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

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 ≥40, 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 at the bottom).

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

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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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).

Author

Title

Journal

Study Type

Level

Question

N=

Groups;age

Controls;age

Outcomes

Type of Responder

AMH

AFC

FSH

Stimulation

Cancellation

Oocytes Collected

Embryos Transferred

Stage (Cleavage , Blastocyst)

Fresh or Frozen Cycle

Implantation rate

Clinical Pregnancy Rate

Live-birth Rate

Cost of Treatment

Aneuploidy

Method of Determine Aneuploidy

Conclusions

Strengths and Limitations

Quality of Study

Total number of articles: 766; included articles: 21

Include:

Ata B, Yakin K, Balaban B and Urman B

Embryo implantation rates in natural and stimulated assisted reproduction treatment cycles in poor responders

Reprod Biomed Online 2008; 17: 207-12

cohort

2

natural or modified

304= women/ poor responders in previous cycle

30= natural cycle (38.2±4.9)

Gonadotropin only= 54 (37.5±4, NS); Long GnRH Agonist= 52 (34.6±4.9, 0.002); Co-flare= 52 (37±3.8, NS); Microdose Flare= 26 (38±2.7, NS); Antagonist= 90 (37.5±4.7, NS)

implantation, CPR, oocytes retrieved

poor responders

NA

NA

Day-3 FSH: Natural= 15.2±8.9; Gonadotropin only= 12.2±8.3, NS; Long GnRH Agonist= 6±2.8, 0.0001; Co-flare= 10.1±6.2, NS; Microdose Flare= 13.3±9.9, NS; Antagonist= 12.5±5.7, NS

Natural= hCG trigger when 17 mm dom follicle; Gonadotropin only= 300-600 IU d2 or 3 of cycle; Long GnRH Agonist= 0.1 mg leuprolide acetate, 0.1 mg triptorelin, 800 μg nafarelin, or 900 μg buserelin acetate on d21, 225-600 IU exog gn; Co-flare= 600 μg buserelin acetate or 600 μg nafarelin and 300-600 IU exog gn, GnRH analog halved on d6; Microdose Flare= OCP pre-tx, s.c. 50 μg LA 2x/d, 300-600 IU exog gn; Antagonist= OCP pre-tx or late luteal estradiol valerate tabs, gn on d2, 0.25 mg GnRH ant on d6

NA

Natural= 1.2±0.4; Gonadotropin only= 2.1±1.8, 0.009; Long GnRH Agonist= 4.0±2.4, 0.0001; Co-flare= 2.6±1.6, 0.0001; Microdose Flare= 2.0±1.0, 0.0002; Antagonist= 2.5±1.3, 0.0001

NA

cleavage

SET only

NA

Natural= 6/30 (20.0, 6-34); Gonadotropin only= 3/54 (5.6, 0-12); Long GnRH Agonist= 2/52 (3.8, 0-9); Co-flare= 1/52 (1.9, 0-6); Microdose Flare= 4/26 (15.4, 2-30); Antagonist= 13/90 (14.4, 7-22), P=0.083

NA

NA

NA

NA

Natural cycle IVF may be a treatment choice with acceptable outcomes in poor responders.

Limitations: retrospective; women not equally distributed among groups; non-randomized; physicians chose protocol; possible selection bias

B: Good Quality

Awonuga AO and 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

cohort

2

oral agents

31= non- and poor responders with CC stim208= poor responders with CC or buserelin/hMG

20= poor responders (53 CC IVF cycles); 37.3 yrs

11= non-responders (30 CC IVF cycles), 38.2 yrs; also shows results of 1st CC cycle vs previous buserelin/hMG cycles in 188 poor responders

oocytes collected, fertilization, embryos transferred, implantation, CPR

poor responders (cycles cancelled after buserelin/hMG stim; 1 or no follicles >10 mm on day 9 or ≤3 oocytes)

NA

NA

day 3 FSH: Nonresponders= 13.4 IU/L; Poor responders= 9.1

50 mg CC daily for 5 days, starting on day 1 of cycle

Buserelin/hMG= 38.8% (101/260) vs 1st CC= 37.6% (18/49) CC in non- and poor responders= 36.7%

Nonresponders= 1 (0-3); rate 61.5% (32/52); Poor responders= 1 (0-4); rate 55.9% (57/102)

Nonresponders= 1 (1-3); Poor responders= 1 (1-3)

cleavage

CC stim, Per oocyte collected: Nonresponders= 3.4% (1/29), Poor responders= 13.9% (5/36) Per ET, CC vs previous Buserelin/hMG: CC= 17.6% (3/17), Bus/hMG= 11.6% (23/197)

CC stim, Per oocyte collected: Nonresponders= 3.3% (1/30), Poor responders= 7.5% (4/53)

Per ET, CC vs previous Buserelin/hMG: CC= 10% (2/20), Bus/hMG= 12.6% (20/159)

NA

NA

NA

CPR was slightly higher (NS) with long protocol GnRHa/hMG than CC in non- and poor responders. CPR with CC stim did not differ significantly btwn non- and poor responders, although there was a trend toward better CPR in poor responders.

Limitations: retrospective, nonrandomized; small sample size; lacked statistical power

C: Low Quality or Major Flaws

Bassil S, Godin PA and Donnez J

Outcome of in-vitro fertilization through natural cycles in poor responders

Hum Reprod 1999; 14: 1262-5

cohort

2

natural or modified

11= patients in whom tx was cancelled or failed to conceive because of poor response (failed to achieve estradiol >200 pg/ml or developed ≤1 follicle; mean age 26.6±6 yrs

16= natural cycles

25= previous stimulated cycles

CPR, cancellation, fertilization

poor responders

NA

# follicles >15 mm in diameter= Natural cycles, 14

mean day 3 FSH: Unstimulated= 12.9±6.4 mIU/ml

10,000 IU hCG

Stimulated= 48% (12) vs Unstimulated= 18.8% (3)

Per retrieval: Stimulated= 1.5 vs Unstimulated= 0.9

# cycles w/embryos transferred: Stimulated= 20% (5) vs Unstimulated= 37.5% (6)

48-72 h after retrieval

NA

Stimulated= -% (0) vs Unstimulated= 18.8% (3)

1 live birth in natural cycles

NA

Triploidy= 2, ICSI cycles

NA

Natural cycle IVF may be a treatment choice with acceptable outcomes in poor responders.

