTs not assessed in the Cochrane review have compared laser-assisted hatching with the standard of care. Shi et al (2016) evaluated 178 patients of advanced maternal age (age range, 35-42 years).^2, 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 (2016) assessed 413 women (mean age, 33 years).^3, 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 the clinical pregnancy rate among women younger than 38 years old. The age groupings (ie, <38 years vs ≥38 years) were not specifically discussed as a prespecified subgroup analysis. Neither trial reported live birth rates.

Retrospective Studies

Knudtson et al (2017), in a retrospective cohort study, analyzed live birth rates in women who underwent first-cycle, autologous frozen embryo transfer.^4, From data reported between 2004 and 2013 to the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System, 151,533 cycles were identified, 70,738 (46.7%) with assisted hatching and 80795 (53.3%) without. Assisted hatching had a significantly lower live birth rate (34.2%) than nonassisted hatching (35.4%; p<0.001). Also, older patients (age ≥38 years) who received assisted hatching were associated with lower live birth rates (p≤0.05). The study was limited by the retrospective nature of the database, incomplete data, and the inability due to deidentification to link thawed cycles to original retrieval and insemination techniques.

Kissin et al (2014) retrospectively reviewed data on assisted hatching in the U. S. from 2000 to 2010.^5, Data were taken from the Centers for Disease Control and Prevention's National Assisted Reproductive Technology Surveillance System. The analysis of outcomes was limited to fresh autologous IVF cycles for which a transfer was performed on day three or five. For the total patient population (n=536,852), rates of implantation, clinical pregnancy, and live births were significantly lower when assisted hatching was used. For example, the live birth rate was 28.3% with assisted hatching and 36.5% without (adjusted odds ratio [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% vs 13.5%; AOR=1.43; 95% CI, 1.34 to 1.52).

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 heterogeneous 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 (eg, 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 two or three of development, when it has between four and eight 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 implantation and pregnancy rates. In addition, if co-culture results in a higher implantation rate, fewer embryos could be transferred in each cycle, decreasing the 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 (ie, oviducts) to nonhuman cells (ie, fetal bovine uterine or oviduct cells) to established cell lines (ie, Vero cells or bovine kidney cells).

Clinical Context and Therapy Purpose

The purpose of IVF with embryo co-culture in patients with infertility is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does IVF with embryo co-culture to treat infertility improve the net health outcome?

The following PICOs were used to select literature to inform this review.

Patients

The relevant population of interest are patients who are infertile.

Interventions

The therapy being considered is IVF with embryo co-culture.

IVF with embryo co-culture is performed by gynecologists in an outpatient setting.

Comparators

The following practice is currently being used to make decisions about infertility: IVF without embryo co-culture.

Outcomes

The general outcomes of interest are live birth rates and infant abnormalities. Follow-up is measured to confirm successful pregnancy up to successful birth.

Randomized Controlled Trials

Currently, no standardized method of co-culture has emerged, and clinical trials have generally not found that co-culture is associated with improved implantation or pregnancy rates.^{6,7,8,9,10,11,} For example, Wetzels et al (1998) reported on an RCT that assigned IVF treatments to co-culture with human fibroblasts or no culture.^11, Patients in the 2 groups were stratified by age (older or younger than 36 years) and prior IVF attempts (yes vs no). The trialists reported that fibroblast co-culture did not affect the implantation or pregnancy rates. More recently, Ohl et al (2015) reported on a novel co-culture technique involving autologous endometrial cell co-culture.^12, 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 have not found improved implantation or pregnancy rates after co-culture. A 2015 RCT has 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

Clinical Context and Therapy Purpose

The purpose of cryopreservation of ovarian tissue in patients with cancer who will undergo treatment that could precipitate infertility is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does the cryopreservation of ovarian tissue treat infertility and improve the net health outcome?

The following PICOs were used to select literature to inform this review.

Patients

The relevant population of interest are cancer patients who undergo treatment that could precipitate infertility.

Interventions

The therapy being considered is cryopreservation of ovarian tissue.

Cryopreservation of ovarian tissue is performed by gynecologists in an outpatient setting.

Comparators

The following practice is currently being used to make decisions about infertility: cryopreservation of embryos but not of ovarian tissue.

Outcomes

The general outcomes of interest are live birth rates and infant abnormalities. Follow-up is measured to confirm successful pregnancy up to successful birth.

