Alejandro Chávez Badiola1 and Nadia Suarez1
Department of Reproductive Medicine, New Hope Fertility Center, Mexico, Mexico
Alejandro Chávez BadiolaMedical Director
This book chapter gives an overview about the current status of natural cycle IVF in the literature. It points out indications, more precisely, for patient groups’ in which natural cycle IVF might be beneficial. Then, the most important advantages of this technique are explained, which above all, is the better endometrium, receptivity, compared with conventional IVF. The biggest disadvantage of natural cycle IVF is the high cancelation rate due to premature ovulation and low oocyte recovery rate. But, clinics with experience in this technique are happy to offer a more natural and more patient-friendly alternative to conventional IVF, which gives after, all reasonable results for low costs, especially, if patients are ready to wait a little bit longer for a positive result.
Natural cycle IVFEndometrium receptivityPremature ovulationOocyte recovery rateCumulative pregnancy rateNatural approachLow cost
The methods currently used in infertile patients are too extreme and too expensive, and alternative approaches are being sought, including minimal stimulation IVF, natural cycle IVF, and maturing human oocytes in vitro (Edwards 2007).
The first child born after IVF was conceived in a spontaneous menstrual cycle; however, natural cycle IVF has since been largely ignored, mostly due to the advances in ovarian stimulation. Years of efforts in research have been spent refining and enhancing the process of ovarian stimulation, having to deal as well with the known complications of multiple pregnancy and ovarian hyperstimulation syndrome (OHSS) (Luke et al. 2010). However, in the last few years, the definition of success has changed toward achieving one healthy pregnancy that can come from one good embryo, therefore aiming towards a more physiological approach, which includes less medication and higher quality in the laboratories.
In spite of the advances in ovarian stimulation, and the reassuring available data to this day regarding the long-term risks of ovarian or other hormone-dependent cancers, there are still a group of women that do not respond adequately to high-dose controlled ovarian hyperstimulation (COH) or wish to have the most natural and physiological medical approach. So in a natural cycle, a lower-risk procedure is combined with a patient-friendly treatment.
A total of 795 cycles of unstimulated IVF were reported to SART in 2006 and 2007. Patients <35 years old represented 41 % of the total stimulated IVF cycles, compared with just 21.5 % of the unstimulated IVF cycles. Nearly half (45.5 %) of the unstimulated IVF cycles were performed in patients ≥41 years of age (30 % in patients aged >42 years). Conversely, only 15 % of stimulated IVF cycles were performed in patients ≥41 years of age (5.8 % in patients aged >42 years) (Gordon et al. 2013).
In a recent analysis of SART, it was revealed that only 13 and 16 % of the clinics in the USA performed unstimulated IVF in 2006 and 2007, respectively, which only represented <1.5 % of the total cycles initiated at those clinics (Gordon et al. 2013).
In patients with an expected good response, the use of COH increases the risk for ovarian hyperstimulation syndrome (OHSS); on the other hand, the reduced number of ultrasounds in a natural cycle, (two or three per cycle) as well as the absence of hormonal medication, can make this procedure less expensive and emotionally easier. And when time is an important issue for the couples, in a natural cycle, there’s no need for waiting due to the recovery that the ovaries sometimes need as consequence of the hormonal stimulation, and doing the fresh transfer also provides results within that same cycle. Another issue is endometrial receptivity; one possible mechanism of impairment is advancement of the receptive phase due to the high hormonal levels achieved during COH, resulting in embryo–endometrium asynchrony (Shapiro et al. 2011), but this issue will be addressed further in this chapter.
Nargund et al. (2001) performed one of the most representative studies, in 2001, with 181 cycles and with 48 % of patients being >35 years old. It reported 81.6 % successful retrievals, with a pregnancy rate of 12.7 % per cycle and a cumulative rate after four cycles of 46 %. In patients <35 years old, more than half the initiated cycles (54 %) reached ET, with a pregnancy rate per ET of 35.9 %. The implantation rate was statistically higher in unstimulated IVF cycles compared with stimulated IVF cycle in patients between 35 and 42 years of age, and there was no significant difference in patients aged <35 years. There were no pregnancies from unstimulated IVF in those >42 years of age. For all ages, the clinical pregnancy rates per initiated cycle, retrieval, and transfer were 9.6 %, 13.5 %, and 26.1 %, respectively. Similarly, for all ages (including >42 years), the live birth rates per initiated cycle, retrieval, and transfer were 7.3 %, 10.3 %, and 19.9 %, respectively (Gordon et al. 2013).