Limitations: small sample size, non-randomized

C: Low Quality or Major Flaws

Bastu E, Buyru F, Ozsurmeli M, Demiral I, Dogan M and Yeh J

A randomized, single-blind, 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

RCT

1

oral agents

95= patients with poor ovarian reserve (18-42 yrs)

31= treated with 450 IU gonadotropins (36.94±3.33)

31= treated with 300 IU gonadotropins (35±3.10)33= treated with 150 IU gonadotropins in combo with letrozole (37.52±4.06)

# oocytes retrieved, total dose of gn, stim duration, # cycles cancelled, # eggs retrieved, fertilization, # cycles ET, CPR, OPR

poor responders with 2 of 3 Bologna criteria

450 IU= 0.55±0.35; 300 IU= 0.71±0.28; 150 IU= 0.64±0.41, NS

450 IU= 4; 300 IU= 3; 150 IU= 4, NS

day 3 FSH: 450 IU= 11.01±2.34; 300 IU= 10.63±3.95; 150 IU= 13.12±3.79, NS

group 1: 450 IU gonadotropins, 8.77±1.65 days; group 2: 300 IU gonadotropins, 9.65±2.74 days; group 3: 150 IU gonadotropins and letrozole 5 mg/d, 9.88±1.82 days

450 IU= 29% (9/31); 300 IU= 26% (8/31); 150 IU= 24% (8/33), NS

450 IU= 3.35±1.58; 300 IU= 3.65±1.50; 150 IU= 3.45±1.92, NS

450 IU= 1.10±0.75; 300 IU= 0.87±0.52; 150 IU= 1.06±0.83, NS

cleavage

fresh

450 IU= 13.3%; 300 IU= 14.2%; 150 IU= 14.7%, NS

Per started cycle: 450 IU= 13% (4/31); 300 IU= 16% (5/31); 150 IU= 15% (5/33), >NSPer ET: 450 IU= 18% (4/22); 300 IU= 22% (5/23); 150 IU= 20% (5/25), NS

NA

NA

NA

NA

Mild stim with letrozole was as effective as stim with higher doses of gonadotropins in poor responders.

Strengths: randomized, single-blind, prospective, Bologna criteria to define PORLimitations: underpowered to detect differences in PR

B: Good Quality

Dor J, Ben-Shlomo I, Levran D, Rudak E, Yunish M and 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

cohort

2

oral agents

1,099= IVF patients

341= CC/ hMG (mean age 33.7); 365= hMG alone (mean age 33.6); 393= GnRH-a/ hMG (mean age 34.9)

cancellation, total pregnancies, ongoing pregnancies

cancellation was due to early luteinization or poor response

NA

NA

NA

CC/hMG: CC 100 mg/d cycle days 5-9 and hMG, 150 IU/d of FSH and LH from day 8 of cycle; hMG alone: hMG 225 IU/d from day 3 of cycle; GnRH-a + hMG: GnRH-a D-Trp-LH-releasing hormone 3.2 mg microcapsules, hMG 150 IU/d from cycle day 15

*hMG alone over the age of 36 had the highest cancellation rate= P<0.05 *GnRH-a/hMG in age ≥40 had highest poor response= P<0.05 CC/hMG: 9.4% early luteinization, 4.7% poor response hMG: 13.7% early luteinization, 6% poor response GnRH-a/hMG: 3.6% early luteinization, 4.3% poor response Total: 8.7% early luteinization, 5% poor response

CC/hMG: 5.2±3.1 hMG: 6.8±5.6 GnRH-a/hMG: 9.1±6.5 P<0.001 (GnRH-a/hMG vs CC/hMG or hMG)

CC/hMG in age ≥40 had a mean of 1.52±0.22 embryos vs 2.95±0.17 in pts ≤35 yrs

unclear

fresh?

Implantation: CC/hMG: 18.2% (110/604) hMG: 7.9% (59/743) GnRH-a/hMG: 6.7% (66/989) P<0.001 (CC/hMG vs GnRH-a/hMG or hMG)

CPR: CC/hMG: 31.4% (92) hMG: 15.7% (46) GnRH-a/hMG: 16.9% (61) P<0.0001 (CC/hMG vs GnRH-a/hMG or hMG)

Deliveries:CC/hMG: 20.5% (60)hMG: 11.6% (34) GnRH-a/hMG: 9.7% (35)P<0.0002 (CC/hMG vs GnRH-a/hMG or hMG)

NA

NA

NA

CC/hMG was effective in all age groups. Authors recommend HMG along for ≤35 yrs, because of increased premature luteinization in those >35 yrs. "Unacceptably high" rate of poor response in women ≥40 yrs with GnRH-a in long protocol. Authors: drug regimen should be based on woman's age and previous response.

Limitations: retrospective. Very old study, likely no longer relevant. Did not adjust for confounders.

