Open Access

The myths surrounding mild stimulation in vitro fertilization (IVF)

Reproductive Biology and Endocrinology201715:48

https://doi.org/10.1186/s12958-017-0266-1

Received: 21 April 2017

Accepted: 17 June 2017

Published: 24 June 2017

Abstract

So-called mild controlled ovarian hyperstimulation (mCOH) has in recent years increased in popularity, claiming to be safer and more patient-friendly, while also improving in vitro fertilization (IVF) outcomes. We here challenge the International Society for Mild Approaches in Assisted Reproduction (ISMAAR) definition of mild stimulation, and especially address four fundamental issues, where our review found conventional COH (cCOH) advantageous over mCOH. They are: prevalence of severe ovarian hyperstimulation syndrome (OHSS), oocyte/embryo quality, pregnancy/live birth rates, and cost. We conclude that an objective review of the literature does not support the routine utilization of mCOH in assisted reproduction.

Keywords

Ovarian stimulationAneuploidyCost-effectivenessOvarian hyperstimulation syndrome (OHSS)In vitro fertilization (IVF)Pregnancy ratesLive birth rates

Background

Controlled ovarian hyperstimulation (COH) is essential for in vitro fertilization (IVF) success since it facilitates recruitment of multiple oocytes and, thereby, also often allows for multiple embryo transfers (ETs) [1], without causing ovarian hyperstimulation syndrome (OHSS). In recent years, milder approaches to COH have become increasingly popular, aiming to offer safer and more patient-friendly approaches to reduce patient stress, complications such as OHSS, and cost of IVF cycles [2, 3], while allegedly improving endometrial receptivity, embryo quality and implantation potential [4].

Since investigators used various different definitions and terminologies to describe mild controlled ovarian hyperstimulation (mCOH), the Rotterdam-based International Society for Mild Approaches in Assisted Reproduction (ISMAAR) Consensus Group on Terminology for Ovarian Stimulation for IVF, in 2007, proposed a concise and simplified revised nomenclature for different approaches to ovarian stimulation for IVF [5].

The term natural or unstimulated cycle IVF was proposed when IVF is carried out during a spontaneous menstrual cycle without gonadotropin support, aiming to collect the naturally selected single oocyte of the cycle. mCOH was defined as follicle stimulating hormone (FSH) or human menopausal gonadotropin (HMG) 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, aiming for collection of 2–7 oocytes. cCOH was defined by use of GnRH analogues (long/flare agonist or antagonist protocols) with conventional doses of stimulation with FSH or HMG, aiming to collect eight or more oocytes.

These definitions can, however, be quite confusing. For example, offering mCOH with a daily gonadotropin dose <150 IU, some patients may respond more vigorously than expected, yielding more than 8 oocytes. Such an oocyte count, however, is already in the cCOH range defined by ISMAAR. How, then, should such a cycle be defined, According to stimulation (mCOH), or patient response (cCOH)?

Four other fundamental issues require review:

Prevalence of severe OHSS

Best IVF is characterized by balance between optimal ovarian stimulation with successful treatment outcomes and minimal rates of severe OHSS and/or (especially higher order) multiple pregnancies. Individualization of treatments, based on patient risk factors, cycle responses, elective single embryo transfer and the option of freezing all embryos have in susceptible cases the potential of reducing the risks and severity of the syndrome [6]. Withholding ovulation-inducing triggers of hCG, or replacing hCG with GnRH agonist (GnRHa) triggers may further reduce severe early OHSS. Especially GnRHa trigger, combining GnRH antagonist co-treatment and GnRHa trigger, has recently been increasinly utilized to eliminate severe early OHSS in support the OHSS-free clinic [7, 8].

Significantly reduced clinical pregnancies and increased first trimester pregnancy loss with such treatments [9, 10], however, popularized efforts to improve reproductive outcome through all-freeze policies, fresh transfers with intensive luteal support and fresh transfers with low-dose hCG supplementation. We previously published a comprehensive review of suggested strategies, to which the reader is referred [6]. It addresses the role of GnRH-antagonists in COH protocols, the use of different luteal rescue protocols, the role of cabergoline and the ability to transfer embryos at blastocyst stage.

Utilizing this knowledge, severe OHSS is no longer a complication to fear, as we practically, have eliminated it from our practice for over a decade.

