Total fertilization failure (TFF) is the failure of all metaphase II oocytes to fertilize in ART cycles. The phenomenon represents a known cause of infertility, affecting 1–3% of ICSI cycles. Oocyte activation deficiency (OAD) is the leading cause of fertilization failure, attributed to sperm- or oocyte-related issues, although until recently little attention has been given to oocyte-related deficiencies. Different strategies for overcoming TFF have been proposed in clinical settings, mainly using artificial oocyte activation (AOA) by calcium ionophores. Typically, AOA has been blindly applied with no previous diagnosis testing and, therefore, not considering the origin of the deficiency. The scarcity of data available and the heterogeneous population subjected to AOA make it challenging to draw firm conclusions about the efficacy and safety of AOA treatments.

OBJECTIVE AND RATIONALE

TFF leads to an unexpected, premature termination of ART, which inflicts a substantial psychological and financial burden on patients. This review aims to provide a substantial update on: the pathophysiology of fertilization failure, focusing both on sperm- and oocyte-related factors; the relevance of diagnostic testing to determine the cause of OAD; and the effectiveness and safety of AOA treatments to overcome fertilization failure.

SEARCH METHODS

Relevant studies were identified in the English-language literature using PubMed search terms, including fertilization failure, AOA, phospholipase C zeta (PLCζ), PLCZ1 mutations, oocyte-related factors, wee1-like protein kinase 2 (WEE2) mutations, PAT1 homolog 2 (PATL2) mutations, tubulin beta-8 chain (TUBB8) mutations, and transducin-like enhancer protein 6 (TLE6) mutations. All relevant publications until November 2022 were critically evaluated and discussed.

OUTCOMES

Fertilization failure after ART has been predominantly associated with PLCζ deficiencies in sperm. The reason relates to the well-established inability of defective PLCζ to trigger the characteristic pattern of intracellular Ca2+ oscillations responsible for activating specific molecular pathways in the oocyte that lead to meiosis resumption and completion. However, oocyte deficiencies have recently emerged to play critical roles in fertilization failure. Specifically, mutations have been identified in genes such as WEE2, PATL2, TUBB8, and TLE6. Such mutations translate into altered protein synthesis that results in defective transduction of the physiological Ca2+ signal needed for maturation-promoting factor (MPF) inactivation, which is indispensable for oocyte activation. The effectiveness of AOA treatments is closely related to identifying the causal factor of fertilization failure. Various diagnostic tests have been developed to determine the cause of OAD, including heterologous and homologous tests, particle image velocimetry, immunostaining, and genetic tests. On this basis, it has been shown that conventional AOA strategies, based on inducing the calcium oscillations, are highly effective in overcoming fertilization failure caused by PLCζ-sperm deficiencies. In contrast, oocyte-related deficiencies might be successfully managed using alternative AOA promoters that induce MPF inactivation and meiosis resumption. Such agents include cycloheximide, N,N,N′,N′-tetrakis(2-pyridylmethyl)ethane-1,2-diamine (TPEN), roscovitine, and WEE2 complementary RNA. In addition, when OAD is caused by oocyte dysmaturity, applying a modified ovarian stimulation protocol and trigger could improve fertilization.