Infertility is one of the most common problems that couples face up nowadays. Whether the cause is due to a female reproductive pathology or a male one, when the medical or surgical treatments aimed to raise the rate of spontaneous pregnancies fail, the possibility of in vitro fertilization (IVF) is considered.
The process of IVF involves several stages, beginning with controlled ovarian hyperstimulation and ovulation triggering, continuing with follicle aspiration and gametes incubation, and completing with embryo selection and the intrauterine transfer. This process failure can occur during any of these stages, which is why a number of complementary therapies are the subject of recent studies.
This article aims at analyzing the studies from literature that have followed alternative therapies used in order to improve the results of IVF.
PubMed database was searched for studies: 1) published from January 2010 to 2020; 2) written in English; 3) that analyzed complementary therapies used during the IVF process.
Most alternative therapies focus on the psychosocial factors aiming to reduce anxiety, distress and depression, which according to some studies could lead to improved outcomes for women undergoing IVF(1).
Acupuncture is a widely discussed complementary therapy used by women undergoing IVF, with contradictory results in different studies. Some studies suggested that acupuncture may be beneficial for women with poor ovarian response, improving clinical pregnancy rates (CPR), anti-Müllerian hormone (AMH) levels, antral follicle count (AFC) and the number of retrieved oocytes(2). One study, including women undergoing IVF-ET and having poor ovarian response, observed that acupuncture in combination with specific medication (oral administration of clomiphene, injections of menotropins, chorionic gonadotrophin triggering etc.) improved the ovarian function and the level of hormones, facilitating IVF success(3). On the other hand, a randomized clinical trial conducted by Smith et al., including 848 women, half of them receiving acupuncture at the time of ovarian stimulation and embryo transfer and half of them receiving sham acupuncture, concluded that there was no significant difference in live birth rates between the two groups, which do not support the use of this therapy(4). From the same area of alternative therapies, the effect of auricular acupressure applied during the period from oocyte retrieval to embryo transfer was analyzed by Qu et al. in a prospective randomized controlled trial. They concluded that this therapy could relieve anxiety associated with IVF and, through raising the levels of neuropeptide Y in the follicular fluid, could improve IVF outcomes(5).
Massage is another adjuvant therapy used in assisted reproductive techniques. Okhowat et al. designed a retrospective observational study that analyzed IVF patients who underwent deep relaxation massage on an oscillating device (andullation) prior to embryo transfer in comparison to a group of patients not receiving this therapy. The results support the use of andullation, suggesting that it improves embryo implantation, probably through enhancing endorphin release, reducing uterine contraction and increasing blood flow in the abdominal region(6).
Yoga might be also used as an alternative therapy for stress reduction for women undergoing in vitro fertilization, increasing the success of this treatment(7).
Other therapies aiming to improve IVF success rates focus on intrauterine administration of different substances that could help implantation after embryo transfer. Recent evidence suggests that local immune cells at the implantation site might actively contribute to embryo implantation. Intrauterine administration of autologous peripheral blood mononuclear cells (PBMCs) activated by HCG is one of the options studied in the last few years. According to four different studies, PBMC administered intrauterine increases the rates of clinical pregnancy, live birth and implantation, but only in patients with repeated implantation failure (at least three failures)(8-11). As well, another study concluded that, for women with repeated implantation failure, the intrauterine administration of PBMC, treated with corticotropin-releasing hormone (CRH) prior to blastocyst transfer, significantly improved the clinical pregnancy rate(12).
Nowadays, an adjuvant therapy gaining popularity in many fields of medicine is the administration of platelet-rich plasma (PRP). Platelets are well known for their high concentration in several growth factors, such as platelet-derived growth factor, vascular endothelial growth factor, transforming growth factor b, insulin-like growth factor and epidermal growth factor, which play key roles in tissue repair mechanisms. That’s why the effect of PRP was recently tested on the endometrium of women undergoing IVF who had recurrent implantation failure (RIF), possible due to the inability of endometrium to achieve optimal lining. Five studies showed that intrauterine infusion of autologous PRP improves the endometrial receptivity to embryo implantation, IVF success and pregnancy outcome, especially in patients with RIF history. Only three of these studies concluded that endometrial thickness (EMT) was higher and reached the appropriate growth after PRP administration in women with suboptimal endometrial lining(13-15). The other two studies observed an improvement in the IVF success rate no matter if the endometrium reached the appropriate growth for embryo transfer or not, considering that autologous PRP could restore the endometrial receptivity of damaged endometrium through other mechanisms than increasing the EMT(16,17). Moreover, PRP intrauterine administration has the advantage of being a simple, inexpensive procedure, without associated complications.
Another problem frequently encountered during IVF process is the poor response to gonadotropin stimulation in the stage of controlled ovarian stimulation, with a prevalence of 9% to 24%(18). Based on the same qualities of PRP mentioned before, the intraovarian injection of PRP might increase the number of oocytes in patients with poor ovarian response, the mechanisms leading to this result not being well known. It is thought that PRP could increase the follicles blood flow, enhancing their ability to respond to gonadotropins, nutrients and growth factors. Moreover, VEGF, which is highly abundant in platelets, seems to regulate folliculogenesis and prevent follicular atresia. PRP injection may also activate postnatal oogenesis in the ovary, leading to the formation of new primordial follicles(19). Sills et al. studied the effect of intraovarian injection of calcium gluconate activated PRP in four women with diminished ovarian reserve as determined by at least one prior IVF cycle cancelled for poor follicular recruitment response or estimated by serum AMH and/or FSH. They observed increased AMH and significantly decreased FSH levels, sufficient to permit metaphase II oocytes retrieval. At the end of the process, at least one embryo was obtained from the IVF cycles in all patients(20). Sfakianoudis et al. also investigated the effect of autologous PRP ovarian infusion in three poor responder patients having failed IVF attempts, poor oocyte yield, poor embryo quality and rejecting the option of oocyte donation. They observed as well a significant FSH decrease and AMH increase, and the final results were successful live births(21).
Another option for improving results in poor ovarian responders or in patients with diminished ovarian reserve (DOR) undergoing IVF seems to be dehydroepiandrosterone (DHEA) supplementation. Androgens are known to influence ovarian follicular growth, to promote follicular recruitment and to increase the number of primary and preantral follicles(22). Unfortunately, again, there are trials with opposite results. Yeung et al. concluded in their trial that no statistically significant improvements in ovarian response markers or in IVF outcomes were found after pretreatment with DHEA in poor ovarian responders(23). On the other hand, Xu et al. summed up in their meta-analysis that in patients treated with DHEA, increases in the number of retrieved oocytes, clinical pregnancy rate and live births rate were identified, suggesting that DHEA supplementation improves the outcomes of IVF in women with DOR or POR(24).
Alternative therapies used nowadays for improving IVF outcomes are still under trial and need further research, considering that studies are few, most of them including small groups of patients, frequently providing contradictory results. We can assume that alternative therapies that focus on distress reduction, such as acupuncture, massage and yoga, might have a beneficial effect on patients undergoing IVF. However, we consider that the intrauterine administration of PBMC or PRP, the intraovarian injection of PRP or DHEA supplementation are complementary therapies of greater importance that might soon demonstrate a significant impact on IVF results.