IVF Protocols Compared in Advanced Age Poor Responders

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IVF protocols compared in advanced age Poor Responders

Natural Cycle Results in Lower Implantation Failure than Ovarian Stimulation in Advanced-Age Poor Responders Undergoing IVF: Fertility Outcomes from 585 Patients

A retrospective single-center cohort study was performed to assess the fertility outcomes of natural cycle IVF (no gonadotrophins) vs conventional IVF (high-dose gonadotrophins) in women over 40 years of age with poor ovarian response.

Poor ovarian response was defined by the Bologna criteria, where 2 of the following must be met;

  • Advanced maternal age
  • Abnormal ovarian reserve biomarker (AMH < 0.5–1.1ng/mL; AFC < 5–7)
  • Previous poor ovarian response (≤ 3 oocytes following conventional stimulation)
  • Two episodes of poor ovarian response after maximum stimulation

In this study a total of 585 women met the inclusion exclusion criteria, with 230 undergoing natural cycle IVF and 355 conventional IVF. The natural cycle IVF group were not administered any medication to assist with the selection and recruitment of follicles. Follicle growth was monitored via transvaginal sonography, until mean diameter reached 16µm at which stage a trigger shot of hCG was injected and oocytes retrieved 36 hours later.

In the conventional IVF cycle for poor responders, follitropin alfa (starting dose 225 IU) and lutropin alfa (75 IU), was administered daily beginning on cycle day 2. Once the follicles reached 16µm in diameter, GnRH antagonist was taken, and follicles monitored until 18-20µm in diameter (plus estradiol > 200pg/ml), at which stage a trigger shot of hCG was injected and oocytes retrieved 36 hours later.

Following retrieval of oocytes from both groups, embryos were fertilized via ICSI and left to develop till day 3 (72 hours) before being transferred back for implantation. Luteal phase support was kept identical for all women.

Baseline characteristics of women from both groups showed no difference in median age, BMI, menarche, previous pregnancies, FSH, AFC and smoking status, although AMH levels were higher in the conventional IVF group (1.46 vs 0.58). Cycle wise, the total number of ovarian cycles undertaken was 1119, with 576 natural cycle IVF and 543 conventional IVF.

Initial analysis showed that overall pregnancy rate per patient was not statistically different between conventional and natural IVF (19.72% vs 15.65%), resulting in similar live birth rates (72% vs 61%).

However overall pregnancy rate per IVF cycle (12.89% vs 6.25%) and pregnancy rates in patients, with at least 1 transfer (28.11% vs 18.85%) was significantly higher in the conventional IVF group. The number of embyro transfers was also significantly higher in the conventional group (765 vs 277).

Interestingly the pregnancy rate per transfer was actually higher in the natural IVF group (13% vs 9.1%), as was the implantation rate (13% vs 8.28%), suggesting that natural IVF cycles may be a valid option for some women.

Nevertheless this study confirms previous findings which show that a higher number of natural IVF cycles is required, to match the success rate of conventional IVF, resulting in a longer time to pregnancy.


This study comparing IVF protocols in poor responders, confirmed that conventional (high-dose gonadotrophins) stimulation results in a higher pregnancy rate per IVF cycle (12.89% vs 6.25%) compared to natural IVF (no gonadotrophins), although implantation and pregnancy rates per transfer is lower.


  1. Retrospective study
  2. AMH levels significantly different between the 2 study groups

Similar studies

Sunkara S K, et al. (2016). Live birth and perinatal outcomes following stimulated and unstimulated IVF: analysis of over two decades of a nationwide data. https://doi.org/10.1093/humrep/dew184

Von Wolff M, et al. (2014). Modified natural cycle in vitro fertilization an alternative in vitro fertilization treatment with lower costs per achieved pregnancy but longer treatment time. https://pubmed.ncbi.nlm.nih.gov/25552127/

Groen H, et al. (2013). Modified natural cycle versus controlled ovarian hyperstimulation IVF: a cost-effectiveness evaluation of three simulated treatment scenarios. https://doi.org/10.1093/humrep/det386

Schimberni M, et al. (2009). Natural-cycle in vitro fertilization in poor responder patients: a survey of 500 consecutive cycles. https://doi.org/10.1016/j.fertnstert.2008.07.1765


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