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The role of immunotherapy in in vitro fertilization: a guideline (2018)


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Adjuvant immunotherapy treatments in in vitro fertilization (IVF) aim to improve the outcome of assisted reproductive technology (ART) in both the general ART population as well as subgroups such as patients with recurrent miscarriage or implantation failure. The purpose of this guideline is to evaluate the role of immunomodulating therapy in ART. Unfortunately, many of the evaluated therapies lack robust evidence from well-designed adequately powered randomized controlled trials to support their use. Immunotherapies reviewed in the present document are either not associated with improved live-birth outcome in IVF or have been insufficiently studied to make definitive recommendations. (Fertil Steril® 2018;110:387–400. ©2018 by American Society for Reproductive Medicine.)

Successful outcomes in assisted reproductive technology (ART) cycles depend on the developmental competence of transferred embryo(s) and endometrial receptivity. Multiple factors are believed to be involved in endometrial receptivity, including the hormonal preparation of the endometrium, contractility of the myometrium, and the interaction between the embryo and endometrium, the latter of which inherently involves immunological mechanisms. In an effort to improve outcomes in ART cycles in general, and in patients with recurrent implantation failure and/or pregnancy loss, aduvant immunotherapies have been introduced into in vitro fertilization (IVF) treatment cycles. The rationale behind the use of these therapies is that they may correct an immunological imbalance resulting in improved and sustained implantation of the developing embryo, ultimately leading to improved live-birth outcome. While some of these medications (e.g., aspirin and corticosteroids) have been used for many years and are relatively low cost, others (e.g., intravenous fat emulsions and granulocyte colony–stimulating factor [GCSF]) are newer, of higher cost, and with risks that have been poorly characterized. It is imperative that physicians providing ART treatments have a full understanding of the potential risks and benefits associated with adjuvant immunotherapy in order to appropriately counsel patients regarding their use. In the absence of well-designed adequately powered randomized controlled trials (RCTs), or other methodologically rigorous quantitative assessment design studies, patients must be informed of uncertain benefits and risks (1). In some investigations, adjuvant immunotherapies have been administered based on the results of immunological testing. Given the lack of a clear relationship between immunophenotypes and ART outcomes, the use of immunological testing in the general ART population cannot be recommended (2, 3). The present guideline is based on a systematic review of the literature regarding immunotherapy in IVF with the goal of informing the practitioner about how to provide evidence-based care.


LIMITATIONS OF THE LITERATURE

Multiple challenges exist in interpreting the literature related to immunotherapy and IVF outcomes, which includes few well-designed randomized studies. Many of the cited investigations are more than 20 years old, and their applicability to modern ART is uncertain. Additionally,many of the investigations are underpowered and/or address surrogate outcomes such as embryo development and clinical pregnancy rate rather than live birth. Multiple investigations also include combined treatment regimens rather than single-component treatments, so it is difficult to attribute any change in outcome to a given treatment. Some of the investigated therapies (e.g., aspirin) may have multiple mechanisms of action, such that an observed effect may or may not be due to an immunological mechanism. Finally, many of the cited studies include narrowly defined populations based on immunological testing which may not be readily available and/or reproducible.


METHODS

This clinical practice guideline was based on a systematic review of the literature performed in the electronic database MEDLINE through PubMed on August 17, 2017. No limit or filter was used for the time period covered or English language, but articles were subsequently culled for English language. This electronic search and examination of reference lists from primary and review articles yielded 1,525 studies, of which 96 studies were included.

A combination of the following medical subject headings or text words were used: abdominal pain/chemically induced; acetylsalicylic acid; adalimumab; adjuvants, immunologic; adrenocorticotropic hormone; adverse; adrenal cortex hormones; allogenic leukocyte immunization; alloimmunization; antibodies, anticardiolipin; antibodies, antinuclear; antibodies, antiphospholipid; anti-cardiolipin antibody; antigens; anti-nuclear antibodies; anti-nuclear antibody; antinuclear antibodies; antinuclear antibody; antiphospholipid antibody; antiphospholipid antibodies; antithyroid antibody; antithyroid antibodies; aspirin; assisted reproduction; autoantibodies; corticosteroid/s; corticotropin-releasing hormone; cost; cytokine; cytokines; dexamethasone; drug costs; embryo implantation; embryo transfer; Enbrel; estrogen/s; etanercept; fertility agents, female/adverse effects; fertilization in vitro/methods; filgrastim; G-CSF; glucocorticoid/s; GM-CSF; granulocyte colony-stimulating factor; harm; HLA; HLA antigens; human leukocyte antigen; Humira; ICSI; IL-10; IL-17; IL-27; immune modulatory; immune therapy; immunoglobulins, intravenous; immunoglobulins/therapeutic use; immunologic tests; immunomodulation; immunomodulatory; immunosuppression; immunotherapy; in vitro fertilisation; in vitro fertilization; interleukin-10; interleukin-17; interleukin-27; intracytoplasmic sperm injection; intralipid; intralipid infusion; intrauterine insemination; intravenous immunoglobulin; intravenous immunoglobulins, human; intravenous lipids; irritable bowel syndrome/chemically induced; IVF; IUI; killer cells, natural; leukocyte antibodies; leukocyte antibody; lupus anticoagulant; lupus coagulation inhibitor; methylprednisolone; natural killer cells; nausea/chemically induced; ovulation induction; prednisone; progesterone; regulatory T cells; risk; safety; sperm injections, intracytoplasmic; steroid/s; T cells; T regulatory cells; tacrolimus; Th1; Th1 cells; Th2; Th2 cells; thyroid peroxidase antibodies; thyroid peroxidase antibody; TNF; transforming growth factor beta; Treg cells; tumor necrosis factor; tumour necrosis factor; tumor necrosis factoralpha; vomiting/chemically induced.

Initially, titles and abstracts of potentially relevant articles were screened and reviewed to develop inclusion/exclusion criteria. Only studies that met the inclusion criteria were assessed in the final analysis. Studies were eligible if they met one of the following criteria: primary evidence (clinical trials) that assessed the effectiveness of a procedure correlated with an outcome measure (pregnancy, ovulation, or live-birth rates); meta-analyses; and relevant articles from bibliographies of identified articles (Table 1).

Four members of an independent task force reviewed the full articles of all citations that potentially matched the predefined selection criteria. Final inclusion or exclusion decisions were made on examination of the articles in full. Disagreements about inclusion among reviewers were discussed and resolved by consensus or arbitration after consultation with an independent reviewer/epidemiologist.

Table 1. Summary of inclusion/exclusion criteria.


Include Exclude
Level I and II studies, systematic reviews, meta-analyses Level III studies: series, case reports, reviews, opinions, off topic
Human studies Animal studies
English Non-English
Studies with a comparison group Studies without a comparison group
Studies with a primary focus on IVF Non-IVF fertility treatment
Aspirin as monotherapy for IVF outcomes Agents that are both immunomodulating and have other
progestational effects
Corticosteroids during ovarian stimulation Anticardiolipin studies that focus on recurrent pregnancy loss
Peri-implantation corticosteroids Anticoagulants
G-CSF and GM-CSF and embryo development, aneuploidy,
endometrial thickness, or IVF outcomes
Antithyroid antibodies
Intravenous fat emulsions and IVF outcomes DHEA
IVIG and IVF outcomes IUI
Adalimumab and IVF outcomes Metformin
Peripheral mononuclear cells and IVF outcomes OHSS
Seminal plasma and IVF outcomes PCOS
Antibody-free preparation of spermatozoa and IVF outcomes Thyroid
Tacrolimus and IVF outcomes Vasodilators
  Uterine relaxants
  Patients on immunomodulation therapy for known autoimmune
conditions (e.g., rheumatoid arthritis)
  Progesterone (with mixed hormonal and immunological properties)
  Hypertensive complications
  Aspirin in combination with other therapies
Note: DHEA = dehydroepiandrosterone; G-CSF = granulocyte colony–stimulating factor; GM-CSF = granulocyte/macrophage colony–stimulating factor; IUI = intrauterine insemination; IVIG = intravenous immunoglobulin; IVF = in vitro fertilization; OHSS = ovarian hyperstimulation syndrome; PCOS = polycystic ovary syndrome.

Level of Evidence

The level of the evidence was evaluated using the following grading system and is assigned for each reference in the bibliography:


Level I

  • Systematic review of randomized controlled trials (RCTs)
  • RCTs


Level II

  • Systematic review of a combination of RCTs, controlled trials without randomization, and cohort studies
  • Controlled trials without randomization
  • Cohort studies
  • Case-control studies


Level III

  • Descriptive studies, case series, case reports, letters, nonsystematic reviews, opinions based on clinical experience, and reports of expert committees


Quality of Evidence

The quality of the evidence was evaluated using the following grading system, adapted from the Johns Hopkins Nursing Evidence-based Practice grading system, and is assigned for each reference in the bibliography:


A: High Quality

  • Consistent, generalizable results; sufficient sample size for the study design; adequate control; definitive conclusions; consistent recommendations based on a comprehensive literature review that includes thorough reference to scientific evidence


B: Good Quality

  • Reasonably consistent results; sufficient sample size for the study design; some control; fairly definitive conclusions; reasonably consistent recommendations based on a fairly comprehensive literature review that includes some reference to scientific evidence


C: Low Quality or Major Flaws

  • Little evidence with inconsistent results; insufficient sample size for the study design; conclusions cannot be drawn


Strength of Recommendations

The entirety of the literature was then used to develop recommendations based on the quality of the literature. The strength of the recommendation was evaluated as follows:

Grade A: There is good evidence to support the recommendations, either for or against. (From consistent Level-I studies of High quality [Grade A])

Grade B: There is fair evidence to support the recommendations, either for or against. (From principally Level-II studies of Good quality [Grade B])

Grade C: There is insufficient evidence to support the recommendations, either for or against. (From Level-II studies of Low quality [Grade C], or when there are conflicting data from studies of Good quality)


Aspirin

Aspirin has been investigated as a means to increase blood flow to the ovaries and thereby improve oocyte yield and/ or quality, and increase blood flow to the uterus which may improve endometrial thickness and receptivity (4, 5). With theoretical mechanisms of action that could involve both anti-inflammatory and anti-platelet activity, aspirin has been investigated as an attractive potential adjuvant to IVF.

Five RCTs investigating the use of aspirin in ART reported outcomes for implantation rate. Four of these did not show a benefit of aspirin for implantation rate in IVF (6–9), while the remaining trial (n=149, aspirin group) did show a significantly improved implantation rate with aspirin use (10). A retrospective cohort study also failed to demonstrate a benefit of aspirin for implantation rate, and found a statistically significantly higher fertilization rate in the nonaspirin group (54.7% aspirin vs. 58.2% no aspirin, respectively, P<.01) (11).

Nine RCTs reported an association between aspirin and pregnancy rate in IVF; pregnancy rate was variably defined. Several studies defined clinical pregnancy as presence of a gestational sac (6, 12) or fetal cardiac activity (6,8–10,13), while the remaining studies did not specify how pregnancy was defined (14–16). While a single RCT of 298 patients undergoing IVF for tubal factor infertility showed a significantly improved pregnancy rate among women who received low-dose aspirin (45% vs. 28%, P<.05) (10), eight RCTs showed no benefit of aspirin use for pregnancy rate in ART (6,8,9,12–16). There was no benefit of aspirin for pregnancy rate in three cohort studies (11, 17, 18), while two cohort studies showed a higher pregnancy rate with aspirin use (19, 20).

Multiple RCTs have failed to demonstrate a benefit of aspirin for live-birth rate (13, 14, 16, 21) or ongoing pregnancy rate (7) in ART, and there are no RCTs that have shown an improved live-birth rate. There are three retrospective analyses demonstrating an association with aspirin and higher live-birth rate: 74.8% aspirin vs. 63.7% controls, P<.05; 27.2% aspirin vs. 23.2% controls (odds ratio [OR] 1.2; confidence interval [CI] 1.0–1.6); and adjusted OR 1.48, CI 1.08–2.02, respectively (19, 20, 22). However, two other retrospective analyses published around the same time failed to show an association with live-birth rate and aspirin use (11, 18). Another more recent study showed no benefit for ongoing pregnancy rate with aspirin (17).

A meta-analysis of six RCTs comparing aspirin to placebo or no treatment during IVF/intracytoplasmic sperm injection (ICSI) found no beneficial effect on pregnancy (risk ratio [RR] 1.09; 95% CI 0.92–1.29), live-birth rate per cycle (RR 0.87; 95% CI 0.57–1.34), or live-birth rate per embryo transfer (ET) (RR 1.08; 95% CI 0.83–1.40) (23). Similarly, another meta-analysis published the same year included seven trials of participants undergoing controlled ovarian stimulation (COS), IVF, or ICSI, and found no benefit of aspirin compared to placebo or no treatment for clinical pregnancy rate (RR 1.11; 95% CI 0.95–1.31) or live-birth rate (RR 0.94; 95% CI 0.64–1.39), although this study lacked power when studies were pooled (24). In contrast, a meta-analysis of 10 RCTs, including a reanalysis of a prior meta-analysis (23), showed that aspirin may increase clinical pregnancy rates (fixed effects RR 1.15; 95% CI 1.03–1.27), although there was a large variation in results among included studies (25). A metaanalysis of 10 RCTs published a few years later found no improvement in clinical pregnancy rate (pooled OR 0.86; 95% CI 0.69–1.1) or ongoing pregnancy rate (pooled OR 0.85; 95% CI 0.65–1.1) (26). A more recent meta-analysis of 17 RCTs comparing aspirin with no aspirin or placebo in IVF/ICSI couples showed a higher pregnancy rate (OR 1.19; 95% CI 1.01–1.39) but did not show a benefit for live-birth rate (OR 1.08; 95% CI 0.90–1.29) (27). Most recently, a Cochrane systematic review of 13 low- to moderate-quality trials of subfertile women undergoing ART showed no benefit of aspirin in IVF for pregnancy (RR 1.03; 95% CI 0.91–1.17; 10 trials) or live-birth rates (RR 0.91; 95% CI 0.72–1.15; 3 trials) (28).

Aspirin monotherapy has also been investigated for use in specific populations undergoing IVF. Among recipients of oocyte donation, low-dose aspirin improved implantation rate but not live-birth rate in patients with a thin endometrium (16).

While aspirin is an inexpensive therapy with little overall risk, studies do not demonstrate that it improves the success of IVF. Therefore, its use is not recommended for use in the general IVF population. (See Supplemental Table 1, listing aspirin dosing and/or timing and IVF outcomes.)


Summary Statements

  • Given the lack of evidence to support improved IVF outcomes, there is good evidence to recommend against the routine use of low-dose aspirin to improve the outcome of live birth in ART cycles in the general population. (From Level-I studies of Good and High quality). (Grade A).


