“Consistency is a virtue of an ass. No thinking human being can be tied down to a view once expressed in the name of consistency. More important than consistency is responsibility. A responsible person must learn to unlearn what he has learned. A responsible person must have the courage to rethink and change his thoughts. Of course there must be good and sufficient reason for unlearning what he has learned and for recasting his thoughts. There can be no finality in rethinking.”
—Emerson
Ever since the birth of the first test-tube baby three decades ago, lured by the marvels of this promising technology, its seemingly versatile applications and the demands of the patient in need, clinicians, scientists and researchers have left no stone unturned to optimize the initially poor success rates with the technique. Fast-paced innovations in drugs, stimulation protocols, laboratory protocols, culture media, instrumentation and techniques have taken the success and acceptance of assisted reproductive technology (ART) to new blinding heights, blanketing the associated complications. So much so, man has barely stopped a breath to reflect on core issues, balance the benefits against the drawbacks, question the integrity of the technique and rethink: Are we absolutely justified? Have we succeeded with the technique, the patient or both? Do the success rates subjectively define success? Does the financial, medical and psychological input outweigh the ultimate outcome? Is ART the right of the monetarily privileged few or can the technique be cherished by any patient in need? Indeed it is time to rethink!
THE CONCERNS
Multiple Gestations, Perinatal Morbidity and Mortality
According to a comprehensive analysis by The International Committee for Monitoring Assisted Reproductive Technology (ICMART) of the World practice and results in ART for the year 2002 from 53 countries by type of ART, women's age, number of embryos transferred and multiple births, a delivery rate (DR) per aspiration of 22.4% for conventional IVF and 21.2% for ICSI from over 601, 243 initiated cycles with an overall twin rate of 25.7% per delivery and a triplet rate of 2.5% has been reported.1 Multiple birth infants are at significant risk for a number of adverse outcomes, including preterm delivery, low birth weight, congenital malformations, fetal and infant deaths and long-term morbidity and disability among survivors.2 The perinatal mortality is 5–6 times higher among twins compared with singletons. Obstetric complications associated with multiple pregnancy include prenatal screening problems, an increased incidence of pre-eclampsia and eclampsia, antepartum hemorrhage, preterm labor, intrauterine growth retardation and surgical and assisted delivery.2 An increase in the percentage of premature babies (<37 weeks) from 13.5% for singletons to 61.3% for twins and 94.2% for triplets and in the perinatal mortality (10.7, 29.6 and 71.2 per 1000 babies), and a 20.0% abortion rate per clinical pregnancy in fresh cycles with large differences (2.4–47.3%), far too large to be explained only by chance, has been reported.1 Monozygotic and particularly, monochorionic twins have been associated with a 5-fold increase in fetal/perinatal loss and ten times more likely to be affected by an antenatally acquired cerebral lesion.3
Though the percentage of transfers with ≥ 4 embryos has decreased from 15.4% to 13.7% in fresh cycles and the overall proportions of twin and triplet pregnancies has decreased (from 26.5% to 25.7% and from 2.9% to 2.5%, respectively), since 2000, the transfer of ≥4 embryos continues to remain high in South Korea (53.7%), Latin America (37.9%), India (37.2%) and UAE (37.2%), but low (0–0.5%) in 11 countries in Europe and Australia.1 Based on the data from the World Collaborative Report on Assisted Reproductive Technology, 2002, Figure 1.1 illustrates a comparison of the percentage of the number of embryos (i.e. single, double, triple and ≥ 4), while Figures 1.2 illustrates a comparison of the ART outcomes and multiple gestation rates across different regions of the world. From this data, it is clearly evident that the percentage of triplet pregnancies is directly proportional to the transfer of ≥ 4 embryos (Figures 1.3) with Latin America reporting the highest percentages of triplet pregnancies (6.7%) and transfer of ≥ 4 embryos (37.9%) and Australia/New Zealand (ANZ) the least (0.5% and 0.8%, respectively). Triplet rates in Europe and ANZ were approximately half those of the USA and 5-fold less than in Latin America. The mean number of embryos transferred was correlated with the triplet rate (r ¼ 0.48, P < 0.001).2
Fig. 1.1: Comparison of the number of embryos transferred (%) across the different regions of the world
Fig. 1.2: Comparison of the pregnancy outcome and multiple gestation rate (%) across the different regions of the world
The fact that the average number of transferred embryos was not related to the PR after the transfer of more than two embryos, that the average number of embryos transferred was reduced, and that, delivery per aspiration was increased in 2002, should encourage embryo transfer policies that reduce the risk of multiple birth.1 (Figures 1.1 and 1.2).
