For purposes of this entire policy, Aetna covers diagnostic infertility services to determine the cause of infertility and treatment only when specific coverage is provided under the terms of a member’s benefits plan. All coverage is subject to the terms and conditions of the plan. The following discussion is applicable only to members whose plans cover infertility services.
For purposes of this policy, a member is considered infertile if he or she is unable to conceive or produce conception after 1 year of frequent, unprotected heterosexual sexual intercourse, or 6 months of frequent, unprotected heterosexual sexual intercourse if the female partner is over age 35 years. Alternately, a woman without a male partner may be considered infertile if she is unable to conceive or produce conception after at least 12 cycles of donor insemination (6 cycles for women aged 35 or older). However, this definition of infertility may vary due to state mandates and plan customization; please check plan documents.
Note: Most plans exclude coverage of infertility services for couples in which either of the partners has had a previous sterilization procedure, with or without surgical reversal, and for females who have undergone a hysterectomy. Individuals who have undergone genital gender reassignment surgery (female to male or male to female) are considered to have undergone elective sterilization and are also not eligible for infertility services under these benefit plans. Please check benefit plan descriptions for details. In addition, infertility services for persons who have undergone voluntary sterilization procedures are not covered because such services are not considered treatment of disease. The inability to conceive in a couple who has undergone a voluntary sterilization procedure, including tubal sterilization or vasectomy, with or without surgical reversal, is not the result of disease but the result of an elective procedure intended to prevent conception.
Note: Some plans exclude coverage of infertility services using a woman's own eggs for women with poor ovarian reserve, as determined by measurement of serum FSH, a marker of ovarian reserve, Ovarian responsiveness is determined by measurement of an unmedicated day 3 FSH obtained within the prior 6 months if the woman is older than age 35 or within in the prior 12 months if the woman is 35 years of age or younger. Under these plans, for women who are less than age 40, the day 3 FSH must be less than 19 mIU/mL in their most recent lab test to use their own eggs. For women age 40 and older, their unmedicated day 3 FSH must be less than 19 mIU/mL in all prior tests to use their own eggs. Please check benefit plan descriptions. In addition, infertility services for women with natural menopause in women age 40 years and older are not covered as such services are not considered treatment of disease. Women with ovarian failure who are less than 40 years of age are considered to have premature ovarian failure (also known as premature ovarian insufficiency, primary ovarian insufficiency, or hypergonadotropic hypogonadism). Advanced reproductive technology (in vitro fertilization) services are considered medically necessary for women with premature ovarian failure who are less than 45 years of age.
Infertility services are considered not medically necessary once pregnancy is established and a fetal heartbeat is detected. Infertility services beyond 8 weeks of pregnancy are not considered medically necessary.
Females: Basic Infertility Services
The following services are considered medically necessary for diagnosis and/or treatment of infertility.
The following laboratory studies are considered experimental and investigational:
Note: Many plans exclude coverage of home pregnancy tests and home ovulation test kits. Please check benefit plan descriptions.
The following diagnostic procedures are considered medically necessary:
The following non-surgical treatments are considered medically necessary:
Note: The medications listed above may not be covered for members without pharmacy benefit plans; in addition, some pharmacy benefit plans may exclude or limit coverage of some or all of these medications. Please check benefit plan descriptions for details.
The following non-surgical treatments are considered experimental and investigational:
Leukocyte immunization (immunizing the female partner with the male partner's leukocytes) (See CPB 0348 - Recurrent Pregnancy Loss); and
Dehydroepiandrosterone (DHEA); and
FSH manipulation of women with elevated FSH levels. (An elevated FSH level is a marker of reduced ovarian reserve, as occurs with advancing age. Elevated FSH-related (i.e., age-related) infertility has not been proven to be affected by interventions to reduce FSH levels.); and
Parenteral administration of lipids.
Females: Additional Infertility Services
The following additional services (referred to in some plans as "Comprehensive Infertility Services") may be considered medically necessary if the member is unable to conceive after treatment with Basic Infertility Services, or if the member's diagnosis suggests that there is no reasonable chance of pregnancy as a result of Basic Infertility Services.
Injectable medications (See CPB 0020 - Injectable Medications)
Gonadotropin releasing hormone (GnRH) (luteinizing hormone releasing hormone (LHR-H)) by intermittent subcutaneous injections or by GnRH infusion pump (See CPB 0501 - Gonadotropin-Releasing Hormone Analogs and Antagonists for additional information and limitations.)
Considered medically necessary for the following indications:
Gonadotropins are considered medically necessary for the following indications:
Gonadotropin releasing hormone (GnRH) antagonists
GnRH antagonists (ganirelix acetate (Antagon), cetrorelix acetate (Cetrotide)) are considered medically necessary for women undergoing assisted reproduction techniques (ART) to prevent premature LH surge in women undergoing controlled ovarian stimulation with gonadotropins, allowing the follicles to mature for planned oocyte collection. (Note: coverage of GnRH antagonists for this indication is limited to plans that cover advanced reproductive technologies. Please check benefit plan descriptions for details.)
In-vitro maturation (IVM) of oocytes for infertility treatment is considered experimental and investigational.
Note: Many plans exclude coverage for infertility injectable medications; other plans may limit coverage of ovulation induction cycles with menotropins to six (6) per lifetime. Please check plan documents for details.
Artificial insemination: See section IV below.
Males: Infertility Services
The following services are considered medically necessary for diagnosis and/or treatment of infertility in men:
Serum hormone levels
Semen analysis (volume, pH, liquefaction time, sperm concentration, total sperm number, motility (forward progression), motile sperm per ejaculate, vitality, round cell differentiation (white cells versus germinal), morphology, viscosity, agglutination) is considered medically necessary for the evaluation of infertility in men. Because of the marked inherent variability of semen analyses, an abnormal result should be confirmed by at least one additional sample collected one or more weeks after the first sample.
Note: Seminal alpha-glucosidase, zinc, citric acid, and acid phosphatase are considered experimental and investigational.
Sperm penetration assay (zona-free hamster egg penetration test)
Note: The following sperm function tests are considered experimental and investigational:
Karyotyping of couples with recurrent pregnancy loss (defined as 2 or more consecutive spontaneous abortions) (See CPB 0348 - Recurrent Pregnancy Loss) and for men with severe deficits in semen quality or nonobstructive azoospermia (for consideration of ICSI).
Note: Fine needle aspiration (“mapping”) of testes, and microdissection of the zona are considered experimental and investigational because their efficacy have not been established.
Injectable Endocrine Management:
Human chorionic gonadotropin (hCG) (Novarel, Pregnyl), human menopausal gonadotropin (hMG) (Menopur, Repronex), urofollitropin (Bravelle) and recombinant follitropins (Gonal-F, Gonal-F RFF, Follistim and Follistim AQ) are considered experimental and investigational for idiopathic male infertility (i.e., for men without documented hypogonadotropic hypogonadism), idiopathic microphallus and all other indications in men because they have not been found to be effective for those indications.
Ovidrel (recombinant chorionic gonadotropin alpha, rhCG), Cetrotide (cetrorelix acetate), Ganirelix (ganerelix acetate), and Luveris (lutropin alpha) are considered experimental and investigational for use in males, including but not limited to any type of male infertility.
Note: Many plans that otherwise cover infertility treatments exclude coverage for infertility injectable medications. Please check benefit plan descriptions.
Note: Most plans exclude coverage for reversal of sterilization procedures. This would include vasectomy. Please check benefit plan descriptions for details.
Surgical correction of epididymal blockage for men with obstructive azoospermia.
Note: Under most Aetna benefit plans, self-administered prescription medications are covered under the pharmacy benefit. Please check benefit plan descriptions.
Donor insemination is considered medically necessary for the following indications:
Many Aetna plans that otherwise cover infertility services exclude coverage of fees associated with donor insemination (including semen donor recruitment, selection and screening, and cryostorage of sperm). In addition, cryopreservation of semen not covered as it is not considered treatment of disease. Please check benefit plan descriptions for details.
* Some plans limit coverage of donor insemination to couples who are infertile. Under these plans, donor insemination would not be covered for these indications (infectious disease in male partner, high risk of transmitting a genetic disorder) as these do not meet the contractual definition of infertility. Please check benefit plan descriptions.
Note: Some Aetna benefit plans may exclude coverage of artificial insemination (AI). For Aetna benefit plans that cover artificial insemination, coverage is typically limited to six (6) cycles per lifetime. Please check benefit plan descriptions.
Advanced Reproductive Technology
The following Advanced Reproductive Technologies (ART) procedures are considered medically necessary for women with infertility that meet either of the following criteria:
Couples for whom natural or artificial insemination would not be expected to be effective and ART would be expected to be the only effective treatment, including:
Women with tubal factor infertility:
Failure to conceive after pelvic surgery with restoration of normal pelvic anatomy (see section I. E above for pelvic surgery procedures for infertility):
After trying to conceive for 3 months if 40 years of age or older.
Unilateral hydrosalpinx with failure to conceive:
After trying to conceive for 6 months if 40 years of age or older.
Inadvertent ovarian hyperstimulation (estradiol level was greater than 1,000 pg/ml plus greater than 3 follicles greater than 16 mm or 4 to 8 follicles greater than 14 mm or a larger number of smaller follicles) during preparation for a planned stimulated cycle in women less than 40 years of age.
Note: Coverage is limited to plans with an ART benefit; please check benefit plan descriptions).
Note on coverage of ART for preimplantation genetic diagnosis (PGD): The procedure to obtain the cell sample for PGD (i.e., the embryo biopsy) is covered when medical necessity criteria for PGD are met as set forth in CPB 0358 - Invasive Prenatal Diagnosis of Genetic Diseases. However, under plans that limit coverage of ART to persons who are infertile, the IVF procedure (i.e., the procedures and services required to create the embryos to be tested and the transfer of the appropriate embryos back to the uterus after testing) is covered only for persons with ART benefits who are infertile (please check benefit plan descripitons) and meet medical necessity criteria for ART.
IVF with embryo transfer is considered medically necessary when criteria for ART are met. IVF with embryo transfer includes:
Note on IVF cycles for embryo banking: IVF cycles for the sole purpose of embryo banking (where none of the embryos that are suitable for transfer are used in the current cycle in which they are created, but are frozen for use in a future cycle) is not considered treatment of disease and is not covered.
Gamete intra-fallopian transfer (GIFT) is considered medically necessary as an alternative to IVF for women with female factor infertility. GIFT includes:
GIFT is considered experimental and investigational for person with male factor infertility or unexplained infertility problems because there is insufficient evidence to recommend GIFT over IVF for these indications.
Zygote intra-fallopian transfer (ZIFT), tubal embryo transfer (TET), pronuclear stage tubal embryo transfer (PROUST) is considered medically necessary as an alternative to IVF for women with female factor infertility.
ZIFT is considered experimental and investigational for persons with male factor infertility or unexplained infertility problems because there is insufficient evidence to recommend ZIFT over IVF for these indications.
Specialized sperm retrieval techniques (including vasal sperm aspiration, microsurgical epididymal sperm aspiration (MESA), percutaneous epididymal sperm aspiration (PESA), electroejaculation, testicular sperm aspiration (TESA), microsurgical testicular sperm extraction (TESE), seminal vesicle sperm aspiration, and sperm recovery from bladder or urine for retrograde ejaculation) are considered medically necessary to overcome anejaculation or azoospermia.
Note: Most plans exclude coverage of infertility services for persons who have undergone sterilization. This would include sperm retrieval for men who have undergone vasectomy. Please check benefit plan descriptions for details.
