Advanced Maternal Age in IVF: Still a Challenge? The Present and the Future of Its Treatment

Abstract

Advanced maternal age (AMA; >35 year) is associated with a decline in both ovarian reserve and oocyte competence. At present, no remedies are available to counteract the aging-related fertility decay, however different therapeutic approaches can be offered to women older than 35 year undergoing IVF. This review summarizes the main current strategies proposed for the treatment of AMA: (i) oocyte cryopreservation to conduct fertility preservation for medical reasons or "social freezing" for non-medical reasons, (ii) personalized controlled ovarian stimulation to maximize the exploitation of the ovarian reserve in each patient, (iii) enhancement of embryo selection via blastocyst-stage preimplantation genetic testing for aneuploidies and frozen single embryo transfer, or (iv) oocyte donation in case of minimal/null residual chance of pregnancy. Future strategies and tools are in the pipeline that might minimize the risks of AMA through non-invasive approaches for embryo selection (e.g., molecular analyses of leftover products of IVF, such as spent culture media). These are yet challenging but potentially ground-breaking perspectives promising a lower clinical workload with a higher cost-effectiveness. We also reviewed emerging experimental therapeutic approaches to attempt at restoring maternal reproductive potential, e.g., spindle-chromosomal complex, pronuclear or mitochondrial transfer, and chromosome therapy. In vitro generation of gametes is also an intriguing challenge for the future. Lastly, since infertility is a social issue, social campaigns, and education among future generations are desirable to promote the awareness of the impact of age and lifestyle habits upon fertility. This should be a duty of the clinical operators in this field.

Keywords: advanced maternal age; embryo selection; oocyte cryopreservation; oocyte donation; ovarian stimulation; single embryo transfer.

Figures

Figure 1

Summary of the current and potential future approaches to prevent, compensate or solve the issues related with advanced maternal age on infertility, while limiting the putative concurrent risks. The consequences deriving from the onset of aging-related female infertility might be prevented by performing oocyte cryopreservation ideally when women are younger than 35 year; in the future, social campaigns and education are advisable to promote the awareness of the age-related female fertility decay. The main current strategy to compensate for the consequences of aging on oocyte competence (woman age range: 35–45 year) entails the maximization of the ovarian response by tailoring patients-specific protocols; in the future, oocyte competence might be rescued via promising approaches such as mitochondrial, spindle-chromosomal complex, pronuclear transfer or chromosome therapy, even though all these perspectives still need thorough and careful investigation. Oocyte donation represents the main current option to solve irrecoverable aging-related infertility conditions (woman age range: 40–50 year); the future avant-gardes that are motivating the academic research instead entail the generation of new gametes in vitro [e.g., from induced pluripotent stem cells (iPSCs) or oogonial stem cells (OSCs)]: an intriguing challenge with yet unpredictable outcomes. At last, the increasing maternal age brings about greater reproductive risks for the woman, the pregnancy she will eventually achieve and the new-born: to date, embryo selection via preimplantation genetic testing of aneuploidies (PGT-A) performed by molecular platforms for comprehensive chromosome testing (CCT) on trophectoderm (TE) biopsies represents the most efficient workflow to counteract the hazards derived from embryo chromosomal aneuploidies. Agonist trigger and cycle segmentation are important to minimize the risk of ovarian hyperstimulation syndrome (OHSS) after IVF. Moreover, to avoid the onset of multiple gestations, single embryo transfer (SET) is strongly recommended, especially for euploid blastocysts. In the future, molecular analyses (DNA, mRNA, miRNA, and/or proteins) on leftover products of IVF retrieved via non-invasive procedures (e.g. cumulus cells, spent culture media after IVF) might be implemented clinically to complement (or even replace) invasive approaches of embryo selection thereby aiming at a successful SET. From left to right, the gray arrow represents the increasing maternal age from <30 to 50 year The blue triangle depicts the decreasing maternal fertility, while the orange triangle depicts the increasing risks that could derive from the treatment of infertility and/or the establishment of a pregnancy as the maternal age increases. In light blue, the current and emerging approaches to prevent the fertility decay. In light orange, the current and emerging approaches to compensate it. In green, egg donation is proposed as a current strategy to circumvent the aging issue of female gametes, while emerging still experimental approaches aim at solving this issue. In yellow, we summarized the current strategies recommended to limit the putative risks of an IVF treatment; in the future, non-invasive approaches for embryo selection might be implemented in this workflow to identify the embryo for SET.

