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Comparison of pregnancy rates for poor responders using IVF with mild ovarian stimulation versus conventional IVF: a guideline (2018)


The terms ‘‘natural,’’ ‘‘patient friendly,’’ ‘‘mild,’’ ‘‘minimal,’’ and ‘‘minimally stimulating’’ in vitro fertilization (IVF) have appeared increasingly in the literature, clinic advertising, and the media. Research in the field of ‘‘minimal-stimulation IVF’’ has used several terminologies, causing confusion among clinicians, researchers, and patients. The International Glossary on Infertility and Fertility Care includes definitions developed for specific terms such as ‘‘natural cycle ART,’’ ‘‘modified natural cycle,’’ and ‘‘mild ovarian stimulation for IVF’’ (1). Various approaches to this technique share important features, including the use of oral agents such as clomiphene citrate (CC) and aromatase inhibitors, low-dose exogenous gonadotropins, gonadotropin releasing hormone (GnRH) antagonists, and late follicular-phase administration of human chorionic gonadotropin (hCG) or luteinizing hormone (LH). For the purposes of this document, conventional IVF is defined as controlled ovarian stimulation (COS) with exogenous gonadotropins to induce multiple oocyte development for retrieval. ‘‘Natural-cycle IVF’’ involves monitoring unstimulated ovaries and attempting to retrieve the oocyte from a dominant follicle prior to ovulation. This was the protocol utilized to achieve the first live birth through IVF (2). However, this approach was replaced by protocols utilizing ovarian stimulation with exogenous gonadotropins resulting in decreased cancellation rates, increased number of oocytes retrieved, and, ultimately, increased live-birth rates.

‘‘Modified natural-cycle IVF’’ includes the use of GnRH antagonists in the late follicular phase (sometimes with add-back gonadotropin therapy) and ovulation trigger, typically with hCG. Proposed advantages of natural-cycle IVF include reduced cost per cycle, minimized risk of multiple gestation, lower risk of ovarian hyperstimulation, and less physical and emotional demands on the patient when compared with conventional IVF (3, 4). The lower multiple gestation risk is a direct result of usually obtaining a single oocyte and transferring a single embryo. Possible disadvantages of these strategies include increased chance of cycle cancellation from unexpected ovulation, no oocyte recovery or retrieval of an immature oocyte, and possible lower success rates.

‘‘Mild ovarian stimulation for IVF’’ involves multiple strategies using the following agents as monotherapy or in combination: CC, aromatase inhibitors, low-dose exogenous gonadotropins, GnRH antagonists, and late follicular phase hCG/LH. Some ‘‘low-dose’’ mild IVF protocols utilizing GnRH antagonists involve delaying low-dose gonadotropin stimulation until the mid follicular phase, anywhere between cycle-days 3 to 7. This strategy may lead to the development of fewer oocytes than traditional IVF, with reduced gonadotropins utilized and less cost. Interpreting the literature on mild ovarian stimulation is challenging because the doses of added gonadotropins are not consistent and are similar to those used in conventional IVF in some studies.

Several studies have addressed the question of whether these approaches may be especially beneficial in specific subsets of patients. This document evaluates these strategies with respect to pregnancy and live-birth rates in patients who are expected to be poor responders, based on the Bologna criteria (patients having at least two of the following features: maternal age R40, an abnormal ovarian reserve test, and/or prior poor response to IVF [%3 oocytes with a conventional-stimulation protocol]) (5).

LIMITATIONS OF THE LITERATURE

Several challenges exist when trying to interpret the efficacy of IVF with mild stimulation. There are no standard protocols or standard definitions of poor responders, which can make it challenging to compare studies and perform a meta-analysis. Many studies have a small sample size, which greatly limits their power to detect a difference between groups. Some studies use a similar dose of gonadotropins between the mild- and the standard-stimulation group. Finally, some studies lack an adequate comparison group (the mild-stimulation cycle is compared against the same patient's prior standard IVF cycle), and some use surrogate endpoints, rather than pregnancy or live-birth rates.