The dramatic worldwide increase in the use of ICSI (from 54.4% in 2000 to 60.8% in 2002 in North America, from 45.7% to 53.9% in Europe), reaching 76.1% in Latin America and 92.5% in Middle East in 2002, without foolproof evidence of a concomitant increase in male infertility,1 is cause for concern bearing in mind the associated complications, the cost factor, and the genetic implications of the treatment.
The Availability of ART
The availability of ART in cycles/million across various regions of the world is illustrated in Figures 1.4. There is a wide variation in the availability of ART from two cycles per million inhabitants in Ecuador to 3688 in Israel, with Latin America having the least availability (52 cycles/million) and Australia/NZ cherishing the highest availability (1425 cycles/million).13
Fig. 1.3: Correlation between the number of embryos transferred and multiple gestation rate (%) across the different
This wide variation in the availability of ART across the globe has significant implications with regard to the cost and the quality of treatment imparted. Easier access, higher affordability by improving the cost-effectiveness of ART, and better obstetric and neonatal standards of care could help to bridge this gap and enable a more universal application of the technique, though the geography and economic situation would still be a significant influencing factor.
The Developments
Concerns over the associated obstetric and neonatal complications, increased prematurity, perinatal mortality and morbidity with multiple embryo transfer, the increased costs, risks and patient discomfort with high gonadotropin dose protocols, and imposing regulations in certain countries to streamline the safety of ART use, have resulted in various strategies to reduce the multiple gestation rate and its associated complications. These include the development of more gentle approaches to in vitro fertilization (IVF) and the implementation of elective single embryo transfer (eSET), or alternatively, an individualized embryo transfer policy that utilizes eSET in selected groups of patients at high risk of multiple births, while enabling the transfer of > 1 embryo in patients at low risk. While embryo/fetal reduction may be used as a strategy to reduce the number of multiple births, this intervention raises serious ethical and psychological problems. Though it may be particularly indicated in cases of higher order multiple pregnancies, it can never be justified as a method for reduction of twins.2
A number of organizations, including the Low-Cost IVF Foundation, World Health Organization (WHO), European Society of Human Reproduction and Embryology Special Task Force (ESHRE-STF),4 International Committee for Monitoring ART (ICMART),5, 6 The International Society for Mild Approaches in Assisted Reproduction (ISMAAR)7, 8 and the International Federation of Fertility Societies (IFFS), have been instrumental in devising and promoting purposeful, “safe, effective low-cost ART procedures” and consolidating the appropriate terminology. Procedures, such as pure natural cycle IVF (spontaneous cycle oocyte retrieval), modified natural cycle IVF that uses only ovulation inducing agents [gonadotropin-releasing hormone (GnRH) agonist/human chorionic gonadotropin (hCG)] to trigger final oocyte maturation and ovulation, and mild stimulation IVF that involves low dose stimulation with reduced risks, are gradually gaining acceptance in clinical practice, despite the high cancellation rates and poor success rates. Besides minimizing the stimulation risks and the associated complications, such as multifetal 4pregnancies and ovarian hyperstimulation syndrome (OHSS), these soft protocols reduce the medical, financial and psychological burden on patients with the potential advantage of availing numerous IVF cycles at a reduced overall cost and enhanced cumulative pregnancy rates, especially when combined with the option of embryo vitrification and frozen embryo transfer. The proportion of single embryo transfers has increased from 10.5% to 12.4%, being the highest in Finland (38.5%), Sweden (30.5%) and Australia (25.0%).1 The implementation of a single embryo transfer policy in countries like Sweden has drastically affected a decline in the multiple pregnancy rate from 35% to 5.7% with a successful delivery rate.9 This sharply contrasts the 51% multiple pregnancy rate reported in countries like USA, where regulations are more relaxed.10
Several protocols, such as the GnRH agonist (long-luteal or microdose flare) and antagonist (fixed and flexible regimens combined with single or multiple dose) protocols combined with low dose gonadotropins, mid-late follicular phase gonadotropin administration, and cotreatment with aromatase inhibitors and gonadotropins have been proposed. These can be extended to a versatile group of patients, including poor responders with a history of failed IVF cycles, women with advanced age and women at risk for high dose simulation. The numerous advantages conferred by GnRH antagonists (Cetrorelix/Ganirelix) compared to the long luteal agonist protocol, such as an immediate suppression of gonadotropin concentrations with a preserved pituitary response to endogenous GnRH, absence of flare-up effects and allergic reactions, significant reduction in the duration and dose of gonadotropin stimulation, less aggressive treatment with comparable clinical outcomes, efficacy in preventing the premature luteinizing hormone (LH) surge and excellent patient compliance, make GnRH antagonists an attractive treatment option in such women. Hence, GnRH antagonist have a significant place in mild stimulation IVF and modified natural cycle IVF, yielding genetically higher quality embryos and improved clinical outcomes despite the significantly fewer oocytes and embryos, single embryo transfer, and at decreased costs. The introduction of GnRH antagonist protocols has enabled final oocyte maturation to be triggered with a single bolus of a GnRH agonist (GnRHa) a more physiologic ovulatory stimulus compared to the extended surge (approximately 6 days) associated with hCG. However, the antagonist protocols often necessitate the addition of recombinant LH as addback, hence the benefits must be balanced against the overall cost of treatment.