Oocyte donation is considered medically necessary for managing infertility problems associated with the following conditions, when the infertile member is the intended recipient of the resulting embryos:
Note: Many Aetna plans that otherwise cover infertility services exclude coverage of fees associated with oocyte donation, including recruitment and selection of donors, ovarian stimulation of donors, collection of oocytes from donors, and screening and storage of donor oocytes. Please check benefit plan descriptions for details. Under plans with benefits for IVF that have this exclusion, medically necessary IVF services are covered only once an embryo is created from the donor egg.
Cryopreservation of mature oocytes or embryos is considered medically necessary in women facing infertility due to chemotherapy, pelvic radiotherapy, or other gonadotoxic therapies. Routine use of oocyte cryopreservation in lieu of embryo cryopreservation, oocyte cryopreservation to circumvent reproductive aging in healthy women, cryopreservation of immature oocytes, and laser-assisted necrotic blastomere removal from cryopreserved embryos are considered experimental and investigational. Note: Some Aetna plans have a specific contractual exclusion of coverage of any charges associated with embryo cryopreservation or storage of cryopreserved embryos. Please check benefit plan descriptions. In addition, cryopreservation of embryos and oocytes (other than short-term cryopreservation of embryos that are necessary for contemporaneous use in infertile persons currently under active fertility treatment, or use of cryopreserved embryos or mature oocytes in women facing infertility due to chemotherapy or other gonadotoxic therapies) is not considered treatment of disease and is not covered.
Cryopreservation of sperm is considered medically necessary in men facing infertility due to chemotherapy, pelvic radiotherapy, or other gonadotoxic therapies. Sperm cryopreservation to circumvent reproductive aging in healthy men is considered experimental and investigational. Note: Some Aetna plans have a specific contractual exclusion of coverage of any charges associated with sperm cryopreservation or storage. Please check benefit plan descriptions. In addition, cryopreservation of sperm (other than cryopreserved sperm in men facing infertility due to chemotherapy or other gonadotoxic therapies) is not considered treatment of disease and is not covered.
The following procedures are considered experimental and investigational:
Note: A cycle of ART defined in the CPB may be any of the following: IVF (with fresh embryos), IVF/frozen embryo transfer, GIFT or ZIFT.
Note on elective single embryo transfer: In order to reduce the number of high-order multiple pregnancies, current guidelines from the American Society for Reproductive Medicine (ASRM, 2009) recommend elective single embryo transfer for women under the age of 35 who have no prior IVF cycles or who have had a previous IVF cycle that was successful in producing a pregnancy (i.e., documentation of fetal heartbeat) and who have excess embryos of sufficient quality to warrant cryopreservation. For women who meet these criteria who elect transfer of a single fresh embryo, Aetna will consider transfer of 1 cryopreserved embryo immediately subsequent to the fresh embryo transfer as part of the same IVF cycle, under plans that limit the number of IVF cycles that are covered. Please check benefit plan descriptions for details.
The following numbers of laboratory services per cycle are considered medically necessary.
|Natural monitoring||Clomid monitoring||Clomid IUI||Inj Mon Cycle||Inj IUI||IVF||GIFT||FET Code||PM|
Key: IUI: intra-uterine insemination; Inj: injection; Mon: monthly; IVF: in-vitro fertilization; GIFT: gamete intra-fallopian transfer; FET: frozen embryo transfer; PM: pregnancy monitoring; FSH: follicle stimulating hormone; LH: luteinizing hormone; hCG: human chorionic gonadotropin.
*Note: More than 2 progesterone measurements may be medically necessary for infertile women with irregular and prolonged menstrual cycles. For infertile women with regular menstrual cycles, a mid-luteal serum progesterone measurement (day 21 of a 28-day cycle) is considered medically necessary. For infertile women with irregular menstrual cycles, this test would need to be repeated at the mid-luteal phase and weekly thereafter until the next menstrual cycle starts.
Table: Female Gonadotropin Injectable Vial Management:
|Brand Names||Strength||Insemination Quantity†||ART Quantity‡|
Gonadotropins/Menotropins (Initial Cycle*)
|Examples: Follistim, Gonal F, Bravelle, etc.||75 IU||
Less than age 35 years: 20 ampules (up to 35 ampules if FSH level is greater than 12 and less than 19)
Age 35 to 39 years: 20 to 30 ampules (up to 40 ampules if FSH level is greater than 12 and less than 19)
Age 40 years and older: 40 ampules (up to 50 ampules if FSH level is greater than 12 and less than 19)
Less than age 35 years: 30 to 40 ampules (up to 50 ampules if FSH level is greater than 12 and less than 19)
Age 35 to 39 years: 35 to 45 ampules (up to 55 ampules if FSH is greater than 12 and less than 19)
Age 40 years and older: 45 to 60 ampules (requests for more than 60 ampules are subject to clinical review; if FSH level is greater than 12 and less than 19, request medication protocol and clinical review (BMI, PCOS))
Donor eggs** (all ages): 30 to 40 ampules (up to 50 ampules if FSH level is greater than 12 and less than 19)
|Examples: Follistim, Gonal F, Bravelle, etc. §||150 IU, 300 IU, 450 IU, 600 IU, 900 IU, 450 IU MDV||10 ampules||15 ampules|
Luteinizing Hormone (Initial Cycle*)
|Examples: Luveris, Repronex, Menopur||75 IU||
Less than age 35 years: 1 to 10 ampules
Age 35 to 39 years: 10 to 15 ampules
Age 40 years and older: 15 to 20 ampules
Less than age 35 years: 10 ampules
Age 35 to 39 years: 10 to 20 ampules
Age 40 years and older: 20 to 30 ampules
HCG subcutaneous injections (Initial Cycle*)
|Ovidrel||250 mcg||1 to 2 PFS||1 to 2 PFS|
HCG intramuscular injections (Initial Cycle*)
|HCG low dose||
50 IU vial
10 IU vial
|1 vial||1 vial|
|Examples: Pregnyl, Novarel, HCG||
|1 vial||1 vial|
GnRH Antagonists (Initial Cycle*)
|Ganirelix acetate (prefilled syringe)||250 ug/0.5 ml||3 PFS||4 PFS|
|1 to 7 PFS||1 to 7 PFS|
|Cetrotide||3.0 mg||1 PFS||1 PFS|
Key: ART: advanced reproductive technology; BMI: body mass index; FSH: follicle stimulating hormone; HCG: human chorionic gonadotropin; IU: international units; MDV: multiple dose vial; PCOS: polycystic ovarian syndrome; PFS: prefilled syringe; U: units.
* Refills based upon documentation in cycle sheets.
** Some plans exclude infertility services for ovarian failure; please check benefit plan descriptions.
† Assumes intra-uterine insemination cycle uses medication for 10 days
‡ Assumes ART cycle uses medication for 10 days.
§ For different concentrations use 75 IU as a base.
Table: Male Gonadotropin Injectable Vial Management:
Length of approval
450 unit MDV, 1050 unit MDV
75 unit SDV, 150 unit SDV
150, 300, 600, 900 unit multi dose cartridges
After normalization of serum testosterone levels, use Gonal F concomitantly with hCG: 150 units three times a week; maximum dose 300 units three times a week for up to 18 months
After normalization of serum testosterone levels, use Follistim AQ concomitantly with hCG: 450 units per week (or 225 units twice a week or 150 units three times a week).
hCG intramuscular injections
Examples: Pregnyl, Novarel, hCG
500-1000 units three times per week x 3 weeks followed by same dose twice a week x 3 weeks
4000 units three times per week for 6-9 months, following which dosage may be decreased to 2000 units three times per week for an additional 3 months
*Concomitant recombinant follitropin and human chorionic gonadotropin therapy should be continued for at least 3 to 4 months before improvement in spermatogenesis can be expected.
For purposes of this policy, the following definitions will be used:
Classification of ovulatory disorders:
Anovulation and oligo-ovulation are ovulatory disorders that are estimated to cause 21 % of female fertility problems. The World Health Organization classifies ovulation disorders into 3 groups.
Embryo Quantity and Quality in ART Cycles:
Embryo quantity and quality are considered adequate if an ART cycle produces 3 or more embryos for transfer, each of which are at least 6 to 8 cells (for day 3 transfers) of reasonable quality (grade B or its equivalent) with less than 50 % fragmentation.
Fertilization Rates in IVF Cycles:
Fertilization rates are considered poor if IVF cycles result in less than 50 % fertilization.
Ovarian Reserve in Response to Gonadotropin Stimulation:
Ovarian reserve is considered normal if 3 or more follicles develop and estrogen levels are greater than 500 mIU/ml following ovarian hyperstimulation with gonadotropins. Diminished ovarian reserve is indicated by peak estrogen levels less than 500 mIU/ml or fewer than 3 mature follicles are available at the time of stimulation and retrieval.
Semen Quality and Quantity:
Deficits in semen quantity are considered severe if there are less than 10 million total motile sperm per ejaculate (unwashed specimen) or less than 3 million total motile sperm (washed specimen) on 2 separate occasions at least 2 weeks apart. Deficits in semen quality are considered severe if there are less than 4 % normal forms using Kruger strict morphology.
Table: Semen Analysis: World Health Organization Reference Values
Table: Limits on the Number of Embryos to Transfer
Before proceeding to the next fresh ART cycle, frozen embryo transfer (FET) using cryopreserved embryos must be used if the following numbers of cryopreserved embryos are available:
|Less than 35||35 to 37 years||37 to 39 years||40 years & older|
|Favorable*||1 to 2||2||3||5|
* Favorable = first cycle of IVF, good embryo quality, excess embryos available for cryopreservation, or previous successful IVF cycle.
Source: ASRM, 2013.Background
No fertility treatment other than oocyte donation has been shown to be effective for women over 40 years of age with compromised ovarian reserve. Elevated follicle-stimulating hormone (FSH) and estradiol levels are independent predictors of poor prognosis in older women. Common criteria for normal ovarian reserve are an early follicular phase FSH level of less than 10 mIU/ml and an estradiol level of less than 80 pg/ml (ASRM, 2002). Higher cut-off values for FSH have been reported (as high as 20 to 25 mIU/ml for FSH) because of the use of different FSH assay reference standards. Women with diminished ovarian reserve experience decreased responses to ovulation induction, require higher doses of gonadotropin, have higher in-vitro fertilization (IVF) cycle cancellation rates, and experience lower pregnancy rates through IVF.
Aetna covers ovarian stimulation medications and techniques only for women who have a biologic capacity to effectively respond to ovarian stimulation. Serum FSH is a marker of ovarian responsiveness. Ovarian responsiveness is determined by measurement of an unmedicated day 3 FSH obtained within the prior 6 months if the woman is older than age 35 or in the prior 12 months if the individual is age 35 or younger. In women greater than age 40, any single FSH greater than 19mIU/mL, regardless of subsequent test results that may be lower than 19mIU/mL, are indicative of ovarian insufficiency. In women less than age 40, ovarian responsiveness is demonstrated by any unmedicated day 3 FSH of less than 19mIU/ml. Younger women with a day 3 FSH less than 19mIU/ml have the capacity to respond to ovarian stimulation, even if they have had other day 3 FSH measurements greater than 19 mIU/mL.
Guidelines from the Society for Reproductive Medicine and Society for Assisted Reproductive Technology (Pfeifer et a., 2013) recommend that oocyte cryopreservation with appropriate counseling is recommended in patients facing infertility due to chemotherapy or other gonadotoxic therapies. The guidelines state that 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. The guidelines state that there are not yet sufficient data to recommend oocyte cryopreservation for the sole purpose of circumventing reproductive aging in healthy women. The guidelines state that more data are needed before this technology should be used routinely in lieu of embryo cryopreservation.
