Assisted reproductive technology has been game-changing for many couples struggling with infertility. However, it is not bullet-proof as total fertilisation failure can still occur in 1-3% of all intracytoplasmic sperm injection (ICSI) cycles. This can be devastating to patients who have gone through multiple rounds of stimulations and transfers, hopes and disappointments. Is there anything that can still be tried in such cases?
ICSI fertilisation failure
Studies of fertilisation failure after ICSI has revealed that the predominant cause is oocyte activation failure. In simple terms, the signal for the egg to start the next series of events required for commencing life is faulty.
This could be due to a defect in the male-specific factor carrying the activation signal (PLC ζ), or a failed response to such signal in the egg. There are diagnostic tools that can help determine the cause for ICSI fertilisation failure, which we will cover in the next blog.
Assisted/artificial oocyte activation (AOA)
There are various AOA methods that can help induce egg activation by mimicking events that normally would happen. These methods can be classified into electrical, chemical, and mechanical. Among them, chemical activation is the most commonly used, where eggs are exposed to chemical agents that can increase their internal calcium concentration. These agents include calcium ionophores, strontium chloride, PLC ζ, and ethanol.
Is AOA safe and effective? This is a hard question to answer because the details of AOA methods published to date vary. There is not yet a standardised protocol of how AOA should be performed, which makes drawing generalised conclusion difficult.
On one hand, there is evidence that AOA methods do not result in exactly the same physiological changes as natural egg activation. We do not know how these changes could affect the offspring’s development and health in the long term. Scientists are concerned that these changes are most likely on the epigenetic level, which may be subtle or only come into effect later in life.pro
A 2015 systematic review included 9 human trial studies and concluded that while some studies reported improved ICSI outcomes when combined with AOA, there is not enough evidence to establish the safety and efficacy of AOA yet.
On the bright side, AOA has been able to rescue cycles showing severe male factor infertility or egg maturation. A recent study involving 1125 eggs revealed that AOA could significantly increase the rates of fertilisation, pregnancy and implantation.
Children born after AOA are being closely followed up, however, the number of this group is very small. The first study on the developmental outcome of AOA born children included 21 children and showed reassuring results. These children had cognitive skills, language skills, motor skills and behaviors that are healthy for their age group. No serious health problems were observed. However, due to the small size of this study, it is too early to say that AOA is safe.
In another study that compared children born after AOA and ISCI with children born with ISI only, researchers reported similar pregnancy and development outcomes. These findings again seem to suggest that AOA methods may be relatively safe.
The goal of AOA is to mimic the events during natural egg activation as closely as possible. However, most artificial activating methods to date do not work exactly the same as a functioning sperm. Therefore, the biggest concern right now is not knowing how such differences might affect the offspring.
Children born after AOA are being closely monitored as we speak. Early reports have not found serious health issues with these children, which is reassuring so far. However, we still need a lot more data and long-term follow up studies to draw definitive conclusions on the safety of AOA methods.
For now, AOA is still not a routine treatment for ICSI fertilisation failure, but it is one of the last resorts to try before considering donor options. Having said that, AOA is not suitable for every couple depending on the cause of infertility. Diagnostic testing following ICSI fertilization failure should be explored, which can help your fertility specialist decide whether AOA methods may help.