C: Low Quality or Major Flaws

Dor J, Seidman DS, Ben-Shlomo I, Levran D, Karasik A and 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

cohort

2

oral agents

880= IVF patients (mean age= 35.7)

Poor responders: E2<501 pg/ml; Normal responders: E2<501-1000 pg/ml; High responders: E2>1000 pg/ml Also stratified by # oocytes retrieved: 1-3 and >3

PR, oocytes retrieved

poor, normal, high

NA

NA

NA

CC/hMG: CC 100 mg/d cycle days 5-9 and hMG, 150 IU/d of FSH and LH from day 8 of cycle; hMG alone: hMG 225 IU/d from day 3 of cycle; GnRH-a + hMG: GnRH-a D-Trp-LH-releasing hormone 3.2 mg microcapsules, hMG 150 IU/d from cycle day 15

NA

≤3 oocytes retrieved:CC/hMG= 30.9% (95) vs hMG= 23.3% (83) vs GnRHa/hMG= 19.9% (43) ≥4 oocytes retrieved:CC/hMG= 212 vs hMG= 274 vs GnRHa/hMG= 173

NA

unclear

fresh?

NA

PR: CC/hMG: 27% (83), P<0.05 hMG: 15.1% (54), P<0.005 GnRH-a/hMG: 20.8% (45), NS CC/hMG and 1-3 oocytes had highest PR vs hMG (P=0.08). >3 oocytes: PR SS higher with CC/hMG vs hMG (P<0.001) but NS different from GnRHa/hMG.

NA

NA

NA

NA

Number of oocytes retrieved was a better predictor of IVF outcome than E2 levels. Patients with <3 oocytes may have a poor prognosis. Highest PR in women with few oocytes was when E2 was low. GnRHa was not superior to CC + hMG for tx of poor responders.

Limitations: retrospective; data presented is unclear in places. Very old study, likely no longer relevant. Did not adjust for confounders.

C: Low Quality or Major Flaws

Elizur SE, Aslan D, Shulman A, Weisz B, Bider D and 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

cohort

2

natural or modified

433= poor responders in IVF-ET tx (540 cycles)

52= modified natural cycles with GnRHant (age 39±5.8)

200= GnRH ant (age 38.4±4.7) 288= long GnRH agonist (age 38.1±6)

oocytes retrieved, implantation, PR

poor responders: ≤4 oocytes or E2 <1000 pg/mL

NA

NA

Day-3 FSH:Modified Natural: 10.5±5.8Antagonist: 8.7±4.3Long Agonist: 7.8±3.0

Modified Natural: 0.25 mg/d GnRH ant (13 mm follicle), 2-3 amp hMGAntagonist: hMG or recFSH (min 225 IU/d) on day 2, 0.25 mg/d GnRH ant (13 mm follicle)Long Agonist: 3.75 mg microcapsules GnRHa or multiple dose daily 0.1 mg Decapeptyl on day 21, hMG or recFSH (min 225 IU/d)

Cancelled cycles:Modified Natural: 32.6% (17/52), P<0.05 (modified natural vs ant and long agonist protool)Antagonist: 17% (34/200)Long Agonist: 18.4% (53/288)

Oocytes retrieved:Modified Natural: 1.4±0.5, P<0.05 (modified natural vs ant and long agonist protool)Antagonist: 2.3±1.1Long Agonist: 2.5±1.1

Embryos transferred:Modified Natural: 1.1±0.3, P<0.05 (modified natural vs ant and long agonist protool)Antagonist: 1.8±0.9Long Agonist: 1.9±0.9

NA

NA

Implantation:Modified Natural: 10%Antagonist: 6.75% Long Agonist: 7.4% (NS)

CPR/cycle:Modified Natural: 9.6%Antagonist: 8.5% Long Agonist: 8.6% (NS)CPR/transfer:Modified Natural: 14.3%Antagonist: 10.2% Long Agonist: 10.6% (NS)

NA

NA

NA

NA

Modified natural IVF with GnRH antagonist supplementation is an alternative for poor responders. PR per cycle was similar for all three protocols.

Limitations: retrospective

C: Low Quality or Major Flaws

Feldman B, Seidman DS, Levron J, Bider D, Shulman A, Shine S and Dor J

In vitro fertilization following natural cycles in poor responders

Gynecol Endocrinol 2001; 15: 328-34

cohort

2

natural or modified

22= infertile patients w/poor ovarian response in ≥2 previous tx cycles (age: 39.7±4.7)

22= unstimulated/natural cycles (44 cycles)

22= same patients, previous stimulated cycles with poor response (55 cycles)

oocytes retrieved, PR

poor responders: ≤3 oocytes retrieved after 1 tx cycle with high doses of hMG

NA

NA

Mean serum early FSH:Natural= 13.3±11.3Previous cycles= 15.8±5.9, P=0.2No oocytes retrieved in cycles with >16 U/FSH; fertilization and implantation signif lower when 10-16 U/l FSH vs <10 U/l.

ICSI; unstimulated cycles; no details regarding stimulated cycles

Natural cycles= 31.8%Failure of follicular development= 18%; Premature luteinization= 14%; Unrelated technical problems= 2 retrievals

Oocytes retrieved:Natural= 16/28 retrievalsPrevious stimulated= 88/46 retrievals

Embryos transferred:Natural= 22.7% (10/44)Previous stimulated= 27.2% (15/55)

44-72 hrs after retrieval

fresh

NA

PR/transfer:Natural= 20% (2/10)Previous stimulated= 0% (0/15)PR/retrieval:Natural= 7.1% (2/28)Previous stimulated= 0% (0/46)

9%

NA

NA

NA

Poor responders may benefit from natural cycle IVF, but authors recommend not offering to poor responders with high early follicular phase FSH.