In general, poor-responder women are the patients who, during controlled ovarian hyperstimulation for IVF, show poor follicle growth despite the high dose of medication administered and low levels of serum estradiol. The incidence of poor-responder patients is approximately 10 %, and it is often related to patient age (Schimberni et al. 2009). The management of these patients is still a challenge for many physicians, despite a number of options in protocols available.
Poor responder patients are usually refractory to stimulation protocols; although many treatment strategies have been suggested, the results remain poor, and despite the high quantity of gonadotropins administered, their chances of pregnancy remain very low (Schimberni et al. 2009). Their treatment is generally approached in different ways, either by trying different stimulation protocols using high levels of gonadotropins, changing the dosages or the use of GnRH analogs or antagonists, trying IVF in a natural cycle, or as a last resort, suggesting egg donation. However, egg donation is not an option for many patients who wish to try every option in order to have a child with their own eggs.
In a recent study, Schimberni et al. (2009), performed 500 natural cycles in 294 women considered poor responders. Oocytes were found in 391 cases of oocyte retrieval (78.1 %). After the ICSI procedure, cleaving embryos suitable for transfer were obtained in 285 cycles (57.0 %), but no fertilization or cleaving embryos were obtained in 106 cycles (21.0 %). Pregnancy was observed in 49 cases, with a pregnancy rate of 9.8 % per cycle, 17.1 % per transfer, and 16.7 % per patient.
There have been conflicting results by other groups; in 2004, Kolibianakis et.al. performed a study of 32 patients with FSH ≥12 IU/l, with discouraging results; 32.1 % of the cycles did not result in oocyte retrieval; in 16.9 % in which oocyte retrieval was performed, no oocytes were obtained, and embryo transfer was performed in 19 out of 44 cycles in which oocytes were retrieved (43.2 %), and no ongoing pregnancy was achieved in 78 modified natural cycles (MNCs) (Kolibianakis et al. 2004).
The fact that a large group of patients do not accept oocyte donation poses difficulties in generalizing the study findings, as this is a personal decision related to cultural or religious characteristics, and, ultimately, after proper counseling the decision has to be made by the patient herself.
The implantation window is defined as the limited period during which the uterus is receptive to implantation of the embryo. The presence of an endometrial “implantation window” has been demonstrated. During the receptive phase, the endometrium secretes proteins in a temporary fashion that will be recognized by the embryo and facilitates its growth and differentiation (Lessey 2000). The most cited factors involved in implantation include the formation of luminal epithelial “pinopodes” and expression of adhesion molecules and of cytokines.
Pinopodes were described originally in rats and mice as epithelial projections with pinocytic activity. In normally fertile women, pinopode formation and regression are closely related to serum progesterone concentrations. Pinopodes were demonstrated at the apical surface of the luminal epithelial cell during the implantation window (day 20 ± 22), therefore claimed as a possible receptivity marker, and because of a selective adhesion of blastocysts to pinopode-presenting areas, it emphasizes the importance of endometrial pinopodes as indicators of endometrial receptivity, suggesting that the apical surface of endometrial pinopodes participates directly in the adhesion process of the human blastocyst (Bentin-Ley et al. 1999).