Oocyte/embryo quality

A study by Baart et al. [11] raised concerns after demonstrating lower embryo aneuploidy following mCOH compared to cCOH. While mCOH produced significantly fewer oocytes and embryos, both regimens generated similar numbers of chromosomally normal embryos. Bart et al., therefore, concluded that differences in aneuploid embryos suggests that mitotic segregation errors may increase with growing gonadotropin dosages. On the contrary, several other studies have disputed the aforementioned observation, demonstrating a comparable aneuploidy rate in stimulated and un-stimulated cycles.

In 2012, Labarta et al. [12] compared unstimulated and stimulated IVF cycles in the same young (<35 yrs) egg donors. Using in those days preimplantation genetic screening (PGS) with fluorescence in situ hybridization (FISH) on cleavage-stage embryos, these authors reported similar aneuploidy rates in unstimulated and stimulated cycle (34.8% and 40.6%, respectively), with no in-between group differences in embryo quality and types of chromosomal abnormalities. These aneuploidy rates concurred with 36.4% rates already in 2009 reported by Verpoest et al. in unstimulated cycles [13]. Also in 2012, using similar early-stage PGS technologies, Gleicher et al. [14] in normally fertile women undergoing IVF for sex selection purposes, reported mild increases in aneuploidy with increasing gonadotropin dosages; but those increases were more than compensated for by larger numbers of transferrable euploid embryos in women who received higher gonadotropin stimulation because of larger oocyte yields. Already in1992, Gras et al. [15] reported that the rate of aneuploidy in non-stimulated oocytes was comparable to oocytes obtained after COH with either clomiphene/hMG or the flare GnRHa protocol.

Like Labarta et al. [12] and Gleicher et al. [14], Baart et al. [11] used FISH to determine copy number of only nine chromosome pairs of cleavage-stage embryos on day-3 after fertilization, a method since discarded due to high imprecision [16, 17]. Aneuploidy rates reported by Baart et al. (66% and 67% percent, respectively) were also much higher than those by Labarta et al. [12] and Verpoest et al. [13] (34.8% and 36.4%, respectively). They also compared the aneuploidy rates, comparing presumed aneuploid and mosaic embryos when analyzing two blastomers. As we now know, mosaicism is much more common than previously appreciated and, likely, a normal physiological phenomenon of developing embryos with, still, strong innate abilities to self-correct downstream beyond blastocyst stage [reviewed in [17]]. This was best demonstrated by the achievement of surprisingly high normal live birth rates after transfer of mosaic/aneuploid embryos [1820]. Adding, however, up rates of normal euploid and mosaic embryos in the study by Baart et al. [11], the percentages of clinically likely normal embryos (28+33=61% v.s 39+21=60%), in mCOH and cCOH groups, suddenly, no longer differs.

A recent study [21] of patients undergoing IVF cycles involving COH and trophectoderm biopsy for PGS has demonstrated that the degree of exposure to exogenous gonadotropins did not significantly modify the likelihood of aneuploidy in patients with a normal ovarian response to stimulation (not requiring COH beyond cycle day 12). Patients requiring prolonged COH were demonstrated to have elevated odds of aneuploidy with increasing cumulative gonadotropin dose. Finding that may reflect an increased tendency towards oocyte and embryonic aneuploidy in patients with a diminished response to gonadotropin stimulation.

We, therefore, conclude that there is no reliable evidence to suggest that more aggressive ovarian stimulation increases aneuploidy rates in embryos to significant degrees.

Pregnancy/live birth rates

Several studies have dealt with pregnancy\live birth rates in mCOH vs cCOH, demonstrating a huge heterogeneity in terms of inclusion criteria, numbers of oocyte retrieved/embryo transferred, or day of the transfer. Verberg et al. [22] conducted a meta-analysis, aiming to investigate whether retrieval of low numbers of oocytes following mCOH is associated with impaired implantation rates. Including three randomized controlled trials of a total of 592 first treatment cycles, optimal embryo implantation rates were observed with retrieved 5 oocytes following mCOH (31%), versus 10 oocytes following cCOH (29%). These finding suggest that modest numbers of oocytes following mCOH are not a reflection of poor ovarian response.

Distribution of retrieved oocytes was similar for both protocols (range 0–28), with median (25–75 percentile) of 6 [310] and 9 [612] following mCOH and cCOH, respectively. Overlapping results made it also impossible, to categorized patients to mCOH or cCOH, based on the definition of the Rotterdam ISMAAR Consensus group [5]. Moreover, when comparing ongoing pregnancy rates (PR) per fresh transfer, they were significantly higher in the cCOH vs. mCOH (29% vs 15%; p < 0.001, respectively).