Strengths: prospectiveLimitations: self/historical controls; small sample size

C: Low Quality or Major Flaws

Goswami SK, Das T, Chattopadhyay R, Sawhney V, Kumar J, Chaudhury K, Chakravarty BN and Kabir SN

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

RCT

1

oral agents

38= women with history of poor ovarian response to gonadotropins (age 36-41)

13= women received letrozole and rFSH (age: 38.5 ± 17)

25= women received long GnRH agonist protocol and rFSH (age: 39.1 ± 1.1)

total dose rFSH, E2, # follicles, oocytes retrieved, embyros transferred, endometrial thickness, PR

failed 1-3 IVF attempts due to poor ovarian response to conventional long GnRH agonist stimulation protocol

NA

NA

Basal FSH: Let-FSH= 7.5 ± 2.1GnRH-ag-FSH= 8.6 ± 2.2

Let-FSH: 2.5 mg letrozole daily orally from day 3-7 of menstrual cycle and 75 IU/d s.c. rFSH on days 3 and 8 of cycleGnRH-ag-FSH: daily s.c. 500 μg GnRH agonist, leuprolide acetate from mid-luteal for 14 days, 300 IU/d rFSH s.c. to down-regulated pts

NA

# oocytes retrieved: Let-FSH= 1.6 ± 0.8GnRH-ag-FSH= 2.1 ± 0.7, NS

transferable embryo: Let-FSH= 1.2 ± 0.4GnRH-ag-FSH= 1.3 ± 0.5, NS

40-42 hr at 4-6 cell cleavage stage

fresh

NA

Pregnancy/tx cycle: Let-FSH= 3/13 (23%)GnRH-ag-FSH= 6/25 (24%), NS

NA

NA

NA

NA

Adjunctive use of letrozole may be part of effective low-cost IVF in poor responders.

Strengths: randomized, controlled, single blindLimitations: small number of patients-- just a pilot study. Underpowered. Randomization method not clear. Didn't look at cost as outcome. Lots of typos.

C: Low Quality or Major Flaws

Kedem A, Tsur A, Haas J, Yerushalmi GM, Hourvitz A, Machtinger R and Orvieto R

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

cohort

2

natural or modified

111= women with poor ovarian response (Bologna criteria)

women with POR who had MNC-IVF within 3 months of previous failed conventional IVF/ICSI (age 39 ± 4 yrs)

LBR, PR, oocytes retrieved, embryos transferred

poor responders and a subgroup of "genuine" poor responders who fulfilled 2/3 Bologna criteria and also yielded up to 3 oocytes after COH with min gn daily dose of 300 IU

NA

NA

Comparison of "genuine" poor responders vs poor responders who had only 1 oocyte during conventional IVF:Day 3 FSH:9.3±5.4 vs 10.9±4

modified natural cycle IVF with 0.25 mg/d GnRH-a supplementation, started when follicle 13 mm; 2-3 ampules hMG coadministered daily during GnRH-a tx

NA

MNC "genuine" poor responders vs Previous conventional IVF:0.88±0.96 vs 1.65±0.88, P<.0001MNC vs poor responders who had only 1 oocyte during conventional IVF:0.9±0.8 vs 0.9±0.3, NS

MNC "genuine" poor responders vs Previous conventional IVF:0.5±0.6 vs 0.8±0.8, P<.002MNC vs poor responders who had only 1 oocyte during conventional IVF:0.54±0.6 vs 0.6±0.6, NS

cleavage? Not specified

fresh? (no mention of freezing)

NA

CPR/cycle:MNC "genuine" poor responders vs Previous conventional IVF:0.9% (1) vs 0; OPR: 0.9% (1) vs 0MNC vs poor responders who had only 1 oocyte during conventional IVF:0 vs 0

Delivery rate/cycle:MNC "genuine" poor responders vs Previous conventional IVF:0.9% (1) vs 0

NA

NA

NA

Modified natural IVF was of no benefit for genuine poor ovarian responders.

Limitations: historic/retrospective

C: Low Quality or Major Flaws

Klinkert ER, Broekmans FJ, Looman CW, Habbema JD and te Velde ER

Expected poor responders on the basis of an antral follicle count do not benefit from a higher starting dose of gonadotrophins in IVF treatment: a randomized controlled trial

Hum Reprod 2005; 20: 611-5

RCT

1

FSH only

52= IVF patients with AFC <5 follicles 2-5 mm

26= rec'd 150 IU rFSH(40.4 yrs [36.6-44.5])

26= rec'd 300 IU rFSH(42.2 yrs [33.7-44.6])

# oocytes, poor response, ongoing pregnancy (12 wks gestation)

poor response (<4 oocytes at retrieval or cancellation due to insufficient follicle growth): 65% 150 IU group, 62% 300 IU group

NA

# follicles ≥10 mm: 150 IU rFSH= 4 (1-8)300 IU rFSH= 3 (0-8), P=.18

Basal FSH:150 IU rFSH= 9.3 (5.5-22.6)300 IU rFSH= 12 (5.8-20.8)(42.2 yrs [33.7-44.6])

long suppression protocol; leuprolide acetate; 150 IU rFSH= doubled dose after 7 days if E2 <200 pmol/l or 10 days if <500 pmol/l; fixed dose in 300 IU group

Cancellations (low response): 150 IU rFSH= 5 (19%) 300 IU rFSH= 6 (23%), P=.73

median= 3 for both groups (P=.79); difference in mean #= 0.3 (150 IU group; P=.69

# embryos transferred: 150 IU rFSH= 1 (1-3)300 IU rFSH= 2 (1-2), P=.45

NA

NA

NA

CPR: 3 (12%) 150 IU group, 1 (4%) 300 IU group, P=.30Ongoing: 2 (8%) 150 IU group, 1 (4%) 300 IU group, P=.55

NA

NA

NA

NA

Expected poor response patients (<5 AFC) likely will not benefit from higher starting dose of gonadotropins in IVF.