The American College of Obstetricians and Gynecologists (ACOG) practice bulletin on bariatric surgery and pregnancy (2009) stated that bariatric surgery should not be considered a treatment for infertility.
Although anti-mullerian hormone (AMH) levels appears to be associated with declining ovarian function, there is no consensus on the appropriate threshold value. An assessment by the Institute for Clinical and Health Policy (Pichon-Riviere, et al., 2009) found no clear evidence on the usefulness of AMH in the assisted reproduction program clinical practice setting. The assessment found less evidence for the utility of AMH in other clinical practice settings. Guidelines from the American Society for Reproductive Medicine (2012) concluded "There is mounting evidence to support the use of AMH as a screening test for poor ovarian response, but more data are needed. There is emerging evidence to suggest that a low AMH level (e.g., undetectable AMH) has high specificity as a screen for poor ovarian response but insufficient evidence to suggest its use to screen for failure to conceive."
Steiner (2009) stated that serum and urinary markers of ovarian reserve -- follicular phase inhibin B, FSH, and anti-mullerian hormone (AMH) levels -- are physiologically associated with ovarian aging, decline with chronologic age, and appear to predict later stages of reproductive aging including the menopause transition and menopause. In infertile women, they can be used to predict low oocyte yield and treatment failure in women undergoing IVF. These markers seem to be affected by common ovarian toxicants, such as smoking, which advance the age at menopause. Although available for commercial use, home test kits have not been shown to predict fertility or infertility in the general population. Clinical use of these markers is limited by the variety of assays, lack of definitive thresholds, and their intercycle variability in older women. Results should be conveyed with caution when highly discrepant with age, in the obese, and in women with irregular menstrual cycles. The author stated that further research is needed to assess their predictive value for determining fertility in the general population.
Nelson et al (2009) stated that individualization of controlled ovarian stimulation (COS) for assisted conception is complicated by variable ovarian response to FSH. These researchers hypothesized that AMH may facilitate treatment strategies for women undergoing COS, to optimize safety and clinical pregnancy rates. A prospective cohort study of 538 patients in 2 centers with differential COS strategies based on a centralized AMH measurement was performed. Anti-Mullerian hormone was associated with oocyte yield after ovarian stimulation in both centers, and a "reduced" AMH (1 to less than 5 pmol/L) was associated with a reduced clinical pregnancy rate. Women with a "normal" AMH (5 to less than 15 pmol/L) treated with a long GnRH-agonist protocol (both centers) showed a low incidence of excess response (0 %) and poor response (0 %). In women with "high" AMH (greater than 15 pmol/L), the antagonist protocol eliminated the need for complete cryo-preservation of embryos due to excess response (p < 0.001) and showed a higher fresh cycle clinical pregnancy rate than agonist cycles odds ratio (OR) 4.40 (95 % confidence interval [CI]: 1.95 to 9.93), p < 0.001]. The authors concluded that the use of circulating AMH to individualize treatment strategies for COS may result in reduced clinical risk, optimized treatment burden and maintained pregnancy rates, and is worthy of prospective randomized examination.
Nardo et al (2009) evaluated the clinical value of basal AMH measurements compared with other available determinants, apart from chronologic age, in the prediction of ovarian response to gonadotrophin stimulation. Women undergoing their first cycle of controlled ovarian hyperstimulation (COH) for IVF were subject of this study. Basal levels of FSH and AMH as well as antral follicle count (AFC) were measured in 165 subjects. All patients were followed prospectively and their cycle outcomes recorded. Main outcome measures included predictive value of FSH, AMH, and AFC for extremes of ovarian response to stimulation. Out of the 165 women, 134 were defined as normal responders, 15 as poor responders, and 16 as high responders. Subjects in the poor response group were significantly older then those in the other 2 groups. Anti-Müllerian hormone levels and AFC were markedly raised in the high responders and decreased in the poor responders. Compared with FSH and AFC, AMH performed better in the prediction of excessive response to ovarian stimulation-AMH area under receiver operating characteristic curve (ROC(AUC)) 0.81, FSH ROC(AUC) 0.66, AFC ROC(AUC) 0.69. For poor response, AMH (ROC(AUC) 0.88) was a significantly better predictor than FSH (ROC(AUC) 0.63) but not AFC (ROC(AUC) 0.81). Anti-Mullerian hormone prediction of ovarian response was independent of age and polycystic ovarian syndrome (PCOS). Anti-Mullerian hormone cutoffs of greater than 3.75 ng/ml and less than 1.0 ng/ml would have modest sensitivity and specificity in predicting the extremes of response. The authors concluded that circulating AMH has the ability to predict excessive and poor response to stimulation with exogenous gonadotrophins. Overall, this biomarker is superior to basal FSH and AFC, and has the potential to be incorporated in to work-up protocols to predict patient's ovarian response to treatment and to individualize strategies aiming at reducing the cancellation rate and the iatrogenic complications of COH.
Su and associates (2010) examined if AMH and inhibin B were impacted by breast cancer treatment by comparing cancer survivors to age-matched control women and determined the association between these hormones and post-chemotherapy menstrual pattern. Breast cancer patients (n = 127) with American Joint Committee on Cancer stage I to III disease who were pre-menopausal at diagnosis were enrolled post-chemotherapy and observed. The primary end point was chemotherapy-related amenorrhea (CRA) (greater than or equal to 12 months of amenorrhea following chemotherapy). Matched pair analyses compared AMH, inhibin B, and FSH levels between cancer and age-matched control subjects. Associations between hormones, CRA status, and change in CRA status over time were assessed. The median age of the patients at chemotherapy was 43.2 years (range of 26.7 to 57.8 years). At enrollment, median follow-up since chemotherapy was 2.1 years, and 55 % of subjects had CRA. Compared with age-matched controls, cancer subjects had significantly lower AMH (p = 0.004) and inhibin B (p < 0.001) and higher FSH (p < 0.001). Inhibin B (p = 0.001) and AMH (p = 0.002) were found to be significantly associated with risk of CRA, even after controlling for FSH. Anti-mullerian hormone was significantly lower (p = 0.03) and FSH was significantly higher (p = 0.04) in menstruating subjects who developed subsequent CRA. The authors concluded that AMH and inhibin B are 2 additional measures of post-chemotherapy ovarian function in late reproductive-aged breast cancer survivors. They stated that with further research and validation, these hormones may supplement limited current tools for assessing and predicting post-chemotherapy ovarian function.
In a Cochrane review, Duffy et al (2010) the effectiveness of adjuvant growth hormone (GH) in IVF protocols. These investigators searched the Cochrane Menstrual Disorders and Subfertility Groups trials register (June 2009), the Cochrane Central Register of Controlled Trials (Cochrane Library Issue 2, 2009), MEDLINE (1966 to June 2009), EMBASE (1988 to June 2009) and Biological Abstracts (1969 to June 2009). All randomized controlled trials were included if they addressed the research question and provided outcome data for intervention and control participants. Assessment of trial risk of bias and extraction of relevant data was performed independently by 2 reviewers. A total of 10 studies (440 subfertile couples) were included. Results of the meta-analysis demonstrated no difference in outcome measures and adverse events in the routine use of adjuvant GH in IVF protocols. However, meta-analysis demonstrated a statistically significant difference in both live birth rates and pregnancy rates favoring the use of adjuvant GH in IVF protocols in women who are considered poor responders without increasing adverse events, OR 5.39, 95 % CI: 1.89 to 15.35 and OR 3.28, 95 % CI: 1.74 to 6.20 respectively. The authors concluded that although the use of GH in poor responders has been found to show a significant improvement in live birth rates, they were unable to identify which sub-group of poor responders would benefit the most from adjuvant GH. The result needs to be interpreted with caution, the included trials were few in number and small sample size. Thus, before recommending GH adjuvant in IVF, further research is needed to fully define its role.
Guidelines from the American Society for Reproductive Medicine (2012) concluded that "inhibin B is not a reliabe measure of ovarian reserve" and that "the routine use of inhibin B as a measure of ovarian reserve is not recommended."
In a meta-analysis, Toulis et al (2010) evaluated the diagnostic accuracy of inhibin B and AMH as markers of persistent spermatogenesis in men with non-obstructive azoospermia (NOA). A search was conducted in the electronic databases MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials from inception through June 2009. A total of 36 different studies reported data on the predictive value of 1 or more index markers (serum inhibin B: 32 studies, seminal inhibin B: 5 studies, serum AMH: 2 studies, seminal AMH: 4 studies) and were included in the systematic review. Nine studies, which had serum inhibin B as index marker, met the predefined criteria and were included in the meta-analysis. Serum inhibin B showed a sensitivity of 0.65 (95 % CI: 0.56 to 0.74) and a specificity of 0.83 (CI: 0.64 to 0.93) for the prediction of the presence of sperm in testicular sperm extraction (TESE). When the pre-test probability of 41 % was incorporated in a Fagan's nomogram, resulted in a positive post-test probability of 73 % and a negative post-test probability of 23 % for the presence of sperm in TESE. The authors concluded that serum inhibin B can not serve as a stand-alone marker of persistent spermatogenesis in men with NOA. Although limited, evidence on serum AMH and serum/seminal AMH do not support their diagnostic value in men with NOA.
Steiner et al (2011) generated estimates of the association between markers of ovarian aging and natural fertility in a community sample at risk for ovarian aging. Women aged 30 to 44 years with no history of infertility who had been trying to conceive for less than 3 months provided early-follicular phase serum and urine (n = 100). Subsequently, these women kept a diary to record menstrual bleeding and intercourse and conducted standardized pregnancy testing for up to 6 months. Serum was analyzed for estradiol, FSH, AMH, and inhibin B. Urine was analyzed for FSH and estrone 3-glucuronide. Diary data on menstrual cycle day and patterns of intercourse were used to calculate day-specific fecundability ratios. Sixty-three percent of participants conceived within 6 months. After adjusting for age, 18 women (18 %) with serum AMH levels of 0.7 ng/ml or less had significantly reduced fecundability given intercourse on a fertile day compared with women with higher AMH levels (fecundability ratio 0.38; 95 % CI: 0.08 to 0.91). The day-specific fecundability for women with early-follicular phase serum FSH values greater than 10 mIU/ml compared with women with lower FSH levels was also reduced, although nonsignificantly (11 % of women affected; fecundability ratio 0.44; 95 % CI: 0.08 to 1.10). The association with urinary FSH was weaker (27 % women affected; fecundability ratio 0.61; 95 % CI: 0.26 to 1.26), and the associations for the other markers were weaker still. The authors concluded that early-follicular phase AMH appears to be associated with natural fertility in the general population. Moreover, they stated that larger studies are needed to confirm these findings and to explore the way the different endocrine markers interact as potential joint predictors of fertility.
In a meta-analysis, Polyzos and associates (2010) examined the effect of double versus single intra-uterine insemination (IUI) per treatment cycle in women with unexplained infertility. Main outcome measure was clinical pregnancy rates per couple. Electronic searches of the Cochrane Central Trials Registry and Medline without year and language restriction through March 2009 were performed; hand searching of the abstract books of the European Society of Human Reproduction and Embryology and American Society for Reproductive Medicine annual meetings (2001 to 2008) was carried out. A total of 6 randomized trials, involving 829 women, were included in the analysis. Fifty-four (13.6 %) clinical pregnancies were recorded for treatment with double IUI and 62 (14.4 %) for treatment with single IUI. There was no significant difference between the single and double IUI groups in the probability for clinical pregnancy (OR, 0.92; 95 % CI: 0.58 to 1.45; p = 0.715). The authors concluded that double IUI offers no clear benefit in the overall clinical pregnancy rate in couples with unexplained infertility.