Case Series

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, radiotherapy, or surgery, frequently due to malignant diseases. There are a few case reports assessing the return of ovarian function using this technique.^13,14, There are also case series describing live births using cryopreserved ovarian tissue.^15,16,17, However, in general, the technique is not standardized and insufficiently studied to determine the success rate.^18,19, Johnson and Patrizio (2011) commented on whole ovary freezing as a fertility preservation technique in women with disease or disease treatment that threaten their reproductive tract function.^20, 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

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

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 a large amount of water when the oocyte is frozen, ice crystals may 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 two 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.

Clinical Context and Therapy Purpose

The purpose of cryopreservation of oocytes in cancer patients who will undergo treatment that might precipitate infertility is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does the cryopreservation of oocytes treat infertility improve and the net health outcome?

The following PICOs were used to select literature to inform this review.

Patients

The relevant population of interest are cancer patients who undergo treatment that might precipitate infertility.

Interventions

The therapy being considered is cryopreservation of oocytes.

Cryopreservation of oocytes is performed by gynecologists in an outpatient setting.

Comparators

The following practice is currently being used to make decisions about infertility: cryopreservation of embryos but not of ovarian tissue.

Outcomes

The general outcomes of interest are live birth rates and infant abnormalities. Follow-up is measured to confirm successful pregnancy up to successful birth.

Systematic Reviews

The American Society for Reproductive Medicine and Society for Assisted Reproductive Technology (2013) updated their joint guidelines on mature oocyte cryopreservation.^21, A systematic review of the literature, conducted as part of guideline development, identified four 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 (eg, 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 (n=600) cited in the guidelines was published by Cobo et al (2010) in Spain.^22, 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 noninferior to fresh oocyte transfer according to a prespecified margin of difference. The guidelines noted that the available data might not be generalizable to the U. S., to clinics with less experience with these techniques, or to other populations (eg, older women, cancer patients). The authors stated that data from the U. S. are available only from a few clinics and report on young highly select populations. Pregnancy outcomes and rates of congenital anomalies were not discussed.

Observational Studies

After the American Society for Reproductive Medicine and Society for Assisted Reproductive Technology guidelines were released, Levi Setti et al (2013) in Italy published an observational study.^23, 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% (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 U. S. Moreover, there is a lack of published data on success rates with cryopreserved oocytes in women who froze oocytes because they were undergoing chemotherapy. Data on health outcomes (eg, clinical pregnancy rate, live birth rate) in the population of interest are needed.

Blastocyst Transfer

The most common days for embryo transfer in the clinical IVF setting are day three or day five. Embryo transfer at the blastocyst stage on day five continues to be less common than cleavage-stage transfer on day three. 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 increased 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 concerns due to uncertainties about the effects of the culture microenvironment, as well as early indicators of a higher rate of adverse pregnancy outcomes.

Clinical Context and Therapy Purpose

The purpose of IVF with blastocyst transfer in patients with infertility is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does IVF with blastocyst transfer treat infertility and improve the net health outcome?

The following PICOs were used to select literature to inform this review.

Patients

The relevant population of interest are patients who are infertile.

Interventions

The therapy being considered is IVF with blastocyst transfer.

IVF with blastocyst transfer is performed by gynecologists in an outpatient setting.

Comparators

The following practice is currently being used to make decisions about infertility: IVF without cleavage-stage transfer.

Outcomes

The general outcomes of interest are live birth rates and infant abnormalities. Follow-up is measured to confirm successful pregnancy up to successful birth.

Systematic Reviews

Several systematic reviews of studies comparing outcomes associated with blastocyst-stage transfer with those of earlier stage transfer have been published. Only the Cochrane review by Glujovsky et al (2012) included RCTs.^24, They identified 23 RCTs, 12 of which reported on the rates of live births 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). Glujovsky et al (2016), in their updated Cochrane review, placed more emphasis 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.^25, Data from 4 new studies, 3 of which were published studies^26,27,28, and resulted in a total of 27 parallel-design RCTs that included 4031 couples or women. 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 intracytoplasmic sperm injection (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 was 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 pregnancies (OR=1.05, 95% CI, 0.83 to 1.33; 19 RCTs, 3019 women, I²=30%, low-quality evidence) or miscarriages (OR=1.15, 95% CI, 0.88 to 1.50; 18 RCTs, 2917 women, I²=0%, low-quality evidence). Reviewers reported that the main limitation of the RCTs assessed was a high-risk of bias, which was associated with failure to describe acceptable methods of randomization and unclear or high-risk of attrition bias.