Strengths: randomized, controlledLimitations: Underpowered

B: Good Quality

Kuroda K, Kitade M, Kumakiri J, Jinushi M, Shinjo A, Ozaki R, Ikemoto Y, Katoh N and Takeda S

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

case-control

2

oral agents

41= hypergonadotropic poor responders (69 cycles) with diminished ovarian reserve

10 (20 cycles)= E2, 41 yrs (37-45) 11 (21 cycles)= CC, 41 yrs (36-44) 20 (28 cycles)= CC+E2, 41 yrs (31-46)

10 (20 cycles)= E2, 41 yrs (37-45) 11 (21 cycles)= CC, 41 yrs (36-44) 20 (28 cycles)= CC+E2, 41 yrs (31-46)

# oocytes, # embryos transferred, PR, LBR, AMH, FSH

hypergonadotropic poor responders (Bologna criteria) who had experienced cancellation of oocyte retrieval; severe DOR= all three features of Bologna criteria and elevated FSH (>15 mIU/mL)

AMH: E2 group= 0.2 ± 0.3 P= .258 CC group= 0.4 ± 0.4 CC+E2= 0.2 ± 0.3

NA

Basal FSH: E2= 18.8 ± 2.5 CC= 17 ± 2.9 CC+E2= 19.8 ± 3.4 P=.075

oral E2 1.0 mg/d100 mg/d CCboth CC and E2

Past history for cancellation for oocyte retrieval (times): E2= 0 (0-3) CC= 0 (0-3) CC+E2= 2 (1-5) P=.028

# oocytes (per cycle): E2= 0.5 ± 0.6 CC= 0.8 ± 0.7 CC+E2= 1.2 ± 1.1 P=.033 # MII oocytes (per cycle): E2= 0.3 ± 0.5 CC= 0.7 ± 0.6 CC+E2= 0.8 ± 0.8 P=.036

# transferred embryos/ET: E2= 1.0 CC= 1.0 CC+E2= 1.0 P= 1.00

cleavage

frozen

NA

CPR (cycle): E2= 5 (1%) CC= 4.8 (1%) CC+E2= 10.7 (3%) P=.725 CPR (ET): E2= 25 (1%) CC= 14.3 (1%) CC+E2= 27.3 (3%) P=1.00

LBR (cycle): E2= 5 (1%) CC= 0 (0%) CC+E2= 7.1 (2%) P=.624 LBR (ET): E2= 25 (1%) CC= 0 (0%) CC+E2= 22.2 (2%) P=.400

NA

NA

NA

CC plus E2 was effective in patients with DOR to lower cancellation rate of oocyte retrieval and increase number of retrieved oocytes, but did not improve PR at late reproductive ages.

Limitations: hypergonadotropic DOR may have had low sensitivity for LH trigger by GnRHa due to elevated LH levels at ovulation induction; no comparison data with COH cycle; excluded severe DOR patients with very high FSH (>40 mIU/mL); small sample size; lacked statistical power

C: Low Quality or Major Flaws

Lainas TG, Sfontouris IA, Venetis CA, Lainas GT, Zorzovilis IZ, Tarlatzis BC and Kolibianakis EM

Live birth rates after modified natural cycle compared with high-dose FSH stimulation using GnRH antagonists in poor responders

Hum Reprod 2015; 30: 2321-30

cohort

2

natural or modified

325= IVF patients, poor responders

161= modified natural cycles (106 women); 41.3±0.4 yrs; 40.4-42.1

164= HDFSH-ant cycles (136 women); 40.7±0.3 yrs; 40.0-41.3

LBR; secondary: CPR, OPR, cancellation # oocytes

poor ovarian response(Bologna criteria); AFC ≤5, >12 IU/l basal FSH, ≥1 previous failed IVF cycles w/≤3 oocytes retrieved using a high gn dose

NA

AFC: MNC= 2.6±0.1; 2.4-2.8 HDFSH-ant= 2.8±0.1; 2.7-3.0

Basal FSH: MNC= 23.5±1.1; 21.3-25.7 HDFSH-ant= 21.4±1.2; 19.1-23.7

MNC group= 150 IU rFSH and 0.25 mg GnRH-ant Flexible GnRH-ant= rFSH on d2 or d3, starting 300 IU/d to max 450 IU; daily 0.25 mg cetrorelix

Cycle cancellation per started cycle: MNC= 7.5 (12%); 3.1-11.8 HDFSH= 16.5 (27%); 10.7-22.2, P=0.020

# oocytes retrieved: MNC= 1.1±0.1; 1.0-1.2 HDFSH-ant= 2.4±0.1; 2.1-2.6, P=.001

# embryos transferred: MNC= 0.7±0.1; 0.6-0.9 HDFSH-ant= 1.4±0.1; 1.2-1.5, P=.001

cleavage

fresh? (no mention of freezing)

NA

CPR: MNC= 14 (8.7%; 4.1-13.3) HDFSH= 15 (9.1%; 4.9-13.4) OPR: MNC= 12 (7.5%; 3.1-11.8) HDFSH= 6 (3.7%; 0.8-6.5)

LBR: MNC= 12 (7.5%; 3.1-11.8) HDFSH= 5 (3.1%; 0.4-5.7) Probability of live birth= signif higher in MNC vs HDFSH (OR: 4.01, 1.14-14.09)

NA

NA

NA

LBRs are signif higher in MNC vs HDFSH GnRH-ant cycles in poor responder patients.