Guercini et al (2005) reported that in chronic prostatitis there are many causes that may provoke a therapeutical failure of a systemic antibiotic treatment. At the moment a consensus has not been reached on the effectiveness of the many therapeutical options that are available with not one of these approaches being effective in all patients. In the authors' view the main causes of treatment failure are the well-known hurdle to antibiotic diffusion inside the glandular parenchyma associated with the so-called intra-prostatic bacterial biofilms and the possible presence of local auto-immune reactions. Given this background, these researchers tested ultrasound-guided intra-prostate infiltration of a cocktail of antibiotics and betamethasone, for a therapeutical options. A total of 320 patients, referred for treatment because of symptoms indicative of chronic prostatitis, were enrolled in this study. The inclusion criteria were the severity of the symptoms and the failure of repeated cycles of antibiotics in the previous 12 months. At the initial consultation patients completed the NIH Prostatitis Symptoms Index (NIH-CPSI). All underwent: (i) digital rectal examination (DRE), (ii) transrectal prostatic ultrasound scan (TRUS), (iii) uroflowmetry, (iv) cultures of first voiding and after prostatic massage urine and cultures of sperm for saprophytic and pathogen germs, yeasts and protozoa, (v) DNA amplification with polymerase chain reaction (PCR) on urine and sperm, for Chlamydia trachomatis, Mycoplasmas (Ureaplasma urealyticum and Mycoplasma hominis), Gonococcus, HPV and HCV. Patients on the basis of laboratory results received a cocktail of antibiotics associated with betamethasone. The cocktail was administered as prostate infiltration. Administration was repeated after 7 and 14 days. Final assessment of the effectiveness of therapy included not only the NIH-CPSI scores but also the patient's subjective judgement expressed as a "percentage overall improvement". The percentage judgements were arbitrarily divided into 4 classes: (i) 0 to 30 %: no improvement (Class I); (ii) 30 to 50 %: satisfactory improvement (Class II); (iii) 50 to 80 %: good improvement (Class III); and (iv) 80 to 100 %: cured (Class IV). Statistical analysis of the results showed 68 % of patients were included in the Class IV and 13 % were non-responders (Class I). The authors concluded that this is one of the more valid therapeutical approaches to chronic bacterial or abacterial prostatitis; but it also required more studies.
McGrath et al (2009) stated that cycle-dependent fluctuations in natural killer (NK) cell populations in endometrium and circulation may differ, contributing to unexplained infertility. They conducted a study whereby NK cell phenotypes were determined by flow cytometry in endometrial biopsies and matched blood samples. While circulating and endometrial T cell populations remained constant throughout the menstrual cycle in fertile and infertile women, circulating NK cells in infertile women increased during the secretory phase. However, increased expression of CD94, CD158b (secretory phase), and CD158a (proliferative phase) by endometrial NK cells from infertile women was observed. These changes were not reflected in the circulation. In infertile women, changes in circulating NK cell percentages were found exclusively during the secretory phase and not in endometrium; cycle-related changes in NK receptor expression were observed only in infertile endometrium. While having exciting implications for understanding NK cell function in fertility, these data emphasized the difficulty in attaching diagnostic or prognostic significance to NK cell analyses in individual patients.
Winger et al (2011) examined if quantification of peripheral blood Treg cell levels could be used as an indicator of miscarriage risk in newly pregnant women with a history of immunologic reproductive failure. A total of 54 pregnant women with a history of immunologic infertility and/or pregnancy loss were retrospectively evaluated (mean age of 36.7 +/- 4.9 years, 2.8 +/- 2.5 previous miscarriages; 1.5 +/- 1.9 previous IVF failures). Twenty-three of these women experienced another first trimester miscarriage, and 31 of these women continued their current pregnancies past 12 weeks ("pregnancy success"). The following immunologic parameters were assessed in the first trimester: NK cell 50:1 cytotoxicity, CD56(+) 16(+) CD3(-) (NK), CD56(+) CD3(+) (NKT), TNFα/IL-10, IFNγ/IL-10, CD4(+) CD25(-) Foxp3(+), total CD4(+) Foxp3(+) (CD4(+) CD25(+) Foxp3 plus CD25(-) Foxp3(+)), and CD4(+) CD25(+) Foxp3(+) levels. Patients with successful ongoing pregnancies experienced a mean (CD4(+) CD25(+) Foxp3(+)) "Treg" level of 0.72 +/- 0.52 %, while those that miscarried in the first trimester experienced a mean Treg level of 0.37 +/- 0.29 % (p = 0.005). Markers not significantly different between the loss and success groups were NK 50:1 cytotoxicity (p = 0.63), CD56(+) 16(+) 3(+) NK cells (p = 0.63), CD56(+) 3(+) NKT (p = 0.30), TNFα(+) IL-10(+) (p = 0.13), IFNg(+) IL-10(+) (p = 0.63), and CD4(+) 25(-) Foxp3(+) cells (p = 0.10), although total CD4(+) Foxp3(+) levels remained significant (p = 0.02) and CD4(+) 25(+) Foxp3(+) showed the most significant difference (p = 0.005). Mean day of blood draw was 49.2 +/- 36.1 days pregnant (median of 39.0 days). In addition, patients with a low Treg level (less than 0.7 %) in the first trimester experienced a significantly lower ongoing pregnancy rate than those with a higher Treg level (greater than 0.7 %) in the first trimester [44 % (15/34) versus 80 % (16/20); p = 0.01]. Of the 18 successful pregnancies with sequential Treg results, 85 % (11/13) showed a T-regulatory-cell-level increase (mean Treg change 0.33 +/- 0.32), while only 40 % (2/5) of the failed pregnancies showed a Treg increase (mean Treg change -0.08 +/- 0.28; p = 0.02). The authors concluded that from these data, they proposed that CD4(+) CD25(+) Foxp3(+) T regulatory cells may serve as a superior pregnancy marker for assessing miscarriage risk in newly pregnant women. Moreover, they stated that larger follow-up studies are needed for confirmation.
In a prospective, randomized controlled trial, Ben-Meir et al (2010) examined if supplementation with hCG throughout the secretory phase of hormonally modulated cycles of frozen-thawed embryos might positively affect the outcome of such cycles. Patients were randomly divided into 2 groups by the last digit of their identification number. Group A received the authors’standard protocol for endometrial preparation, whereas group B patients were given an additional 250 microg of recombinant hCG on day of progesterone (P) initiation, the day of embryo transfer, and 6 days later. Throughout the cycle, and to compare between the groups, serial ultrasound examinations and hormonal tests of E(2) and P serum levels were obtained. Main outcome measures were implantation and clinical pregnancy rates (PR). A total of 165 patients were enrolled in this study -- 78 in the control group and 87 in the hCG-treated group. Progesterone levels and endometrial thickness were similar throughout the cycle in both groups. The E(2) level was significantly higher in group B on the day of embryo transfer and 6 days later. The PRs did not differ between the 2 groups (28.2 % and 32.2 % for groups A and B, respectively). Similarly, the implantation rates were comparable between the groups (12.7 % and 14.9 %, respectively). The authors concluded that no advantage was found concerning PR and implantation rate by supplementing the secretory phase with hCG in patients undergoing transfer of frozen-thawed embryo in hormonally modulated cycles.
In a systematic review and meta-analysis, Momeni et al (2011) evaluated the relationship between endometrial thickness on the day of hCG administration and pregnancy outcome in in-vitro fertilization cycles. These investigators identified 484 articles using Cochrane library, PubMed, Web of Science, and Embase searches with various key words including endometrial thickness, pregnancy, assisted reproductive technology, endometrial pattern, and in-vitro fertilization. A total of 14 studies with data on endometrial thickness and outcome were selected, representing 4,922 cycles (2,204 pregnant and 2,718 non-pregnant). The meta-analysis with a random effects model was performed using comprehensive meta-analysis software. These researchers calculated the standardized mean difference, odds ratio (OR), and 95 % confidence intervals (CIs). There was a significant difference in the mean endometrial thickness between pregnant and non-pregnant groups (p < 0.001), with a standardized mean difference of 0.4 mm (95 % CI: 0.22 to 0.58). The OR for pregnancy was 1.40 (95 % CI: 1.24 to 1.58). The authors concluded that the mean endometrial thickness was significantly higher in pregnant women compared to non-pregnant. The mean difference between 2 groups was less than 1 mm, which may not be clinically meaningful. Moreover, they stated that although there may be a relationship between endometrial thickness and pregnancy, implantation potential is probably more complex than a single ultrasound measurement can determine.
van der Linden et al (2011) determined the relative safety and effectiveness of methods of luteal phase support in subfertile women undergoing assisted reproductive technology (ART). These investigators searched the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, CINAHL, Database of Abstracts of Reviews of Effects (DARE), LILACS, conference abstracts on the ISI Web of Knowledge, OpenSigle for grey literature from Europe, and ongoing clinical trials registered online. The final search was in February 2011. Randomized controlled trials of luteal phase support in ART investigating progesterone, hCG or GnRH agonist supplementation in IVF or intra-cytoplasmic sperm injection (ICSI) cycles. Quasi-randomized trials and trials using frozen transfers or donor oocyte cycles were excluded. These researchers extracted data per women and 3 review authors independently assessed risk of bias. They contacted the original authors when data were missing or the risk of bias was unclear; and they entered all data in 6 different comparisons. These investigators calculated the Peto odds ratio (Peto OR) for each comparison. A total of 69 studies with 16,327 women were included. The authors assessed most of the studies as having an unclear risk of bias, which we interpreted as a high-risk of bias. Because of the great number of different comparisons, the average number of included studies in a single comparison was only 1.5 for live birth and 6.1 for clinical pregnancy. Five studies (746 women) compared hCG versus placebo or no treatment. There was no evidence of a difference between hCG and placebo or no treatment except for ongoing pregnancy: Peto OR 1.75 (95 % CI: 1.09 to 2.81), suggesting a benefit from hCG. There was a significantly higher risk of ovarian hyper-stimulation syndrome (OHSS) when hCG was used (Peto OR 3.62, 95 % CI: 1.85 to 7.06). There were 8 studies (875 women) in the second comparison, progesterone versus placebo or no treatment. The results suggested a significant effect in favor of progesterone for the live birth rate (Peto OR 2.95, 95 % CI: 1.02 to 8.56) based on one study. For clinical pregnancy (CPR) the results also suggested a significant result in favor of progesterone (Peto OR 1.83, 95 % CI: 1.29 to 2.61) based on seven studies. For the other outcomes the results indicated no difference in effect. The third comparison (15 studies, 2,117 women) investigated progesterone versus hCG regimens. The hCG regimens were subgrouped into comparisons of progesterone versus hCG and progesterone versus progesterone + hCG. The results did not indicate a difference of effect between the interventions, except for OHSS. Subgroup analysis of progesterone versus progesterone + hCG showed a significant benefit from progesterone (Peto OR 0.45, 95 % CI: 0.26 to 0.79). The fourth comparison (9 studies, 1,571 women) compared progesterone versus progesterone + estrogen. Outcomes were subgrouped by route of administration. The results for clinical pregnancy rate in the subgroup progesterone versus progesterone + transdermal oestrogen suggested a significant benefit from progesterone + estrogen. There was no evidence of a difference in effect for other outcomes. Six studies (1,646 women) investigated progesterone versus progesterone + GnRH agonist. These researchers subgrouped the studies for single-dose GnRH agonist and multiple-dose GnRH agonist. For the live birth, clinical pregnancy and ongoing pregnancy rate the results suggested a significant effect in favor of progesterone + GnRH agonist. The Peto OR for the live birth rate was 2.44 (95 % CI: 1.62 to 3.67), for the clinical pregnancy rate was 1.36 (95 % CI: 1.11 to 1.66) and for the ongoing pregnancy rate was 1.31 (95 % CI: 1.03 to 1.67). The results for miscarriage and multiple pregnancies did not indicate a difference of effect. The last comparison (32 studies, 9,839 women) investigated different progesterone regimens: Intra-muscular (IM) versus oral administration, IM versus vaginal or rectal administration, vaginal or rectal versus oral administration, low-dose vaginal versus high-dose vaginal progesterone administration, short protocol versus long protocol and micronized progesterone versus synthetic progesterone. The main results of this comparison did not indicate a difference of effect except in some subgroup analyses. For the outcome clinical pregnancy, subgroup analysis of micronized progesterone versus synthetic progesterone showed a significant benefit from synthetic progesterone (Peto OR 0.79, 95 % CI: 0.65 to 0.96). For the outcome multiple pregnancies, the subgroup analysis of IM progesterone versus oral progesterone suggested a significant benefit from oral progesterone (Peto OR 4.39, 95 % CI: 1.28 to 15.01). The authors concluded that this review showed a significant effect in favor of progesterone for luteal phase support, favoring synthetic progesterone over micronized progesterone. Overall, the addition of other substances such as estrogen or hCG did not seem to improve outcomes. They also found no evidence favoring a specific route or duration of administration of progesterone. These investigators found that hCG, or hCG plus progesterone, was associated with a higher risk of OHSS. The use of hCG should therefore be avoided. There were significant results showing a benefit from addition of GnRH agonist to progesterone for the outcomes of live birth, clinical pregnancy and ongoing pregnancy. For now, progesterone seems to be the best option as luteal phase support, with better pregnancy results when synthetic progesterone is used.