Maheshwari et al (2013) identified 8 observational studies analyzing singleton births following embryo transfer at the blastocyst or cleavage stage and reporting obstetric and/or perinatal outcomes.^29, Meta-analysis of 6 studies found a significantly higher rate of preterm delivery at less than 37 weeks after blastocyst-stage transfer compared with cleavage-stage transfer (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 vs cleavage-stage embryo transfer.

Observational Studies

A retrospective cohort study by Kallen et al (2010) reported on risks associated with blastocyst transfer.^30, Data were taken from the Swedish Medical Birth Register. There were 1311 infants born after blastocyst transfer and 12562 born after cleavage-stage transfer. There were no significant differences in the rates of multiple births (10% after blastocyst transfer vs 8.9% after cleavage-stage transfer). Among singleton births, the rate of preterm birth (<32 weeks) was 1.7% (18/1071) in the blastocyst transfer group and 1.35% (142/10513) 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 AOR was 1.44 (95% CI, 0.87 to 2.40). The rate of low birth weight singletons (<1500 g or <2500 g) 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 (eg, spina bifida, cardiovascular defects, cleft palate) after blastocyst transfer (61/1311 [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 Appearance, Pulse, Grimace, Activity and Respiration scores, intracranial hemorrhage rates, respiratory diagnoses, or cardiovascular malformations. Respiratory diagnoses were given to 94 (7.2%) of 1311 infants born after blastocyst transfer and to 774 (6.2%) of 12562 after cleavage-stage transfer (OR=1.15; 95% CI, 0.90 to 1.47).

Ginström Ernstad et al (2016) published another retrospective registry cohort study using data crosslinked across the Swedish Medical Birth Register, the Register of Birth Defects, and the National Patient Register.^31, 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, 25747 after cleavage-stage transfer, and 1196394 after spontaneous conception. Singletons born after blastocyst transfer had no increased risk of birth defects compared with singletons born after the 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 with singletons born after spontaneous conception, a higher risk of preterm birth (<37 weeks) was detected (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; 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; 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 evaluated in the Cochrane review was a high-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 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.

ICSI for Male Factor Infertility

ICSI is performed in cases ofMFI when either insufficient numbers of sperm, abnormal sperm morphology, or poor sperm motility preclude unassisted IVF. Fertilization rates represent an intermediate outcome; the final outcome is the number of pregnancies per initiated cycle or per embryo transfer.

Clinical Context and Therapy Purpose

The purpose of IVF with ICSI in patients with MFI is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does IVF with ICSI treat MFI and improve the net health outcome?

The following PICOs were used to select literature to inform this review.

Patients

The relevant population of interest are men with MFI.

Interventions

The therapy being considered is IVF with ICSI.

IVF with ICSI is performed by gynecologists in an outpatient setting.

Comparators

The following practice is currently being used to make decisions about infertility: IVF without ICSI.

Outcomes

The general outcomes of interest are live birth rates and infant abnormalities. Follow-up is measured in months to confirm successful birth.

Case Series

The number of pregnancies per cycle and per embryo transfers, reported in relatively large series published in the mid-1990s, ranged between 45% and 50%.^{32,33,34,35,36,} At the time, those rates were very competitive with those of the standard IVF.

More recently, Borges et al (2017) retrospectively analyzed ICSI outcomes for patients with MFI compared with isolated tubal factor infertility (TFI).^37, Nine hundred twenty-two ICSI cycles (743 for MFI, 179 for TFI) performed between 2010 and 2016 were identified. No significant differences were observed between the groups for rates of implantation (MFI=35.5% vs TFI=32%, p=0.34), pregnancy (MFI=46.9% vs TFI=40.9%, p=0.184), and miscarriage (MFI 10.3% vs TFI 10.6%, p=0.572); rates remained similar even after women were stratified into groups by age (≤35 years: MFI=531 vs TFI=112; >35 years: MFI=212 vs TFI=67). The study was limited by its retrospective design and by the fact that MFI severity could not be determined because patients were not categorized by diagnosis.

Boulet et al (2015) published a large retrospective analysis of the outcomes following ICSI vs standard IVF (data captured from the Centers for Disease Control and Prevention's National Assisted Reproductive Technology Surveillance System from 2008 to 2012).^38, During that time, there were data on 494907 fresh IVF cycles. A total of 74.6% of cycles used ICSI, with 92.9% of the cycles involving MFI and 64.5% of the cycles not. Among couples with MFI, there was a statistically significantly lower rate of implantation after ICSI (25.5%) than after standard IVF (25.6%; p=0.02); however, this difference between groups was not clinically significant. Rates of clinical intrauterine pregnancy and live birth did not differ significantly between ICSI and standard IVF. In couples without MFI, implantation, clinical pregnancy, and live birth rates were all significantly higher with standard IVF than with ICSI.