There are several studies comparing the implantation rates between unstimulated and stimulated IVF cycles, which demonstrated a statistically higher implantation rate in several age categories. This finding may support the observation of improved endometrial receptivity in unstimulated cycles (Gordon et al. 2013). In a study published by Shapiro, in 2011, where fresh vs. frozen embryo transfer was compared, the clinical pregnancy rate per transfer was significantly greater in the cryopreservation group than in the fresh group. The clinical pregnancy rate per transfer was 84.0 % in the cryopreservation group and 54.7 % in the fresh group. The implantation rates were 70.8 % and 38.9 %, respectively. The ongoing pregnancy rates per transfer (at 10 weeks gestation) were 78.0 % and 50.9 %, respectively. The attributable risk percentage of implantation failure due to reduced endometrial receptivity in the fresh group was 64.7 %. These results strongly suggest impaired endometrial receptivity in fresh ET cycles after COH (Shapiro et al. 2011).
The only study performing biopsies in the preovulatory phase showed accentuated proliferative aspects and early secretory changes, even before any serum progesterone rise was observed (Marchini et al. 1991). In the peri-ovulatory phase, generally advanced endometrial maturation was observed. On the day of oocyte retrieval, an advancement of 2 ± 4 days was reported in 100 % (Ubaldi et al. 1997) and 45.5 % (Lass et al. 1998) of cycles.
The endometrial development in IVF cycles is most likely due to several factors. An early and increased exposure to progesterone of the endometrium in stimulated cycles may explain early secretory transformation. Elevated serum E2 concentrations in stimulated cycles have also been associated with more frequent glandular–stromal dysynchrony (Bourgain and Devroey 2003).
The use of Letrozole is a valid alternative, considering its stimulatory effect on the ovaries and the favorable effect on the endometrium. In a recent study, performed in eight patients monitored in an unstimulated cycle, and a cycle with Letrozole from day 3 to 7, the presence of pinopodes, which is considered a marker of endometrial receptivity, was confirmed through biopsies during the implantation window, suggesting that the aromatase inhibitor Letrozole may be an alternative for COH considering its moderate stimulatory effect on the ovary and its favorable effect on endometrial morphology (Cortínez et al. 2005).
There is strong evidence from histological observations and expression of implantation window markers that ovarian stimulation for IVF alters the luteal phase endometrial development.
There is an increased rate of cycle cancelation with natural cycle IVF because of premature LH surge, ovulation, failure to retrieve an oocyte, fertilization failure, or embryo arrest. Although the majority of initiated cycles result in oocyte retrievals (71.1 %), the reported percentage of cycles that result in ET ranged from 54 % in the youngest patients to 23 % in the patients >42 years old. The advocates for unstimulated IVF have suggested that natural cycle IVF be a series of treatments to obtain a cumulative pregnancy rate. Many patients have a strong preference for natural cycle IVF over stimulated IVF and are willing to undergo a greater number of simpler treatments to obtain a successful pregnancy (Gordon et al. 2013).
One of the main disadvantages of natural cycle IVF is a high cancelation rate because of premature LH surges or premature ovulation.
The planning of oocyte retrieval, based on a LH rise, requires frequent monitoring and round-the-clock oocyte retrieval and laboratory facilities. There are two approaches in planning oocyte retrieval; the first is the use of hCG for the triggering of final oocyte maturation, and it allows for a certain degree of planning. Flushing of the follicle during oocyte retrieval may increase the probability of retrieving the egg during the procedure, with a reported actual retrieval of 28.6–86.1 % per cycle (Pelinck et al. 2002; Verberg et al. 2009). The second approach is to plan the oocyte retrieval according to the timing of spontaneous LH surges. With this approach there is a reported retrieval of 65–89.5 % per cycle (Pelinck et al. 2002).
To improve outcomes while preserving the advantages of natural cycle IVF, modifications have been made. In the “modified” natural cycle, the occurrence of a premature LH rise is prevented by the use of a GnRH antagonist during the late follicular phase, starting when the follicle is between 12 and 17 mm. The growth of the dominant follicle is supported by the addition of gonadotropins (Verberg et al. 2009). One large study analyzed the cumulative pregnancy rate after three modified natural IVF cycles in good-prognosis patients. A total of 844 cycles in 350 patients of 36 years of age with no previous IVF treatment were included. The ongoing pregnancy rate per cycle was 8.3 and 20.8 % after up to three cycles. The number of canceled cycles related to a rise in LH or ovulation in this study was 13 % per started cycle, compared with an average of 20 % reported following natural cycle IVF (Pelinck et al. 2008).