Since mCOH cycles more frequently than cCOH cycles fail to reach embryo transfer, outcome analysis with reference cycle start (“intent to treat”) would, likely, demonstrate even more impressive differences in favor of cCOH.

More impressive difference was also found comparing stimulated to unstimulated cycles. Sunkara et al. [23] recently analyzed anonymous data obtained from the Human Fertilisation and Embryology Authority (HFEA), involving 584,835 stimulated IVF cycles and 6168 unstimulated IVF cycles. The overall live birth rates were 4.7% per cycle following unstimulated fresh IVF versus 22.5% following stimulated fresh IVF. In other words, 3.5 times as many unstimulated IVF cycles are required to achieve one live birth compared to stimulated IVF.

Above noted advantages of cCOH were demonstrated in first fresh-cycle transfers. Those advantages would also become even more obvious if additional frozen-thawed cycle were to be included. Moreover, optimal embryo implantation rates observed with 5 oocytes following mCOH [22] are really irrelevant because they fall far below the required oocyte yields for a live birth, reported to be 14–15 metaphase II oocytes, 10 day-2 or day-3 embryos or 5 blastocysts in 70% of patients [24, 25].

It was recently also demonstrated [26], that the cumulative live birth rate (LBR) following the transfer of all fresh and frozen–thawed embryos after a single ovarian stimulation, significantly increases with the number of oocytes retrieved. High responders (>15 oocytes) demonstrated a significantly higher LBR not only versus poor (0–3 oocytes) and suboptimal [49] responders, but also versus women with normal [1015] ovarian response. While suboptimal responders had a better outcome compared with poor ovarian responders, this group had a significantly lower cumulative LBR compared with normal ovarian responders [26].

Cost

Groen et al. [27] evaluated the cost-effectiveness of modified natural cycle (MNC) versus cCOH. MNC was not cost-effective, as conventional COH dominated MNC with a higher cumulative LBR and lower cost per patient. LBR per cycle was 3.8 higher in the conventional vs. MNC COH (23% and 6%, respectively), while the cost was 1.8 higher (2110 vs 1150 Euro. Extrapolating the data to mCOH, which involves more medication (gonadotropins), and taking into consideration the total reproductive potential of each initiated IVF cycle (i.e. fresh plus subsequent frozen/thawed transfers) with reference point cycle start (i.e.,” intent to treat”) [25], cCOH would be advantageous in term of cost-effectiveness per cumulative LBR.

Conclusion

mCOH has been proposed to provide safer and more patient-friendly IVF, with improving outcomes. Upon careful review, it offers none of these advantages. Regarding occurrence of severe OHSS, oocyte/embryo quality, pregnancy/live birth rates and cost, cCOH is at least comparable or sometime superior over mCOH, discrediting the concept of using mCOH in routine IVF. Further large prospective studies are needed to compare and clarify the role of mCOH vs cCOH in the different subgroups of patients. Moreover, these studies may help fertility specialists in individualization and careful tailoring of the COH protocol for optimizing IVF success.

Abbreviations

cCOH: 

Conventional controlled ovarian hyperstimulation

COH: 

Controlled ovarian hyperstimulation

ET: 

embryo transfers

FISH: 

fluorescence in situ hybridization

GnRHa: 

GnRH agonist

HFEA: 

Human Fertilisation and Embryology Authority

HMG: 

human menopausal gonadotropin

ISMAAR: 

International Society for Mild Approaches in Assisted Reproduction

IVF: 

in vitro fertilization

mCOH: 

mild controlled ovarian hyperstimulation

MNC: 

modified natural cycle

OHSS: 

ovarian hyperstimulation syndrome

PGS: 

preimplantation genetic screening

Declarations

Acknowledgements

The authors would like to thank the ‘Memorial Fund Griffini Miglierina’ within the ‘Fondazione Comunitaria del Varesotto Onlus’ for non-restricted financial support to Dr. VSV during the completion of the study.

Funding

This manuscript was not supported by specific funding.

Authors' contributions

All authors contributed to the concept of the manuscript; R.O. wrote the first draft of the manuscript. All authors, however, contributed to substantial changes of the manuscript in further drafts. The final draft before submission was approved by all authors.