The Results
Though the poor success rates with natural cycle IVF, mainly attributed to premature LH surge and high cycle cancellation rates owing to a failure to reach the oocyte retrieval or embryo transfer stage, remain some of the major draw-backs of this approach, encouraging results have been reported by several studies, especially with the introduction of GnRH agonists and antagonist. Natural cycle IVF in young poor responders has been shown to be as effective as the microdose-flare GnRHa protocol with better implantation rates (14.9% vs. 5.5%, respectively),11 and compared to conventional IVF stimulation cycles with higher number of cycles being scheduled for oocyte retrieval (81.3% vs. 52%, respectively) and higher clinical pregnancy rate/ started cycle (18.8% vs. 0%, respectively).12 It has also succeeded as a first ART approach in aged patients (37-43 years) with elevated basal FSH levels and reduced antral follicle counts with advantages of natural selection of oocytes, better embryo quality, better endometrial receptivity, and overall pregnancy rates (11.5% per cycle, 20.0% per ET) comparable with those of conventional IVF-ET and not impaired by a single embryo transfer with the additional possibility of multiple cycles at reduced costs, thus outweighing the inherently poor prognosis13 and inadvertent cycle cancellation. Moreover, a 27% reduction in exogenous FSH and significantly higher conception rates in the patients in whom ≤ 4 oocytes were retrieved have been reported following mild ovarian stimulation protocols with GnRH antagonist co-treatment compared to profound stimulation (67% vs. 7%, respectively; P < 0.01) with GnRH agonist co treatment.14 Mild ovarian stimulation with 150 IU/day recombinant FSH (cycle day 5) and late follicular phase GnRH antagonist co treatment in women less than 38 years of age is reported to result in ongoing pregnancy rates of 28% per elective SET.15 Gerris et al.16 reported a significant reduction in multiple pregnancy rates from 33.6% to 18.6% with preserved clinical pregnancy rates following elective single embryo transfer in only 20.4% selected women with good quality day 3 embryos.16
Result analysis
Appropriate recognition of measures of success is very essential in evaluating the efficacy of natural cycle IVF and mild stimulation protocols so that quality care can be imparted without compromising success. Rather than the number of oocytes retrieved, the emphasis should be on the quality of oocytes, and the developmental and implantation potential of the embryos thus generated. Despite the simplification in the clinical protocol, mild approaches to IVF demand technical expertise in the laboratory procedures including gamete handling, oocyte, embryo and blastocyst grading, to maximize the chances of success.
Results must be interpreted in terms of mature, singleton delivery rates rather than a crude measure in terms of live birth rates/cycle, to rule out the confounding complications and achieve a true success rate with emphasis on the cost/cycle. To better evaluate ART results, it is necessary to use a cumulative PR that arises from the sum of fresh pregnancies and additional FET pregnancies resulting from the same aspiration rather than the sum the fresh and frozen pregnancies of the same year, whether they come from the same aspiration 5or not, as is currently the ICMART trend. The latter is methodologically imperfect as it slightly underestimates the actual rate if there is a relative increase in FET and may be applied only if the proportions of aspirations and FET remain constant over time.1
CONCLUSION
The proven manifold advantages of natural cycle IVF and mild stimulation approaches for IVF, albeit preliminary, as against the numerous complications, patient burden, discomfort and high costs of strong stimulation protocols is definitely food for thought, clearly paving the way in favor of the former. However, a unifying approach with regard to the terminology of protocols under this umbrella, methodologically correct interpretation of the success, and embryo and blastocyst grading schemes is mandatory. To optimize the results with natural cycle IVF and mild stimulation IVF protocols, careful patient selection with an individualized treatment protocol and application of eSET on the basis of the patient response and prognosis is essential. Large prospective randomized controlled studies would endorse the apparent benefits of these more physiological approaches to IVF, promoting the concept of low cost in vitro fertilization (IVF) and make it a universally practiced and accessible technique. A little reflection in time on the problems that have stubbornly been linked with the practice ART has given ART a new perspective with focused objectives. Further rethought with an aim to achieve these objectives in practice can, perhaps, create a win-all situation for every patient in need.