Figure 2

The current clinical strategies to treat advanced maternal age (AMA) in IVF. The oocytes retrieved from a young patient undergoing controlled ovarian stimulation (COS) and oocyte pick-up (OPU) are cryopreserved (i) to be used from the same woman years later thereby preventing the onset of infertility due to medical or non-medical reasons (in blue), or (ii) to be used from a different woman indicated to egg donation (in green). The main strategy to compensate for the age-related infertility in AMA patients is to tailor COS on each woman peculiar characteristics attempting at maximizing the ovarian response. Indeed, while the live birth rate (LBR) per fresh embryo transfer (ET; i.e., only first transfer accounted) plateaus when more than 15 oocytes are retrieved (in gray), the cumulative LBR (CLBR) per cycle (i.e., all consecutive fresh and frozen ETs accounted) instead keeps increasing at any age (in orange). Data adapted from (30).

Figure 3

The theory behind preimplantation genetic testing of aneuploidies (PGT-A) and the related workflow. For both non-PGT and PGT-A cycles, a woman undergoes controlled ovarian stimulation (COS), oocyte pick-up (OPU), intracytoplasmatic sperm injection (ICSI) conducted with male partner's sperm, and embryo culture to the blastocyst stage. The differences between non-PGT and PGT-A cycles instead entail for the latter (in yellow): (i) the trophectoderm (TE) biopsy of the blastocysts obtained, (ii) the molecular comprehensive chromosome testing (CCT) of the biopsied fragment, (iii) the definition of euploid blastocysts (in green), which are selected for embryo transfer (ET), and (iv) the definition of aneuploid blastocysts (in red), which are instead prevented from being transferred. In an advanced maternal age (AMA) population (e.g., 39 year mean maternal age), the aneuploidy rate at the blastocyst stage is about 50–55%. In theory, if all the untested blastocysts obtained after a non-PGT and all the euploid blastocysts diagnosed after a PGT-A cycle would be transferred, the latter strategy is expected to bring about (i) the same cumulative live birth rate (CLBR, i.e., the number of babies born per cycle; in blue), (ii) a lower miscarriage rate (in orange), (iii) less ETs resulting in an implantation failure with a negative pregnancy test (in gray), and (iv) no chromosomally-abnormal pregnancy (in black). Data adapted from Capalbo et al. (5), Franasiak et al. (6), Dahdouh et al. (115), Chen et al. (116), and Ubaldi et al. (117).

Figure 4

Potential future therapeutic approaches to treat advanced maternal age (AMA) infertility. To compensate before fertilization. The approaches that have been theorized are: •The spindle-chromosomal complex transfer from the mature oocyte of an infertile AMA woman (in orange) to the oocyte of a young donor (whose spindle-chromosomal complex was previously removed; in gray). The latter oocyte should be then used to perform IVF; •The transfer of additional mitochondria to the oocyte of an infertile AMA woman. The source of the additional mitochondria might be a donated oocyte (in gray). Also autologous sources have been proposed, i.e., oocytes obtained from ovarian biopsies and in vitro maturation (IVM), other immature oocytes that cannot be used for IVF, ovarian somatic cells (e.g., cumulus or granulosa cells) (all in orange). Some groups reported that autologous mitochondria can be obtained also from oogonial stem cells (OSCs) isolated from ovarian biopsies (in green); •Chromosome therapy to correct meiotic aneuploidies in the oocyte. To compensate after fertilization. The approaches that have been theorized are •The use of the sperm from male partner (in orange) to fertilize both the patient's (in orange) and the donor's egg(s) (in gray), to then remove the pronuclei from the zygote originating from the latter and replace them with the pronuclei from the zygote originating from the former (i.e., pronuclear transfer); •Chromosome therapy to correct aneuploidies in the zygote. To solve (in green). Two strategies have been theorized: •The isolation of OSCs from ovarian biopsies retrieved from the infertile patient to then trigger the formation of new autologous oocytes by either transplanting them back in the ovary or by performing IVM; •The isolation of somatic cells, that are then transformed into induced pluripotent stem cells (iPSCs), which are finally differentiated into new autologous oocytes. Of note, all these putative future therapeutic strategies are still experimental and/or raised biological, genetic, technical, and ethical concerns.