Limitations: retrospective; low CPR in all groups (<10%); concern for bias

B: Good Quality

Lindheim SR, Vidali A, Ditkoff E, Sauer MV and 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

cohort

2

natural or modified

57= poor responders

Grp 1= 27 patients with poor response (≤3 follicles) who underwent oocyte aspiration; 36.7±1 yr

Grp 2= 30 patients who previously had poor response (cancellation) to IVF and natural cycle IVF; 37±3.6 yrs

Implantation, PR, oocytes retrieved, embryos transferred

poor responders: ≤3 follicles and/or previous cancelled IVF cycles

NA

NA

Day 3 FSH: Grp 1: 12 ± 1.2 mIU/mlGrp 2: 11.1 ± 1.2 mIU/ml

Grp 1: luteal phase GnRHa wit s.c. leuprolide acetate 1.0 mg/d (0.5 mg/d when E2 <30 pg/ml), 300 IU/d HMG Grp 2: natural cycles

Cancellation: Grp 1= 0.0% (0/27) Grp 2= 14.3% (5/35)

# oocytes: Grp 1: 2.3 ± 0.1 mIU/ml, P<.01 Grp 2: 1.1 ± 0.1 mIU/ml

# ETs: Grp 1: 114 ± 0.2 Grp 2: 1.1 ± 0.1

48-72 hrs after retrieval

fresh

Implantation: Grp 1= 7 ± 4, P<.01 Grp 2= 33 ± 9

PR/retrieval: Grp 1= 7.4% (2/27) Grp 2= 16.6% (5/30) PR/ET: Grp 1= 9.5% (2/21) Grp 2= 17.9% (5/28)

NA

NA

NA

NA

Authors recommend natural cycles in patients <40 yrs and without male factor. Similar PR. Greater number of oocytes retrieved but signif lower fertilization and implantation rates in group 1.

Limitations: small sample size, non-randomized, no controls/controls were patients who previously had poor response

C: Low Quality or Major Flaws

Mohsen IA and 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

RCT

1

oral agents

60= poor ovarian responders undergoing ICSI

30= letrozole/ antagonist (mild stim); 38.32 ± 3.23 yrs

30= GnRH-a protocol (microdose flare); 38.12 ± 3.87 yrs

CPR, cancellation, embryos transferred, oocytes retrieved

poor ovarian responders (≥1 failed IVF cycle, ≤4 oocytes retrieved when Gn start dose 300 IU/d) undergoing ICSI

NA

NA

Basal FSH: Grp 1/mild stim= 10.31 ± 2.91 Grp 2/ microdose= 9.97 ± 2.82, P=.648

Grp 1: letrozole 2.5 mg 2x/d cycle days 2-6, cycle day 7 hMG 150 IU s.c. daily; GnRH-ant, 0.25 mg s.c. cetrorelix (14 mm follicle) Grp 2: 40 mcg s.c. b.i.d. leuprolide acetate from d2, s.c. hMG 300 IU daily from cycle d3

Cancellation: Grp 1/mild stim= (6) 20% Grp 2/ microdose= (5) 16.6% P=.739, OR 1.250, 0.336, 4.644

Retrieved oocytes: Grp 1/mild stim= 5.14 ± 2.45 Grp 2/ microdose= 5.11 ± 1.29, P=.953

Transferred embryos: Grp 1/mild stim= 2.03 ± 0.8 Grp 2/ microdose= 2.09 ± 1.05, P=.804

cleavage

fresh

NA

CPR/cycle: Grp 1/mild stim= (4) 13.3% Grp 2/ microdose= (5) 16.6% P=.718, OR 0.769, 0.185, 3.198

NA

NA

NA

NA

Authors recommend letrozole/antagonist protocol as a cost-effective (no cost data given) and patient-friendly option for poor ovarian responders without compromising rate of success.

Strengths: randomized, controlled. Limitations: Small sample size, no sample size calculation performed. Underpowered to show any difference in pregnancy or live birth.

C: Low Quality or Major Flaws

Morgia F, Sbracia M, Schimberni M, Giallonardo A, Piscitelli C, Giannini P and Aragona C

A controlled trial of natural cycle versus microdose gonadotropin-releasing hormone analog flare cycles in poor responders undergoing in vitro fertilization

Fertil Steril 2004; 81: 1542-7

RCT

1

natural or modified

129= IVF patients (39.3 ± 3.6 yrs, range 30-43)

59= women who rec'd 114 natural IVF cycles

70= women who rec'd 101 COH with microdose GnRH analog flare

# oocytes retrieved, PR per cycle, PR per transfer, implantation

poor responders in a previous IVF cycle (≤3 follicles or cycle cancelled b/c of no follicle activation)

NA

NA

NA

Natural cycles Microdose GnRH analog flare: 0.05 mg buserelin s.c. 2x/d from 1st d of cycle and 600 IU pFSH from cycle d3

NA

Cycles with oocytes: Natural= 77.2% COH= 82.2%

# embryos/ transfer: Natural= 1.0 COH= 1.8 ± 0.4, NS

48-72 hrs after retrieval

fresh

Implantation: Natural= 14.9% COH= 5.5%, P=.05

Pregnancy/cycle: Natural= 6.1% COH= 6.9%, NS Pregnancy/transfer: Natural= 14.9% COH= 10.1%, NS

NA

NA

NA

NA

Natural cycle IVF was at least as effective as COH in poor responders, especially younger patients, with a better implantation rate.

Strengths: pts treated with same protocolLimitations: controls were women of younger age; no sample size calculation

B: Good Quality

Pilehvari S, ShahrokhTehraninejad E, Hosseinrashidi B, Keikhah F, Haghollahi F and Aziminekoo E

Comparison Pregnancy Outcomes Between Minimal Stimulation Protocol and Conventional GnRH Antagonist Protocols in Poor Ovarian Responders

J Family Reprod Health 2016; 10: 35-42

RCT

1

oral agents

77= poor ovarian responders in IVF

42= minimal stimulation group; 40.64 ± 4.86 yrs

35= conventional group; 38.89 ± 3.88 yrs

# retrieved oocytes, chemical PR

Poor responders (Bologna criteria): ≥40 yrs, <3 oocytes in conventional stim protocol, AFC <5-7 follicles or AMH <0.5-1.1 ng/ml

AMH: minimal stimulation group= 0.48 ± 0.61 conventional group= 0.64 ± 0.47, P= .19

NA

Basal FSH: minimal stimulation group= 10.55 ± 5.51 conventional group= 8.53 ± 5.43, P= .11