METHODS

This clinical practice guideline was based on systematic reviews of the literature performed in the electronic database MEDLINE through PubMed January 18–November 7, 2017. No limit or filter was used for the time period covered or English language, but articles were subsequently culled for English language. These electronic searches and examination of reference lists from primary and review articles yielded 766 studies, of which 21 studies were included (Evidence Table, available online). A combination of the following medical subject headings or text words were used: advanced maternal age; affordable; assisted reproduction; bank; banking; cost analysis;  cost benefit; cost effective; costs; cryopreservation; cryopreserve; diminished ovarian; economic; embryo; fertilization in vitro/ economics; fertilization in vitro/methods; freeze; freezing; frozen; gonadotropins; ICSI; in vitro fertilisation; in vitro fertilization; intracytoplasmic sperm injection; IVF; low cost; low dose; low ovarian; low resource; low responder; low response; low dose; maternal aging; micro dose; microdose; mild; mild ovarian stimulation; mild stimulation; mildly; mini dose; minidose; minimal; minimal stimulation; modified; modified cycle; natural; natural cycle; no stimulation; not stimulated; ovarian stimulation; ovary; ovulation induction; ovulation induction/economics; patient friendly; patient satisfaction; poor ovarian; poor responder; poor response; psychometrics; reduced ovarian; reproductive age; reproductive aging; sperm injections, intracytoplasmic; stimulated cycle; stimulation; stimulation protocol; thawed; unstimulated; vitrification; vitrified; vitrify. 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. 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).

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

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

Table 1. Summary of inclusion/exclusion criteria.


Include Exclude
  • Level I and II studies, systematic reviews, meta-analyses
  • Human studies
  • English
  • Studies with a comparison group
  • Fresh cycles
  • Frozen-thawed cycles
  • ICSI
  • Day-3 transfers
  • Day-5 transfers
  • Women ≥40 y
  • Mild ovarian-stimulation protocols: ≤150 IU gonadotropins, cycles
  • with oral agents, or no stimulation with or without antagonists
  • Comparison groups, conventional stimulation: >150 IU
  • gonadotropins with luteal down-regulation, antagonists, flare
  • Women <40 y with diminished ovarian reserve based on AMH <1.1
  • or AFC <7 (ESHRE criteria, Ferraretti 2011 [5])
  • Women with proven low response:≤3 oocytes retrieved with ≥150
  • IU/d FSH (ESHRE criteria, Ferraretti 2011 [5])
  • Level III studies: descriptive studies, case series, case reports, letters, nonsystematic reviews, off-topic studies, opinions, and reports of expert committees
  • Animal studies
  • Non-English
  • Studies without a comparison group
  • PCOS patients
  • GIFT
  • IUI
  • IVM
Note: AMH = antimullerian hormone; AFC = antral follicle count; ESHRE = European Society of Human Reproduction and Embryology; FSH = follicle-stimulating hormone; GIFT = gamete intrafallopian transfer; ICSI = intracytoplasmic sperm injection; IUI = Intrauterine insemination; IVM = In vitro maturation; PCOS = polycystic ovary syndrome.

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, high-quality [Grade A] studies)

Grade B: There is fair evidence to support the recommendations, either for or against.

(From principally Level-II, good-quality [Grade B] studies)

Grade C: There is insufficient evidence to support the recommendations, either for or against.

(From Level-II, low-quality [Grade C] studies, or when there is conflicting data from good-quality studies)

IS MILD OVARIAN STIMULATION WITH LOW-DOSE GONADOTROPINS ALONE AS EFFECTIVE AS NORMAL- OR HIGH-STIMULATION PROTOCOLS FOR POOR-RESPONDER PATIENTS?

There are two randomized controlled trials (RCTs) that showed similar clinical pregnancy rates in poor-responder patients receiving mild ovarian stimulation vs standard high-dose stimulation IVF (6, 7). One open-labeled, multicenter, randomized, controlled non-inferiority trial included patients older than 35 years, with baseline follicle-stimulating hormone (FSH) >10 IU/ml, antral follicle count (AFC) ≤5, or history of poor ovarian response or cycle cancellation (6). Patients (mean age 36 years in both groups) either received mild ovarian stimulation (fixed 150 IU FSH and antagonist, n=195) or conventional stimulation (fixed 450 IU human menopausal gonadotropins [hMG] and long, mid-luteal agonist, n=199). No significant differences were observed between mild and conventional ovarian stimulations, respectively, in clinical pregnancy rate (15.3% vs 15.5%, risk ratio [RR] 0.86; 95% confidence interval [CI] 0.55–1.34) and biochemical pregnancy (20% vs 18%; RR 1.10; 95% CI 0.66–1.84) per number of women, and early pregnancy loss (16.6% vs 12.9%; RR 1.20; 95% CI 0.36–4.17) and twin pregnancy (10% vs 22.5%; RR 0.41; 95% CI 0.10–1.65) per number of clinical pregnancies. The duration of ovarian stimulation was significantly lower in the mild vs conventional strategy (8.42 ± 2.89 vs 9.67 ± 3.10) with a mean difference of -1.2 days (95% CI -1.88 to -0.62). Also, a significantly lower amount of gonadotropins was used in the mild-stimulation strategy, with a mean difference of -3135 IU (95% CI -3331 to -2940) (6). This study did not report on cumulative pregnancy rates with supernumerary embryos, nor did it report on live-birth rates.