Oocyte Recovery Rate
In a study performed by Janssens et al. (2000) in which 50 patients with tubal infertility from 22 to 38 years of age were included, a total of 75 cycles were performed, reporting an oocyte recovery rate of 66.6 % per started cycle and 82.0 % per oocyte retrieval. It is unavoidable that in the use of a natural cycle, the risk of not recovering an oocyte is a present risk; however, the procedure is considered less painful and easier since there is only a need for one puncture, and a new attempt can be made in the immediate next cycle. The next attempt is usually easier, and having a background of the patient’s cycle allows decreasing the amount of visits to the clinic and predicting more accurately the proper time for the retrieval (Janssens et al. 2000).
Nargund et al. published a study, in 2001, on 52 women, where they performed a total of 181 cycles, 3.49 cycles per woman (Nargund et al. 2001).
There were 174 oocyte retrieval procedures undertaken, of which 142 resulted in at least one oocyte retrieved (81.6 %). Two oocytes were retrieved in ten cycles (5.7 %) with only one fertilized, due to immaturity of the second one. Seven patients ovulated spontaneously. Of the 142 successful collections, 100 (70 %) were fertilized, and 96 embryos were transferred. Twenty-three resulted in pregnancy (24 %) per embryo transfer and 16 (16.7 % per embryo transfer) in live births. These results gave a success rate of 12.7 and 8.8 % per cycle, respectively. The rates for 174 oocyte retrieval procedures were 13.2 and 9.2 per oocyte retrieval, respectively.
After four cycles, the cumulative probability of a pregnancy was 46 and 32 % for a live birth.
These results show that natural cycle IVF is an effective method of treatment for ovulatory women, and the 32 % live birth rate is comparable to the 34 % for women in conventional IVF.
Pelinck et al. (2007) published, in 2007, a cohort study, in which 256 patients started 1048 treatment cycles (4.1 per patient). Ninety-four cycles (9.0 %) were canceled before planning oocyte retrieval. A further 98 cycles (10.3 % per planned oocyte retrieval) were canceled at the time of planned oocyte retrieval in one case because of inaccessibility of the ovary and in 97 cases because unexpected ovulation had occurred. Out of 856 oocyte retrievals, 625 were successful (73.0 % per attempt). In 453 cycles, fertilization occurred (72.5 % per successful oocyte retrieval). In 382 cycles, embryo transfer was done (36.5 % per started cycle; 61.1 % per successful oocyte retrieval). In 104 cycles, a pregnancy was obtained. The pregnancy rate was 9.9 % per started cycle. Three out of 104 pregnancies were twins (2.9 %), of which one occurred after transfer of one single embryo and two occurred after double embryo transfer (DET); the ongoing pregnancy rate was 7.9 % per started cycle.
In this study, a cumulative pregnancy rate of 40.6 % was obtained after nine cycles. Dropout rates were high, especially in higher cycle numbers. Considering the advantages of natural cycle IVF, the very low multiple pregnancy rate and negligible risk of OHSS in particular, this modality of treatment is again shown as a valuable option for patients requiring IVF.
In our clinic, in the year 2011, 165 natural cycles were performed, which correspond to 27 % of all cycles for that year, with 30 % being performed in patients ≤35 years old.
There have been considerable changes in the practice of assisted reproduction; in this new approach, we believe natural cycles will have an important role. There is a large group of women that for personal, moral, or medical reasons are not candidates or do not wish to use conventional IVF. Another important group of women will not respond well to large doses of hormonal medications, making natural cycles the most viable choice. Even though the outcome of four cycles of natural cycle IVF was found to be equal to a single cycle of IVF with COH, it can be concluded that the natural cycle IVF is safer with less stress and less expense.
We can conclude that natural cycle IVF is a safe and patient-friendly treatment. Despite the advantages of this approach, low efficacy in the early stages of its use has made it’s use limited; however, its use in consecutive cycles in a selected population may result in improved results that would ultimately give women one more opportunity to achieve a pregnancy as naturally as possible.
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