Corticosteroids

During ovarian stimulation. Corticosteroids are steroid hormones produced in the adrenal cortex in response to adrenocorticotropic hormone from the anterior pituitary. Synthetic forms (dexamethasone, hydrocortisone, prednisolone, methylprednisolone, and 16-methyl prednisolone) have been investigated for their potential ability to improve ovarian response to COS, to reduce the amount of exogenous gonadotropins required, and to optimize the intrauterine environment to increase the likelihood of implantation after IVF. In addition, corticosteroids have been hypothesized to improve the outcome of IVF with conventional insemination in cases where the male partner has sperm autoantibodies. The rationale for using corticosteroids to improve ovarian response to COS is based on several possible mechanisms by which corticosteroids can affect ovarian function. Dexamethasone may directly mediate proper folliculogenesis, as it acts as a substrate for the enzyme 11-beta-hydroxysteroid dehydrogenase type I which is found in luteinized granulosa cells and oocytes (29, 30). Corticosteroids can suppress elevated androgen levels, type I which are considered detrimental to normal folliculogenesis, by acting on the ovaries, adrenals, and pituitary glands. Furthermore, these agents could sensitize the ovaries to the actions of exogenous gonadotropins by increasing production of growth factors such as insulin-like growth factor (IGF)-1. A significant rise in follicular cortisol has been observed prior to ovulation, suggesting that corticosteroids may play an important role in oocyte maturation and ovulation (31–33).

Despite differing study designs and inclusion criteria, several Level-I studies (34–37) have refuted the hypothesis that the administration of corticosteroids during COS leads to an improvement in ovarian response or clinical outcomes. A trial randomized 78 normo-ovulatory women with tubal factor infertility to receive 0.5 mg or 1 mg of dexamethasone during COS vs. no treatment (34). This trial demonstrated no improvement in implantation rate (controls 13%, dexamethasone 0.5 mg 11%, and dexamethasone 1 mg 12%) or pregnancy rate (controls 20%, dexamethasone 0.5 mg 16.5%, and dexamethasone 1 mg 20.8%) (34). Another trial randomized 42 patients with unexplained or anovulatory infertility and a history of poor response in at least two prior IVF cycles to 0.5 mg dexamethasone during COS or no treatment, but found no benefit of treatment with low-dose dexamethasone in the studied population of low responders (36). A third RCT also demonstrated no improvement in implantation (8.1% treatment vs. 7.8% controls) or pregnancy rate (13.5% treatment vs. 12.8% controls) (35). A later trial randomized 313 patients under age 39 years to either 10 mg daily oral prednisolone or no treatment for 4 weeks, starting on the first day of ovarian stimulation (37). There was no difference in ongoing pregnancy or deliveries between the treatment groups (prednisolone 39.6% vs. controls 37.1%). The results of these trials were consistent in demonstrating that treatment with corticosteroids during COS did not significantly affect the number of developing follicles (36), oocyte yield, fertilization, or clinical pregnancy rate (34, 36, 37). These trials were limited by their lack of a placebo and failure to provide a power analysis to demonstrate an adequate sample size to evaluate the hypothesis that corticosteroids improve ovarian response to COS. A more recent two-center, double-blinded RCT randomized 290 patients to 1 mg dexamethasone or placebo and found a reduced rate of cycle cancellation for poor response in the treatment group (2.8%) vs. controls (12.4%, P<.002) (29). However, there were no significant differences in fertilization, implantation, or clinical pregnancy rate per cycle start. Another RCT included 395 first-time IVF patients with normal ovarian reserve who were treated daily with low-dose aspirin (100 mg) combined with prednisone (10 mg/day from the beginning of ovarian stimulation to ET, 30 mg/day for 5 days starting from the day of transfer, and 10 mg/d thereafter, until the day of pregnancy test) (15). Patients in the treatment group were compared with control patients who did not receive a placebo. The treatment group had significantly improved ovarian response, with higher estradiol levels on the day of human chorionic gonadotropin (hCG) trigger (2,082 ± 741 vs. 1,728 ± 672, P<.001) and significantly more oocytes retrieved (14.0 ± 6.5 vs. 10.5 ± 5.1, P<.001) (15). Despite these outcomes, fertilization, implantation, clinical pregnancy, and early pregnancy loss rates were similar. A meta-analysis also did not identify a difference in pregnancy rate, clinical pregnancy rate, or implantation rate in women undergoing IVF/ICSI and treated with prednisolone vs. controls (pregnancy rate: RR 1.02, 95% CI 0.84–1.24; clinical pregnancy rate: RR 1.01, 95% CI 0.82–1.24; implantation rate: RR 1.04, 95% CI 0.85–1.28) (38).

There are two RCTs that contradict these findings and report on corticosteroids positively impacting pregnancy rates in patients undergoing ovarian stimulation (39, 40). One of these trials randomized 146 hyperandrogenemic, infertile patients undergoing COS with exogenous gonadotropins and/or clomiphene citrate to receive 7.5 mg of oral prednisolone daily from cycle day 1 until pregnancy or menstrual bleeding or no treatment (39). Treatment suppressed serum dehydroepiandrosterone sulfate (DHEA-S) and testosterone and led to improved follicular response, signified by significantly higher estradiol levels on the day of hCG trigger and clinical pregnancy rate (prednisolone group 21.9% vs. no prednisolone 8.2%, P=.037) (39). Another RCT included patients (N=129; n=64 received treatment) with endometriosis and/or tubal factor infertility who received daily prednisolone (10 mg from cycle day 3, increased to 60 mg from oocyte retrieval to ET) (40). Corticosteroid treatment significantly improved the pregnancy rate in patients with endometriosis and tubal factor infertility, whereas treatment did not have a benefit in the patients with tubal factor alone (40). In the subset of patients who tested positive for autoantibodies (antinuclear antibodies [ANA], lupus anticoagulant, anticardiolipin antibody and/or rheumatoid factor), those who received corticosteroids had a significantly higher pregnancy rate (40.9% vs. 14.8%, P<.05) (40). However, the comparison of these subgroups may have been confounded by differences in baseline characteristics as randomization was not performed according to autoantibody status. The results of these RCTs should be interpreted with caution as they are limited by a lack of a power analysis, significant sources of heterogeneity in the treatment protocol (such as the number of embryos transferred), and limited generalizability to today's IVF treatment paradigm, as they were published over 20 years ago. The most recent study, a meta-analysis published in 2017, included four RCTs (involving a total of 416 couples with various infertility diagnoses) which demonstrated that daily corticosteroids (10 mg prednisolone or 0.5 mg dexamethasone during ovarian stimulation up until oocyte retrieval) did not impact clinical pregnancy or livebirth rate (31).

While several retrospective, observational studies have reported that corticosteroid treatment may improve IVF success rates, these studies are limited by significant methodologic flaws (41–46). (See Supplemental Table 2, listing the use of corticosteroids and IVF outcomes and study limitations.)

Peri-implantation corticosteroids.
Uterine receptivity is regulated by locally acting growth factors and cytokines (47–50) that have important roles in mediating immunological and non-immunological activity within the endometrium. Natural killer (NK) cells play an important role in maintaining maternal-fetal immune tolerance and regulating trophoblast invasion (38). Aberrant cytokine activity and overactivity of NK cells have been associated with implantation failure and early pregnancy loss (47, 51–53). The administration of corticosteroids around the time of implantation has been proposed as a strategy to normalize NK cell activity and cytokine expression, and suppress inflammatory mediators to improve endometrial receptivity and the odds of successful implantation (47, 54, 55).

Several RCTs have failed to demonstrate any effect of peri-implantation corticosteroids on ET outcome (35, 47, 56, 57). An RCT which randomized 99 normo-ovulatory women with tubal factor infertility to 0.5 mg dexamethasone for 5 days from time of ovulation to ET, reported a lack of improvement in implantation, clinical pregnancy, or livebirth rates (35). Similarly, there was no difference (P>.05) in implantation (16% vs. 11%), clinical pregnancy (43.5% vs. 32.3%), or ongoing pregnancy rate (30.7% vs. 28%) in a trial of 75 IVF patients randomized to receive either 60 mg prednisone daily for 4 days from time of oocyte retrieval, or placebo, respectively (57). Both of these trials lacked power analyses to demonstrate an adequate sample size to detect a meaningful effect on clinical outcome. A larger study of 206 patients randomized to receive either methylprednisone or placebo at the time of oocyte retrieval in fresh transfer cycles or a day prior to embryo thaw in frozen ET cycles, reported no difference in implantation or clinical pregnancy rate in either group (56). A lack of effect of periimplantation corticosteroid administration on clinical outcome was reiterated by a recent, large, systematic review which included 14 RCTs involving 1,879 patients who received either corticosteroids or no treatment prior to transfer (47) as well as a prospective cohort study (58).

The only studies to report that peri-implantation corticosteroid treatment improved ET outcome involved patients with serum autoantibodies. Autoimmune thyroid disorders are characterized by the presence of antithyroid antibodies, such as antithyroid peroxidase and/or thyroglobulin. Thyroid autoimmunity has been associated with recurrent pregnancy loss, preterm birth, and recurrent IVF failure (59). A single study randomized patients with anti-thyroglobulin and thyroid peroxidase antibodies (n=60; age ≤38 years) to receive either 5 mg prednisolone daily from day of oocyte retrieval to pregnancy test or no treatment (59). The treatment group had higher clinical pregnancy and live-birth rates compared with the control group (clinical pregnancy: 46.6% vs. 16.6%, P=.03; live birth: 46.6% vs. 20%, P=.055) (59). A retrospective cohort study of 120 women positive for serum ANA reported that patients who received prednisolone (in a dose ranging from 15 to 60 mg per day, starting the day after oocyte retrieval) had significantly higher implantation and clinical pregnancy rates than ANA-positive women who did not receive corticosteroids (60). However, there was no significant difference in live-birth rate. This study may have been underpowered to analyze the effect of the intervention on live-birth rate. The results should be interpreted with caution as this was a retrospective, nonrandomized study involving a non-uniform intervention, with the corticosteroid dose being adjusted according to patient tolerance of side effects (60). Several other retrospective cohort studies have demonstrated corticosteroid treatment to have a positive clinical impact in autoantibody-positive subjects (43–46). However, all these studies were confounded by the fact that treated subjects underwent co-administration of corticosteroids with aspirin. Two small cohort studies suggested that glucocorticoid treatment was associated with improved pregnancy rates in the setting of assisted hatching (61) and tubal factor infertility (62). However, both investigations were limited by small sample size, no live-birth outcome, and inappropriate statistical analyses (considering repeat cycles as independent observations).

The only Level-I study to assess the efficacy of corticosteroids for autoimmune-mediated male infertility reported that randomization of men with antisperm antibodies to 20 mg of prednisolone daily for 2 weeks prior to IVF vs. no treatment did not reduce the amount of sperm-bound antibody and did not improve IVF outcome (63). Of note, this study was underpowered and did not account for female factor infertility.


Summary Statements

  • There is good evidence to recommend against the routine use of corticosteroids during stimulation to improve the outcome of live birth in ART cycles in the general population. (From principally Level-I studies of Good quality). (Grade A).
  • There is good evidence to recommend against the routine use of corticosteroids during the implantation window to improve the outcome of live birth in ART cycles in the general population. (From principally Level-I studies of Good quality). (Grade A).
  • Additional studies are needed to determine if there are any subpopulations where benefit may exist but are not proven.


Granulocyte Colony–stimulating Factor (G-CSF) and Granulocyte/Macrophage Colony–stimulating Factor (GM-CSF)

Discovery of granulocyte/macrophage colony-stimulating factor (GM-CSF) and G-CSF production and receptors in reproductive tissues and impaired fertility of model animals with introduced mutations in these cytokines raised hope that supplementation of embryo cultures could improve IVF outcomes (64). Several aspects were investigated in this guideline: 1) improvement of embryo development or lowering of the aneuploidy rate, 2) improvement in endometrial thickness, and 3) overall IVF/pregnancy outcomes.

The studies evaluated to determine if clinical use of GMCSF/ G-CSF improves embryo development/aneuploidy outcomes include three randomized trials (65–67) and three Level-II studies (two cohort studies (68, 69) and one systematic review) (70). One Level-I study showed no benefit to the euploidy rate (34.8% treatment vs. 33.3% controls) of developing embryos (65). Another large multicenter RCT (N=1,332 unselected women 25-39 years undergoing IVF) demonstrated no improvement in embryo development with GM-CSF treatment vs. controls (normally developed embryos OR 0.98 [0.91–1.05]) (67). One investigation used donated surplus 2-4 cell embryos as a cohort, cultured in media supplemented with 2 ng/ml recombinant human (rh)GM-CSF and observed to blastocyst stage. GM-CSF improved the yield of implantation-competent blastocysts in human IVF (37/49 GM-CSF vs. 15/50 control culture, P<.0001) (68). No ETs were performed, making clinical outcomes unevaluable. Another cohort study directly investigated clinical outcomes, but failed to demonstrate improvement in embryo quality, clinical pregnancy rate, or live-birth rate (69). A single RCT that used unfertilized oocytes activated by the calcium ionophore A23187 with or without GM-CSF suggested improved activated embryo development rates and quality (66). However, as calcium ionophores are not used in regular clinical practice and are focused on abnormal fertilization events only, the generalizability is unclear and not clinically applicable. A systematic review in agreement with these data found no improvement in implantation rate and pregnancy rate outcomes (70).

With respect to endometrial thickness, four randomized trials (71–74), five cohort studies (75–79), and three Level-II systematic reviews (80–82) were evaluated for this guideline. Use of G-CSF administered as an intrauterine infusion was not associated with increased endometrial thickness in one Level-I study (72) and show inconsistent association with increased thickness in Level-II studies (75–79). G-CSF was associated with increased endometrial thickness in one Level-I study which focused on women with a thin endometrium (74). These studies are limited by heterogeneous populations, but suggest that G-CSF might benefit patients with recurrent implantation failure or those with an unresponsive endometrium more than unselected populations.

The impact of G-CSF or GM-CSF treatment on IVF outcomes has been evaluated in six randomized trials (67, 71–73, 83, 84), seven cohort studies (75–79, 85, 86), and five Level-II systematic reviews (69, 70, 80–82). Use of G-CSF is associated with improved implantation rate, clinical pregnancy rate, or both in three of five RCTs (71, 83, 84), but live-birth rate was not assessed in any included RCTs assessing G-CSF. The largest multicenter RCT of GMCSF treatment (N=1,332 unselected women 25-39 years undergoing IVF) demonstrated improved implantation rate (23% vs. 18.7%, P=.02) and live-birth rate/transfer (28.9% vs. 24.1%, P=.03), with sub-analysis suggesting specific benefit regarding live birth in women with a history of recurrent miscarriage (29.6% vs. 23.1%, P=.02) (67). However, the improvement in outcome was only observed in suboptimal culture conditions (low human serum albumin [HSA] concentration) used in the first 620 subjects and not in the remaining 529 subjects, where a normal (higher) HSA concentration was used. In normal culture conditions, there was no improvement in any pregnancy outcome. Four of seven Level-II/cohort studies did not show improvement in IVF outcome (75–78), and neither did two Level-II systematic reviews (70, 80), while a third Level-II systematic review suggested that a subset of studies with systemic injection demonstrated increased implantation rate and clinical pregnancy rate (87). Two Level- II meta-analyses showed improvement in implantation rate and clinical pregnancy rate with G-CSF, but the difference was more significant in subgroups of patients with a thin endometrium or repeated IVF failure, not for those with normal endometrial thickness (81, 82). It should be noted that there is a high level of heterogeneity among studies, with variations in study foci, doses, treatment types, and lack of adjustment for meaningful confounders. Taken together, additional investigations are warranted to further evaluate the role of G-CSF in selected subgroups, such as women with recurrent implantation failure and thin endometrium where potential benefit exists but is not consistently demonstrated.