The other RCT evaluated the effect of doubling the starting dose of gonadotropins on ovarian response in IVF patients with a low AFC (7). The study enrolled 52 patients with an AFC of <5 follicles of 2–5 mm diameter before starting their first IVF cycle. Patients were randomized to receive either 150 IU (n=26) or 300 IU (n=26) of recombinant FSH (rFSH) as a starting dose in a long-suppression protocol. Mean age was 40.4 years in the 150 IU group vs 42.2 years in the 300 IU group (P=.77). In patients who were stimulated with the standard dose of 150 IU, the dose was doubled after 7 days of stimulation if the estradiol level was <200 pmol/liter (54.5 pg/mL) or after 10 days if the estradiol was<500 pmol/L (136 pg/mL). The dose was fixed for patients receiving the 300 IU protocol. Patients in the lower-dose group I received 2100 IU (1455–4440 IU) total of gonadotropins and those in the higher-dose group II received 3600 IU (3000–4800 IU). Patients did not differ in the number of oocytes collected (three for both groups, P=.79) and ongoing pregnancy rates (8% for lower FSH dose and 4% for higher FSH dose, P=.55). Eleven patients were cancelled before oocyte retrieval due to poor response (19% in the mild-dose group, 23% in the conventional-dose group, P=.73). The study was likely not powered to demonstrate no difference between the groups regarding pregnancy outcomes.

Summary Statement:
  • In women considered to be poor responders, there is fair evidence that clinical pregnancy rates after IVF are not substantially different when comparing mild ovarian stimulation protocols using low-dose gonadotropins (≤150 IU/d) to conventional-gonadotropin protocols, but there are no data about live-birth rates. From two Level-I, good- to high-quality (Grade A, B) studies. Grade B.


IS MILD OVARIAN STIMULATION WITH ORAL SUPEROVULATION AGENTS (WITH OR WITHOUT LOW-DOSE GONADOTROPINS) AS EFFECTIVE AS NORMAL- OR HIGH-STIMULATION PROTOCOLS FOR POOR-RESPONDER PATIENTS?

Low-dose Gonadotropins and Oral Superovulation Agents

Several RCTs have compared outcomes between mild ovarian stimulation with oral superovulation agents with low-dose gonadotropins and normal- or high-stimulation protocols (8–12). In the largest of these trials, 695 patients with diminished ovarian reserve were randomized to mild stimulation (mean age 38.5 years, 100 mg CC on cycle-days 2–6, 150 IU rFSH per day started on cycle-day 5, GnRH antagonist started on cycle-day 8) or a long GnRH-agonist protocol (mean age 37.5 years, 300–450 IU rFSH per day) (8). Poor responders were defined by the following criteria: day-3 FSH between 10–20 IU/L, antim€ullerian hormone (AMH) between 0.14–1 ng/mL, and AFC between 4–10. Compared to the traditional stimulation group, the mild stimulation group had a significantly lower oocyte yield (2.7 ± 2.3 vs 4.8 ± 3.3, P<.01) and a significantly higher cycle-cancellation rate (13.0% vs 2.7%, P<.01). Although the study was not powered to detect differences in the pregnancy rates, the authors reported similar clinical pregnancy rates per transfer (23.2% vs 19.9%, P=not significant [NS]) and per cycle start (13.2% vs 15.3%, P=NS) (8).

Other published RCTs are limited by factors such as an inadequate sample size to interpret pregnancy outcomes, lack of a consistent definition of poor responder, and the use of surrogate endpoints. In one study, 95 patients meeting two out of three Bologna criteria were randomized to one of three arms: 450 IU gonadotropins per day (n=31), 300 IU gonadotropins per day (n=31), or 150 IU gonadotropins per day plus letrozole 5 mg/day for the first 5 days of stimulation (n=33) (9). There was no significant difference in the mean number of oocytes retrieved among the three groups (3.4 ± 1.6 vs 3.7 ± 1.5 vs 3.5 ± 1.9, P=NS). The study was not powered to examine clinical pregnancy rate per started cycle (4/31 [13%] vs 5/31 [16%] vs 5/33 [15%], P=NS) (9).