Morley et al (2013) stated that recurrent miscarriage (RM) is defined as the loss of 3 or more consecutive pregnancies. Further research is required to understand the causes of RM, which remain unknown for many couples. Human chorionic gonadotropin is vital for maintaining the corpus luteum, but may have additional roles during implantation which support its use as a therapeutic agent for RM. In a Cochrane review, these investigators determined the efficacy of hCG in preventing further miscarriage in women with a history of unexplained RM. They searched the Cochrane Pregnancy and Childbirth Group's Trials Register (September 30, 2012) and reference lists of retrieved studies. Randomized controlled trials investigating the efficacy of hCG versus placebo or no treatment in preventing RM were included for analysis. Quasi-randomized trials were included. Cluster-randomized trials and trials with a cross-over design were excluded. Two review authors independently assessed trials for inclusion and assessed the methodological quality of each study. Date were extracted by 2 review authors and checked for accuracy. These investigators included 5 studies (involving 596 women). Meta-analysis suggested a statistically significant reduction in miscarriage rate using hCG. The number of women needed to treat to prevent subsequent pregnancy loss was 7. However, when 2 studies of weaker methodological quality were removed, there was no longer a statistically significant benefit (risk ratio 0.74; 95 % CI: 0.44 to 1.23). There were no documented adverse effects of using hCG. The authors concluded that the evidence supporting hCG supplementation to prevent RM remains equivocal. A well-designed randomized controlled trial of adequate power and methodological quality is required to determine whether hCG is beneficial in RM.
Also, an UpToDate review on “Overview of treatment of female infertility” (Kuohung and Hornstein, 2014) does not mention the use of human chorionic gonadotropin as a management tool.
Current guidelines recommend hCG in men only for pituitary hypogonadism to address infertility issues. It is not recommended for long-term use outside of infertility treatment. The European Association of Urology’s guidelines on “Male hypogonadism” (Dohle et al, 2012) noted that “In patients with secondary hypogonadism and fertility issues, and in selected cases of primary hypogonadism, hCG treatment can be chosen to support endogenous testosterone production for the period of infertility treatment. The dosage has to be adjusted individually to prevent suppression of FSH serum levels. hCG treatment has higher costs than testosterone treatment. There is insufficient information about the therapeutic and adverse effects of long-term hCG treatment. This type of treatment can therefore not be recommended for male hypogonadism, except in patients in whom fertility treatment is an issue”.
In a Cochrane review, Siristatidis et al (2013) compared outcomes associated with in-vitro maturation (IVM) followed by IVF or ICSI versus conventional IVF or ICSI, among women with PCOS undergoing assisted reproductive technologies (ART). These searched the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register of controlled trials to May 2013 for any relevant trials identified from the title, abstract, or keyword sections. This was followed by a search of the electronic database MEDLINE, EMBASE, LILACS and CINAHL, without language restriction. They also performed a manual search of the references of all retrieved articles; sought unpublished papers and abstracts submitted to international conferences, searched the clinicaltrials.gov and WHO portal registries for submitted protocols of clinical trials, and contacted experts. In addition, these researchers examined the National Institute of Clinical Excellence (NICE) fertility assessment and treatment guidelines and hand-searched reference lists of relevant articles (from 1970 to May 2013). All randomized controlled trials (RCTs) on the intention to perform IVM before IVF or ICSI compared with conventional IVF or ICSI for subfertile women with PCOS. Three review authors independently assessed eligibility and quality of trials. Primary outcome measure was live birth rate per randomized woman. There were no RCTs suitable for inclusion in the review, although there are currently 3 ongoing trials that have not yet reported results. The authors concluded that although promising data on the IVM technique have been published, unfortunately there is still no evidence from RCTs upon which to base any practice recommendations regarding IVM before IVF or ICSI for women with PCOS.
Furthermore, an UpToDate review on “Fertility preservation in patients undergoing gonadotoxic treatment or gonadal resection” (Sonmezer and Oktay, 2014) states that “When embryo cryopreservation is not feasible, cryopreservation of oocytes matured in vivo is a reasonable option. In vitro maturation of oocytes is an investigational procedure; implantation and ongoing pregnancy rates are lower than with conventional in vitro fertilization (IVF) using in vivo matured oocytes”.
Chen et al (2013) stated that reactive oxygen species (ROS) are an array of molecules including oxygen-centered radicals, which are endowed with 1 or more unpaired electrons and non-radical oxygen derivatives such as hydrogen peroxide, which behave, to a large extent, like a double-edged sword in human sperm biology. These investigators reviewed the current knowledge of ROS in sperm physiology and pathology, as well as related therapies in spermatozoal dysfunction. They searched for keywords from PUBMED, including reactive oxygen species, oxidative stress, sperm function, and antioxidant therapy. Low levels of ROS exert critical function in normal sperm physiology, such as fertilizing ability (acrosome reaction, hyper-activation, capacitation, and chemotaxis) and sperm motility; while increased ROS generation and/or decreased antioxidant capacity leads to the imbalance between oxidation and reduction in living systems, which is called sperm oxidative stress. This condition was widely considered to be a significant contributory factor to sperm DNA damage/apoptosis, lipid peroxidation, and reduced motility, which in turn, increased risk of male factor infertility/subfertility and birth defects. Under the current status quo, numerous subsequent studies have concentrated on antioxidant therapy. Although utility of such a therapeutic strategy significantly improved sperm function and motility in a myriad of experimental and clinical reports, the overall effectiveness still remains controversial mainly due to non-standardized assay to measure the level of ROS and sperm DNA damage, various antioxidant supplementation strategies, and inadequate fertilization and pregnancy data after clinical treatment. Therefore, standardized assessment and evaluation of ROS and total antioxidant capacity in semen should be established to keep ROS in a physiological level and prevent over-treatment of antioxidants toward reductive stress, which should be kept in mind, especially in assisted reproductive procedure. The authors noted that the significance of large sample size populations, double-blind randomized, placebo-controlled clinical trials of antioxidant therapies is emphasized in this review to achieve optimal ingredients and dosage of antioxidants for patients with reactive oxygen-induced male fertility/subfertility.
Also, an UpToDate review on “Evaluation of male infertility” (Swerdloff and Wang, 2014) states that “Generation of reactive oxygen species may be a cause of sperm dysfunction and a predictor of fertilization in vitro. Reactive oxygen species lead to lipid peroxidation of the sperm membrane and are also deleterious to sperm motility. This is still regarded as a research test and is not often used for diagnosis of a specific sperm defect”.
Cryopreservation of immature oocytes and in vitro maturation are considered experimental procedures. The term in vitro maturation refers to the maturation in culture of immature oocytes after their recovery from follicles that may or may not have been exposed to exogenous FSH but were not exposed to eitehr exogenous LH or hCG prior to retrieval to induce meiotic resumption. Guidelines from the American Society for Reproductive Medicine (2013) state that in vitro maturation should only be performed as an experimental procedure in specialized centers for carefully selected patients evaluatinb both efficacy and safety. The guidlines state that the intitial results of in vitro maturation suggest the potential for clinical application. However, at this time, patients must be made aware that the implantation and pregnancy rates are significantly lower than with standard IVF, limiting more universal utilization.
Chighizola and de Jesus (2014) noted that since the late 1980s some publications have proposed that antiphospholipid antibodies (aPL) may have some relationship with infertility, considering reported deleterious effects that aPL exert on trophoblast proliferation and growth. Although not included in current classification criteria for antiphospholipid syndrome, many physicians investigated for aPL in patients with a history of infertility, including antibodies not listed in classification criteria, and most of those patients will receive anticoagulant therapy if any of those antibodies have a result considered positive. These investigators performed a review of literature searching for studies that investigated the association of aPL and infertility and if aPL positivity alters IVF outcome. The definition of infertility, routine work-up to exclude other causes of infertility, definition of IVF failure as inclusion criteria and control populations were heterogeneous among studies. Most of them enrolled women over 40 years of age, and exclusion of other confounding factors was also inconsistent. Of 29 studies that assessed aPL positivity rates in infertile women, the majority had small sample sizes, implying a lack of power, and 13 (44.8 %) reported higher frequency of aPL in infertile patients compared to controls, but most of them investigated a panel of non-criteria aPL tests, whose clinical significance is highly controversial. Only 2 studies investigated all 3 criteria tests, and medium-high titer of anticardiolipin cut-off conforming to international guidelines was used in 1 study. Considering IVF outcome, there was also disparity in this definition: few studies assessed the live birth rate, others the implantation rate. Of 14 publications that addressed the relationship between aPL and IVF outcome, only 2 described a detrimental effect of these autoantibodies. The authors concluded that available data do not support an association between aPL and infertility, and aPL positivity does not seem to influence IVF outcome. They stated that well-designed clinical studies recruiting women with a clear diagnosis of infertility and a high-risk aPL profile should be performed to test whether clinically relevant aPL do-or not-exert an effect on human fertility.
Furthermore, an UpToDate review on “Evaluation of female infertility” (Kuohung and Hornstein, 2015b) states that “Testing for antibodies -- Routine testing for antiphospholipid, antisperm, antinuclear, and antithyroid antibodies is not supported by existing data. Although an association between antiphospholipid antibodies and recurrent pregnancy loss has been established, the other autoimmune factors remain under investigation as markers of fertility treatment failure”.