Summary Statements

  • There is insufficient evidence to recommend for or against local G-CSF to improve endometrial thickness in women with thin endometrium or clinical pregnancy rates with IVF. (From principally Level-I studies of Good quality and Level-II studies of Low and Good quality with inconsistent findings). (Grade C).
  • There is insufficient evidence to recommend for or against G-CSF or GM-CSF administered locally or systemically to improve IVF outcomes. (From principally Level-I studies of Good quality and Level-II studies of Low and Good quality with inconsistent findings). (Grade C).


Intravenous Fat Emulsions

Intravenous fat emulsions used for parental nutrition have been shown to inhibit pro-inflammatory mediators (88). In an early murine model, the rate of spontaneous abortion was significantly reduced with the administration of intravenous fat emulsions (89), which is thought to reduce the activity of NK cells within the endometrium.

One RCT has evaluated intravenous fat emulsions as an intervention in 296 women (n=144 in the treatment group, n=152 controls) with unexplained secondary infertility, recurrent spontaneous abortion, and elevated NK cell activity (>12%) (90). This study showed that infusion of intravenous fat emulsions given on the day of oocyte retrieval was associated with a statistically significant increase in ongoing pregnancy rate and live-birth rate (treatment group 37.5% vs. controls 22.4%, P=.005), a nonsignificant increase in chemical pregnancy rate, and a nonsignificant reduction in spontaneous abortion rate (90). A prospective cohort study intended as a pilot to investigate the effectiveness of intravenous fat emulsions on outcomes of women aged 40–42 years undergoing IVF-ET was terminated early because preliminary data showed no live births in the intravenous fat emulsion group and a 30% live-birth rate in the untreated controls (91).


Summary Statement

  • There is insufficient evidence to routinely recommend intravenous fat emulsions for infertile women pursuing IVF. (From one Level-I study of High quality and one Level-II study of Low quality). (Grade C).
  • Additional studies are needed to identify populations where benefits may exist but are not proven.


Intravenous Immunoglobulin (IVIG)

Anti-inflammatory and immune-modulating properties of intravenous immunoglobulin (IVIG) have been considered as potential treatment for failed IVF and recurrent pregnancy loss given the hypothesized role of inflammatory bias in these conditions. Despite interest, only two small randomized trials (92, 93) have assessed the effect of IVIG administration on IVF outcomes. Additionally, 10 Level-II studies, 7 of which are cohort studies (94–100) and 3 are systematic reviews (101–103), are included in this guideline examine IVIG and IVF.

IVIG was associated with improved implantation rate (treatment group 8/45 [17.7%] vs. placebo 4/61 [6.5%], P<.05), but not pregnancy rate (treatment group 6/18 [33.3%] vs. placebo 4/21 [19.1%], not significant [NS]) in one RCT of 39 women with ≥2 very early abortions (<8 weeks) or biochemical pregnancies and ≥3 failed attempts of ET after IVF (93). Another more recent and welldesigned Level-I study of 51 women with repeat unexplained IVF failure showed no significant improvement in live-birth rate (treatment group 4/26 [15%] vs. controls 3/25 [12%], P=.52); however, there were only seven pregnancies total (92). Seven Level-II studies, showed improvement with IVIG in at least some parameters (95–98, 100–103), but with a very high level of heterogeneity among studies. Six studies showed improved live-birth rate (96–98, 100–102). Two cohort studies employed analysis of NK/NKT cell expansion or T helper (Th)1:Th2 ratio in the peripheral blood for immune stratification of treatment and response (97, 100). One of these studies was observational, retrospective, and with an unusually high live-birth rate (recurrent implantation failure group 80% vs. 17.9%, P=.0001; recurrent miscarriage group 96.3% vs. 30.8%, P=.0001) (97), while the other study, also retrospective, demonstrated an improvement in implantation rate specifically in patients with elevated Th1:Th2 ratio (45% IVIG vs. 22% control) (100). Given the expense, unclear stratification criteria, and risk associated with use, use of IVIG should be considered only in the context of well-designed prospective trials.


Summary Statements

  • There is insufficient evidence to recommend IVIG administration as part of IVF to improve IVF outcomes. (From two Level-I, but underpowered, studies, one Good quality and one Low quality). (Grade C).
  • Subpopulations that benefit from treatment may exist, but additional high-quality experimental RCTs are needed to define indications and explore risks and benefits.


Adalimumab

Considerable success in the treatment of autoimmune diseases with disease-modifying agents such as adalimumab (tumor necrosis factor alpha [TNFa] blocking antibody, Humira®) raises hope that patients with abnormally high TNF secretion may benefit from treatment in conjunction with IVF. A single collaborative group of investigators has explored this hypothesis, with interesting, but unreplicated, results (98, 99, 104, 105). These studies employed a Th1:Th2 ratio assessment by flow cytometry (TNFa:interleukin [IL]-10 intracellular ratio after activation by phorbol ester/calcium ionofore) and an NK cell cytotoxicity assay (K562 cell-line killing, indirectly) to stratify patients into a high-TNFa group that was subsequently treated with adalimumab alone or in combination with IVIG compared with a control group, with all patients also receiving a low molecular-weight heparin (LMWH) and low-dose aspirin. One of the reports showed a statistically significant elevation in live-birth rate among patients treated with adalimumab or IVIG compared with controls (50% [3/6] adalimumab vs. 0% [0/5] controls) (98). This was a small study of 75 subfertile women with Th1/Th2 cytokine elevation who were assigned to one of four different arms (assignment was based on laboratory results and patient acceptance of treatment): Group I, 41 patients received both IVIG and adalimumab; Group II, 23 patients received IVIG; Group III, 6 patients received adalimumab; and Group IV, 5 patients received neither IVIG nor adalimumab (98). A different report from the same group correlated the degree of correction of purported Th1:Th2 ‘‘abnormality’’ with implantation rate and live-birth rate, and only with subset selection of patients with ‘‘inadequate cytokine suppression’’ with those where optimal treatment outcome was obtained was there a correlation with implantation rate (104). Finally, their most recent retrospective analysis of this dataset also examined embryo development cohort quality (that the authors term ‘‘die-off ratio’’) and found that treatment with adalimumab eliminated the correlation between cohort quality and implantation rate (105).

Although interesting, these studies suffer from multiple challenges to interpretation. First, they are all retrospective observational studies, where these agents were used without any attempt at randomization or prospective standardization. Second, stability and meaning of clinical Th1:Th2 ratio or NK cytotoxicity assays are poorly defined and not in routine clinical use even among the immunology/rheumatology community. Third, these studies were not conducted in accordance with current standards for human protection (98, 99, 104). Fourth, these investigations had small sample sizes and extensive heterogeneity in treatments and multiple medications (adalimumab, IVIG, LMWH, aspirin, and even dexamethasone). Although the concept and approach are interesting, it is difficult to ascertain what conclusions can be drawn from these studies, beyond the need for both validation of the diagnostic assays used and a prospective, randomized trial to directly assess the role for TNF inhibitors in IVF (with or without pretreatment immune stratification). Consequently, these therapies should only be used in the context of exploratory, Institutional Review Board (IRB)-approved studies. These trials should also consider risk associated with treatment. While the potential risks associated with short-term use of adalimumab are unknown, long-term use (greater than 12 weeks) has been associated with an increased risk of serious infection and malignancy (106).


Summary Statement

  • There is insufficient evidence to recommend adalimumab treatment to improve IVF outcome. (From Level-II studies of Low quality). (Grade C).


Peripheral Mononuclear Cells

Successful embryo implantation requires a receptive endometrium with an optimal level of local inflammation. Aberrant cell signaling leading to immune dysfunction has been implicated in implantation failure, especially in cases of repeated failed IVF-ET. One possible mechanism may involve poor lymphocyte recruitment within the endometrium. Intrauterine infusion of peripheral blood mononuclear cells (PBMC) has been investigated as a possible therapy for patients with recurrent implantation failure, based on the rationale that maternal immune cells are necessary to achieve immune tolerance to embryonic implantation and placentation. While the precise mechanism of action is unclear, one RCT investigated the efficacy of PBMCs (107). This trial randomized patients with a history of repeated implantation failure to receive either autologous PBMCs cultured and instilled into the endometrial cavity prior to transfer or to standard ET, without pretreatment (107). The treatment group experienced a significantly increased clinical pregnancy rate (P<.05) and reduced, but not significant, early pregnancy loss rate. However, these findings are limited by the study's small sample size and the lack of a power analysis. Furthermore, the study included only poor-prognosis patients with a history of repeated IVF failure, contributing to potential selection bias and limiting the generalizability of the findings. A second, nonrandomized Level-II study of poor quality suggested that treatment with PBMCs improved live-birth rate in women with more than four failed transfers and in those with endometrial thickness between 7 and 8 mm (108).


Summary Statement

  • There is insufficient evidence to recommend intrauterine infusion of autologous peripheral mononuclear cells prior to ET to improve IVF outcome. (From one Level-I study of Low quality and one Level-II study of Low quality). (Grade C).


Seminal Plasma

Instillation of seminal plasma into the uterus and/or cervix at the time of ovum pickup for IVF has been investigated as a strategy to improve pregnancy rates in fresh ET cycles. In some animal models this step appears essential for ART (109) and has been theorized to improve endometrial receptivity and/or immune tolerance (110, 111).

Available RCTs investigating the use of seminal plasma insemination have all shown a statistically nonsignificant increase in pregnancy rate compared to either placebo or no intervention (112–115). Of these, two showed an increase in implantation rate with administration of seminal plasma, although one increase was statistically significant (34.7% vs. 27.5%, P=.026) (112), while the other was not (21.4% vs. 16.9%, P=.71) (113). A meta-analysis of seven RCTs showed a statistically significant improvement in clinical pregnancy rate but no significant improvement in ongoing pregnancy or live-birth rate with seminal plasma insemination (116).


Summary Statement

  • There is fair evidence that seminal plasma insemination as part of IVF improves clinical pregnancy rate (From Level-I studies of Good and High quality). (Grade B). However, there is fair evidence that it does not improve ongoing pregnancy or live-birth rates. (From underpowered Level-I studies of Good quality). (Grade B).


Spermatozoa, Antibody-free Preparation

Antibody-free preparation of spermatozoa has been investigated as a technique to reduce the potential impact of antisperm antibodies on fertilization rates in couples with antisperm antibody-positive male partners. These investigations were primarily conducted to develop techniques to prevent failed fertilization following conventional insemination prior to the development of ICSI. Antisperm antibodies have been reported in as many as 10% of infertile couples (117), and may impair either sperm transport or zona penetration (118). Both of these mechanisms have been proposed as possible barriers to natural conception and success with intrauterine insemination (IUI) in these couples. However, presence of both immunoglobulin G (IgG) and immunoglobulin A (IgA) antibodies is associated with lower fertilization rates in IVF (119, 120).

One RCT of 36 patients assessed the benefit of chymotrypsin-galactose treatment of sperm vs. sperm incubated in culture medium in patients with over 50% antisperm antibodies, IgG, IgA, or both (121). Chymotrypsin-galactose treatment was associated with an improvement in fertilization rate (46.7% vs. 27.3%, P<.05) and a nonsignificant increase in pregnancy rate (per patient 32% vs. 18.2%, P=.34; per cycle 21.1% vs. 9.5%, P=.23), but the percentage of sperm bound with antibodies was not reduced (121). In another study using couples as their own controls, an antibody-free preparation of sperm in a cohort of 18 couples with an antibody-positive male partner undergoing 24 IVF cycles did not improve fertilization rates compared with untreated sperm (122).


Summary Statements

  • There is insufficient evidence to support the recommendation either for or against antibody-free preparation of spermatozoa in improving IVF outcomes. (From one Level-I study of Low quality and one Level-II study of Low quality). (Grade C). This procedure has been rendered obsolete by the use of ICSI.


Tacrolimus

The establishment of a healthy pregnancy requires maternal immune tolerance to the invading trophoblast to ensure successful implantation and adequate placentation and fetal growth. Th1 and Th2 mediate immune rejection and tolerance, with recurrent implantation failure being associated with a high peripheral blood Th1/Th2 ratio. A Th1 immune response is associated with allograft, as well as embryo, rejection (123, 124). Based on this rationale, a prospective study (125) evaluated the effect of treating patients with recurrent implantation failure with tacrolimus—an immunosuppressive drug that inhibits antigen-induced lymphocytic proliferation, cytotoxic T-cell formation, IL-2 receptor expression, and the production of IL-2 and interferon-gamma. The study included patients with a history of at least five prior failed IVF cycles and elevated peripheral blood Th1/Th2 ratios and compared the outcomes of patients who received 1 to 3 mg tacrolimus 2 days prior to ET. When comparing IVF outcome of treated patients (n=25) and untreated controls (n=17), the treated cohort had significantly higher clinical pregnancy (per ET, treated 64% vs. untreated 0%, P<.0001) and live-birth rates (treated 60% vs. untreated 0%, P<.0001) (125). These results should be interpreted with caution as the study was subject to selection bias due to lack of randomization and a small sample size.


Summary Statement

  • There is insufficient evidence to recommend tacrolimus to improve IVF-ET outcome. (From a single Level-II study of Low quality). (Grade C).


HARMS AND BENEFITS

While short-term use of some of the immunotherapies reviewed in this document (e.g., aspirin and corticosteroids) are unlikely to be associated with long-term harm, for others there are known risks, and a full accounting of these risks must be weighed against any potential benefits. For example, IVIG use has been associated with fever, hypotension, tachycardia, thromboembolic complications, and anaphylactic reactions (126). As a pooled blood product, IVIG use is also associated with an inherent risk of infectious disease. While intravenous fat emulsion infusions are generally well tolerated, jaundice and hyperthermia have been reported (127). Cytokines such as G-CSF are used in healthy donors in the setting of blood and marrow transplantation. In this setting, common side effects associated with systemic administration include bone pain and myalgias (128). Tacrolimus is most commonly used as an immunosuppressant to prevent whole organ rejection. In this setting, known side effects include nephrotoxicity, neurotoxicity, hypertention, and diabetogenic effects (129). With each of the above agents, risk and side-effect profiles associated with short-term use, such as in the setting of IVF, are poorly characterized.

Beyond the risks to the patient herself with the use of immunotherapy, these agents may cause harm in the present treatment cycle. In a trial of low-dose aspirin vs. untreated controls, the aspirin group required a higher dose of follicle stimulating hormone prior to oocyte retrieval and had a higher number of immature oocytes (17). Additionally, the authors noted that ‘‘the ratio of good quality embryo per retrieved oocytes was strongly unbalanced between the two groups with a clear advantage for the untreated group and, for the treated one, at lower dose of LDA [low-dose aspirin]’’ (17). Intravenous fat emulsion treatment also may be associated with harm in the present treatment cycle; authors cancelled their study investigating the effectiveness of intravenous fat emulsions on outcomes of women aged 40–42 years undergoing IVF-ET due to no live births in the intravenous fat emulsion group and a 30% live-birth rate in untreated controls (91). While medications such as aspirin and corticosteroids are inexpensive, others such as IVIG and adalimumab are costly, and their use may give false hope to patients who are struggling with infertility. Most of these therapies should only be used under IRB-approved protocols.


CONCLUSIONS

Immunotherapies aimed at improving the likelihood of live birth in IVF treatment have largely proven to be ineffective or have been insufficiently investigated to make definitive recommendations for their use. In some cases, the use of these adjuvants has been associated with improved surrogate outcomes such as clinical pregnancy. However, these studies tend to involve narrowly defined subgroups of patients identified through immunological testing, which frequently is not widely available, reproducible, or recommended. Given the uncertain benefits and meaningful risks of immunotherapy, future studies should focus on well-defined subgroups where potential for benefit exists but is not consistently demonstrated. A careful assessment of risks associated with therapy must be undertaken in the design of adequately powered RCTs investigating immunotherapies as adjuvants in ART treatment. These investigations should focus on the outcome of live birth. If benefit is demonstrated, then the evaluation of cost-effectiveness is a priority given the high cost of some immunotherapy treatments.