REFERENCES
- de Mouzon J, Lancaster P, Nygren KG, Sullivan E, Zegers-Hochschild F, Mansour R, et al. International Committee for Monitoring Assisted Reproductive Technology (ICMART):, World Collaborative Report on Assisted Reproductive Technology, 2002. Hum Reprod 2009;24:2310–2320.
- Hazekamp J, Bergh C, Wennerholm UB, Hovatta O, Karlström PO, Selbing A. Avoiding multiple pregnancies in ART. Consideration of new strategies. Hum Reprod 2000;15:1217–1219.
- Petersen B, Nelson NB, Watson L, Stanley E. Twins, triplets and cerebral palsy in births in Western Australia the 1980's. BMJ 1993;307:1239–1243.
- ESHRE Special Task Force on “Developing Countries and Infertility” http://www.eshre.com/ESHRE/English/Task-forces/Task-force-Developing-Countries-and-Infertility/page.aspx/274.
- WHO – ICMART-LCIVFF/IFFS International meeting on Assisted reproductive technologies: Common terminology and management in low-resource settings. 2-3 December, 2008, WHO, Geneva.
- Zegers-Hochschild F, Nygren K-G, Adamson GD, de Mouzon J, Lancaster P, Mansour R, Sullivan E on behalf of The International Committee Monitoring Assisted Reproductive Technologies. The ICMART glossary on ART terminology. Hum Reprod 2006;21:1968–1970.
- The ISMAAR proposal on terminology for ovarian stimulation for IVF. Nargund G, Fauser BC, Macklon NS, Ombelet W, Nygren K, Frydman R; Rotterdam ISMAAR Consensus Group on Terminology for Ovarian Stimulation for IVF. Hum Reprod. 2007;22:2801–2804.
- Nargund G, Fauser BC, Macklon NS, Ombelet W, Nygren K, Frydman R. Rotterdam ISMAAR Consensus Group on Terminology for Ovarian Stimulation for IVF. The ISMAAR proposal on terminology for ovarian stimulation for IVF. Hum Reprod 2007;22:2801–2804.
- Karkstrom PO, Bergh C. Reducing number of embryos transferred in Sweden impact on delivery and multiple birth rates. Hum Reprod 2007;22:2202–2207.
- Wright C, Chang J, Jeng G, Chen M, Macaluso M. Assisted reproductive technology surveillance – United States, 2004. MMWR Surveill Summ 2007;56:1–22.
- Morgia F, Sbracia M, Schimberni M, Giallonardo A, Piscitelli C, Giannini P, 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;81:1542–1547.
- Bassil S, Godin PA, Donnez J. Outcome of in-vitro fertilization through natural cycles in poor responders. Hum Reprod 1999;14:1262–1265.
- Papaleo E, De Santis L, Fusi F, Doldi N, Brigante C, Marelli G, et al. Natural cycle as first approach in aged patients with elevated follicle-stimulating hormone undergoing intracytoplasmic sperm injection: A pilot study. Gynecol Endocrinol 2006;22:351–354.
- Hohmann FP, Macklon NS, Fauser BC. A randomized comparison of two ovarian stimulation protocols with gonadotropin-releasing hormone (GnRH) antagonist cotreatment for in vitro fertilization commencing recombinant follicle-stimulating hormone on cycle day 2 or 5 with the standard long GnRH agonist protocol. J Clin Endocrinol Metab 2003;88:166–173.
- Verberg MF, Eijkemans MJ, Macklon NS, Heijnen EM, Fauser BC, Broekmans FJ. Predictors of ongoing pregnancy after single-embryo transfer following mild ovarian stimulation for IVF. Fertil Steril 2008;89:1159–1165.
- Gerris J, De Neuborg D, Mangelshots K, Van Royen E, Vercruysen M, Barudy-Vasquez J et al. Elective single embryo transfer halves the twinning rate without decrease in the ongoing clinical pregnancy rate of an IVF/ICSI programme. Hum Reprod 2002;17:2626–2631.