In a Cochrane review, McDonnell et al (2014) examined the effectiveness and safety of functional ovarian cyst aspiration prior to ovarian stimulation versus a conservative approach in women with an ovarian cyst who were undergoing IVF or ICSI. These investigators searched the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, CINAHL, ClinicalTrials.gov, Google Scholar and PubMed. The evidence was current to April 2014 and no language restrictions were applied. These researchers included all RCTs comparing functional ovarian cyst aspiration versus conservative management of ovarian cysts that have been seen on transvaginal ultrasound (TVS) prior to COH for IVF or ICSI. Ovarian cysts were defined as simple, functional ovarian cysts greater than 20 mm in diameter. Oocyte donors and women undergoing donor oocyte cycles were excluded. Study selection, data extraction and risk of bias assessments were conducted independently by 2 review authors. The primary outcome measures were live birth rate and adverse events. The overall quality of the evidence for each comparison was rated using GRADE methods. A total of 3 studies were eligible for inclusion (n = 339), all of which used agonist protocols. Neither live birth rate nor adverse events were reported by any of the included studies. There was no conclusive evidence of a difference between the group who underwent ovarian cyst aspiration and the conservatively managed group in the clinical pregnancy rate (OR 1.40, 95 % CI: 0.67 to 2.94, 3 studies, 339 women, I(2) = 0 %, low-quality evidence). This suggested that if the clinical pregnancy rate in women with conservative management was assumed to be 5 %, the chance following cyst aspiration would be between 4 % and 14 %. There was no evidence of a difference between the groups in the mean number of follicles recruited (0.55 follicles, 95 % CI: -0.48 to 1.59, 2 studies, 159 women, I(2) = 0 %, low-quality evidence) or mean number of oocytes collected (0.41 oocytes, 95 % CI: -0.04 to 0.85, 3 studies, 339 women, I(2) = 0 %, low-quality evidence). Findings for the cancellation rate (2 studies) were inconsistent but neither study reported a benefit for the aspiration group. The main limitations of the evidence were imprecision, inconsistency, questionable applicability, and poor reporting of study methods. The authors concluded that there is insufficient evidence to determine whether drainage of functional ovarian cysts prior to controlled ovarian hyperstimulation influences live birth rate, clinical pregnancy rate, number of follicles recruited, or oocytes collected in women with a functional ovarian cyst. They stated that the findings of this review do not provide supportive evidence for this approach, particularly in view of the requirement for anesthesia, extra cost, psychological stress and risk of surgical complications.
Gleicher et al (2014) noted that a few years ago the ASRM, the European Society for Human Reproduction and Embryology (ESHRE) and the British Fertility Society declared preimplantation genetic screening (PGS#1) ineffective in improving IVF pregnancy rates and in reducing miscarriage rates. These investigators reviewed a presumably upgraded form of the procedure (PGS#2) that has recently been re-introduced. PGS#2 in comparison to PGS#1 is characterized by: (i) trophectoderm biopsy on day 5/6 embryos in place of day-3 embryo biopsy; and (ii) fluorescence in-situ hybridization (FISH) of limited chromosome numbers is replaced by techniques, allowing aneuploidy assessments of all 24 chromosome pairs. Reviewing the literature, the authors were unable to identify properly conducted prospective clinical trials in which IVF outcomes were assessed based on "intent-to-treat". Whether PGS#2 improves IVF outcomes can, therefore, not be determined. Re-assessments of data, alleged to support the effectiveness of PGS#2, indeed, suggested the opposite. Like with PGS#1, the introduction of PGS#2 into unrestricted IVF practice again appears premature, and threatens to repeat the PGS#1 experience, when thousands of women experienced reductions in IVF pregnancy chances, while expecting improvements. The authors concluded that PGS#2 is an unproven and still experimental procedure, which, until evidence suggests otherwise, should only be offered under study conditions, and with appropriate informed consents.
Lee et al (2015) examined if preimplantation genetic diagnosis for aneuploidy (PGD-A) with analysis of all chromosomes during ART is clinically and cost effective? These investigators performed a systematic review of the literature for full text English language articles using MEDLINE, EMBASE, SCOPUS, Cochrane Library databases, NHS Economic Evaluation Database and EconLit. The Downs and Black scoring check-list was used to assess the quality of studies. Clinical effectiveness was measured in terms of pregnancy, live birth and miscarriage rates. A total of 19 articles meeting the inclusion criteria, comprising 3 RCTs in young and good prognosis patients and 16 observation studies were identified; 5 of the observational studies included a control group of patients where embryos were selected based on morphological criteria (matched cohort studies). Of the 5 studies that included a control group and reported implantation rates, 4 studies (including 2 RCTs) demonstrated improved implantation rates in the PGD-A group. Of the 8 studies that included a control group, 6 studies (including 2 RCTs) reported significantly higher pregnancy rates in the PGD-A group, and in the remaining 2 studies, equivalent pregnancies rates were reported despite fewer embryos being transferred in the PGD-A group. The 3 RCTs demonstrated benefit in young and good prognosis patients in terms of clinical pregnancy rates and the use of single embryo transfer. However, studies relating to patients of advanced maternal age, recurrent miscarriage and implantation failure were restricted to matched cohort studies, limiting the ability to draw meaningful conclusions. The authors concluded that given the uncertain role of PGD-A techniques, high-quality experimental studies using intention-to-treat analysis and cumulative live birth rates including the comparative outcomes from remaining cryopreserved embryos are needed to evaluate the overall role of PGD-A in the clinical setting. It is only in this way that the true contribution of PGD-A to ART can be understood.
There is some evidence that in women with high T-helper 1/T-helper 2 (Th1/Th2) ratios, there is an increased incidence of pregnancy loss and infertility. Thus, this test has been used by infertility specialists. However, there are no studies demonstrating the clinical utility of these measurements. A review by Ly et al (2010) stated: “Th1 dominance may well be a result of the miscarriage rather than a cause, and much more basic knowledge is needed about the complex cytokine networks in pregnancy and the correlation between cytokine production in peripheral mononuclear cells and decidual lymphocytes before tests measuring cytokines can be introduced in clinical practice”.
Ozkan et al (2014) noted that implantation necessitates complex interactions among the developing embryo, decidualizing endometrium, and developing maternal immune tolerance and/or alterations in cellular and humoral immune responses. Over-stimulation of Th1 or Th2 cytokines in systemic and local environments, alterations of the prevalence of interleukin-17 (IL-17) and regulatory T cell (Treg) cytokines have also been suggested to contribute to the pathogenesis of implantation failure. These researchers investigated the plasma levels of IL-4, IL-6, IL-10, tumor necrosis factor-alpha (TNFα), gamma interferon (IFNγ), transforming growth factor-beta (TGFβ), IL-17, IL-35, and suppressors of cytokine signaling 3 (SOCS3) in infertile and fertile women. This case-control study was conducted with 80 women suffering from unexplained infertility and 40 fertile women. Peripheral venous blood samples were drawn on day 21 of the menstrual cycle. The extracted plasma samples were assayed by an enzyme linked immunosorbent assay (ELISA). Statistical analysis was performed using SPSS version 16.0. The main findings were as follows: despite the significantly high IL-17 and IL-35 plasma levels of infertile women, IL-35/IL-17 ratio was significantly lower in the infertile group compared with that in the fertile group; SOCS3 plasma levels showed an inverse relation with plasma levels of all cytokines except IL-35; increased plasma IL-17 levels (greater than 3.42 pg/ml) have a negative impact on fertility; TNFα/IL-10, IFNγ/IL-10, IFNγ/IL-6, and IFNγ/IL-4 ratios were significantly higher in infertile group compared with those in the fertile group. The authors concluded that it is not possible to show the major immunological factor(s) of unexplained infertility, but these findings pointed out that the decreased suppressor activity of the immune system may play a role in implantation failure.
Furthermore, UpToDate reviews on “Overview of infertility” (Kuohung and Hornstein, 2015a) and “Evaluation of female infertility” (Kuohung and Hornstein, 2015b) do not mention the use of Th1/Th2 ratio or intracellular cytokine assay as a management tool.
|CPT Codes / HCPCS Codes / ICD-9 Codes|
|CPT codes covered if selection criteria are met:|
|0058T||Cryopreservation; reproductive tissue, ovarian|
|49203||Excision or destruction, open, intra-abdominal tumors, cysts or endometriomas, 1 or more peritoneal, mesenteric, or retroperitoneal primary or secondary tumors; largest tumor 5 cm diameter or less|
|49204||largest tumor 5.1 - 10.0 cm diameter|
|49205||largest tumor greater than 10.0 cm diameter|
|49320||Laparoscopy, abdomen, peritoneum, and omentum, diagnostic, with or without collection of specimen(s) by brushing or washing (separate procedure)|
|49321||Laparoscopy, surgical; with biopsy (single or multiple)|
|49322||with aspiration of cavity or cyst (eg, ovarian cyst) (single or multiple)|
|52402||Cystourethroscopy with transurethral resection or incision of ejaculatory ducts|
|54500||Biopsy of testis, needle (separate procedure)|
|54505||Biopsy of testis, incisional (separate procedure)|
|54640||Orchiopexy, inguinal approach, with or without hernia repair|
|54650||Orchiopexy, abdominal approach, for intra-abdominal testis (eg, Fowler-Stephens)|
|54692||Laparoscopy, surgical; orchiopexy for intra-abdominal testis|
|54800||Biopsy of epididymis, needle|
|54830||Excision of local lesion of epididymis|
|54840||Excision of spermatocele, with or without epididymectomy|
|54865||Exploration of epididymis, with or without biopsy|
|54900||Epididymovasostomy, anastamosis of epididymis to vas deferens; unilateral|
|55000||Puncture aspiration of hydrocele, tunica vaginalis, with or without injection of medication|
|55040||Excision of hydrocele; unilateral|
|55060||Repair of tunica vaginalis hydrocele (Bottle type)|
|55300||Vasotomy for vasograms, seminal vesiculograms, or epididymograms, unilateral or bilateral|
|55500||Excision of hydrocele of spermatic cord, unilateral (separate procedure)|
|55530||Excision of varicocele or ligation of spermatic veins for varicocele; (separate procedure)|
|55540||with hernia repair|
|57530||Trachelectomy (cervicectomy), amputation of cervix (separate procedure)|
|58100||Endometrial sampling (biopsy) with or without endocervical sampling (biopsy), without cervical dilation, any method (separate procedure)|
|58120||Dilation and curettage, diagnostic and/or therapeutic (nonobstetrical)|