Competing interests

RO is the journal’ EIC. VSV and NG have nothing to declare.

Consent for publication

NA.

Ethics approval and consent to participate

Not applicable (a review article).

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Authors’ Affiliations

(1)
Infertility and IVF unit, Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Tel Hashomer
(2)
The Tarnesby-Tarnowski Chair for Family Planning and Fertility Regulation, Sackler Faculty of Medicine, Tel-Aviv University
(3)
Centro Scienze Natalità, Department of Obstetrics and Gynecology, IRCCS Ospedale San Raffaele
(4)
The Center for Human Reproduction
(5)
Foundation for Reproductive Medicine
(6)
Laboratory of Stem Cell Biology and Molecular Embryology, The Rockefeller University
(7)
Department of Obstetrics and Gynecology, University of Vienna School of Medicine

References

  1. Penzias AS. Improving results with assisted reproductive technologies: individualized patient-tailored strategies for ovulation induction. Reprod Biomed Online. 2004;9:43–6.View ArticlePubMedGoogle Scholar
  2. Pelinck MJ, Vogel NEA, Hoek A, Simons AHM, Arts EGJM, Mochtar MH, et al. Cumulative pregnancy rates after three cycles of minimal stimulation IVF and results according to subfertility diagnosis: a multicentre cohort study. Hum Reprod. 2006;21:2375–83.View ArticlePubMedGoogle Scholar
  3. Heijnen E, Marinus JC, De Klerk C, Polinder S, Beckers NGM, Klinkert ER, et al. A mild treatment strategy for in-vitro fertilisation: a randomised non-inferiority trial. Lancet. 2007;369:743–9.View ArticlePubMedGoogle Scholar
  4. Verberg MFG, Macklon NS, Nargund G, Frydman R, Devroey P, Broekmans FJ, et al. Mild ovarian stimulation for IVF. Hum Reprod Update. 2009;15:13–29.View ArticlePubMedGoogle Scholar
  5. Nargund G, Fauser BCJM, Macklon NS, Ombelet W, Nygren K, Frydman R. For the Rotterdam ISMAAR Consensus Group on Terminology for Ovarian Stimulation for IVF. The ISMAAR proposal on terminology for ovarian stimulation for IVF. Hum Reprod. 2007;22:2801–4.View ArticlePubMedGoogle Scholar
  6. Orvieto R. Ovarian hyperstimulation syndrome- an optimal solution for an unresolved enigma. J Ov Res. 2013;6:77.View ArticleGoogle Scholar
  7. Orvieto R. Can we eliminate severe ovarian hyperstimulation syndrome? Hum Reprod. 2005;20:320–2.View ArticlePubMedGoogle Scholar
  8. Devroey P, Polyzos NP, Blockeel C. An OHSS-Free Clinic by segmentation of IVF treatment. Hum Reprod. 2011;6:2593–7.View ArticleGoogle Scholar
  9. Griesinger G, Diedrich K, Devroey P, Kolibianakis EM. GnRH agonist for triggering final oocyte maturation in the GnRH antagonist ovarian hyperstimulation protocol: a systematic review and meta-analysis. Hum Reprod Update. 2006;12:159–68.View ArticlePubMedGoogle Scholar
  10. Orvieto R, Rabinson J, Meltzer S, Zohav E, Anteby E, Homburg R. Substituting HCG with GnRH agonist to trigger final follicular maturation–a retrospective comparison of three different ovarian stimulation protocols. Reprod Biomed Online. 2006;13:198–201.View ArticlePubMedGoogle Scholar
  11. Baart EB, Martini E, Eijkemans MJ, Van Opstal D, Beckers NG, Verhoeff A, et al. Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial. Hum Reprod. 2007;22:980–8.View ArticlePubMedGoogle Scholar
  12. Labarta E, Bosch E, Alama P, Rubio C, Rodrigo L, Pellicer A. Moderate ovarian stimulation does not increase the incidence of human embryo chromosomal abnormalities in in vitro fertilization cycles. J Clin EndocrinolMetab. 2012;97:1987–94.View ArticleGoogle Scholar
  13. Verpoest W, Fauser BC, Papanikolaou E, Staessen C, Van Landuyt L, Donoso P, et al. Chromosomal aneuploidy in embryos conceived with unstimulated cycle IVF. Hum Reprod. 2008;23:2369–71.View ArticlePubMedGoogle Scholar