Another small study randomized 58 poor responders (based on Bologna Criteria) to either traditional-dose IVF (starting at 300 IU of gonadotropins, with maximum at 450 IU) vs a mild ovarian-stimulation protocol with 100 mg CC on days 2–6 of the cycle, adding an antagonist and 150 IU of gonadotropins when a lead follicle was ≥14 mm (13). There were significantly more oocytes retrieved in the traditional-stimulation group (3.0 vs 1.0, P<.001), but the study was not powered to detect a difference in live-birth rates (12.0% vs 9.1%, P=.719) (13).

In a small pilot study, 38 women with poor ovarian response were randomized to letrozole 2.5 mg/day for cycle-days 3–7 with 75 IU rFSH on days 3 and 8, or to a long GnRH agonist protocol with 300–450 IU rFSH per day (10). The total dose of rFSH was significantly lower in the letrozole group (150 ± 0 IU vs 2,865 ± 228 IU, P<.001), but the study was not powered to show a difference in the mean number of oocytes retrieved (1.6 ± 0.8 vs 2.1 ± 0.7, P=NS) or clinical pregnancy rate per treatment cycle (3/13 [23%] vs 6/25 [24%], P=NS) (10). Another small RCT demonstrated similar clinical pregnancy rates per cycle start among 60 women assigned to an antagonist protocol with letrozole 5mg for cycle days 2–6 and 150 IU highly purified hMG daily starting on cycle-day 7, or to a microdose GnRH agonist–flare protocol with 300 IU hMG per day (4/30 [13.3%] vs 5/30 [16.6%], P¼.72; odds ratio [OR]=77; 95% CI .19–3.20) (11). In another small study, 77 women with poor response were randomized to 100 mg CC for 5 days followed by 150 IU hMG per day (n=42), or to standard stimulation with at least 300 IU hMG per day (n=35) (12). Only one clinical pregnancy was achieved in each group (12). Finally, one group published two retrospective studies demonstrating improved pregnancy rates with CC/hMG compared with hMG alone or GnRH agonist–hMG (14, 15). These studies were limited by overlap between study populations, inadequate sample size to assess differences in pregnancy outcomes, and lack of adjustment for confounders.

Summary Statement:
  • In women considered to be poor responders, there is fair evidence that clinical pregnancy rates after IVF are not substantially different when comparing mild ovarian stimulation protocols using a combination of oral agents and low-dose gonadotropins (≤150 IU/d) to conventional-gonadotropin protocols. Data about oocyte yield are mixed. From two Level-I, good- to high-quality (Grade A, B) and several low-quality studies (Grade C). (Grade B).


Oral Agents Alone

Only one RCT has compared outcomes between oral agents alone and conventional high-dose gonadotropin stimulation among poor responders undergoing IVF (16). In that study, 291 women (mean age 38 years in both groups) with elevated FSH or a previous poor response were randomized to 150 mg CC per day (n=145) or GnRH-agonist protocol with 450 IU rFSH per day (n=146). The study was continued for 2 years but terminated early due to poor recruitment. Delivery rates were similarly poor between groups (3% vs 5%, P=.77), but the study was not adequately powered to compare the strategies for this outcome (16). Two small retrospective studies demonstrated similarly low clinical pregnancy rates regardless of stimulation protocol (17, 18).

Summary Statement:
  • In women considered to be poor responders, there is insufficient evidence to recommend for or against IVF with mild ovarian stimulation using oral agents alone over conventional-gonadotropin stimulation. From one Level-I and two Level-II, low-quality (Grade B and C) studies. Grade C.


ARE NATURAL OR MODIFIED-NATURAL CYCLES AS EFFECTIVE AS NORMAL- OR HIGH-STIMULATION PROTOCOLS FOR POOR-RESPONDER PATIENTS?