Min stim= 100 mg/d CC on cycle d2 for 5 days, 150 IU/d hMG on cycle d5 Conventional= 300 IU/d gn on cycle d2 GnRH-ant protocol for both groups according to flexible protocol

cycle cancellation: minimal stimulation group= 12 (28.6%) conventional group= 11 (31.4%), P= .78

# retrieved oocytes: minimal stimulation group= 2.2 ± 1.71 conventional group= 2.79 ± 1.96, P= .17

# transferred embryos: minimal stimulation group= 1.64 ± 0.81 conventional group= 1.74 ± 0.73, P= .54

cleavage

fresh (no mention of freezing)

NA

CPR: minimal stimulation group= 1 (4%) conventional group= 1 (5.6%), P= .05

NA

NA

NA

Minimal stimulation protocol with lower doses of gonadotropin and low risk factors resulted in similar # of oocytes retrieved and PR compared with conventional antagonist protocol.

Strengths: randomized, controlledLimitations: small study, randomization method not clear, lots of typos in manuscript; underpowered

C: Low Quality or Major Flaws

Ragni G, Levi-Setti PE, Fadini R, Brigante C, Scarduelli C, Alagna F, Arfuso V, Mignini-Renzini M, Candiani M, Paffoni A, Somigliana E

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 Dec 18;10:114

RCT Found in Song 2016 meta-analysis

1

oral agents and cost

291= women w/ d3 FSH >12 IU/ml ≥2 times or previous poor response to hyperstimulation

145= 150 mg/d CC from d3 to d7; age: 38.6 ± 2.9 yrs

146= short protocol with GnRH agonist 0.1 mg and rFSH 450 IU daily; age: 38.5 ± 3.1 yrs

delivery rate per started cycle

women with compromised ovarian reserve, poor responders; d3 FSH >12 IU/ml ≥2 times or previous poor response to hyperstimulation

AMH: CC= 0.71 ± 1.0 High-dose rFSH= 0.76 ± 1.0, P=0.67

Total AFC: CC= 3.4 ± 2.5 High-dose rFSH= 3.9 ± 2.6, P=0.10

d3 serum FSH: CC= 14.6 ± 8.9 High-dose rFSH= 13.6 ± 9.0, P=0.68

150 mg/d CC from d3 to d7 short protocol with GnRH agonist 0.1 mg and rFSH 450 IU daily

Cancelled cycles: CC= 21 (14%) High-dose rFSH= 21 (14%), P= 1.00

Oocytes retrieved: CC= 1.1 ± 1.1 rFSH= 2.0 ± 1.8, P<0.001

# embryos transferred: CC= 1.5 ± 0.7 rFSH= 1.7 ± 0.7, P=0.06

cleavage

fresh

Implantation: CC= 11% (9/84) rFSH= 9% (12/136) P=0.64

PR/cycle: CC= 5% (8/145) rFSH= 6% (9/146) PR/retrieval: CC= 6% (8/124) rFSH= 7% (9/125) PR/ET: CC= 14% (8/56) rFSH= 11% (9/79), P=.81

DR/cycle: CC= 3% (5/145) rFSH= 5% (7/146), P=.77 DR/retrieval: CC= 4% (5/124) rFSH= 6% (7/125), P=.78 PR/ET: CC= 9% (5/56) rFSH= 9% (7/79),

Mean cost per delivery: CC= €81,294 high-dose rFSH= €113,107

NA

NA

In women with compromised ovarian reserve selected for IVF, ovarian stim with CC or high-dose gn led to similar chances of pregnancy. CC is less expensive than high-dose gn.

Strengths: randomized, controlled, non-inferiorityLimitations: not blinded; study interrupted after scheduled 2 yrs recruitment before reaching sample size. Therefore, underpowered to draw conclusions.

B: Good Quality

Revelli A, Chiado A, Dalmasso P, Stabile V, Evangelista F, Basso G and Benedetto C

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

RCT

1

oral agents

695= women with expected poor ovarian response and low ovarian reserve

355= received mild protocol; 38.4±3.3 yrs

340= received long protocol; 37.6±3.6 yrs

oocytes retrieved, embryos transferred, implantation, CPR

expected poor ovarian response: d3 FSH 10-20 IU/l and E2 <80 pg/ml; AMH 0.14-1.0 ng/ml; AFC 4-10

AMH: Mild= 0.70 ± .39 Long= .69 ± .37, NS

AFC: Mild= 5.3 ± 2.6 Long= 6.1 ± 2.7, NS

FSH: Mild= 12.4 ± 4.6 Long= 13.5 ± 2.8, NS

Mild: CC 100 mg/d 5 days, 150 IU/d s.c. Gn from 5th day, GnRH-ant 0.25 mg/d s.c. from 8th day Long: 0.8 mg/d GnRHa and high-dose Gn 300-450 IU/d

Mild= 13% Long= 2.7%, P<0.01

retrieved oocytes/ OPU: Mild= 2.7±2.3 Long= 4.8 ± 3.3, P<0.01

transferred embryos: Mild= 1.8±1.7 Long= 2.7 ± 2.3, P<0.01

cleavage

fresh and frozen

Implantation: Mild= 15.2% Long= 12.3%, NS

CPR/started cycle: Mild=13.2% Long= 15.3% CPR/OPU: Mild= 15.2% Long= 15.7% CPR/ET: Mild= 23.2% Long= 19.9%, NS

NA

NA

NA

NA

Mild stim led to lower consumption of exogenous gn. Long protocol resulted in less cycles cancelled, more oocytes, and more embryos. Both protocols had comparable implantation, clinical pregnancy, and ongoing pregnancy rates. The mild protocol is an alternative to the long protocol with comparable success rates and less medications.