Adverse Events

A systematic review and meta-analysis by Massaro et al (2015) examined adverse events related to ICSI and standard IVF without ICSI.^39, Twenty-two observational studies were included; no RCTs were identified. Meta-analysis of 12 studies found a significantly increased odds of congenital genitourinary malformations in children conceived using ICSI vs standard IVF (pooled OR=1.27; 95% 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 four studies considered at low-risk of bias did not determine whether ICSI was associated with a statistically increased odds of genitourinary malformations.

Section Summary: ICSI for MFI

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 (eg, selection bias). A 2015 meta-analysis of observational studies found a significantly higher rate of congenital genitourinary malformations in children born after ICSI vs IVF, but there was no significant difference when only studies with low-risk of bias were analyzed. RCTs comparing health outcomes after ICSI for MFI with standard IVF would strengthen the evidence base.

Cryopreservation of Testicular Tissue in Adult Men With Azoospermia

Testicular sperm extraction refers to the collection of sperm from testicular tissue in men with azoospermia. Extraction of testicular sperm may be performed during or subsequent to a diagnostic biopsy, specifically for the collection of spermatozoa. Spermatozoa may be isolated immediately and a portion used for an ICSI procedure during oocyte retrieval from the partner, with the remainder cryopreserved. Alternatively, the entire tissue sample can be cryopreserved with portion thawed and sperm isolation performed at subsequent ICSI cycles.

Clinical Context and Therapy Purpose

The purpose of the cryopreservation of testicular tissue as part of ICSI in patients with azoospermia is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does the cryopreservation of testicular tissue as part of ICSI treat azoospermia and improve the net health outcome?

The following PICOs were used to select literature to inform this review.

Patients

The relevant population of interest are men who are infertile.

Interventions

The therapy being considered is cryopreservation of testicular tissue as part of ICSI.

Comparators

The following practice is currently being used to make decisions about infertility: IVF without cryopreservation of testicular tissue.

Outcomes

The general outcomes of interest are live birth rates and infant abnormalities. Follow-up is measured in months to confirm successful birth.

Case Series

Testicular tissue extraction appears to be a well-established component of the overall ICSI procedure; cryopreservation of either the isolated sperm or the tissue sample eliminates the need for multiple biopsies to obtain fresh tissue in the event of a failed initial ICSI cycle.^40, However, clinical trials evaluating health outcomes after cryopreservation of testicular tissue in adult men with azoospermia were not identified.

Section Summary: Cryopreservation of Testicular Tissue in Adult Men With Azoospermia

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 With Cancer

A potential application of cryopreservation of testicular tissue is its potential to preserve the reproductive capacity in prepubertal boys undergoing cancer chemotherapy; cryopreservation of ejaculate is not an option in these patients.

Clinical Context and Therapy Purpose

The purpose of the cryopreservation of testicular tissue in prepubertal boys with cancer is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does the cryopreservation of testicular tissue from prepubertal boys with cancer improve the net health outcome?

The following PICOs were used to select literature to inform this review.

Patients

The relevant population of interest are prepubertal boys with cancer.

Interventions

The therapy being considered is the cryopreservation of testicular tissue.

Comparators

The following practice is currently being used to make decisions about infertility: no cryopreservation of testicular tissue.

Outcomes

The general outcomes of interest are live birth rates and infant abnormalities. Follow-up is measured in months to confirm successful birth.

Modeling Studies

It has been 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.^41,42,

Section Summary: Cryopreservation of Testicular Tissue in Prepubertal Boys With Cancer

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

Potential Adverse Events to Offspring Conceived Via Assisted Reproduction

Systematic Reviews

Several systematic reviews have addressed the risk of birth defects.^43,44,45,46, A systematic review by Kettner et al (2015) considered potential adverse events in children of various ages.^43, Reviewers included controlled studies reporting at least one postnatal morbidity outcome in children who were and were not conceived using assisted reproduction. 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 assisted reproductive technologies: chronic diseases (two studies), cancer (three studies), and allergic disease (five studies). Findings were mixed on the risk of infectious and parasitic diseases. In the 8 studies examining this outcome, the odds varied between 0.37 and 5.7, and most results were not statistically significant. Rates of asthma or obstructive bronchitis were examined in eight studies; three found significantly increased risk in children conceived by assisted reproductive technologies vs conceived spontaneously.