|58140||Myomectomy, excision of fibroid tumor(s) of uterus, 1 to 4 intramural myoma(s) with total weight of 250 g or less and/or removal of surface myomas; abdominal approach|
|58146||Myomectomy, excision of fibroid tumor(s) of uterus, 5 or more intramural myomas and/or intramural myomas with total weight greater than 250 g, abdominal approach|
|58321||Artificial insemination; intra-cervical|
|58323||Sperm washing for artificial insemination|
|58340||Catheterization and introduction of saline or contrast material for saline infusion sonohysterography (SIS) or hysterosalpingography|
|58345||Transcervical introduction of fallopian tube catheter for diagnosis and/or re-establishing patency (any method), with or without hysterosalpingography|
|58350||Chromotubation of oviduct, including materials|
|58545||Laparoscopy, surgical, myomectomy, excision; 1 to 4 intramural myomas with total weight of 250 g or less and/or removal of surface myomas|
|58546||5 or more intramural myomas and/or intramural myomas with total weight greater than 250 g|
|58555||Hysteroscopy, diagnostic (separate procedure)|
|58558||Hysteroscopy, surgical; with sampling (biopsy) of endometrium and/or polypectomy, with or without D & C|
|58559||with lysis of intrauterine adhesions (any method)|
|58560||with division or resection of intrauterine septum (any method)|
|58561||with removal of leiomyomata|
|58562||with removal of impacted foreign body|
|58563||with endometrial ablation (eg, endometrial resection, electrosurgical ablation, thermoablation)|
|58600||Ligation or transection of fallopian tube(s), abdominal or vaginal approach, unilateral or bilateral|
|58660||Laparoscopy, surgical; with lysis of adhesions (salpingolysis, ovariolysis) (separate procedure)|
|58661||with removal of adnexal structures (partial or total oophorectomy and/or salpingectomy)|
|58662||with fulguration or excision of lesions of the ovary, pelvic viscera, or peritoneal surface by any method|
|58673||with salpingostomy (salpingoneostomy)|
|58700||Salpingectomy, complete or partial, unilateral or bilateral (separate procedure)|
|58720||Salpingo-oophorectomy, complete or partial, unilateral or bilateral (separate procedure)|
|58740||Lysis of adhesions (salpingolysis, ovariolysis)|
|58800||Drainage of ovarian cyst(s), unilateral or bilateral (separate procedure); vaginal approach|
|58820||Drainage of ovarian abscess; vaginal approach, open|
|58900||Biopsy of ovary, unilateral or bilateral (separate procedure)|
|58920||Wedge resection or bisection of ovary, unilateral or bilateral|
|58925||Ovarian cystectomy, unilateral or bilateral|
|58970||Follicle puncture for oocyte retrieval, any method|
|58974||Embryo transfer, intrauterine [not covered for the transfer of embryos derived from cryopreserved oocytes]|
|58976||Gamete, zygote, or embryo intrafallopian transfer, any method [not covered for the transfer of embryos derived from cryopreserved oocytes]|
|70480||Computed tomography, orbit, sella, or posterior fossa or outer, middle, or inner ear; without contrast material|
|70481||with contrast material(s)|
|70482||without contrast material, followed by contrast material(s) and further sections|
|70540||Magnetic resonance (eg, proton) imaging, orbit, face, and/or neck; without contrast material(s)|
|70542||with contrast material(s)|
|70543||without contrast material(s), followed by contrast material(s) and further sequences|
|74440||Vasography, vesiculography, or epididymography, radiological supervision and interpretation|
|74740||Hysterosalpingography, radiological supervision and interpretation|
|74742||Transcervical catheterization of fallopian tube, radiological supervision and interpretation|
|76831||Saline infusion sonohysterography(SIS), including color flow Doppler, when performed|
|76856||Ultrasound, pelvic (nonobstetric), real time with image documentation; complete|
|76857||limited or follow-up (e.g., for follicles)|
|76870||Ultrasound, scrotum and contents|
|80400||ACTH stimulation panel; for adrenal insufficiency|
|80402||for 21 hydroxylase deficiency|
|80406||for 3 beta-hydroxydehydrogenase deficiency|
|80412||Corticotropic releasing hormone (CRH) stimulation panel|
|80414||Chorionic gonadotropin stimulation panel; testosterone response|
|80418||Combined rapid anterior pituitary evaluation panel|
|80426||Gonadotropin releasing hormone stimulation panel|
|80428||Growth hormone stimulation panel (eg, arginine infusion, l-dopa administration)|
|80438||Thyrotropin releasing hormone (TRH) stimulation panel; one hour|
|82024||Adrenocorticotropic hormone (ACTH)|
|82465||Cholesterol, serum or whole blood, total|
|82951||Glucose: tolerance test (GTT), three specimens (includes glucose)|
|83001||Gonadotropin; follicle stimulating hormone (FSH) [not covered for urinary FSH CLIA waived test with modifier QW]|
|83002||luteinizing hormone (LH)|
|83003||Growth hormone, human (HGH) (somatotropin)|
|83718||Lipoprotein, direct measurement; high density cholesterol (HDL cholesterol)|
|84233||Receptor assay; estrogen|
|84270||Sex hormone binding globulin (SHBG)|
|84443||Thyroid stimulating hormone (TSH)|
|84702||Gonadotropin, chorionic (hCG); quantitative|
|86277||Growth hormone, human (HGH), antibody|
|86689||HTLV or HIV antibody, confirmatory test (eg, western blot )|
|86703||HIV-1 and HIV-2, single result|
|86704||Hepatitis B core antibody (HBcAb); total|
|86706||Hepatitis B surface antibody (HBsAb)|
|86803||Hepatitis C antibody|
|86804||confirmatory test (eg, immunoblot)|
|87110||Culture, chlamydia, any source|
|87340||Infectious agent antigen detection by enzyme immunoassay technique, qualitative or semiquantitative, multiple-step method; hepatitis B surface antigen (HBsAg)|
|87341||hepatitis B surface antigen (HBsAg) neutralization|
|87491||Chlamydia trachomatis, amplified probe technique|
|87492||Chlamydia trachomatis, quantification|
|87810||Infectious agent detection by immunoassay with direct optical observation; Chlamydia trachomatis|
|88245||Chromosome analysis for breakage syndromes; baseline Sister Chromatid Exchange (SCE), 20-25 cells|
|88248||baseline breakage, score 50-100 cells, count 20 cells, 2 karyotypes (eg, for ataxia telangectasia, Fanconi anemia, fragile X)|
|88249||score 100 cells, clastogen stress (eg, diepoxybutane, mitomycin C, ionizing radiation, UV radiation)|
|88261||Chromosome analysis; count 5 cells, 1 karyotype, with banding|
|88262||count 15-20 cells, 2 karyotypes, with banding|
|88263||count 45 cells for mosaicism, 2 karyotypes, with banding|
|88264||analyze 20-25 cells|
|88271||Molecular cytogenetics: DNA probe, each (eg, FISH)|
|88272||chromosomal in situ hybridization, analyze 3-5 cells (eg, for derivatives and markers)|
|88273||chromosomal in situ hybridization, analyze 10-30 cells (eg, for microdeletions)|
|88274||interphase in situ hybridization, analyze 25-99 cells|
|88275||interphase in situ hybridization, analyze 100-300 cells|
|88280||Chromosome analysis; additional karyotypes, each study|
|88283||additional specialized banding technique (eg, NOR, C-banding)|
|88285||additional cells counted, each study|
|88289||additional high resolution study|
|88291||Cytogenics and molecular cytogenetics, interpretation and report|
|89250||Culture of oocyte(s)/embryo(s), less than 4 days; [not covered for the transfer of embryos derived from cryopreserved oocytes]|
|89251||with co-culture of oocyte(s)/embryos [not covered for the transfer of embryos derived from cryopreserved oocytes]|
|89253||Assisted embryo hatching, microtechniques (any method)|
|89254||Oocyte identification from follicular fluid|
|89255||Preparation of embryo for transfer (any method)|
|89257||Sperm identification from aspiration (other than seminal fluid)|
|89258||Cryopreservation; embryo(s) [for infertility due to pelvic radiotherapy or chemotherapy]|
|89259||sperm [for infertility due to pelvic radiotherapy or chemotherapy]|
|89260||Sperm isolation; simple prep (e.g., sperm wash and swim-up) for insemination or diagnosis with semen analysis|
|89261||complex prep (eg, Percoll gradient, albumin gradient) for insemination or diagnosis with semen analysis|
|89264||Sperm identification from testis tissue, fresh or cryopreserved|
|89268||Insemination of oocytes|
|89272||Extended culture of oocyte(s)/embryo(s), 4-7 days|
|89280||Assisted oocyte fertilization, microtechnique; less than or equal to 10 oocytes[not covered for the transfer of embryos derived from cryopreserved oocytes]|
|89281||greater than 10 oocytes [not covered for the transfer of embryos derived from cryopreserved oocytes]|
|89300||Semen analysis; presence and/or motility of sperm including Huhner test (post coital)|
|89310||motility and count (not including Huhner test)|
|89320||volume, count, motility, and differential|
|89321||sperm presence and motility of sperm, if performed|
|89322||volume, count, motility, and differential using strict morphologic criteria (eg, Kruger)|
|89329||Sperm evaluation; hamster penetration test|
|89330||cervical mucus penetration test, with or without spinnbarkeit test|
|89331||Sperm evaluation, for retrograde ejaculation, urine (sperm concentration, motility, and morphology, as indicated)|
|89337||Cryopreservation, mature oocyte(s)|
|90706||Rubella virus vaccine, live, for subcutaneous use|
|90739 - 90748||Hepatitis B vaccine|
|93975||Duplex scan of arterial inflow and venous outflow of abdominal, pelvic, scrotal contents and/or retroperitoneal organs; complete study|
|96040||Medical genetics and genetic counseling services, each 30 minutes face-to-face with patient/family|
|CPT codes not covered for indications listed in the CPB:|
|0087T||Sperm evaluation, Hyaluronan sperm binding test|
|0357T||Cryopreservation; immature oocyte(s)|
|10021||Fine needle aspiration; without imaging guidance|
|10022||with imaging guidance|
|43631 - 43635
43644 - 43645
43770 - 43775
43842 - 43848
43886 - 43888
|81400||Molecular pathology procedure, Level 1(eg, identification of single germline variant [eg, SNP] by techniques such as restriction enzyme digestion or melt curve analysis) [ITGB3 (integrin, beta 3 [platelet glycoprotein IIIa]|
|83001 - QW||Gonadotropin; follicle stimulating hormone (FSH) [urinary FSH - CLIA waived test]|
|83520||Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified [not covered for the Th1/Th2 ratio]|
|86146||Beta 2 Glycoprotein I antibody, each|
|86147||Cardiolipin (phospholipid) antibody, each Ig class|
|86148||Anti-phosphatidylserine (phospholipid) antibody|
|86357||Natural killer (NK) cells, total count[not covered for female infertility]|
|88184 - 88185||Flow cytometry, cell surface, cytoplasmic, or nuclear marker, technical component only; first marker and each additional [reproductive immunophenotyping]|
|88187 - 88189||Flow cytometry, interpretation; 2 to 8 markers, 9 to 15 markers, 16 or more markers [reproductive immunophenotyping]|
|89290 - 89291||Biopsy, oocyte polar body or embryo blastomere, microtechnique (for pre-implantation genetic diagnosis); less than, equal to, or greater than 5 embryos [not covered for preimplantation genetic screening]|
|89335||Cryopreservation, reproductive tissue, testicular|
|89342||Storage (per year); embryo(s)|
|89344||reproductive tissue, testicular/ovarian|
|89352||Thawing of cryopreserved; embryo(s)|
|89354||reproductive tissue, testicular/ovarian|
|89356||oocytes, each aliquot|
|Other CPT codes related to the CPB:|
|90460 - 90461||Immunization administration through 18 years of age via any route of administration, with counseling by physician or other qualified health care professional|