The use of natural cycles or modified-natural cycles in poor responders has been evaluated in limited studies. One RCT included 140 consecutive patients who were randomized to either natural-cycle IVF vs microdose-flare cycles, although the authors note that 11 women assigned to the natural group refused the randomization and chose another treatment (19). There were 59 patients (mean age 39.3 years) who underwent 114 natural cycles, and 70 patients (mean age 42.1 years) who underwent 101 microdose-flare cycles. The pregnancy rate per cycle was low in both groups: 6.1% in the natural-cycle group and 6.9% in the traditional-stimulation group (P=NS) (19).

Several retrospective studies have evaluated stimulation protocols in poor responders, some including comparison groups (20–22), while others used patients' previous failed cycles (23–26) as a comparison. One of the largest studies with comparison groups included 304 patients, 30 of whom underwent a natural cycle versus the remainder who underwent one of several traditional-stimulation protocols (20). No significant difference among the groups was found in clinical pregnancy rates per transfer for natural cycle (20.0%), gonadotropin-only (5.6%), long-agonist (3.8%), co-flare (1.9%), microdose-flare (15.4%), or antagonist (14.4%) protocol (P=.083) (20). When comparing natural cycle and all combined traditional stimulations, clinical pregnancy rates per transfer were 20% versus 0.08%, P=.051 (ASRM Practice Committee calculation by Fisher's exact test). A significant limitation to this retrospective study is that cycles cancelled before retrieval or transfers were not reported (20). Another study included 433 patients, 52 of whom underwent a modified-natural cycle vs traditional stimulation with either a long-agonist (n=288) or antagonist (n=200) protocol (21). The per-cycle clinical pregnancy rates were 9.6% for modified-natural cycle, 8.5% for antagonist protocol, and 8.6% for long-agonist protocol (P=NS) (21).

Using the definition of poor responder based on the Bologna criteria, a retrospective cohort study included poor responders who underwent 161 cycles (n=106 women, mean age 41.3 years) of modified natural-cycle IVF or 164 cycles (n=136 women, mean age 40.7 years) of high-dose FSH IVF (dose varied between 300 IU and 450 IU/day) (22). In the modified-natural cycle group, ultrasound monitoring started on day 6, and when a 14mm follicle was present, 150 IU of rFSH and GnRH antagonist were initiated concomitantly and continued daily thereafter until the day of hCG administration when the follicle reached a mean diameter of ≥16 mm. Live-birth rates were significantly higher in the modified-natural cycle vs high-dose group (7.5%, 95% CI 3.1–11.8 vs 3.1%, 95% CI 0.4–5.7; OR 4.01, 95% CI 1.14–14.09), after adjusting for basal FSH, female age, and cause of infertility. There was also a significantly lower total gonadotropin dose (490.0 ± 35.2 IU vs 2826.1 ± 93.7 IU, P<.001) and proportion of cancelled cycles (7.5% vs 16.5%, P=.02) in the modified natural-cycle group. While this study suggests that modified natural-cycle IVF is associated with a higher probability of live birth and significantly lower gonadotropin consumption compared with the high-dose FSH protocol, any conclusions should be viewed with caution, due to the study's retrospective nature and low live-birth rate (<10%) in both groups (22).

A small retrospective cohort study compared women with poor response; group 1 consisted of 27 women treated with up to 8 ampules per day of FSH who proceeded to retrieval with %3 dominant follicles, and group 2 included 30 women (35 cycles) with prior cancelled traditional IVF cycles with subsequent natural-cycle IVF (26). Pregnancy rates per retrieval were not significantly different between groups 1 and 2, respectively (2/27 [7.4%] vs 5/30 [16.6%]), though the study design and the small sample size limit conclusions for this study (26). Other small cohort studies using the patients’ previous failed cycles with traditional stimulation showed feasibility, but are not able to demonstrate effectiveness (23–25).

Summary Statement:
  • In women considered to be poor responders, there is fair evidence that clinical pregnancy rates after IVF are not substantially different when comparing natural-cycle protocols to conventional-gonadotropin protocols. From two small RCTs and several Level-II, low- to good-quality (Grade B and C) studies. Grade B.


WHAT IS THE COST-EFFECTIVENESS OF IVF WITH MILD OVARIAN STIMULATION COMPARED WITH CONVENTIONAL IVF IN POOR RESPONDERS?

