Recent advances in enhancing ART outcomes

Assisted reproductive technology: An overview

The advent of assisted reproductive technologies (ART) in the 19^th century was hailed as major obstetrical achievement in the management of infertility. The first child conceived with frozen-thawed sperm was born in 1953, and the first in-vitro fertilization (IVF) baby in 1978. This was followed by the introduction of intracytoplasmic sperm injection (ICSI) in 1992, which overcame the major obstacles pertaining to male infertility. In the successive decades, the technologies continued to develop apace opening up new paradigms of parenthood. The timeline of major ART milestones (1978-2004) is depicted in figure 1.

The building blocks of progress have been assembled over the past years by researchers, whose core objective has been to abate all seemingly insurmountable obstacles to conception in infertile individuals. Despite the initial set back in 1980s, researchers continued to refine the techniques in ART, and expanded the options for infertility management. Today, ART not only serves as a substitute for natural conception but also potentially prevents the birth of a disabled child (due to pre-implantation diagnostic advances), and additionally helps single women and same sex couples to have children.^1-3

Progress in ART

The knowledge-base regarding ARTs has grown significantly enabling several innovations in the techniques and procedures. Information gleaned from studies suggests that the use of ARTs has expanded from tubal infertility to include ovulation disorders, male factor infertility and compromised ovarian reserve.

Nowadays, IVF has increasingly become commonplace across infertility clinics. Novel IVF-based methods, such as cryopreservation using vitrification, micromanipulation of gametes and embryos, and pre-implantation genetic diagnosis (PGD), have provided prospective parents with a bewildering variety of reproductive options.^1,4-6       Consequently ART services have gained immense popularity worldwide and the number of ART cycles have dramatically increased.⁷

Albeit ART performance in overcoming natural barriers to conception is apparently remarkable, there is persuasive evidence derived from studies suggestive of a less than 50% success rate in IVF cycles.⁸   Complications that occur during ovulation induction, oocyte retrieval, and post-operatively, jeopardize pregnancy outcomes. Thereby, improving diagnostic modalities and modifying treatment protocols to enhance IVF success rates are increasingly becoming the hot topics for research.⁹

Diagnostic and therapeutic innovations for enhancing ART outcomes

Prior to 1990, methods to avoid transmission of sex-linked conditions in the fetus during IVF were limited to performing chorionic villus sampling or amniocentesis and terminating pregnancy if the fetus was found to be affected. In 1990, however, PGD was introduced and successfully applied clinically to prevent two X-linked conditions in offsprings produced from IVF: adrenoleukodystrophy and X-linked mental retardation. The subsequent years thereby witnessed an increase in the breadth and popularity of PGD; however, the evidence supporting its use simultaneously evolved to become equivocal.¹   While few studies^10,11     indicated that PGD increased the embryo implantation rate and reduced miscarriage rate, a trial by Gianaroli et al¹²   comparing the outcome after blastocyst transfer combined with aneuploidy screening in women with advanced maternal age revealed no changes in implantation or pregnancy outcomes. Another clinical trial¹³   also failed to demonstrate noteworthy improvements in conception rates using PGD for aneuploidy screening. However, Li et al¹⁴  , in a recent study performed PGD and simultaneous pre-implantation genetic screening (PGS) using single nucleotide polymorphism (SNP) microarrays for couples with balanced chromosome rearrangements in Chinese population. They demonstrated the clinical pregnancy rate per IVF cycle to be 54% and suggested SNP microarray PGD/PGS to be a promising strategy to maximize the pregnancy potential of patients with known parental chromosomal translocations.

While these diagnostic modalities became routine for prenatal genetic diagnosis, researchers posited that they required testing in an aggressive manner and may thereby be invasive to the growing embryo. Consequently, noninvasive prenatal diagnosis (NIPD) and noninvasive prenatal testing (NIPT) were developed and introduced offering attractive options in prenatal diagnosis for carriers of single gene disorders and chromosomal constitution in fetuses.¹⁵

While diagnostic research has made great strides in the recent years, the development of novel therapeutic interventions for enhancing IVF outcomes has also been an impressive success. Desirable outcomes have been obtained with the use of ART even in women with advanced reproductive age. The phenomenon of the gradual decline of a woman’s fecundability with increasing age is better understood today, yielding the possibility of precise, targeted therapies for this subpopulation.¹⁶   The use of laser-assisted hatching in women ≥ 35 years has been supported by several investigators. Studies have shown assisted hatching to substantially contributed to enhanced implantation, conception and live birth rates in these women.¹⁷

The management of poor responders in IVF cycles has also remained a vexing challenge. Researchers posit that poor response in IVF yields lesser oocytes, is associated with poorer pregnancy perspective, and portends the failure of cycle.¹⁸   While a large number of studies have been published in literature, consensus regarding the most efficient treatment to improve the ovarian response and the clinical outcomes in poor responders is lacking.¹⁹   It is believed that there is no single approach that is successful for all patients, and it is very difficult to develop or assess any protocol to improve the IVF outcomes in this group of patients. Nonetheless, evolving evidences suggest that determination of basal cycle day 3 serum FSH, LH, anti-Mullerian hormone (AMH) and estradiol levels, and the estimation of the basal antral follicular count by transvaginal ultrasonography, are the preferred screening tests for ovarian reserve. Together with the woman’s age, these tests help determine the ovarian stimulation regimen to be chosen for the cycle treatment.

Furthermore, several advances have been made to address the needs of infertile men. Previously, IVF procedure was much less effective when semen parameters were below the reference values for concentration (oligozoospermia), motility (asthenozoospermia), and morphology (teratozoopermia), Besides, there were barely any options available for azoospermic men. However, the advent of ICSI markedly improved fertilization rates and yielded promising outcomes for infertile men. It not only helped to overcome the fertilization barriers presented by oligo-, astheno-, and teratozoospermia, but also yielded a new possibility for azoospermic males to achieve fertility. In the recent past, attempts have also been made to perform ICSI in the safest possible manner to minimize the theoretical hazards of this procedure. Rapid advances are being made to allow operators to simulate physiological conditions in the laboratory, preventing potential damage to the gametes. Prevention of fertilization by DNA-damaged and chromosomal-unbalanced spermatozoa by selecting ICSI sperm by motility and/or maturation markers such as hyaluronic acid or other zona pellucida receptors, now appears to be possible. Furthermore, novel non-invasive imaging techniques are being developed to serve as viable tools for helping in the morphological selection of ICSI spermatozoa.^1,20

References

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17. Hsieh YY, Huang CC, Cheng TC, Chang CC, Tsai HD, Lee MS. Laser-assisted hatching of embryos is better than the chemical method for enhancing the pregnancy rate in women with advanced age. Fertil Steril. 2002 Jul;78(1):179-82.
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19. Davis OK. IVF stimulation: protocols for poor responders. Methods Mol Biol. 2014;1154:329-41.
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