UNANSWERED QUESTIONS

  • Future studies of adjuvant immunotherapy in IVF should be adequately powered for the primary outcome of live birth and focus on populations where the potential for benefit exists, but has not been conclusively demonstrated, including conditions such as implantation failure and recurrent miscarriage.
  • Side-effect profiles for immunotherapies should be carefully documented in subsequent RCTs.
  • Subsequent RCTs investigating immunotherapies should focus on a single agent within a given study. Ideally, these investigations would be multicenter in order to increase the generalizability of the trial results. Immunological testing as part of these trials should be standardized to improve reproducibility of findings.
  • G-CSF/GM-CSF should be reserved for investigational trials in selected subpopulations.
  • Until clear and consistent relationships are demonstrated between immunophenotypes and ART outcomes, routine immunological testing in the general ART population cannot be recommended.


SUMMARY

  • Given the lack of evidence to support improved IVF outcomes, there is good evidence to recommend against the routine use of low-dose aspirin to improve the outcome of live birth in ART cycles in the general population. (From Level-I studies of Good and High quality). (Grade A).
  • There is good evidence to recommend against the routine use of corticosteroids during stimulation to improve the outcome of live birth in ART cycles in the general population. (From principally Level-I studies of Good quality). (Grade A).
  • There is good evidence to recommend against the routine use of corticosteroids during the implantation window to improve the outcome of live birth in ART cycles in the general population. (From principally Level-I studies of Good quality). (Grade A).
  • There is insufficient evidence to recommend for or against local G-CSF to improve endometrial thickness in women with thin endometrium or clinical pregnancy rates with IVF. (From principally Level-I studies of Good quality and Level-II studies of Low and Good quality with inconsistent findings). (Grade C).
  • There is insufficient evidence to recommend for or against G-CSF or GM-CSF administered locally or systemically to improve IVF outcomes. (From principally Level-I studies of Good quality and Level-II studies of Low and Good quality with inconsistent findings). (Grade C).
  • There is insufficient evidence to routinely recommend intravenous fat emulsions for infertile women pursuing IVF. (From one Level-I study of High quality and one Level-II study of Low quality). (Grade C).
  • There is insufficient evidence to recommend IVIG administration as part of IVF to improve IVF outcomes. (From two Level-I, but underpowered, studies, one Good quality and one Low quality). (Grade C).
  • There is insufficient evidence to recommend adalimumab treatment to improve IVF outcome. (From Level-II studies of Low quality). (Grade C).
  • There is insufficient evidence to recommend intrauterine infusion of autologous peripheral mononuclear cells prior to ET to improve IVF outcome. (From one Level-I study of Low quality and one Level-II study of Low quality). (Grade C).
  • There is fair evidence that seminal plasma insemination as part of IVF improves clinical pregnancy rate (From Level-I studies of Good and High quality). (Grade B). However, there is fair evidence that it does not improve ongoing pregnancy or live-birth rates. (From underpowered Level-I studies of Good quality). (Grade B).
  • There is insufficient evidence to support the recommendation either for or against antibody-free preparation of spermatozoa in improving IVF outcomes. (From one Level-I study of Low quality and one Level-II study of Low quality). (Grade C). This procedure has been rendered obsolete by the use of ICSI.
  • There is insufficient evidence to recommend tacrolimus to improve IVF-ET outcome. (From a single Level-II study of Low quality). (Grade C).


RECOMMENDATIONS

  • Immunotherapies reviewed in the present document are either not associated with improved live-birth outcome in IVF or have been insufficiently studied to make definitive conclusions regarding benefits and risks. In the absence of well-designed adequately powered RCTs, patients must be informed of uncertain benefits and risks associated with immunotherapy.
  • There is no evidence to suggest screening for these conditions in an asymptomatic population.


Acknowledgments:

This report was developed under the direction of the Practice Committee of the American Society for Reproductive Medicine as a service to its members and other practicing clinicians. Although this document reflects appropriate management of a problem encountered in the practice of reproductive medicine, it is not intended to be the only approved standard of practice or to dictate an exclusive course of treatment. Other plans of management may be appropriate, taking into account the needs of the individual patient, available resources, and institutional or clinical practice limitations. The Practice Committee and the Board of Directors of the American Society for Reproductive Medicine have approved this report.

This document was reviewed by ASRM members and their input was considered in the preparation of the final document. The Practice Committee acknowledges the special contribution of Karl Hansen, MD, PhD, Aleksandar Stanic- Kostic, MD, PhD, Lucky Sekhon, MD, Heather Burks, MD, Alison Zimon, MD, and Carla Stec, MA, in the preparation of this document. The following members of the ASRM Practice Committee participated in the development of this document. All Committee members disclosed commercial and financial relationships with manufacturers or distributors of goods or services used to treat patients. Members of the Committee who were found to have conflicts of interest based on the relationships disclosed did not participate in the discussion or development of this document.

Alan Penzias, M.D.; Kristin Bendikson, M.D.; Samantha Butts, M.D., M.S.C.E.; Christos Coutifaris, M.D., Ph.D.; Tommaso Falcone, M.D.; Susan Gitlin, Ph.D.; Clarisa Gracia, M.D., M.S.C.E.; Karl Hansen, M.D., Ph.D.; Sangita Jindal, Ph.D.; Jennifer Mersereau, M.D.; Randall Odem, M.D.; Robert Rebar, M.D.; Richard Reindollar, M.D.; Mitchell Rosen, M.D.; Jay Sandlow, M.D.; Peter Schlegel, M.D.; Dale Stovall, M.D., Michael Vernon, Ph.D.

Supplemental Table 1. Studies on aspirin and IVF outcomes included in this systematic review


STUDY TYPE N= GROUPS DOSE AND/OR TIMING OUTCOME
Check 1998 RCT 36= women ≤42 years who did not conceive with fresh ET and had frozen embryos for another transfer 18= women treated with low-dose aspirin;
18= women did not receive aspirin
81 mg aspirin from cycle-day 2 through pregnancy testing No positive effect of low-dose aspirin on PR after FET: CPR (gestational sac): aspirin = 11.1% controls= 33.3%, P<.05; IR: aspirin = 2.9% (2/68) vs controls= 10.9% (7/64), P=.064.
Dentali 2012 SR/MA 17 RCTs; 6,403 IVF/ICSI patients Patients who received low-dose aspirin vs patients who received placebo/no treatment Low-dose aspirin, varies among studies Results do not support the use of low-dose aspirin: PR: 17 studies, 6403 patients; aspirin 1139/3506 (32.5%) vs placebo/no treatment 850/2897 (29.3%); LBR: 6 studies, 2600 patients; aspirin 330/1312 (25.2%) vs placebo/no treatment 306/1288 (23.8%); aspirin not effective: OR 1.08; 0.90, 1.29; P=.43.
Dirckx 2009 RCT 193= women undergoing a first or second IVF/ICSI cycle (181= had ET) 97= women received aspirin; 96= women received placebo Aspirin, daily oral 100 mg, with OCP, before stimulation and continued until confirmation of pregnancy No difference between aspirin and placebo groups in a first or second IVF/ICSI cycle in CPR (fetal heart/cycle: aspirin = 31/97 [32%] vs placebo= 30/96 [31%], P=.916, OR 1.033, 95% CI 0.565-1.890) or LBR (per cycle: aspirin = 24 [25%] vs placebo= 27 [28%], OR 0.840, 95% CI 0.445-1.587).
Duvan 2006 RCT 200= patients undergoing first ICSI cycle Grp A: 41= patients received aspirin 100 mg/d;
Grp B: 50= received prednisolone 10 mg/d;
Grp C: 56= aspirin 100 mg/d + prednisolone 10 mg/d; Grp D: 40= received placebo
Aspirin, daily 100 mg Treatment with low-dose aspirin had no positive effect and no statistical difference on IR or PR in patients undergoing first ICSI cycles. (Per inclusion/exclusion criteria: focus was on groups A and D.)
Frattarelli 2008 Cohort 1,250= patients undergoing IVF with diagnosis of poor response (≤5 oocytes, poor quality oocytes and/or embryos) and/or diminished ovarian reserve 417= received 81 mg aspirin; 833= received no aspirin Low-dose (81 mg) aspirin Pregnancy outcomes were not improved by the use of aspirin: IR: aspirin = 134/742 (18.1%), No aspirin = 282/1429 (19.7%), P=.35, RR 0.92 (0.76, 1.1), Power 0.15, number needed to show SS= 21,133; PR: aspirin = 116/417 (27.8%), No aspirin = 250/833 (30%), P=.42, RR 0.93 (0.77, 1.12), Power 0.12, number needed to show SS= 17,420; LBR: aspirin = 149/833 (17.9%), No aspirin = 72/417 (17.3%), P=.79, RR 0.97 (0.75, 1.25), Power 0.06, number needed to show SS= 255,400
Frattarelli 2006 Cohort 503= infertile women undergoing donor oocyte ART cycles 123= adjunct therapy; 380= no adjunct therapy 81 mg aspirin =80, vaginal micronized 17beta-estradiol 2 mg/day= 27, sildenafil 100 mg/day= 16 Sonographic endometrial thickness improved significantly without the use of adjunct therapy (P<.05). Adjuvants improved outcome rates for overall population and those with peak mock endometrial thickness <8mm. In subgroup analysis, only aspirin was associated with significant improvement in: PR: All adjuvants= 87.8% (P<.01), Aspirin = 88.8% (P<.05), Estradiol= 85.2% (NS), Sildenafil= 87.5% (NS), Controls= 76.8%; Adjuvant therapy vs No for PR: P<.01; RR 1.14 (1.05-1.25); LBR: All adjuvants= 74.8% (P<.05), Aspirin = 76.3% (P<.05), Estradiol= 74.1% (NS), Sildenafil= 68.8% (NS), Controls= 63.7%; Adjuvant therapy vs No for LBR: P<.05; RR 1.17 (1.03-1.33).
Gelbaya 2007 SR/MA 6 RCTs; IVF and/or ICSI population RCTs comparing aspirin vs placebo or no treatment in standard IVF and/or ICSI population Low-dose aspirin alone (75-150 mg/day) Low-dose aspirin had no beneficial effect on: CPR/ET (6 studies, 2515 patients): no significant difference between aspirin (35.3%) and placebo or no treatment (31.5%) (RR 1.09, 0.92-1.29); LBR/cycle (1 study, 374 patients): 17.2% aspirin vs 19.7% no aspirin (RR 0.87; 0.57-1.34). LBR/ET (2 studies, 1729 patients): 25.4% aspirin vs 22.8% no aspirin (RR 1.08; 0.83-1.40).
Gizzo 2014 Cohort 206= normo-responders with idiopathic primary infertility and referred to second or third IVF treatment 106= idiopathic infertile women received low-dose aspirin; 100= untreated controls Low-dose aspirin (100 mg/day) No difference in PR, OPR, and pregnancy failures. Treated group used higher dose of gonadotropins, had higher number of follicles at pickup, more follicles >16mm and more retrieved oocytes but lower quality of obtained embryos. Untreated group showed better outcomes regarding retrieved oocytes/number of follicles, mature oocytes/retrieved oocytes, fertilized oocytes/mature oocytes, and good embryo quality/mature oocytes. PR: Treated 26.4% vs Untreated 26%. Ongoing pregnancy: Treated 17% vs Untreated 20%.
Groeneveld 2011 MA 10= RCTs 6 studies provided IPD= 81-374 patients per study, 1119 patients total (556 in text/557 in abstract= aspirin, 562= placebo) vs placebo or no drug treatment 75-150 mg aspirin/day (no combined treatments); in studies that provided patient data: aspirin treatment before ET and continued until ≥10 weeks gestational age Aspirin did not improve pregnancy rates after IVF. CPR: studies w/IPD= 1118 pts: aspirin 160/556 (28.8%), placebo 179/562 (31.9%), pooled OR 0.86 (0.67-1.1). Ongoing pregnancy: 1097 pts: aspirin 129 (23.6%), placebo 147 (26.7%), pooled OR 0.85 (0.65-1.1). Studies w/IPD= OR 0.89 (0.69-1.2); Studies w/random confirmed= OR 0.94 (0.76-1.17); All 10 RCTs= OR 1.07 (0.81-1.41).
Haapsamo 2010 RCT 487= patients underwent IVF/ICSI 242= received aspirin; live birth/ET grp: received aspirin=52; 245= received placebo; live birth/ET grp: received placebo=55 100 mg aspirin daily, starting on first day of gonadotropin stimulation Incidence of hypertensive complications did not differ SS between low-dose aspirin and placebo groups, when medication was started with gonadotropin stimulation and continued until delivery in unselected pregnant IVF/ICSI women. Hypertensive pregnancy complications: 15.4% (8/52) aspirin vs 18.2% (10/55) placebo, P=0.70. LBR: aspirin 22.9% vs placebo 24%, P=0.78.
Hurst 2005 Cohort 316= consecutive IVF cycles 72= cycles received aspirin; 244= controls, no aspirin 80 mg aspirin/ daily at start of luteal leuprolide Low-dose aspirin had no beneficial effect on pregnancy or live-birth rates, endometrial thickness, or ovarian response in IVF patients. IR: aspirin 21% vs controls 30%, P=.01. PR: aspirin 48% vs controls 57%, P=.18. LBR: aspirin 29% vs controls 41%, P=.07.
Khairy 2007 SR/MA 7= RCTs; 1,241= women Women undergoing COH, IVF, or ICSI and d3 ET vs placebo or no supplement Low-dose aspirin Evidence does not support the use of aspirin in IVF or ICSI treatment. CPR: no benefit with aspirin (RR 1.11; 0.95, 1.31). LBR: no benefit with aspirin (RR 0.94; 0.64, 1.39).
Lambers 2009 RCT 169= non-tubal IVF patients with previous failed conception 84= patients received aspirin; 85= received placebo 100 mg aspirin Low-dose aspirin admin during IVF does not improve CPR of non-tubal factor IVF patients with previous failed conception. Ongoing pregnancy at 12 weeks: 35.4% aspirin vs 31.0% placebo, P=.677.
Moini 2007 RCT 145= infertile women undergoing IVF 73= patients received aspirin; 73= patients received placebo 100 mg aspirin, until menstruation/negative pregnancy test (or through 12 weeks pregnant) Low-dose aspirin in a standard long IVF protocol for oocyte retrieval did not improve IR or PR. IR: 17.9% treated, 12.8% controls, NS. CPR (fetal heart): 45.5% treated, 33.3% controls, NS.
Pakkila 2005 RCT 374= women to undergo IVF/ICSI 186= women received aspirin; 188= women received placebo 100 mg aspirin, started on 1st day of stimulation until menstruation or negative pregnancy test; pregnant women continued until delivery Low-dose aspirin does not have any beneficial effect on ovarian responsiveness, PR, and pregnancy outcome in unselected women undergoing IVF/ICSI.
Rubinstein 1999 RCT 298= infertile patients undergoing IVF 149= pts received aspirin; 149= pts received placebo 100 mg aspirin/day Low-dose aspirin significantly improves ovarian responsiveness, uterine and ovarian blood flow velocity, IR, and PR in IVF patients
Ruopp 2008 MA 10= RCTs
Subgroup analyses of: fresh ET; studies included by Gelbaya 2007
low-dose aspirin vs placebo 75-100 mg aspirin Aspirin may increase clinical pregnancy rates. CPR/ET: 10 studies, n=2801 cycles, fixed effects RR 1.15 (1.03, 1.27). Subgroup: fresh ET: CPR/ET: 9 studies, n=2765 cycles, fixed effects RR 1.16 (1.04, 1.29). Subgroup: Gelbaya 2007: CPR: 6 studies, n=2515 cycles, fixed effects RR 1.12 (1.00, 1.25).
Shirlow 2017 Cohort 13,372= transfers (1,904= ≥1 [up to 9] adjuvants used) ≥1 adjuvant= 1,904 transfers; No adjuvants= 11,468 transfers 13 adjuvants: intralipid (= 311), steroids (= 997), melatonin (= 341), coenzyme Q10 (= 25), filgrastim (= 102), testosterone (= 82), DHEA (= 75), growth hormone (= 120), antibiotics (= 274), hCG (= 189), aspirin (= 431), enoxaparin/heparin (= 834), prolactin antagonists (= 58); details/doses provided in paper Most adjuvants failed to demonstrate significant benefit to success of embryo transfers. Aspirin (LBR) and steroids (pregnancy loss, LBR) showed potentially beneficial outcomes.
Siristatidis 2016 SR/MA 13= trials, 2653= participants Patients received 80-100 mg aspirin; placebo (8 studies) or no treatment 10 studies: 100 mg aspirin; 3 studies: 80 mg aspirin. Aspirin given at start of down-regulation in most studies. Duration of treatment varied. No evidence in favor of routine use of aspirin to improve PR for a general IVF population.
Urman 2000 RCT 275= patients undergoing 1st ICSI cycle with ejaculated sperm for male infertility 139= received aspirin; 136= did not receive aspirin 80 mg aspirin/ daily at start of stimulation Low-dose aspirin did not improve IR or PR in an unselected group of patients undergoing ICSI.
Waldenstrom 2004 Cohort 1380= consecutive IVF cycles
1022= patients
703= received aspirin; 677= no treatment 75 mg aspirin/day in one dose from day of ET until pregnancy test Aspirin (vs no treatment) significantly improved chemical and clinical pregnancies by 5% and births by 4%. However, all outcomes after adjustment for the number of embryos transferred were not significantly different between treatment groups.
Weckstein 1997 RCT 28= oocyte donation recipients with an endometrial thickness <8 mm 15= recipients received low-dose aspirin in addition to standard hormone replacement; 13= recipients did not receive aspirin Low-dose (81 mg) aspirin daily; 100 mg P IM daily and 50 mg bd vaginally 2 days before ET Low-dose aspirin improved IR in oocyte donation recipients with a thin endometrium. However, live-birth rates were not different between groups in all patients combined or when restricted to those with endometrium <8mm.
ACA= anticardiolipin antibody; ANA= antinuclear antibody; AOA= antiovarian antibody; APA= antiphospholipid antibody; ART= assisted reproductive technology; ATA= antithyroid antibody; BD= twice a day; CC= clomiphene citrate; CI= confidence interval; COH= controlled ovarian hyperstimulation; CPR= clinical pregnancy rate; DNA= deoxyribonucleic acid; ET= embryo transfer; FET= frozen embryo transfer; FSH= follicle-stimulating hormone; GN= gonadotropins; hCG= human chorionic gonadotropin; hMG= human menopausal gonadotropins; ICSI= intracytoplasmic sperm injection; IM= intramuscular; IPD= individual patient data; IR= implantation rate; IVF= in vitro fertilization; LAC= lupus anticoagulant; LBR= live-birth rate; MA= meta-analysis; OCP= oral contraceptive pill; OR= odds ratio; PR= pregnancy rate; RCT= randomized controlled trial; RR= risk ratio; SAB= spontaneous abortion; SR= systematic review; SS= statistically significant