In poor-responder patients, a non-blinded RCT published in 2012 evaluated costs as well as delivery rates per started cycle (16). Women with a day-3 serum FSH >12 IU/mL on at least two occasions or prior poor response to hyperstimulation were included, with a mean age of 38 years in both groups. The two-armed study compared 148 women who were treated with CC 150 mg/day from day 3 to day 7 of the cycle with 156 women who were treated with 450 IU of rFSH with GnRH agonist in a short-protocol format, both with day-2 or -3 embryo transfers. The study included a single treatment cycle for each group. The study was continued for 2 years but terminated early due to poor recruitment, which limits the power to determine a difference between the groups. The live-birth rate per started cycle in the CC group was 3% (95% CI 1%–7%) and in the high-dose gonadotropin group was 5% (95% CI 2%–9%; P=.77). Included costs were calculated based only on medications and medical procedures for infertility, not pregnancy-related costs. The mean costs per patient cycle were €2,803 and €5,423 for the CC and high-dose gonadotropin groups, respectively. The mean costs per delivery were €81,294 and €113,107 in the CC and high-dose gonadotropin groups, respectively (16). The authors did not perform a complete sensitivity analysis to determine the outcomes based on a variety of costs. This study concluded that in poor responders, mild stimulation IVF is cost-effective, though live-birth rates were extremely low in both groups.

Summary Statement:
  • In women considered to be poor responders, there is fair evidence to support the recommendation that mild ovarian stimulation is cost-effective, though live-birth rates are extremely low in both groups. From one Level-I, good-quality (Grade B) study. Grade B.


CONCLUSIONS

Mild ovarian-stimulation protocols with IVF generally aim to use less medication compared with conventional IVF. In patients expected to be poor responders with IVF (based on poor response to a prior IVF cycle, age ≥40 years, and/or Bologna criteria), pregnancy rates tend to be low regardless of protocol. There is fair to good evidence that clinical pregnancy rates are not substantially different using mild stimulation protocols compared with conventional IVF in poor-responder populations. Based on one study, mild stimulation with CC was cost-effective compared to conventional IVF with high-dose gonadotropins.

UNANSWERED QUESTIONS

  • Current studies do not compare different mild ovarian stimulation protocols directly to determine if one is superior for the poor-responder population with respect to cost and pregnancy outcomes.
  • It is unknown if the aggregation of embryos from multiple mild-stimulation cycles as compared with a single traditional-dose IVF cycle is more effective or costly.
  • Future studies should evaluate if there are other potential benefits of mild-stimulation protocols, such as improved neonatal outcomes or lower complication rates.
  • Future studies need to compare cumulative pregnancy rates between traditional- and mild-stimulation protocols.
  • Future studies should include the outcome of live birth.


SUMMARY

  • In women considered to be poor responders, there is fair evidence that clinical pregnancy rates after IVF are not substantially different when comparing mild ovarian stimulation protocols using low-dose gonadotropins (≤150 IU/day) to conventional-gonadotropin protocols, but there are no data about live-birth rates. From two Level-I, good- to high-quality (Grade A, B) studies. Grade B.
  • In women considered to be poor responders, there is fair evidence that clinical pregnancy rates after IVF are not substantially different when comparing mild ovarian stimulation protocols using a combination of oral agents and low-dose gonadotropins (≤150 IU/d) to conventional-gonadotropin protocols. Data about oocyte yield are mixed. From two Level-I, good- to high-quality (Grade A, B) and several low-quality studies (Grade C). (Grade B).
  • In women considered to be poor responders, there is insufficient evidence to recommend for or against IVF with mild ovarian stimulation using oral agents alone over conventional gonadotropin stimulation. From one Level- I and two Level-II, low- to good-quality (Grade B and C) studies. Grade C.
  • In women considered to be poor responders, there is fair evidence that clinical pregnancy rates after IVF are not substantially different when comparing natural-cycle protocols to conventional-gonadotropin protocols. From two small RCTs and several Level-II, low- to good-quality (Grade B and C) studies. Grade B.
  • In women considered to be poor responders, there is fair evidence to support the recommendation that mild ovarian stimulation is cost-effective, though live-birth rates are extremely low in both groups. From one Level-I, good quality (Grade B) study. Grade B.


RECOMMENDATIONS

  • In patients who are classified as poor responders and pursuing IVF, strong consideration should be given to a mild ovarian-stimulation protocol (low-dose gonadotropins with or without oral agents) due to lower costs and comparable low pregnancy rates compared with traditional IVF stimulation protocols.


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 Jennifer Mersereau, M.D., Silvina Bocca, M.D., Ph.D., Jennifer Eaton,M.D., Jason Franasiak,M.D., Samantha Pfeifer,M.D., Aimee Seungdamrong,M.D., and EricWidra,M.D., in the preparation of this document.