Strengths: large, prospective, randomized. Limitations: Not intention to treat; did not analyze patients with cancelled cycles (no retrieval); in min stim grp, many cancelled b/f retrieval or did not have embryos to transfer; no mention of # of embryos frozen, option for FET

A: High Quality

Siristatidis C, Salamalekis G, Dafopoulos K, Basios G, Vogiatzi P, Papantoniou N

Mild Versus Conventional Ovarian Stimulation for Poor Responders Undergoing IVF/ICSI

In Vivo. 2017 Mar-Apr;31(2):231-237

RCT

1

natural or modified

58= poor responders undergoing IVF/ICSI

33= mild stim group; 39.0 (34.0-45.0) yrs

25= conventional stim group; 40.0 (33.0-45.0) yrs

primary: number cumulus oocyte complexes (COCs) retrieved; secondary: LBR, CPR, miscarriage

poor responders (Bologna criteria) undergoing IVF/ICSI

AMH: Mild 1.6 (0.3-7.8) vs Conventional 1.7 (0.2-4.7), P=0.205

AFC: Mild 3.0 (2.0-7.0) vs Conventional 4.0 (1.0-9.7), P=0.062

FSH: Mild 8.9 (3.5-17.8) vs Conventional 8.2 (3.7-19.4), P=0.745

Mild: 100 mg CC and 0.25 mg cetrorelix with 150 IU gonadotropins daily. Conventional: long GnRH agonist (0.1 mg triptorelin s.c. daily at midluteal phase) or antagonist protocols (cycle day 2 cetrorelix or ganirelix when lead follicle ≥14 mm)

Cancellation: Mild 36.4% (19.0-53.7) vs Conventional 12% (1.7-25.7), P=.036

COCs: Mild 1.0 (0.0-4.0) vs Conventional 3.0 (0.0-8.4), P<.001. MII: Mild 1.0 (0.0-4.0) vs Conventional 2.0 (0.0-7.4), P=.001

Transferred embryos: Mild 1.0 (0.0-2.3) vs Conventional 2.0 (0.0-3.0), P=.003

ET performed either 2 or 3 days after oocyte retrieval

No. of frozen embryos: Mild 0.0 (0.0-1.3) vs Conventional 0.0 (0.0-3.0), P=.046

CPR: Mild 12.1% (4.0-23.9) vs Conventional 20.0% (3.1-36.9), P=.412

LBR: Mild 9.1% (1.3-19.4) vs Conventional 12% (1.7-25.7), P=.719

Mild ovarian stimulation resulted in fewer number of COCs than conventional stimulation group of poor responders undergoing IVF/ICSI. Secondary outcomes of CPR and LBR were similar between the groups, but favored the conventional group.

Strengths: RandomizedLimitations: study underpowered; started as an RCT but had problems with randomization; lack of randomization; small cohort size; two conventional protocols (controls)

C: Low Quality or Major Flaws

Youssef MA, van Wely M, Al-Inany H, Madani T, Jahangiri N, Khodabakhshi S, Alhalabi M, Akhondi M, Ansaripour S, Tokhmechy R, Zarandi L, Rizk A, El-Mohamedy M, Shaeer E, Khattab M, Mochtar MH and van der Veen F

A mild ovarian stimulation strategy in women with poor ovarian reserve undergoing IVF: a multicenter randomized non-inferiority trial

Hum Reprod 2017; 32: 112-118

RCT

1

FSH only

394= subfertile women with poor ovarian reserve undergoing IVF

195= women rec'd mild ovarian stim; 35.5±3.9 yrs

199= women rec'd conventional ovarian stim; 36.6±4.3

Primary: ongoing PR per randomized woman; Secondary: CPR, biochemical PR, multiple pregnancy, early pregnancy loss, oocytes retrieved, # metaphase II oocytes, fertilization, embryos obtained, # ETs, total FSH/HMG, cancellation

advanced maternal age and/or women with poor ovarian reserve; pts eligible if ≥35 yrs, FSH >10 IU/ml, AFC ≤5, poor ovarian reserve, or cycle cancellation during previous IVF cycle

AMH: Mild= 0.5 ± 0.6Conventional= 0.6 ± 0.6

AFC: Mild= 5.3 ± 1.6Conventional= 6.4 ± 2.9

FSH: Mild= 11.4 ± 4.3Conventional= 10.5 ± 4.0

Mild: 150 IU FSH and pituitary down-regulation with GnRH-ant Conventional: 450 IU hMG and pituitary down-regulation with long mid-luteal GnRH agonist

Cancellation: Mild= 26.6%; 52 Conventional= 18.6%, 37RR 1.5 (0.96-2.5)

Oocytes retrieved: Mild= 3.3 ± 3.5 (median= 2); 95% CI 2.3-4 Conventional= 5.0 ± 4 (median= 4); 95% CI 4.3-5.5MD -1.6 (-2.5 to -0.89)

Embryos transferred: Mild= 0.8 ± 1.3 (median= 2); 95% CI 0.6-1.0 Conventional= 0.8 ± 1.2 (median= 2); 95% CI 0.6-0.9MD -0.19 (-0.48 to -0.09)

cleavage

fresh and frozen

NA

CPR/# women: Mild= 30 (15.3%) Conventional= 31 (15.5%) RR 0.86 (0.55-1.34) OPR ≥12 wks, # women: Mild= 25 (12.8%) Conventional= 27 (13.6%) RR 0.95 (0.57-1.57)

NA

NA

NA

NA

Mild ovarian stim in women with poor ovarian reserve undergoing IVF leads to similar ongoing pregnancy rates as conventional ovarian stimulation strategy.

Strengths: open label, multicenter, randomized, analysis based on intention to treat Limitations: lack of data re cryo of surplus embryos; no LBR; pregnancies not followed to full term; does not assess cumulative PR with supernumerary embryos

A: High quality