Supplemental Table 2. Studies on corticosteroids and IVF outcomes included in this systematic review


STUDY TYPE N= GROUPS DOSE AND TIMING OUTCOME LIMITATIONS
Ando 1996 Cohort 112= IVF-ET patients 54 IVF-ET patients (99 cycles) = positive for ≥1 ANA, anti-DNA antibody, and LAC; 58 controls (86 cycles) = autoantibody negative 25 mg/day daily IM progesterone initial 7 days and 50 mg/day following 8 days The combined use of low-dose corticosteroid treatment can be effective for autoantibody-positive women. Treatment group also had endometriosis, whereas controls did not; small sample size without power analysis; did not account for ovarian reserve.
Bider 1996 (HR) RCT 78= infertile, normo-ovulatory women with tubal factor infertility Group A= 24 patients; Group B= 27 patients received 0.5 mg dexamethasone;
Group C= 27
Patients rec’d 1 mg dexamethasone; Group D= 78 previous cycles of same patients (additional control group)
0.5 mg or 1 mg dexamethasone, nightly, starting first day of hMG and discontinued on day after ET Addition of up to 1 mg dexamethasone in ovulation induction protocol did not improve IVF-ET outcome in patients with tubal factor infertility. Limited sample size; no power analysis.
Bider 1996 (F&S) RCT 99= normo-ovulatory women tubal factor infertility 52 patients= received 0.5 mg dexamethasone; 47 patients= did not receive dexamethasone 0.5 mg dexamethasone, orally for 5 nights, starting on day of ovulation Administration of 0.5 mg dexamethasone for a short period to patients with tubal factor infertility did not improve implantation or pregnancy rates. Limited sample size; no power analysis.
Bider 1997 RCT 42= low responders, all had ≥2 previous cycles w/ GN for unexplained infertility or anovulation after failed response to CC Grp A= 20 patients received dexamethasone; Grp B= 22 controls;
Grp C= 42 patients, before dexamethasone
0.5 mg dexamethasone given nightly in combination with hMG, starting on day 4 of menstrual cycle No clinical benefit of daily, low-dose dexamethasone (long-acting corticosteroid) as an adjuvant for low responders during GN therapy. Nonplacebo-controlled; no power analysis performed to indicate sufficient sample size.
Boomsma 2012 SR/MA 14= RCTs (1,879 couples) Subfertile women undergoing IVF or ICSI Differing treatments: (methyl)prednisolone, dexamethasone, hydrocortisone with prednisolone; dose schedule and length of treatment varied No clear evidence that peri-implantation glucocorticoids in ART cycles significantly improved clinical outcome. Use of glucocorticoids in a subgroup of women undergoing IVF (not ICSI) was associated with improved PR (borderline statistical significance). Heterogeneity in design and inclusion/exclusion criteria of included studies.
Cohen 1990 Cohort 32= patients had 1-3 zona-dissected embryos replaced; male factor couples with long duration of infertility 18 patients= treatment group received methylprednisolone (and tetracycline); 14= controls did not receive methylprednisolone or tetracycline Low-dose immunosuppression with 16 mg/day methylprednisolone (plus tetracycline) during first 4 days after oocyte retrieval Methylprednisolone supports implantation of embryos with small holes in their zonae. Nonrandomized; small sample size (no power analysis); limited generalizability (zona dissection, population with various male factor infertility issues); some patients were counted more than once in the treatment group, thus, their statistical analysis was invalid (tests were for independent data).
Dan 2015 MA 5= RCTs; prednisolone administration for unexplained recurrent miscarriage (3 studies) or ICSI (2 studies) Women with unexplained recurrent miscarriage and women undergoing ICSI; controls: placebo, aspirin plus heparin Prednisolone, 5-20 mg or 10 mL; 1 study combined with low-dose aspirin and heparin; 1 study combined with aspirin Prednisolone may improve pregnancy outcomes in women with idiopathic recurrent miscarriage. Its efficacy in women undergoing ICSI was not significant. Differing doses, protocols, control groups; age of all women <40 years; small number of studies included; lacked adequate sample size.
Forges 2006 Cohort 100= patients with serum antiovarian autoantibodies (AOA) and ≥2 previously failed IVF attempts 100= cycles with prednisolone; 100= cycles without corticosteroids Corticosteroid 0.5 mg/kg/day prednisolone Immunological monitoring during IVF was useful to identify patients with AOA. Corticosteroid treatment led to significantly higher IR and LBR, increased CPR, and lower SAB. Nonrandomized; used patients as their own controls (retrospectively assessed former IVF cycle stimulation); positive results in intervention cycle may be due to “regression to the mean” phenomenon.
Geva 2000 Cohort 76= infertile patients with ≥3 IVF-ET failures 52= patients seropositive for non-organ-specific autoantibodies and repeated IVF-ET failure received prednisone plus aspirin; 24= untreated controls 10 mg prednisone and 100 mg aspirin/day, 4 weeks before ovulation induction; if pregnancy, prednisone stopped at 18th week, aspirin continued until 6 weeks postpartum Combined treatment of prednisone for immunosuppression and aspirin as an anti-thrombotic agent before ovulation induction may improve PR in autoantibody seropositive patients with repeated IVF-ET failures. No increased incidence of pregnancy complications. Observational; nonrandomized; no steroid-only group (therefore unable to separate the effects of aspirin vs corticosteroids alone).
Hasegawa 1998 Cohort 307= female IVF patients with autoantibodies (antinuclear and antiphospholipid); 607= ET cycles ANA-/APA-, no treatment= 350 cycles; ANA+/APA-, no treatment= 155 cycles; ANA+/APA-, with treatment= 69 cycles; ANA+/APA+, no treatment= 18 cycles; ANA+/APA+, with treatment= 15 cycles 10 mg prednisolone/day and 81 mg aspirin/day on 1st day of hMG, continued until confirmed pregnancy Prednisolone plus low-dose aspirin may improve IR in women with autoantibodies undergoing IVF-ET. Retrospective; nonrandomized
Kalampokas 2017 MA 4= RCTs (2 in quantitative synthesis); 416= women Subfertile couples with any cause of infertility ≥1 year and undergoing IVF/ICSI Glucococorticoid supplementation (10 mg prednisolone; 0.5 mg dexamethasone daily) The safety and effectiveness of glucocorticoid adminstration in IVF/ICSI female patients is unclear due to the small number of studies and low event rates. Low or very low quality of evidence for all outcomes (mainly imprecision).
Keay 2001 RCT 290= patients <40 years undergoing gonadotropin stimulation prior to IVF 145= patients received 1 mg dexamethasone; 145= patients received placebo tablets (400 μg folic acid) Low-dose (1 mg) dexamethasone on 1st day of GN until night before oocyte retrieval Low-dose dexamethasone co-treatment reduces the incidence of poor ovarian response. It may increase CPR. Main outcomes of interest not well defined.
Kemeter 1986 RCT 146= IVF patients 73= patients received prednisolone 7.5 mg/day for one cycle in addition to CC and/or GN; 73= patients did not receive corticosteroids Prednisolone 7.5 mg/day (2.5 mg in mornings, 5 mg in evenings for one cycle, daily for a month) Routine prednisolone administration in addition to CC and GN improves follicle maturation and, as a result, overall PR. Higher proportion of transfers involving multiple embryos, differing ET technique, etc.; multiple, potential confounders; limited sample size; no power analysis done.
Kim 1997 RCT 129= IVF-ET patients Received corticosteroids:
21= patients with endometriosis + tubal factor, 54 IVF-ET cycles and 43= patients with pure tubal factor, 81 cycles.
Did not receive corticosteroids:
21= patients with endometriosis + tubal factor, 57 cycles and 44= patients with pure tubal factor, 84 cycles.
Prednisolone daily oral dose 10 mg from cycle day 3 until oocyte retrieval, increased to 60 mg from evening of oocyte retrieval for 4 days after Corticosteroids could improve CPR in endometriosis patients undergoing IVF-ET and may be more effective in patients with positive autoantibodies. Treatment population had a combination of endometriosis +/- autoantibodies, unable to pinpoint the treatment target or if a combination of factors; no power analysis; limited sample size.
Lahteenmaki 1995 RCT 53= men with positive results in spermatozoal mixed antiglobulin reaction and serum tray agglutination tests, with female partner <40 years 27= men received prednisolone; 26= men received placebo 20 mg prednisolone or placebo daily for 2 weeks prior to IVF Low-dose prednisolone does not lower sperm-bound antibody numbers and does not improve IVF outcome. Infertility diagnosis of female partner not controlled for; no power analysis to assess sample size adequacy.
Lee 1994 Cohort 175= infertile women <40 years with tubal factor, IVF-ET patients Study: 104 (group A) = received FSH/HMG (16 or 60 mg); controls (0 mg); 76 (grp A1) = first IVF attempt; 28 (grp A2) = ≥1 previous IVF failure; 71 (group B) = received GnRHa/FSH/HMG (16 or 60 mg); controls (0 mg);
40 (grp B1) = first IVF attempt; 31 (grp B2) = ≥1 previous IVF failure
Corticosteroid 0, 16, or 60 mg - 16β-methylprednisolone at oocyte retrieval Immunosuppression with corticosteroid (16β-methylprednisolone) had no effect on pregnancy or miscarriage rates of IVF-ET patients with embryos with intact zona pellucida. Total number of women in group B small for statistical significance; not randomized; no sample size/power calculation; not placebo controlled.
Litwicka 2015 RCT 194= euthyroid women affected by thyroid autoimmunity 30= ATA-positive untreated and 30= ATA-positive treated with corticosteroid; 134= controls Prednisolone (deltacortene 5 mg) from day of oocyte retrieval until day of pregnancy test Prednisolone may improve CPR and reduce miscarriage after IVF in patients with thyroid autoimmunity. No power analysis; no placebo/blinding of subjects and investigators.
Moffitt 1995 RCT 206= IVF-ET (stimulation and cryopreservation) patients 103= cycles treated with glucocorticoids; 28= cryopreservation cycles with glucocorticoids; 103= cycles with placebo; 33= cryopreservation cycles with placebo 4 doses of 4 mg 6-α-methylprednisolone for 4 evenings starting evening of retrieval or evening before thawing cryopreserved embryos; 250 mg tetracycline 4x/day for 4 days starting with initiation of study medication Glucocorticoids plus antibiotic treatment for transfers of nonmicromanipulated embryos do not seem to have an effect on PR or IR in stimulation or cryopreservation cycles. Mixed IVF-FET protocols (included both natural and cryosynthetic).
Mottla 1996 RCT 75= IVF patients <40 years 39 (51%)= patients received prednisone; 36 (49%)= patients received placebo Prednisone (3 20 mg tablets of 1,2-dehydrocortisone daily) Results suggest increased IR and CPR in group treated with glucocorticoid vs placebo, but little difference in ongoing pregnancy rates. Possible type II error; limited number of patients, so not possible to analyze by patient diagnosis.
Polak de Fried 1993 Cohort 56= IVF-ET patients, all with tubal factor infertility; 91 cycles Grp A: 23 patients in IVF-ET treatment cycles: Grp A2 (26 cycles) = received corticosteroids; Grp A1 (27 cycles) = did not receive corticosteroids; Grp B (38 cycles): 33 patients received corticosteroids in first IVF-ET attempt 60 mg methylprednisone for 4 days, starting on day of retrieval Corticosteroids for a short period of time could improve IR and PR in patients undergoing IVF-ET. Nonrandomized; groups' age and ovarian reserve unaccounted for; paired analysis of patients with prior failed IVF-ET biased (selection bias, as well as by regression to the mean); the third group of first- time IVF patients all underwent treatment with no comparison control group; small sample size; patients serving as their own controls; group C had no control group.
Polanski 2014 SR 3= studies (1 RCT [abstract], 2 case-control) evaluating adjuvant therapies in women undergoing ART where natural killer (NK) cell numbers and/or activity were assessed 2 studies reported the use of IVIg; 1 reported use of prednisolone; Controls: Low-molecular weight heparin (LMWH) + corticosteroids, No intervention, No medications 25 g IVIg + 20 mg LMWH + corticosteroids (pregnisolone 10 mg or dexamethasone 1 mg); 400 mg/kg IVIg or IgG; 20 mg prednisolone Beneficial effect of interventions shown on CPR and LBR, but the review does not support the use of IVIg or prednisolone in women with elevated absolute numbers or activity of NK cells undergoing ART due to poor quality of the evidence. One RCT is an abstract with no blinding; differing study populations; lack of statistical power; method of data presentation (per couple or per cycle); use of additional meds; differing dosages; data heterogeneity.
Revelli 2008 RCT 395= IVF patients with good pregnancy prognosis and normal ovarian reserve, first treatment cycle 97= patients received aspirin + prednisone; 298= patients received no treatment 100 mg aspirin from first day of stimulation until pregnancy test, stopped 24 hours before ovum pickup; prednisone: 10 mg/day 1 until day before ET, 30 mg/day for 5 days from day of ET, 10 mg/day again, until pregnancy test Aspirin plus prednisone improves ovarian responsiveness but did not significantly improve uterine blood fluxes, PR, and IR. The treatment may help prevent OHSS. Not placebo controlled or blinded; combined therapy of aspirin + corticosteroids makes it difficult to draw conclusions regarding corticosteroid effect alone; treatment group had significantly higher number of embryos transferred.
Taniguchi 2005 Cohort 120= women with measurement for ANA who had 223 IVF-ET cycles Cycles:
62= Grp 1/ no tx, ANA-
105= Grp 2/ tx, ANA-
15= Grp 3/ no tx, ANA+
41= Grp 4/ tx, ANA+
Prednisolone (15-60 mg/day for 5 days) starting 1 day after oocyte retrieval IR, CPR, and LBR after IVF-ET were low when ANA were detected. Prednisolone significantly improved IR and CPR, but not LBR. Retrospective; nonrandomized; dose was adjusted according to whether patient had side effects (non-uniform intervention); bias toward using prednisone in patients with prior failed IVF; basic demographics of four groups not reported; no power analysis; small sample size, especially after stratification into four study groups.
Ubaldi 2002 RCT 315= ICSI cycles; patients <39 years with ≤3 ICSI attempts 159= cycles with prednisolone; 156= cycles, no prednisolone Low-dose prednisolone (10 mg/day in 2 doses), starting on 1st day of stimulation for 4 weeks Low-dose prednisolone in addition to standard protocol before and after ET did not have a significant effect on PR or IR. Multiple cycles from same patient included (unequal weighting of particular patients); no placebo in controls; lack of power analysis.
Ying 2012 Cohort 116= infertile women positive for anticardiolipin antibody (ACA); 116=IVF-ET cycles 56= women pretreated with methylprednisolone plus low-dose aspirin before IVF (ACA+ group); 60= patients without treatment (untreated ACA+ group);
518= infertile women negative for ACA, controls (ACA- group)
ACA+ grp: daily 8 mg oral methylprednisolone plus 50 mg aspirin up to 3 months before IVF Pretreatment with methylprednisolone plus low-dose aspirin can improve embryo quality and increase IR and PR in ACA-seropositive patients Retrospective; nonrandomized (bias in ACA+ patients who were treated vs not treated); no power analysis; no treatment arm of corticosteroids alone (dual steroid-aspirin treatment makes it unclear whether aspirin was the reason for a difference in outcome).
Zhu 2013 Cohort 299= infertile women, IVF/ICSI cycles 66= ANA+ group: infertile women, first IVF/ICSI cycles without prednisone plus low-dose aspirin (28 IVF, 38 ICSI); Subgroups: Titre≤1:320 (46 cycles), Titre>1:320 (20 cycles); Subgroups: ANA+ cycles without prednisone+aspirin (=21), ANA+ cycles with prednisone+aspirin (=21) Daily oral dose of 10 mg prednisone plus 100 mg aspirin up to 3 months before second IVF/ICSI cycle ANA could have a detrimental effect on IVF/ICSI outcomes that may not be titre dependent. ANA+ group had significantly lower MII oocytes rate, normal fertilization, PR, and IR, and higher abnormal fertilization and early miscarriage rates. Prednisone plus low-dose aspirin adjuvant treatment could be useful in ANA+ patients, which increased the number of 2PN, perfect and available embryos, and IR. Retrospective; patients decided whether to receive therapy; comparison between first and subsequent IVF/ICSI cycles.
ACA= anticardiolipin antibody; ANA= antinuclear antibody; AOA= antiovarian antibody; APA= antiphospholipid antibody; ART= assisted reproductive technology; ATA= antithyroid antibody; BD= twice a day; CC= clomiphene citrate; CI= confidence interval; COH= controlled ovarian hyperstimulation; CPR= clinical pregnancy rate; DNA= deoxyribonucleic acid; ET= embryo transfer; FET= frozen embryo transfer; FSH= follicle-stimulating hormone; GN= gonadotropins; hCG= human chorionic gonadotropin; hMG= human menopausal gonadotropins; ICSI= intracytoplasmic sperm injection; IM= intramuscular; IPD= individual patient data; IR= implantation rate; IVF= in vitro fertilization; LAC= lupus anticoagulant; LBR= live-birth rate; MA= meta-analysis; OCP= oral contraceptive pill; OR= odds ratio; PR= pregnancy rate; RCT= randomized controlled trial; RR= risk ratio; SAB= spontaneous abortion; SR= systematic review; SS= statistically significant