No external funding was received for the development 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.

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  8. Revelli A, Chiado A, Dalmasso P, Stabile V, Evangelista F, Basso G, et al. Mild vs. "long" protocol for controlled ovarian hyperstimulation in patients with expected poor ovarian responsiveness undergoing in vitro fertilization (IVF): a large prospective randomized trial. J Assist Reprod Genet 2014;31:809–15 (Level I).
  9. Bastu E, Buyru F, OzsurmeliM, Demiral I, DoganM, Yeh J. A randomized, singleblind, prospective trial comparing three different gonadotropin doses with or without addition of letrozole during ovulation stimulation in patients with poor ovarian response. Eur J Obstet Gynecol Reprod Biol 2016;203:30–4 (Level I).
  10. Goswami SK, Das T, Chattopadhyay R, Sawhney V, Kumar J, Chaudhury K, et al. A randomized single-blind controlled trial of letrozole as a low-cost IVF protocol in women with poor ovarian response: a preliminary report. Hum Reprod 2004;19:2031–5 (Level I).
  11. Mohsen IA, El Din RE. Minimal stimulation protocol using letrozole versus microdose flare up GnRH agonist protocol in women with poor ovarian response undergoing ICSI. Gynecol Endocrinol 2013;29:105–8 (Level I).
  12. Pilehvari S, ShahrokhTehraninejad E, Hosseinrashidi B, Keikhah F, Haghollahi F, Aziminekoo E. Comparison pregnancy outcomes between minimal stimulation protocol and conventional GnRH antagonist protocols in poor ovarian responders. J Fam Reprod Health 2016;10:35–42 (Level I).
  13. Siristatidis C, Salamalekis G, Dafopoulos K, Basios G, Vogiatzi P, Papantoniou N. Mild versus conventional ovarian stimulation for poor responders undergoing IVF/ICSI. Vivo 2017;31:231–7 (Level II).
  14. Dor J, Ben-Shlomo I, Levran D, Rudak E, Yunish M, Mashiach S. The relative success of gonadotropin-releasing hormone analogue, clomiphene citrate, and gonadotropin in 1,099 cycles of in vitro fertilization. Fertil Steril 1992;58:986–90 (Level II).
  15. Dor J, Seidman DS, Ben-Shlomo I, Levran D, Karasik A, Mashiach S. The prognostic importance of the number of oocytes retrieved and estradiol levels in poor and normal responders in in vitro fertilization (IVF) treatment. J Assist Reprod Genet 1992;9:228–32 (Level II).
  16. Ragni G, Levi-Setti PE, Fadini R, Brigante C, Scarduelli C, Alagna F, et al. Clomiphene citrate versus high doses of gonadotropins for in vitro fertilisation in women with compromised ovarian reserve: a randomised controlled non-inferiority trial. Reprod Biol Endocrinol 2012;10:114 (Level I).
  17. Awonuga AO, Nabi A. In vitro fertilization with low-dose clomiphene citrate stimulation in women who respond poorly to superovulation. J Assist Reprod Genet 1997;14:503–7 (Level II).
  18. Kuroda K, Kitade M, Kumakiri J, Jinushi M, Shinjo A, Ozaki R, et al. Minimum ovarian stimulation involving combined clomiphene citrate and estradiol treatment for in vitro fertilization of Bologna-criteria poor ovarian responders. J Obstet Gynaecol Res 2016;42:178–83 (Level II).
  19. Morgia F, Sbracia M, Schimberni M, Giallonardo A, Piscitelli C, Giannini P, et al. A controlled trial of natural cycle versus microdose gonadotropinreleasing hormone analog flare cycles in poor responders undergoing in vitro fertilization. Fertil Steril 2004;81:1542–7 (Level I).
  20. Ata B, Yakin K, Balaban B, Urman B. Embryo implantation rates in natural and stimulated assisted reproduction treatment cycles in poor responders. Reprod Biomed Online 2008;17:207–12 (Level II).
  21. Elizur SE, Aslan D, Shulman A, Weisz B, Bider D, Dor J. Modified natural cycle using GnRH antagonist can be an optional treatment in poor responders undergoing IVF. J Assist Reprod Genet 2005;22:75–9 (Level II).
  22. Lainas TG, Sfontouris IA, Venetis CA, Lainas GT, Zorzovilis IZ, Tarlatzis BC, et al. Live birth rates after modified natural cycle compared with highdose FSH stimulation using GnRH antagonists in poor responders. Hum Reprod 2015;30:2321–30 (Level II).
  23. Bassil S, Godin PA, Donnez J. Outcome of in-vitro fertilization through natural cycles in poor responders. Hum Reprod 1999;14:1262–5 (Level II).
  24. Feldman B, Seidman DS, Levron J, Bider D, Shulman A, Shine S, et al. In vitro fertilization following natural cycles in poor responders. Gynecol Endocrinol 2001;15:328–34 (Level II).
  25. Kedem A, Tsur A, Haas J, Yerushalmi GM, Hourvitz A,Machtinger R, et al. Is the modified natural in vitro fertilization cycle justified in patients with "genuine" poor response to controlled ovarian hyperstimulation? Fertil Steril 2014;101:1624–8 (Level II).
  26. Lindheim SR, Vidali A, Ditkoff E, Sauer MV, Zinger M. Poor responders to ovarian hyperstimulation may benefit from an attempt at natural-cycle oocyte retrieval. J Assist Reprod Genet 1997;14:174–6 (Level II).