The review with the most data is that by Hansen et al (2013).^45, They examined 45 cohort studies with outcomes in 92671 infants born following assisted reproduction and 3870760 naturally conceived infants. In a pooled analysis, there was a higher risk of birth defects in infants born using reproductive techniques (relative risk, 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 U. S. or Canada (relative risk, 1.38; 95% CI, 1.16 to 1.64). Another review, published by Davies et al (2012), included data on 308974 live births in Australia, 6163 of which used assisted reproductive technologies.^46, There was a higher rate of birth defects after assisted conception (8.3%) compared with births to fertile women who did not use 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 (eg, maternal age, parity, maternal ethnicity, maternal smoking during pregnancy, socioeconomic status; OR=1.28; 95% CI, 1.16 to 1.41).

Registry Studies

A Danish registry study by Bay et al (2013) addressed the risk of childhood and adolescent mental disorders following assisted reproduction.^47, The study included 524 children born after IVF or ICSI and 22009 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 disabilities, disorders of psychological development (eg, autism spectrum disorders, speech and language disorders, others), attention-deficit/hyperactivity disorder or conduct, emotional, or social disorders.

Summary of Evidence

For individuals who have infertility who receive IVF with assisted hatching, the evidence includes RCTs, a systematic review, and retrospective studies. The 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. Clinical pregnancy rates after assisted hatching have been mixed but RCTs have generally not found improvements in 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. The 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, the process was novel and not yet 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 on the technique as well as pregnancy and live birth rates after transplantation. The relevant outcomes are health status measures and treatment-related morbidity. The technique used 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 assessing the technique in related populations. The 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 select 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 infertility who receive IVF with blastocyst transfer, the evidence includes RCTs and meta-analyses. The relevant outcomes are health status measures and treatment-related morbidity. The 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 and did not find increased risks of other outcomes such as a 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 male factor infertility who receive IVF with ICSI, the evidence includes observational studies and a systematic review. The relevant outcomes are health status measures and treatment-related morbidity. No RCTs are available. Observational studies, which are subject to design limitations (eg, 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.

For individuals who have azoospermia who receive cryopreservation of testicular tissue as part of ICSI, the evidence includes no clinical trials. The relevant outcomes are health status measures and treatment-related morbidity. 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 assessing safety and efficacy. 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. The 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.

SUPPLEMENTAL INFORMATION

Clinical Input From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 4 physician specialty societies and 2 academic medical centers while this policy was under review in 2012. There was general agreement that intracytoplasmic sperm injection and cryopreservation of testicular tissue in adult men with azoospermia as part of an intracytoplasmic sperm injection procedure may be considered medically necessary. Three of five reviewers who responded agreed that co-culture of embryos is considered investigational. In addition, four of five reviewers did not agree that blastocyst transfer is investigational; these reviewers considered blastocyst transfer to be medically necessary to decrease multiple gestations. Three of six reviewers agreed that cryopreservation of ovarian tissue or oocytes is investigational. The other three thought that cryopreservation of oocytes, but not ovarian tissue, is medically necessary. Clinical input on other policy statements was more variable.

Practice Guidelines and Position Statements

American Society for Reproductive Medicine and Society for Assisted Reproductive Technology

The American Society for Reproductive Medicine (ASRM) (2018) issued an ethics committee opinion on planned oocyte cryopreservation (OC) for preserving future reproductive potential.^48, The committee states the process is ethical and “serves women’s legitimate interests in reproductive autonomy.” Women who choose OC should be informed of its efficacy, safety, benefits, and risks, and possible long-term health effects on the child. Providers should also provide their clinic’s statistics for successful freeze-thaw and live birth. Women should know that this relatively new technology is still emerging and not all benefits and harms are fully understood.

The ASRM and the Society for Assisted Reproductive Technology (SART) (2014) published joint guidelines on assisted hatching and in vitro fertilization (IVF).^49, The single recommendation in these guidelines stated that assisted hatching should not be used routinely for all patients undergoing IVF.

The ASRM and SART (2013) published joint guidelines on mature OC.^21, The guidelines stated: "evidence indicates that oocyte vitrification and warming should no longer be considered experimental" and 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."

The ASRM and SART (2008) also issued a committee opinion on blastocyst transfer,^51, which was updated in 2013. The opinion concluded that "evidence supports blastocyst transfer in ‘good prognosis' patients." An additional update was issued in 2018. ^48, It did not change the position of the committee.