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  55. Pountain GD, Keogan MT, Hazleman BL, Brown DL. Effects of single dose compared with three days' prednisolone treatment of healthy volunteers: contrasting effects on circulating lymphocyte subsets. J Clin Pathol 1993;46:1089–92 (Background).
  56. Moffitt D, Queenan JT Jr, Veeck LL, Schoolcraft W, Miller CE, Muasher SJ. Low-dose glucocorticoids after in vitro fertilization and embryo transfer have no significant effect on pregnancy rate. Fertil Steril 1995;63:571–7 (Level I).
  57. Mottla GL, Smotrich DB, Gindoff PR, Stillman RJ. Increasing clinical pregnancy rates after IVF/ET. Can immunosuppression help? J Reprod Med 1996;41:889–91 (Level I).
  58. Lee KA, Koo JJ, Yoon TK, Do BR, Ko JJ, Cha KY. Immunosuppression by corticosteroid has no effect on the pregnancy rate in routine in-vitro fertilization/ embryo transfer patients. Hum Reprod 1994;9:1832–5 (Level II).
  59. Litwicka K, Arrivi C, Varricchio MT, Mencacci C, Greco E. In women with thyroid autoimmunity, does low-dose prednisolone administration, compared with no adjuvant therapy, improve in vitro fertilization clinical results? J Obstet Gynaecol Res 2015;41:722–8 (Level I).
  60. Taniguchi F. Results of prednisolone given to improve the outcome of in vitro fertilization-embryo transfer in women with antinuclear antibodies. J Reprod Med 2005;50:383–8 (Level II).
  61. Cohen J, Malter H, Elsner C, Kort H, Massey J, Mayer MP. Immunosuppression supports implantation of zona pellucida dissected human embryos. Fertil Steril 1990;53:662–5 (Level II).
  62. Polak de Fried E, Blanco L, Lancuba S, Asch RH. Improvement of clinical pregnancy rate and implantation rate of in-vitro fertilization-embryo transfer patients by using methylprednisone. Hum Reprod 1993;8:393– 5 (Level II).
  63. Lahteenmaki A, Rasanen M, Hovatta O. Low-dose prednisolone does not improve the outcome of in-vitro fertilization in male immunological infertility. Hum Reprod 1995;10:3124–9 (Level I).
  64. Robertson SA. GM-CSF regulation of embryo development and pregnancy. Cytokine Growth Factor Rev 2007;18:287–98 (Background).
  65. Agerholm I, Loft A, Hald F, Lemmen JG, Munding B, Sorensen PD, et al. Culture of human oocytes with granulocyte-macrophage colony-stimulating factor has no effect on embryonic chromosomal constitution. Reprod Biomed Online 2010;20:477–84 (Level I).
  66. Economou KA, Christopikou D, Tsorva E, Davies S, Mastrominas M, Cazlaris H, et al. The combination of calcium ionophore A23187 and GM-CSF can safely salvage aged human unfertilized oocytes after ICSI. J Assist Reprod Genet 2017;34:33–41 (Level I).
  67. Ziebe S, Loft A, Povlsen BB, Erb K, Agerholm I, Aasted M, et al. A randomized clinical trial to evaluate the effect of granulocyte-macrophage colonystimulating factor (GM-CSF) in embryo culture medium for in vitro fertilization. Fertil Steril 2013;99:1600–9 (Level I).
  68. Sjoblom C, Wikland M, Robertson SA. Granulocyte-macrophage colonystimulating factor promotes human blastocyst development in vitro. Hum Reprod 1999;14:3069–76 (Level II).
  69. Zhou W, Chu D, Sha W, Fu L, Li Y. Effects of granulocyte-macrophage colony- stimulating factor supplementation in culture medium on embryo quality and pregnancy outcome of women aged over 35 years. J Assist Reprod Genet 2016;33:39–47 (Level II).
  70. Siristatidis C, Vogiatzi P, Salamalekis G, Creatsa M, Vrachnis N, Glujovsky D, et al. Granulocyte macrophage colony stimulating factor supplementation in culture media for subfertile women undergoing assisted reproduction technologies: a systematic review. Int J Endocrinol 2013;2013:704967 (Level II).
  71. Aleyasin A, Abediasl Z, Nazari A, Sheikh M. Granulocyte colony-stimulating factor in repeated IVF failure, a randomized trial. Reproduction 2016;151: 637–42 (Level I).
  72. Barad DH, Yu Y, Kushnir VA, Shohat-Tal A, Lazzaroni E, Lee HJ, et al. A randomized clinical trial of endometrial perfusion with granulocyte colony-stimulating factor in in vitro fertilization cycles: impact on endometrial thickness and clinical pregnancy rates. Fertil Steril 2014;101: 710–5 (Level I).
  73. Eftekhar M, Hosseinisadat R, Baradaran R, Naghshineh E. Effect of granulocyte colony stimulating factor (G-CSF) on IVF outcomes in infertile women: An RCT. Int J Reprod Biomed (yazd) 2016;14:341–6 (Level I).
  74. Sarvi F, Arabahmadi M, Alleyassin A, Aghahosseini M, Ghasemi M. Effect of increased endometrial thickness and implantation rate by granulocyte colony-stimulating factor on unresponsive thin endometrium in fresh in vitro fertilization cycles: a randomized clinical trial. Obstet Gynecol Int 2017;2017:3596079 (Level I).
  75. Eftekhar M, Sayadi M, Arabjahvani F. Transvaginal perfusion of G-CSF for infertile women with thin endometrium in frozen ET program: A nonrandomized clinical trial. Iran J Reprod Med 2014;12:661–6 (Level II).
  76. Kunicki M, Lukaszuk K, Liss J, Skowronska P, Szczyptanska J. Granulocyte colony stimulating factor treatment of resistant thin endometrium in women with frozen-thawed blastocyst transfer. Syst Biol Reprod Med 2017;63:49–57 (Level II).
  77. Li Y, Pan P, Chen X, Li L, Li Y, Yang D. Granulocyte colony-stimulating factor administration for infertile women with thin endometrium in frozen embryo transfer program. Reprod Sci 2014;21:381–5 (Level II).
  78. Tehraninejad E, Davari Tanha F, Asadi E, Kamali K, Aziminikoo E, Rezayof E. G-CSF intrauterine for thin endometrium, and pregnancy outcome. J Fam Reprod Health 2015;9:107–12 (Level II).
  79. Xu B, Zhang Q, Hao J, Xu D, Li Y. Two protocols to treat thin endometrium with granulocyte colony-stimulating factor during frozen embryo transfer cycles. Reprod Biomed Online 2015;30:349–58 (Level II).
  80. Cavalcante MB, Costa Fda S, Barini R, Araujo Junior E. Granulocyte colony-stimulating factor and reproductive medicine: A review. Iran J Reprod Med 2015;13:195–202 (Level II).
  81. Xie Y, Zhang T, Tian Z, Zhang J, Wang W, Zhang H, et al. Efficacy of intrauterine perfusion of granulocyte colony-stimulating factor (G-CSF) for Infertile women with thin endometrium: A systematic review and meta-analysis. Am J Reprod Immunol 2017;78 (Level II).
  82. Li J, Mo S, Chen Y. The effect of G-CSF on infertile women undergoing IVF treatment: A meta-analysis. Syst Biol Reprod Med 2017;63:239–47 (Level II).
  83. Davari-tanha F, Tehraninejad ES, Ghazi M, Shahraki Z. The role of G-CSF in recurrent implantation failure: A randomized double blind placebo control trial. Int J Reprod Biomed 2016;14:737–42 (Level I).
  84. Eftekhar M, Miraj S, Farid Mojtahedi M, Neghab N. Efficacy of Intrauterine infusion of granulocyte colony stimulating factor on patients with history of implantation failure: A randomized control trial. Int J Reprod Biomed (yazd) 2016;14:687–90 (Level I).
  85. Santjohanser C, Knieper C, Franz C, Hirv K, Meri O, Schleyer M, et al. Granulocyte-colony stimulating factor as treatment option in patients with recurrent miscarriage. Arch Immunol Ther Exp (warsz) 2013;61:159–64 (Level II).
  86. Tevkin S, Lokshin V, Shishimorova M, Polumiskov V. The frequency of clinical pregnancy and implantation rate after cultivation of embryos in a medium with granulocyte macrophage colony-stimulating factor (GM-CSF) in patients with preceding failed attempts of ART. Gynecol Endocrinol 2014;30 Suppl 1:9–12 (Level II).
  87. Zhao J, Xu B, Xie S, Zhang Q, Li YP. Whether G-CSF administration has beneficial effect on the outcome after assisted reproductive technology? A systematic review and meta-analysis. Reprod Biol Endocrinol 2016;14:62 (Level II).
  88. Granato D, Blum S, Rössle C, Le Boucher J, Malnoë A, Dutot G. Effects of parenteral lipid emulsions with different fatty acid composition on immune cell functions in vitro. JPEN J Parenter Enteral Nutr 2000;24:113–8 (Background).
  89. Clark DA. Intralipid as treatment for recurrent unexplained abortion? Am J Reprod Immunol 1994;32:290–3 (Background).
  90. Dakhly DM, Bayoumi YA, Sharkawy M, Gad Allah SH, Hassan MA, Gouda HM, et al. Intralipid supplementation in women with recurrent spontaneous abortion and elevated levels of natural killer cells. Int J Gynaecol Obstet 2016;135:324–7 (Level I).
  91. Check JH, Check DL. Intravenous intralipid therapy is not beneficial in having a live delivery in women aged 40-42 years with a previous history of miscarriage or failure to conceive despite embryo transfer undergoing in vitro fertilization-embryo transfer. Clin Exp Obstet Gynecol 2016;43:14–5 (Level II).
  92. Stephenson MD, Fluker MR. Treatment of repeated unexplained in vitro fertilization failure with intravenous immunoglobulin: a randomized, placebo-controlled Canadian trial. Fertil Steril 2000;74:1108–13 (Level I).
  93. De Placido G, Zullo F, Mollo A, Cappiello F, Nazzaro A, Colacurci N, et al. Intravenous immunoglobulin (IVIG) in the prevention of implantation failures. Ann N Y Acad Sci 1994;734:232–4 (Level I).
  94. Chernyshov VP, Dons'koi BV, Sudoma IO, Goncharova YO. Multiple immune deviations predictive for IVF failure as possible markers for IVIG therapy. Immunol Lett 2016;176:44–50 (Level II).
  95. Coulam CB, Krysa LW, Bustillo M. Intravenous immunoglobulin for in-vitro fertilization failure. Hum Reprod 1994;9:2265–9 (Level II).
  96. Moraru M, Carbone J, Alecsandru D, Castillo-RamaM, Garcia-Segovia A, Gil J, et al. Intravenous immunoglobulin treatment increased live birth rate in a Spanish cohort of women with recurrent reproductive failure and expanded CD56(þ) cells. Am J Reprod Immunol 2012;68:75–84 (Level II).
  97. Ramos-Medina R, Garcia-Segovia A, Gil J, Carbone J, Aguaron de la Cruz A, Seyfferth A, et al. Experience in IVIg therapy for selected women with recurrent reproductive failure and NK cell expansion. Am J Reprod Immunol 2014;71:458–66 (Level II).
  98. Winger EE, Reed JL, Ashoush S, Ahuja S, El-Toukhy T, Taranissi M. Treatment with adalimumab (Humira) and intravenous immunoglobulin improves pregnancy rates in women undergoing IVF. Am J Reprod Immunol 2009;61:113–20 (Level II).
  99. Winger EE, Reed JL, Ashoush S, El-Toukhy T, Ahuja S, Taranissi M. Birth defect rates in women using Adalimumab (Humira((R)) ) to treat immunologic-based infertility in IVF patients. Am J Reprod Immunol 2011;66:237–41 (Level II).
  100. Winger EE, Reed JL, Ashoush S, El-Toukhy T, Ahuja S, Taranissi M. Elevated preconception CD56þ 16þ and/or Th1:Th2 levels predict benefit from IVIG therapy in subfertile women undergoing IVF. Am J Reprod Immunol 2011;66:394–403 (Level II).
  101. Li J, Chen Y, Liu C, Hu Y, Li L. Intravenous immunoglobulin treatment for repeated IVF/ICSI failure and unexplained infertility: a systematic review and a meta-analysis. Am J Reprod Immunol 2013;70:434–47 (Level II).
  102. Clark DA, Coulam CB, Stricker RB. Is intravenous immunoglobulins (IVIG) efficacious in early pregnancy failure? A critical review and meta-analysis for patients who fail in vitro fertilization and embryo transfer (IVF). J Assist Reprod Genet 2006;23:1–13 (Level II).
  103. Polanski LT, Barbosa MA, Martins WP, Baumgarten MN, Campbell B, Brosens J, et al. Interventions to improve reproductive outcomes in women with elevated natural killer cells undergoing assisted reproduction techniques: a systematic review of literature. Hum Reprod 2014;29:65–75 (Level II).
  104. Winger EE, Reed JL, Ashoush S, El-Toukhy T, Ahuja S, Taranissi M. Degree of TNF-alpha/IL-10 cytokine elevation correlates with IVF success rates in women undergoing treatment with Adalimumab (Humira) and IVIG. Am J Reprod Immunol 2011;65:610–8 (Level II).
  105. Winger EE, Reed JL, Ashoush S, El-Toukhy T, Taranissi M. Die-off ratio correlates with increased TNF-a:IL-10 ratio and decreased IVF success rates correctable with humira. Am J Reprod Immunol 2012;68:428–37 (Level II).
  106. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and Meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006;295:2275–85 (Background).
  107. Madkour A, Bouamoud N, Louanjli N, Kaarouch I, Copin H, Benkhalifa M, et al. Intrauterine insemination of cultured peripheral blood mononuclear cells prior to embryo transfer improves clinical outcome for patients with repeated implantation failures. Zygote 2016;24:58–69 (Level II).
  108. Li S, Wang J, Cheng Y, Zhou D, Yin T, Xu W, et al. Intrauterine administration of hCG-activated autologous human peripheral blood mononuclear cells (PBMC) promotes live birth rates in frozen/thawed embryo transfer cycles of patients with repeated implantation failure. J Reprod Immunol 2017;119:15–22.
  109. Flowers WL, Esbenshade KL. Optimizing management of natural and artificial matings in swine. J Reprod Fertil Suppl 1993;48:217–28 (Background).
  110. Robertson SA, Guerin LR, Moldenhauer LM, Hayball JD. Activating T regulatory cells for tolerance in early pregnancy - the contribution of seminal fluid. J Reprod Immunol 2009;83:109–16 (Background).
  111. Sharkey DJ, Macpherson AM, Tremellen KP, Robertson SA. Seminal plasma differentially regulates inflammatory cytokine gene expression in human cervical and vaginal epithelial cells. Mol Hum Reprod 2007;13:491–501 (Background).
  112. Chicea R, Ispasoiu F, Focsa M. Seminal plasma insemination during ovum-pickup–a method to increase pregnancy rate in IVF/ICSI procedure. A pilot randomized trial. J Assist Reprod Genet 2013;30:569–74 (Level I).
  113. Friedler S, Ben-Ami I, Gidoni Y, Strassburger D, Kasterstein E, Maslansky B, et al. Effect of seminal plasma application to the vaginal vault in in vitro fertilization or intracytoplasmic sperm injection treatment cycles-a double-blind, placebo-controlled, randomized study. J Assist Reprod Genet 2013;30:907–11 (Level I).
  114. von Wolff M, Rösner S, Germeyer A, Jauckus J, Griesinger G, Strowitzki T. Intrauterine instillation of diluted seminal plasma at oocyte pick-up does not increase the IVF pregnancy rate: a double-blind, placebo controlled, randomized study. Hum Reprod 2013;28:3247–52 (Level I).
  115. von Wolff M, Rösner S, Thöne C, Pinheiro RM, Jauckus J, Bruckner T, et al. Intravaginal and intracervical application of seminal plasma in in vitro fertilization or intracytoplasmic sperm injection treatment cycles–a double-blind, placebo-controlled, randomized pilot study. Fertil Steril 2009;91:167–72 (Level I).
  116. Crawford G, Ray A, Gudi A, Shah A, Homburg R. The role of seminal plasma for improved outcomes during in vitro fertilization treatment: review of the literature and meta-analysis. Hum Reprod Update 2015;21:275–84 (Level I).
  117. Ayvaliotis B, Bronson R, Rosenfeld D, Cooper G. Conception rates in couples where autoimmunity to sperm is detected. Fertil Steril 1985;43:739–42 (Background).
  118. Bronson RA, Cooper GW, Rosenfeld DL. Sperm-specific isoantibodies and autoantibodies inhibit the binding of human sperm to the human zona pellucida. Fertil Steril 1982;38:724 (Background).
  119. Junk SM, Matson PL, Yovich JM, Bootsma B, Yovich JL. The fertilization of human oocytes by spermatozoa from men with antispermatozoal antibodies in semen. J In Vitro Fert Embryo Transf 1986;3:350–2 (Background).
  120. de Almeida M, Gazagne I, Jeulin C, Herry M, Belaisch-Allart J, Frydman R, et al. In-vitro processing of sperm with autoantibodies and in-vitro fertilization results. Hum Reprod 1989;4:49–53 (Background).
  121. Katsoff D, Check JH, Bollendorf A, Benfer K. Chymotrypsin-galactose treatment of sperm with antisperm antibodies results in improved pregnancy rates following in vitro fertilization. Am J Reprod Immunol 1995;33:149–54 (Level I).
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Topic Resources