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

MAC 2021 teaser
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
Coding Corner general teaser
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
Covid-19 teaser
Practice Guidance

COVID-19 Resources

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

View the resources
Couple looking at laptop for online patient education materials

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

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
PR Bulletin Icon

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
PR Bulletin Icon

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
PR Bulletin Icon

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
Announcement Icon

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
Announcement Icon

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
Announcement Icon

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
Announcement Icon

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
Announcement Icon

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
Podcast Icon

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
Document Icon

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
Podcast Icon

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
Announcement Icon

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
Coding Icon

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
Videos Icon

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
Document Icon

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
Coding Icon

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
Coding Icon

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
Videos Icon

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
Coding Icon

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
Coding Icon

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
Coding Icon

IVF Billing Forms

I am seeking information on IVF insurance billing guidelines.  View the Answer
Coding Icon

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
Coding Icon

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
Coding Icon

IVF Case Rates

What ICD-10 codes apply to case rates? View the Answer
Coding Icon

Oocyte Denudation

Is there is a separate code for denudation of oocytes?  View the Answer
Coding Icon

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
Coding Icon

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
Coding Icon

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
Coding Icon

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
Coding Icon

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
Coding Icon

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
Videos Icon

Journal Club Global: Natural versus Programmed FET Cycles

A significant portion of IVF cycles now utilize frozen embryo transfer.
View the Video
Document Icon

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
Videos Icon

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
Videos Icon

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
Document Icon

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

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. View the Committee Opinion
Document Icon

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
Advocacy Icon

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
Advocacy Icon

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

Topic Resources

View more on the topic of ovarian stimulation
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ASRM Today: OHSS with Dr. Tarun Jain

In this episode of ASRM Today, Tarun Jain, MD joins the discussion to delve into the recently published OHSS guideline by the ASRM Practice Committee.

Listen to the Episode
Document Icon

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
Coding Icon

Coding of transabdominal vs. transvaginal ultrasound

I recently was informed that CPT 76857 can be used for a transvaginal ultrasound when done for a follicle check by a fertility practice. View the Answer
Coding Icon

Ultrasound for Ovarian Cyst

When a patient has a cyst from a previous Clomid or gonadotropin cycle, is it appropriate to bill the insurance company for the ultrasound with a N83.x? View the Answer
Coding Icon

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
Coding Icon

IVF Lab vs Physician Practice Billing

We are planning to open an IVF lab that is not contracted with insurance companies. View the Answer
Coding Icon

Oocyte Aspiration

Should one bill oocyte aspiration as a bilateral procedure? View the Answer
Videos Icon

Journal Club Global: Management of poor ovarian response

A poor ovarian response to what should otherwise be a successful stimulation cycle presents a clinical conundrum for clinicians. View the Video
Document Icon

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

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. View the Committee Opinion
Document Icon

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
Document Icon

Executive summary of the Stages of Reproductive Aging WorkshopD10: addressing the unfinished agenda of staging reproductive aging (2012)

The aim of this article is to summarize the recommended updates to the 2001 Stages of Reproductive Aging Workshop (STRAW) criteria. View the Committee Guideline
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Abdominal Paracentesis

We do a lot of abdominal paracenteses on patients at our facility.  View the answer