|90471 - 90472||Immunization administration (includes percutaneous intradermal, subcutaneous, or intramuscular injections|
|HCPCS codes covered if selection criteria are met:|
|G0010||Administration of hepatitis B vaccine|
|G0027||Semen analysis; presence and/or motility of sperm excluding Huhner|
|G0123||Screening cytopathology, cervical or vaginal (any reporting system), collected in preservative fluid, automated thin layer preparation, screening by cytotechnologist under physician supervision|
|G0124||Screening cytopathology, cervical or vaginal (any reporting system), collected in preservative fluid, automated thin layer preparation, requiring interpretation by physician|
|G0141 - G0148||Screening cytopathology smears, cervical or vaginal|
|G0472||Hepatitis C antibody screening for individual at high risk and other covered indication(s)|
|J0725||Injection, chorionic gonadotropin, per 1,000 USP units|
|J0900||Injection, testosterone enanthate and estradiol valerate, up to 1cc|
|J1000||Injection, depo-estradiol cypionate, up to 5 mg|
|J1060||Injection, testosterone cypionate and estradiol cypionate, up to 1 ml|
|J1071||Injection, testosterone cypionate, 1mg|
|J1094||Injection, dexamethasone acetate, 1 mg|
|J1100||Injection, dexamethasone sodium phosphate, 1 mg|
|J1380||Injection, estradiol valerate, up to 10 mg|
|J1410||Injection, estrogen conjugated, per 25 mg|
|J1620||Injection, gonadorelin HCI, per 100 mcg|
|J2370||Injection, phenylephrine HCI, up to 1 ml|
|J2675||Injection, progesterone, per 50 mg|
|J3120||Injection, testosterone enanthate, up to 100 mg|
|J3121||Injection, testosterone enanthate, 1mg|
|J3130||Injection, testosterone enanthate, up to 200 mg|
|J3140||Injection, testosterone suspension, up to 50 mg|
|J3145||Injection, testosterone undecanoate, 1 mg|
|J3150||Injection, testosterone propionate, up to 100 mg|
|J3355||Injection, urofollitropin, 75 IU|
|J7506||Prednisone, oral, per 5 mg|
|J8515||Cabergoline, oral, 0.25 mg|
|J8540||Dexamethasone, oral, 0.25 mg|
|J9202||Goserelin acetate implant, per 3.6 mg|
|J9218||Leuprolide acetate, per 1 mg|
|P3000||Screening Papanicolaou smear, cervical or vaginal, up to three smears, by technician under physician supervision|
|P3001||Screening Papanicolaou smear, cervical or vaginal, up to three smears, requiring interpretation by physician|
|Q0115||Post-coital direct, qualitative examinations of vaginal or cervical mucous|
|S0122||Injection, menotropins, 75 IU|
|S0126||Injection, follitropin alfa, 75 IU|
|S0128||Injection, follitropin beta, 75 IU|
|S0132||Injection, ganirelix acetate, 250 mcg [not covered for men]|
|S0187||Tamoxifen citrate, oral, 10 mg|
|S0265||Genetic counseling, under physician supervision, each 15 minutes|
|S2078||Laparoscopic supracervical hysterectomy (subtotal hysterectomy), with or without removal of tube(s), with or without removal of ovary(s)|
|S4011||In vitro fertilization; including but not limited to identification and incubation of mature oocytes, fertilization with sperm, incubation of embryo(s), and subsequent visualization for determination of development|
|S4013||Complete cycle, gamete intrafallopian transfer (GIFT), case rate|
|S4014||Complete cycle, zygote intrafallopian transfer (ZIFT), case rate|
|S4015||Compete in vitro fertilization cycle, not otherwise specified, case rate|
|S4016||Frozen in vitro fertilization cycle, case rate|
|S4017||Incomplete cycle, treatment canceled prior to stimulation, case rate|
|S4018||Frozen embryo transfer procedure canceled before transfer, case rate|
|S4020||In vitro fertilization procedure canceled before aspiration, case rate|
|S4021||In vitro fertilization procedure canceled after aspiration, case rate|
|S4022||Assisted oocyte fertilization, case rate|
|S4023||Donor egg cycle, incomplete, case rate|
|S4025||Donor services for in vitro fertilization (sperm or embryo), case rate|
|S4026||Procurement of donor sperm from sperm bank|
|S4028||Microsurgical epididymal sperm aspiration (MESA)|
|S4035||Stimulated intrauterine insemination (IUI), case rate|
|S4037||Cryopreserved embryo transfer, case rate|
|S4993||Contraceptive pills for birth control|
|S9560||Home injectable therapy; hormonal therapy (e.g., leuprolide, goserelin), including administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem|
|HCPCS codes not covered for indications listed in the CPB:|
|B4185||Parenteral nutrition solution, per 10 grams lipids|
|J1561||Injection, immune globulin, (Gamunex/Gamunex-C/Gammaked), nonlyophilized (e.g., liquid), 500 mg|
|J1566||Injection, immune globulin, intravenous, lyophilized (e.g., powder), not otherwise specified, 500 mg|
|J1568||Injection, immune globulin, (Octagam), intravenous, nonlyophilized (e.g., liquid), 500 mg|
|J1569||Injection, immune globulin, (Gammagard liquid), nonlyophilized, (e.g., liquid), 500 mg|
|J2940||Injection, somatrem, 1 mg|
|J2941||Injection, somatropin, 1 mg|
|Q0515||Injection, sermorelin acetate, 1 mcg|
|S4027||Storage of previously frozen embryos|
|S4030||Sperm procurement and cryopreservation services; initial visit|
|S4031||Sperm procurement and cryopreservation services; subsequent visit|
|S4040||Monitoring and storage of cryopreserved embryos, per 30 days|
|S4042||Management of ovulation induction (interpretation of diagnostic tests and studies, non-face-to-face medical management of the patient), per cycle|
|S9558||Home injectable therapy; growth hormone, including administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem|
|ICD-9 codes covered if selection criteria are met (not all-inclusive):|
|042||Human immunodeficiency virus [HIV] disease [HIV positive male undergoing sperm washing]|
|140.0 - 208.92||Malignant neoplasms, lip, oral cavity, and pharynx, digestive organs and peritoneum, respiratory and intrathoracic organs, bone, connective tissue, skin, and breast, genitourinary organs, other and unspecified sites, lymphatic and hematopoietic tissue|
|209.00 - 209.29||Neuroendocrine tumors, small intestines, appendix, large intestine, rectum. other and unspecified sites|
|209.30 - 209.36||Malignant poorly differentiated neuroendocrine tumors|
|209.75||Secondary merkel cell carcinoma|
|218.0 - 218.9||Uterine leiomyoma|
|220||Benign neoplasm of ovary|
|222.3||Benign neoplasm of epididymis|
|227.3||Benign neoplasm of pituitary gland and craniopharyngeal duct (pouch)|
|236.0 - 236.2||Neoplasm of uncertain behavior of genitourinary organs|
|236.6||Neoplasm of uncertain behavior of other and unspecified male genital organs|
|237.0||Neoplasm of uncertain behavior of pituitary gland and craniopharyngeal duct|
|244.0 - 244.9||Acquired hypothyroidism|
|253.1||Other and unspecified anterior pituitary hyperfunction|
|253.4||Other anterior pituitary disorders|
|256.1||Other ovarian hyperfunction [hypersecretion of ovarian androgens]|
|256.2||Postablative ovarian failure|
|256.31||Premature menopause [poor ovarian reserve]|
|257.2||Other testicular hypofunction|
|603.0 - 603.9||Hydrocele|
|606.0 - 606.9||Infertility, male|
|607.84||Impotence of organic origin|
|608.0 - 608.89||Other specified disorders of male genital organs|
|611.6||Galactorrhea not associated with childbirth|
|614.0 - 614.9||Inflammatory disease of ovary, fallopian tube, pelvic cellular tissue, and peritoneum|
|617.0 - 617.9||Endometriosis|
|620.0 - 620.9||Noninflammatory disorders of ovary, fallopian tube, and broad ligament|
|621.0||Polyp of corpus uteri|
|626.0||Absence of menstruation|
|626.4||Irregular menstrual cycle|
|628.0 - 628.9||Infertility, female|
|752.0||Anomalies of ovaries|
|752.10 - 752.19||Anomalies of fallopian tubes and broad ligaments|
|752.2||Doubling of uterus|
|752.40 - 752.49||Anomalies of cervix, vagina, and external female genitalia|
|752.89||Other specified anomalies of genital organs|
|792.2||Nonspecific abnormal findings in semen|
|793.2||Nonspecific (abnormal) findings on radiological and other examination of other intrathoracic organs [follow-up on hystersalpingography abnormalities]|
|990||Effects of radiation, unspecified|
|995.20||Unspecified adverse effect of unspecified drug, medicinal and biological substance [chemotherapy]|
|V01.79||Contact with or exposure to other viral diseases [partners of persons infected with hepatitis B]|
|V04.3||Need for prophylactic vaccination and inoculation against rubella alone [women susceptible to rubella]|
|V08||Asymptomatic human immunodeficiency virus [HIV] infection status [HIV positive NOS]|
|V59.70 - V59.74||Egg (oocyte) (ovum) donor|
|V74.5||Venereal disease [chlamydia trachomatis screening]|
|V83.01 - V83.02||Asymptomatic and symptomatic hemophilia A carrier|
|V83.81||Cystic fibrosis gene carrier|
|V83.89||Other genetic carrier status [high risk of transmitting a genetic disorder from the female partner to the offspring]|
|ICD-9 codes not covered for indications listed in the CPB (not all-inclusive):|
|302.50 - 302.53||Trans-sexualism [persons with gender reassignment are considered to have elective sterilization]|
|627.0 - 627.9||Menopausal and postmenopausal disorders|
|V07.4||Hormone replacement therapy (postmenopausal)|
|V26.0||Tuboplasty or vasoplasty after previous sterilization|
|V26.51||Tubal ligation status|
|V45.77||Acquired absence of genital organs|
|V49.81||Asymptomatic postmenopausal status (age-related) (natural)|
|Other ICD-9 codes related to the CPB:|
|001.0 - 139.8||Infectious and parasitic diseases|
|209.40 - 209.69||Benign carcinoid tumors, small intestine, appendix, large intestine, rectum, other and unspecified sites|
|209.70 - 209.74, 209.79||Secondary neuroendocrine tumor, unspecified site, distant lymph nodes, liver, bone, peritoneum and other sites|
|210.0 - 239.9||Benign neoplasms, carcinomas in situ, neoplasms of uncertain nature, neoplasms of unspecified nature|
|240.0 - 246.9||Disorders of thyroid gland|
|250.60 - 250.63||Diabetes with neurological manifestations|
|256.39||Other ovarian failure [poor ovarian reserve]|
|357.2||Polyneuropathy in diabetes|
|611.6||Galactorrhea not associated with childbirth|
|614.1||Chronic salpingitis and oophoritis|
|614.2||Salpingitis and oophoritis not specified as acute, subacute, or chronic|
|626.0||Absence of menstruation|
|633.00 - 633.91||Ectopic pregnancy|
|640.00 - 648.94||Complications mainly related to pregnancy|
|752.0 - 752.19||Anomalies of ovaries, fallopian tubes and broad ligaments|
|758.0 - 758.5||Chromosomal anomalies|
|773.0||Hemolytic disease due to Rh isoimmunization|
|905.1||Late effect of fracture of spine and trunk without mention of spinal cord lesion|
|907.2||Late effect of spinal cord injury|
|952.00 - 952.9||Spinal cord injury without evidence of spinal bone injury|
|990||Effects of radiation, unspecified|
|E933.1||Adverse effects of antineoplastic and immunosuppressive drugs|
|V10.40 - V10.49||Personal history of malignant neoplasm of genital organs|
|V13.29||Personal history of other genital system and obstetric disorders|
|V22.0 - V22.1||Normal pregnancy|
|V23.0 - V23.9||Supervision of high-risk pregnancy|
|V26.31 - V26.33||Genetic counseling and testing|
|V26.81||Encounter for assisted reproductive fertility procedure cycle|
|V73.88||Special screening examination for other specified chlamydial diseases|
|V73.98||Special screening for unspecified chlamydial disease|
|V74.5||Special screening for venereal disease|
|V77.6||Special screening for cystic fibrosis|
|V81.6||Special screening for other and unspecified genitourinary conditions|
|V83.81 - V83.89||Genetic carrier status|
|V84.01 - V84.89||Genetic susceptibility to disease|