View more on the topic of assisted reproductive technologies
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Semen analysis and thaw code

Can we use the semen analysis presence and motility (89300) code along with a reproductive tissue thaw code  (89354) View the Answer
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Billing for assisted hatching at biopsy and transfer

We would also like to know if you can bill assisted hatching with biopsy and then assisted hatching again during the transfer cycle. View the Answer
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Diagnosis code for donation

What is the diagnosis code for an embryo donation versus egg donation? View the Answer
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Coding for an endometrial biopsy/Mock cycle

We had patients request us to bill their insurance for the two monitoring visits and the Endo BX and change the diagnosis code to something that is payable.  View the Answer
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IVF-assisted pregnancies constitute 2.5% of all births in 2022

In 2022, the number of babies born from IVF increased from 89,208 in 2021 to 91,771 in 2022. This means that 2.5% of births in the US are a result of ART.

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Fertility and Sterility On Air - Unplugged: March 2024

Topics include: melatonin and implantation (4:38), whole-genome screening of embryos, and bioengineering assisted reproductive technology. Listen to the Episode
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ASRM reacts to Alabama legislation

We are pleased that the legislation passed into law by the Alabama General Assembly will at least allow our members in the state to care for their patients.

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IVF at the SOTU: Fertility care expected to be major focus at State of the Union

Protecting access to IVF care is expected to be a major theme of the State of the Union on Thursday.

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ASRM Responds to Proposed Alabama Legislation

We are proud of our Alabama members and their patients, who have been such incredible advocates working to motivate their legislators to protect IVF.

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Senate Budget Hearing is Well Timed Following Alabama IVF Ruling

ASRM statement regarding the Senate Budget Committee’s hearing entitled: No Rights to Speak of: The Economic Harms of Restricting Reproductive Freedom.

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ASRM Responds to Senate’s Failure to Pass Access to Family Building Act

We are disappointed by the Senate’s failure to meet the moment and pass federal legislation protecting access to in vitro fertilization (IVF).

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ASRM Condemns Profoundly Misguided and Dangerous Court Decision in Alabama

In LePage v Mobile Infirmary Clinic, the Alabama Supreme Court made a decision that flies in the face of medical reality and the needs of the citizens.

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Prevention of moderate and severe ovarian hyperstimulation syndrome: a guideline (2023)

Ovarian hyperstimulation syndrome is a serious complication associatedwith assisted reproductive technology. View the guideline
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ASRM applauds introduction of Access to Family Building Act of 2024

ASRM is thrilled by the introduction of the Access to Family Building Act 

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Guidance for coding limited or follow-up ultrasounds used during an IVF Cycle

I am a coder for a Reproductive Endocrinologist's office and am looking for some guidelines on limited or follow-up ultrasounds used during an IVF Cycle.  View the Answer
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Billing for cryopreservation procedures on different days

I understand that if cryopreservation of oocytes is performed on two separate dates of service, each date of service was billable. View the Answer
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Measurements to report with ultrasound codes

Are there clear guidelines as to what measurements are required in order to bill for each type of ultrasound? VIew the Answer
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Billing IVF lab work

We typically bill our IVF Lab work under the rendering provider who performs the VOR. Who should be the supervising provider for embryology billing? View the Answer
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Estradiol Free versus Total

Should patients with fertility issues be billing Estradiol Free (82681) instead of Estradiol Total (82670)? View the Answer
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IVF coverage denied for Z31.83 diagnosis code

My wife and I have been seeking IVF treatment and coverage was added for infertility treatment (up to $25,000) but our insurer keeps denying it. View the Answer
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Cycle coordination fees and 99499, S4042

I reviewed cycle coordination fees, but see that there is no specific code for cycle management.  View the Answer
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Supervising provider for embryology billing

We typically bill our IVF Lab work under the rendering provider who performs the VOR. Who should be the supervising provider for embryology billing? View the Answer
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The International Glossary on Infertility and Fertility Care, 2017†‡§ (2017)

Terms and definitions currently used infertility care, infertility and medically assisted reproduction (MAR) can have different meanings that are dependent upon the setting, their usage in research or clinical interventions, or among diverse populations.
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Journal Club Global - Revisiting the STAR trial: The Fellows debate PGT-A

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Z Codes Vs. Procedure Codes For Fertility Preservation Counseling

I am trying to understand better when to use the procreative management code vs the fertility preservation counseling and procedure codes. View the Answer
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Unlisted Fertility Treatment CPT Code

Can you please refer me to an unlisted management CPT code for fertility treatment? View the Answer
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Pregnancy Of Unknown Location

What is the most appropriate ICD-10 code for pregnancy of unknown location (not an ectopic pregnancy)?  View the Answer
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Pregnancy Ultrasound

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Limited Monitoring Ultrasound

What is the appropriate code to use for a limited follow-up follicular transvaginal ultrasound? View the Answer
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Limited Transvaginal Ultrasound

One of our clients received information that a repeat limited transvaginal ultrasound should be billed with a limited pelvic ultrasound code (76857). View the Answer
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In Vitro Maturation

Have CPT codes been established for maturation in vitro? View the Answer
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IUI Same Gender

When managing an IUI or IVF cycle for a female same sex couple or a patient that has no exposure to sperm, what ICD 10 diagnosis should be used? View the Answer
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IVF Case Rates

What ICD-10 codes apply to case rates? View the Answer
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Monitoring E&M

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Monitoring FET

What is the correct diagnosis code to use on the follicle ultrasound (76857) for a patient who is undergoing frozen embryo transfer (FET)? View the Answer
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Embryo Storage Fees For Multiple Cycles

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Endometrial Receptivity Analysis

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Flat Fee For Outside Monitoring

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Diagnosis Code For Same-Sex Egg Donation

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Donor Embryos

Could you give guidance for the correct ICD-10 code(s) to use when a patient is doing an Anonymous Donor Embryo Transfer cycle? View the Answer
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Billing at an Outside Clinic for Lab Services

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Board Certified Vs. Non-Board Certified Billing

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Using family members as gamete donors or gestational carriers (2017)

The use of adult intrafamilial gamete donors and gestational surrogates is generally ethically acceptable when all participants are fully informed. View the Committee Document
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Financial ‘‘risk-sharing’’ or refund programs in assisted reproduction: an Ethics Committee opinion (2016)

Financial ‘‘risk-sharing’’ fee structures in assisted reproduction programs charge patients a higher initial fee but provide reduced fees for subsequent cycles and often a partial or complete refund if treatment fails. View the Committee Document
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Correct coding for laboratory procedures during assisted reproductive technology cycles

This document provides updated coding information for services related to assisted reproductive technology procedures. View the Coding Committee Document
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Recommended practices for the management of embryology, andrology, and endocrinology laboratories: a committee opinion (2014)

A general overview for good management practices within the endocrinology, andrology, and embryology laboratories in the United States. View the Recommendation
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Best practices of ASRM and ESHRE: a journey through reproductive medicine (2012)

ASRM and ESHRE are the two largest societies in the world whose members comprise the major experts and professionals working in reproductive medicine. View the Committee Joint Guideline

Topic Resources

View more on the topic of in vitro fertilization (IVF)
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Advocacy in Action

Join the ASRM Advocacy in Action 2024 campaign by making a tax-deductible charitable gift before July 31!  Be part of Advocacy in Action
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ASRM Responds to Senate Vote on IVF Bill

ASRM is disappointed that a filibuster prevented the passage of the Right to IVF Act.