American College of Obstetricians and Gynecologists

The American College of Obstetricians and Gynecologists (2014) endorsed the 2013 ASRM-SART joint guidelines on mature OC.^52, The endorsement was affirmed in 2016.

American Society of Clinical Oncology

The American Society of Clinical Oncology (2018) updated its 2013 guidelines (with no changes to its recommendations) on fertility preservation for patients with cancer.^53,54, 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 for patients who do not have a male partner, do not wish to use donor sperm, or have religious or ethical objections to embryo freezing..."

Agency for Healthcare Research and Quality

Myers et al (2008), in an evidence report conducted for the Agency for Healthcare Research and Quality, evaluated the effectiveness of assisted reproductive technology.^55, They reviewed evidence on the outcomes of interventions used in ovulation induction, superovulation, and IVF for the treatment of infertility. Reviewers concluded that:

"[i]nterventions for which there was sufficient evidence to demonstrate improved pregnancy or live birth rates included: …, a pertinent to this policy: (c) ultrasound-guided embryo transfer, and transfer on day 5 post-fertilization, in couples with a good prognosis; and (d) assisted hatching in couples with previous IVF failure. There was insufficient evidence of other interventions.

Infertility itself is associated with most of the adverse longer-term outcomes."

Reviewers concluded that "[d]espite the large emotional and economic burden resulting from infertility, there was relatively little high-quality evidence to support the choice of specific interventions." This conclusion was based primarily on studies that had pregnancy rates as the primary endpoint, not live births. In addition, studies used multiple assisted hatching techniques.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and 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	100	Jan 2020
NCT02900625	Validation of a Method to Search Residual Disease in Auto-cryopreserved Ovarian Tissues	240	May 2020
NCT02846064	Development of Ovarian 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 DiagnosisOr Treatment Regimen	24	Jan 2021
NCT01993732	Ovarian Tissue Cryopreservation in Females Undergoing Procedures That Will Potentially Lead To Loss of Ovarian Function	15	Dec 2041
Blastocyst transfer
NCT02148393	Elective Blastocyst Vitrification for Endometrial Receptivity Enhancement in High-responder Patients Undergoing in Vitro Fertilisation/Intracytoplasmatic Sperm Injection (IVF/ICSI)	212	Feb 2017
NCT02999958a	Comparison of G-Series Media System With Antioxidants Versus Standard G-Series Media System	128	May 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	Sep 2019
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
Testicular tissue cryopreservation
NCT02872532	Testicular Tissue Cryopreservation for Fertility Preservation in Males Facing Fertility Threatening Diagnoses 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

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Assisted Reproductive Technologies
ART (Assisted Reproductive Technologies)
Assisted Hatching
Assisted Oocyte Fertilization
Co-Culture of Embryo
Cryopreservation, Embryo
Cryopreservation, Oocyte
Cryopreservation, Ovarian Tissue
Cryopreservation, Sperm
Cryopreservation, Testicular Tissue
Embryo Co-Culture
Gamete Intrafallopian Transfer (GIFT)
GIFT (Gamete Intrafallopian Transfer)
ICSI (Intracytoplasmic Sperm Injection)
In Vitro Fertilization (IVF)
IVF (In Vitro Fertilization)
Natural Oocyte Retrieval with Intravaginal Fertilization (NORIF)
NORIF (Natural Oocyte Retrieval with Intravaginal Fertilization)
Reproductive Techniques
Transuterine Fallopian Transfer (TUFT)
TUFT (Transuterine Fallopian Transfer)
ZIFT (Zygote Intrafallopian Transfer)
Zygote Intrafallopian Transfer (ZIFT)

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22. 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. Sep 2010;25(9):2239-2246. PMID 20591872

23. 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. Aug 2013;100(2):396- 401. PMID 23608156

24. 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

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

27. 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

28. 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

29. 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 e1611- 1610. PMID 24083875

30. 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

31. Ginstrm 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

32. 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

33. 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

34. 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

35. 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

36. 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

37. Borges Jr E, Zanetti BF, Braga DPAF, et al. Overcoming male factor infertility with intracytoplasmic sperm injection. Rev Assoc Med Bras (1992). 2017 63(8):697-703. PMID 28977108

38. 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

39. 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

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Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

54500
54800
55400
55870
58321
58322
58323
58970
58974
58976
89240
89250
89251
89252
89253
89254
89255
89257
89258
89259
89260
89261
89264
89268
89272
89280
89281
89335
89337
89342
89343
89344
89346
89352
89353
89354
89356
0058T
0059T
0357T

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