Mild versus conventional ovarian stimulation for IVF in poor, normal and hyper-responders: a systematic review and meta-analysis

Abstract

BACKGROUND Mild ovarian stimulation has emerged as an alternative to conventional IVF with the advantages of being more patient-friendly and less expensive. Inadequate data on pregnancy outcomes and concerns about the cycle cancellation rate (CCR) have prevented mild, or low-dose, IVF from gaining wide acceptance. OBJECTIVE AND RATIONALE To evaluate parallel-group randomised controlled trials (RCTs) on IVF where comparisons were made between a mild (≤150 IU daily dose) and conventional stimulation in terms of clinical outcomes and cost-effectiveness in patients described as poor, normal and non-polycystic ovary syndrome (PCOS) hyper-responders to IVF. SEARCH METHODS Searches with no language restrictions were performed using Medline, Embase, Cochrane central, Pre-Medicine from January 1990 until April 2020, using pre-specified search terms. References of included studies were hand-searched as well as advance access articles to key journals. Only parallel-group RCTs that used ≤150 IU daily dose of gonadotrophin as mild-dose IVF (MD-IVF) and compared with a higher conventional dose (CD-IVF) were included. Studies were grouped under poor, normal or hyper-responders as described by the authors in their inclusion criteria. Women with PCOS were excluded in the hyper-responder group. The risk of bias was assessed as per Cochrane Handbook for the included studies. The quality of evidence (QoE) was assessed according to the GRADE system. PRISMA guidance was followed for review methodology. OUTCOMES A total of 31 RCTs were included in the analysis: 15 in the poor, 14 in the normal and 2 in the hyper-responder group. Live birth rates (LBRs) per randomisation were similar following use of MD-IVF in poor (relative risk (RR) 0.91 (CI 0.68, 1.22)), normal (RR 0.88 (CI 0.69, 1.12)) and hyper-responders (RR 0.98 (CI 0.79, 1.22)) when compared to CD-IVF. QoE was moderate. Cumulative LBRs (5 RCTs, n = 2037) also were similar in all three patient types (RR 0.96 (CI 0.86 1.07) (moderate QoE). Risk of ovarian hyperstimulation syndrome was significantly less with MD-IVF than CD-IVF in both normal (RR 0.22 (CI 0.10, 0.50)) and hyper-responders (RR 0.47 (CI 0.31, 0.72)), with moderate QoE. The CCRs were comparable in poor (RR 1.33 (CI 0.96, 1.85)) and hyper-responders (RR 1.31 (CI 0.98, 1.77)) but increased with MD-IVF among normal responders (RR 2.08 (CI 1.38, 3.14)); all low to very low QoE. Although fewer oocytes were retrieved and fewer embryos created with MD-IVF, the proportion of high-grade embryos was similar in all three population types (low QoE). Compared to CD-IVF, MD-IVF was associated with less gonadotrophin use and lower cost. WIDER IMPLICATIONS This updated review provides reassurance on using MD-IVF not only for the LBR per cycle but also for the cumulative LBR, with moderate QoE. With risks identified with ‘freeze-all’ strategies, it may be time to recommend mild-dose ovarian stimulation for IVF for all categories of women i.e. hyper, poor and normal responders to IVF.

Type and dose of gonadotropins in poor ovarian responders: does it matter?

“…However, different questions on the interpretation of those data were raised by several authors 76 – 78 and the applicability to a wider practice was questioned. In a recent meta-analysis on RCTs by Datta and colleagues, 67 no difference in OPR or LBR was found between mild and conventional stimulation. Mild OS should therefore be considered in poor responders.…”

“…Several investigators propose this as an equally effective alternative, offering advantages in terms of patient friendliness and treatment cost. 67 , 68 Terminology of different types of mild stimulation IVF (MS-IVF) has been defined in a proposal statement from the International Society for Mild Approaches in Assisted Reproduction (ISMAAR). 69 A ‘mild IVF cycle’ is defined as ‘the method when FSH or hMG is administered at lower doses, and/or for a shorter duration in a GnRH antagonist co-treated cycle, or when oral compounds (anti-estrogens, or aromatase inhibitors) are used, either alone or in combination with gonadotropins’.…”

Evaluating different strategies for poor ovarian response management: a retrospective cohort study and literature review

“…Future studies should employ strict criteria for participant selection in order to reduce the bias originating from POR population heterogeneity and should present data originating from a large sample size, a significant parameter increasing the validity of the studies. 17,32,43 In the era of precision medicine, completely individualizing POR patients' management is a defining factor. Future studies are needed to improve POR patient profiling for better understanding the ovarian dynamic of this heterogeneous group of patients.…”

Extended Injection Intervals of Gonadotropins With Superficial Skin Administration In Ivf Treatment Is both Cost-Effective and Patient-Friendly

“…There is a trend of reducing dose/injections of gonadotropins for COS over the last two decades, with an improved patient compliance and lower chance of error during drug administration (21). Fine tuning of the Gn dose, in accordance with potential ovarian response in every single woman as the so-called personalized IVF treatment, has become a safer and more effective IVF practice (22,23). Our work, with enhanced extent of absorption and longer plasma half-life of rFSH, provides the pharmacokinetic basis for a longer interval of Gn injection instead of daily injections (17).…”