View the Press Release
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ASRM Calls for Passage of Family Building Bill

It would increase access to IVF treatments for all Americans, including active-duty service members, veterans, and federal employees.

View the Press Release
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Fertility and Sterility On Air - TOC: May 2024

Topics this month include Iatrogenic and demographic determinants of the national plural birth increase, outcomes between ICSI and IVF with PGT-A. Listen to the Episode
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ASRM publishes IVF one-pagers for media use

The documents lay out the clinical IVF process, summarize oversight of IVF in the U.S., and explain how lawmakers can support access to IVF. 

View the Press Release
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Billing for assisted hatching at biopsy and transfer

We would also like to know if you can bill assisted hatching with biopsy and then assisted hatching again during the transfer cycle. View the Answer
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ASRM Reacts to Cruz/Britt OPED

We are pleased to see Senators Cruz and Britt express their interest in protecting access to IVF.

View the Press Release
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Fertility and Sterility On Air - Unplugged: April 2024

Topics include: IVF in film, a rat model of fallopian tube torsion, comparing letrozole regimens for PCOS, and a review of chronic endometritis. Listen to the Episode
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ASRM Files Amicus Brief in Texas Embryo Case

ASRM has filed an amicus curiae (friend of the court) brief in the case of Antoun v Antoun, which is pending before the Texas Supreme Court. 

View the Press Release
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Survey shows strong support for increased access to fertility treatments

A new public opinion poll reveals strong support for improved access to In Vitro Fertilization (IVF). 

View the Press Release
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National Infertility Awareness Week 2024: Leave Your Mark

Next week is National Infertility Awareness Week, a federally recognized health observance founded to increase awareness of infertility.

View the Press Release
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ASRM Today: ASRM Policy Matters: Post-Alabama IVF decision advocacy roundup with Jessie Losch

Jessie Losch, ASRM Government Affairs Manager, updates ASRM Today on the advocacy efforts underway post the Alabama Supreme Court decision. Listen to the Episode
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IVF-assisted pregnancies constitute 2.5% of all births in 2022

In 2022, the number of babies born from IVF increased from 89,208 in 2021 to 91,771 in 2022. This means that 2.5% of births in the US are a result of ART.

View the Press Release
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Fertility and Sterility On Air - Live from PCRS 2024

Fertility & Sterility on Air brings you the highlights from the 2024 Annual Meeting of the Pacific Coast Reproductive Society. Listen to the Episode
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Fertility and Sterility On Air - Seminal Article: Dr. Jeremy Applebaum

Listen to this interview featuring Dr. Jeremy Applebaum, who recently published "Impact of coronavirus disease 2019 vaccination on live birth rates after IVF" Listen to the Episode
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ASRM provides testimony to Senate Judiciary Committee on threats facing IVF

ASRM shared with the Senate Judiciary Committee the dangers to reproductive medicine nearly two years after the Dobbs decision.

View the Press Release
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Fertility and Sterility On Air - TOC: March 2024

Topics this month include the impact of COVID-19 vaccination on live birth rates after IVF, the "freeze-all" strategy in women with adenomyosis, and more. Listen to the Episode
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ASRM reacts to Alabama legislation

We are pleased that the legislation passed into law by the Alabama General Assembly will at least allow our members in the state to care for their patients.

View the Press Release
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IVF at the SOTU: Fertility care expected to be major focus at State of the Union

Protecting access to IVF care is expected to be a major theme of the State of the Union on Thursday.

View the Press Release
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ASRM Responds to Proposed Alabama Legislation

We are proud of our Alabama members and their patients, who have been such incredible advocates working to motivate their legislators to protect IVF.

View the Press Release
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Senate Budget Hearing is Well Timed Following Alabama IVF Ruling

ASRM statement regarding the Senate Budget Committee’s hearing entitled: No Rights to Speak of: The Economic Harms of Restricting Reproductive Freedom.

View the Press Release
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ASRM Responds to Senate’s Failure to Pass Access to Family Building Act

We are disappointed by the Senate’s failure to meet the moment and pass federal legislation protecting access to in vitro fertilization (IVF).

View the Press Release
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Alabama Supreme Court Rules Frozen Embryos are “Unborn Children” and admonishes IVF’s “Wild West” treatment

Legally Speaking™ on presenting facts and reflecting on the impact and potential implications of  legal developments in ART. View the Column
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ASRM Condemns Profoundly Misguided and Dangerous Court Decision in Alabama

In LePage v Mobile Infirmary Clinic, the Alabama Supreme Court made a decision that flies in the face of medical reality and the needs of the citizens.

View the Press Release
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Fertility and Sterility On Air - TOC: February 2024

Topics this month include the optimial AMH level in oocyte donors, the role of mean number of DNA breakpoints (MDB) in sperm DNA integrity, and more. Listen to the Episode
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Prevention of moderate and severe ovarian hyperstimulation syndrome: a guideline (2023)

Ovarian hyperstimulation syndrome is a serious complication associatedwith assisted reproductive technology. View the guideline
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Fertility and Sterility On Air - Unplugged: January 2024

Topics this month include: HCG as a predictor of pregnancy outcome after IVF, progestin ovulation suppression and embryo development, and more. Listen to the Episode
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ASRM applauds introduction of Access to Family Building Act of 2024

ASRM is thrilled by the introduction of the Access to Family Building Act 

View the Press Release
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Billing IVF lab work

We typically bill our IVF Lab work under the rendering provider who performs the VOR. Who should be the supervising provider for embryology billing? View the Answer
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Journal Club Global: IVM in Clinical Practice: An Idea Whose Time Has Come?

In vitro maturation (IVM) has the potential to make IVF cheaper, safer, and more widely accessible to patients with infertility. View the Video
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Comparison of pregnancy rates for poor responders using IVF with mild ovarian stimulation versus conventional IVF: a guideline (2018)

Mild-stimulation protocols with in vitro fertilization (IVF) generally aim to use less medication than conventional IVF. View the Guideline
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IVF cycle management and facility fees, an overview

How should IVF Cycle Management be coded?  View the Answer
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Limited ultrasound performed by RN

Would it be appropriate to bill a 99211 when an RN is doing a limited ultrasound and documenting findings during an IUI or IVF treatment cycle? View the Answer
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CPT 89253 and 89254 for Assisted hatching

Can I bill CPT codes 89253 and 89254 together? If yes, do I need a modifier on any of the codes? View the Answer
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Journal Club Global - What is the optimal number of oocytes to reach a live-birth following IVF?

The optimal number of oocytes necessary to expect a live birth following in vitro fertilization remains unclear. View the Video
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Patient Education

What is the correct way to bill for the patient education sessions performed by registered nurses to individual patients prior to their IVF cycle? View the Answer
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Pregnancy Ultrasound

Our practice does routine ultrasounds (sac check- 76817) at the end of an IVF cycle and bill with a diagnosis code O09.081, pregnancy resulting from ART.  View the Answer
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IVF Consent Counseling

When a patient is scheduled to undergo IVF and the provider schedules the patient for a 30-minute consultation is this visit billable? View the Answer
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Lab Case Rates

What ICD-10 codes apply to case rates? View the Answer
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In Vitro Maturation

Have CPT codes been established for maturation in vitro? View the Answer
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IUI or IVF

Should other ovarian dysfunction (diagnosis code E28.8) or unspecified ovarian dysfunction (diagnosis code E28.9) can be used for an IUI or an IVF cycle View the Answer
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IV Fluids During Egg Retrieval

Is it appropriate to bill the insurance company for CPT 96360, Under Hydration Infusion when being used in conjunction with IVF retrieval? View the Answer
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IVF Billing Forms

I am seeking information on IVF insurance billing guidelines.  View the Answer
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IVF Billing Globally

Am I correct in assuming that it is duplicate billing for both the ambulatory center and embryology laboratory to bill globally? View the Answer
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IVF Billing of Professional Charges

Are we allowed to bill professional charges under the physician for the embryologist who performs the IVF laboratory services? View the Answer
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IVF Case Rates

What ICD-10 codes apply to case rates? View the Answer
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Oocyte Denudation

Is there is a separate code for denudation of oocytes?  View the Answer
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Ovulation Induction Monitoring for IUI

We would like to clarify the correct ICD 10 diagnosis code for monitoring of an IUI cycle.  View the Answer
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Endometrial Biopsy/Scratch

What CPT code should be used for a “scratch test”?  View the Answer
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Endometriosis and Infertility

For treatment like IVF would we bill with N97.x first or an endometriosis diagnosis? View the Answer
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Follicle Monitoring For Diminished Ovarian Reserve

If a patient has decreased ovarian reserve (ICD-10 E28.8) and patient is undergoing follicle tracking to undergo either an IUI cycle or IVF cycle... View the Answer
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Global Billing Vs Billing Under Provider

For an IVF cycle (that is not being billed global to an insurance plan) is it appropriate to bill the charges under one “global” provider? View the Answer
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Diagnosis of Infertility for IVF Procedure

How important is it to have accurate documentation of the type of infertility diagnosis for IVF procedures?  View the Answer
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Donor Embryos

Could you give guidance for the correct ICD-10 code(s) to use when a patient is doing an Anonymous Donor Embryo Transfer cycle? View the Answer
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Egg Culture and Fertilization

We are billing for the technical component of 89250 and would like to also bill a professional component of the 89250. View the Answer
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Egg Culture and Fertilization: Same Gender

A same-sex male couple requested half their donor eggs be fertilized with sperm from male #1 and the other half fertilized from male #2. View the Answer
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Journal Club Global: Natural versus Programmed FET Cycles

A significant portion of IVF cycles now utilize frozen embryo transfer.
View the Video
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Role of assisted hatching in in vitro fertilization: a guideline (2022)

There is moderate evidence that assisted hatching does not significantly improve live birth rates in fresh assisted reproductive technology cycles View the Committee Opinion
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Journal Club Global - Best Practices of High Performing ART Clinics

This Fertility and Sterility Journal Club Global discusses February’s seminal article, “Common practices among consistently high-performing in vitro fertilization programs in the United States: a 10 year update.” View the Video
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Guidance on the limits to the number of embryos to transfer: a committee opinion (2021)

ASRM's guidelines for the limits on the number of embryos to be transferred during IVF cycles have been further refined ... View the Committee Opinion
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Journal Club Global Live from India - Adjuvants in IVF and IVF Add-Ons for the Endometrium

Many adjuvants have been utilized by IVF centers to improve their success rates. View the Video
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Evidence-based outcomes after oocyte cryopreservation for donor oocyte in vitro fertilization and planned oocyte cryopreservation: a guideline (2021)

A review of success rates, factors that may impact success rates, and  outcomes. View the Committee Opinion
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Development of an emergency plan for in vitro fertilization programs: a committee opinion (2021)

All IVF programs and clinics should have a plan to protect fresh and cryopreserved human specimens (embryos, oocytes, sperm). View the Committee Opinion
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In vitro maturation: a committee opinion (2021)

The results of in vitro maturation (IVM) investigations suggest the potential for wider clinical application.  View the Committee Opinion
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Fertility treatment when the prognosis is very poor or futile: an Ethics Committee opinion (2019)

The Ethics Committee recommends that in vitro fertilization (IVF) centers develop patient-centered policies regarding requests for futile treatment.  View the Committee Opinion
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Blastocyst culture and transfer in clinically assisted reproduction: a committee opinion (2018)

The purposes of this document is to review the literature regarding the clinical application of blastocyst transfer. View the Committee Opinion
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Performing the embryo transfer: a guideline (2017)

A systematic review of the literature was conducted which examined each of the major steps of embryo transfer. Recommendations made for improving pregnancy rates are based on interventions demonstrated to be either beneficial or not beneficial. (Fertil Steril® 2017;107:882–96. ©2017 by American Society for Reproductive Medicine.) View the Committee Guideline
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Financial ‘‘risk-sharing’’ or refund programs in assisted reproduction: an Ethics Committee opinion (2016)

Financial ‘‘risk-sharing’’ fee structures in assisted reproduction programs charge patients a higher initial fee but provide reduced fees for subsequent cycles and often a partial or complete refund if treatment fails. View the Committee Document
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Best practices of ASRM and ESHRE: a journey through reproductive medicine (2012)

ASRM and ESHRE are the two largest societies in the world whose members comprise the major experts and professionals working in reproductive medicine. View the Committee Joint Guideline
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What support for IVF looks like

Bipartisan support for IVF, that is responsible for the birth of over 2% of all babies born in the USA each year, will ensure that families continue to grow. View the advocacy resource
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It takes more than one

Why IVF patients often need multiple embryos to have a baby View the advocacy resource
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Oversight of IVF in the US

In the US, medical care is regulated by a complex and comprehensive network of federal and state regulations and professional oversight. View the advocacy resource
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In Vitro Maturation Special Interest Group (IVMSIG)

IVMSIG strives to define the best strategies to optimize IVM outcomes. Learn more about IVMSIG
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Advocacy Resources

ASRM has prepared resources to help explain and advocate for reproductive rights and the continuation of in vitro fertilization and other fertility treatments. View the advocacy resources

Practice Documents

ASRM Practice Documents have been developed to assist physicians with clinical decisions regarding the care of their patients.

Inclusive language and environment to welcome lesbian, gay, bisexual, transgender, queer, questioning, intersex, and asexual+ patients (2024)

Using inclusive language and creating an inclusive clinical environment to serve lesbian, gay, bisexual, transgender, queer, questioning, intersex, and asexual+ patients is vital to optimizing access to care and patient outcomes. Practical recommendations are made for increasing inclusivity in the clinic, and a glossary of current terms is included.
Practice Committee Documents teaser

Tobacco or marijuana use and infertility: a committee opinion (2023)

In the United States, approximately 21% of adults report some form of tobacco use, although 18% report marijuana use.
Practice Committee Documents teaser

Prevention of moderate and severe ovarian hyperstimulation syndrome: a guideline (2023)

Ovarian hyperstimulation syndrome is a serious complication associatedwith assisted reproductive technology.
Practice Committee Documents teaser

Definition of infertility: a committee opinion (2023)

‘‘Infertility’’ is a disease, condition, or status characterized by several factors.

More Resources

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ASRM Academy on the Go

ASRM MAC Tool 2021

The ASRM Müllerian Anomaly Classification 2021 (MAC2021) includes cervical and vaginal anomalies and standardize terminology within an interactive tool format.

View the MAC Tool
EMR Phrases teaser
Practice Guidance

EMR Shared Phrases/Template Library

This resource includes phrases shared by ASRM physician members to provide a template for individuals to create their own EMR phrases.

View the library
Practice Committee Documents teaser

ASRM Practice Documents

These guidelines have been developed by the ASRM Practice Committee to assist physicians with clinical decisions regarding the care of their patients.

View ASRM Practice Documents
Ethics Committee teaser

ASRM Ethics Opinions

Ethics Committee Reports are drafted by the members of the ASRM Ethics Committee on the tough ethical dilemmas of reproductive medicine.

View ASRM Ethics Opinions
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Practice Guidance

Coding Corner Q & A

The Coding Corner Q & A is a list of previously submitted and answered questions from ASRM members about coding. Answers are available to ASRM Members only.

View the Q & A
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Practice Guidance

COVID-19 Resources

A compendium of ASRM resources concerning the Novel Corona virus (SARS-COV-2) and COVID-19.

View the resources
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Patient Resources

ReproductiveFacts.org provides a wide range of information related to reproductive health and infertility through patient education fact sheets, infographics, videos, and other resources.

View Website