  14. Gleicher N, Kim A, Weghofer A, Barad DH. Lessons from elective in vitro fertilization (IVF) in, principally, non-infertile women. Reprod Biol Endocrinol. 2012;10:48.View ArticlePubMedPubMed CentralGoogle Scholar
  15. Gras L, McBain J, Trounson A, Kola I. The incidence of chromosomal aneuploidy in stimulated and unstimulated (natural) uninseminated human oocytes. Hum Reprod. 1992;7:1396–401.View ArticlePubMedGoogle Scholar
  16. Mastenbroek S, Twisk M, van Echten-Arends J, Sikkema Raddatz B, Kovaar JC, Verhoeve HR, et al. In vitro fertilization with preimplantation genetic screening. N Engl J Med. 2007;357:359.View ArticleGoogle Scholar
  17. Gleicher N, Orvieto R. Is the hypothesis of preimplantation genetic screening (PGS) still supportable? A review. J Ovarian Res. 2017;10:21.View ArticlePubMedGoogle Scholar
  18. Gleicher N, Vidali A, Braverman J, Kushnir VA, Albertini DF, Barad DH. Further evidence against use of PGS in poor prognosis patients: report of normal births after transfer of embryos reported as aneuploid. Fertil Steril. 2015;104(Suppl 3):e9.Google Scholar
  19. Gleicher N, Vidali A, Braverman J, Kushnir VA, Barad DH, Hudson C, Wu YG, Wang Q, Zhang L, Albertini DF. Accuracy of preimplantation genetic screening (PGS) is compromised by degree of mosaicism of human embryos. Reprod Biol Endocrinol 2016b;14:54Google Scholar
  20. Greco E, Minasi G, Fiorentino F. Healthy babies after intrauterine transfer of mosaic aneuploidy blastocysts. N Engl J Med. 2015;373:2089–90.View ArticlePubMedGoogle Scholar
  21. Sekhon L, Shaia K, Santistevan A, Cohn KH, Lee JA, Beim PY, Copperman AB. The cumulative dose of gonadotropins used for controlled ovarian stimulation does not influence the odds of embryonic aneuploidy in patients with normal ovarian response. J Assist Reprod Genet. 2017 Mar 20. doi:10.1007/s10815-017-0909-3. [Epub ahead of print]
  22. Verberg MFG, Eijkemans MJC, Macklon NS, Heijnen EMEW, Baart EB, Hohmann FP, et al. The clinical significance of the retrieval of a low number of oocytes following mild ovarian stimulation for IVF: a meta-analysis. Hum Reprod Update. 2009;15:5–12.View ArticlePubMedGoogle Scholar
  23. Sunkara SK, La Marca A, Polyzos NP, Seed PT, Khalaf Y. Live birth and perinatal outcomes following stimulated and unstimulated IVF: analysis of over two decades of a nationwide data. Hum Reprod. 2016;31:2261–7.View ArticlePubMedGoogle Scholar
  24. Garrido N, Bellver J, Remoh J, Simon C, Pellicer A. Cumulative live-birth rates per total number of embryos needed to reach newborn in consecutive in vitro fertilization (IVF) cycles: a new approach to measuring the likelihood of IVF success. Fertil Steril. 2011;96:40–6.View ArticlePubMedGoogle Scholar
  25. Sunkara SK, Rittenberg V, Raine-Fenning N, Bhattacharya S, Zamora J, Coomarasamy A. Association between the number of eggs and live birth in IVF treatment: an analysis of 400 135 treatment cycles. Hum Reprod. 2011;26:1768–74.View ArticlePubMedGoogle Scholar
  26. Drakopoulos P, Blockeel C, Stoop D, Camus M, de Vos M, Tournaye H, et al. Conventional ovarian stimulation and single embryo transfer for IVF/ICSI. How many oocytes do we need to maximize cumulative live birth rates after utilization of all fresh and frozen embryos? Hum Reprod. 2016;31:370–6.PubMedGoogle Scholar
  27. Groen H, Tonch N, Simons AH, van der Veen F, Hoek A, Land JA. Modified natural cycle versus controlled ovarian hyperstimulation IVF: a cost-effectiveness evaluation of three simulated treatment scenarios. Hum Reprod. 2013;28:3236–46.View ArticlePubMedGoogle Scholar

Copyright

© The Author(s). 2017

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