Calcium ionophore (AOA): proven for fertilisation failure

The study

Study population

The meta-analysis is about couples with fertilisation problems after ICSI, which is an oocyte-activation issue and is often a sperm-side one. Newer studies also extend it to patients whose embryos developed poorly in a previous cycle.

Methodology

• The meta-analysis pooled 22 studies comparing ICSI with calcium ionophore against ICSI alone, for fertilisation, blastocyst formation, implantation, clinical pregnancy, live birth, miscarriage, birth defects and sex ratio.
• The newer development and euploidy studies compared the same patient across two cycles: each patient's earlier cycle without activation served as her own control, which removes a lot of the between-patient noise.

What they found

It roughly doubles pregnancy and live birth for fertilisation failure

Clinical pregnancy (odds ratio 2.14) and live birth (odds ratio 2.65) both rose, and so did fertilisation, blastocyst formation and implantation. The benefit was in patients with previous fertilisation failure or low fertilisation, not in those whose problem was embryo development.

Newer data extends it to embryo development

In a same-patient study of women with poor embryo development (BMC 2022), calcium ionophore raised good-quality day-3 embryos, blastocyst formation and the usable-embryo rate, across age bands including 40 and over, where blastocyst and usable rates still improved even though fertilisation did not.

A preliminary euploidy signal

A same-patient study in women with poor blastocyst formation (Kim 2023) found blastocyst formation rose in every age group except 42 and over, where it was directionally better but the numbers were very small and those patients started with a low blast count. Euploidy was significantly higher in the 35 to 39 band. The authors call for prospective data before drawing euploidy conclusions.

The untested frontier

No study has tested calcium ionophore on women who fertilise normally and have good embryo numbers but a euploidy problem. So using it there is off the current evidence, though it's biologically plausible and hasn't been contradicted.

Is it safe?

Because calcium ionophore is often used in rarer cases of complete fertilisation failure, the safety studies are small, often under 100 women with live-birth groups of 30 or fewer. Within that limit the data is reassuring. A meta-analysis of five studies found no significant difference in birth defects between conventional ICSI and ICSI with AOA. A study of the A23187 ionophore in PGT cycles found congenital malformations within the normal range and a higher blastocyst formation rate. Multicentre work using a ready-to-use ionophore reported apparently healthy offspring, and a case series following children aged three to ten after AOA found reassuring neonatal, developmental and behavioural outcomes, though the authors call it preliminary. There's a theoretical concern, because calcium signalling is involved in genome methylation, that activation could affect imprinting, but the birth-defect data so far doesn't show any indication of that. Adverse events do occur, but at the normal background rate, which points away from calcium ionophore being the cause.

What it means for older women

With age, both a woman's euploidy rate and her fertilisation rate fall, and calcium ionophore touches both. The euploidy side is the harder one for the evidence: the development and euploidy signals so far come from patients selected for poor embryo development, not from older women who fertilise normally and have a euploidy problem. So it's not a proven euploidy treatment, and it shouldn't be sold as one.

The part that gets less attention is fertilisation. Fertilisation rates also fall with age. One study of over 3,000 IVF cycles found the fertilisation rate dropped from about 74% under 30, to 67% at 40 to 44, to 48% at 45 and over, as egg numbers and egg quality decline together. So fertilisation problems, the very thing calcium ionophore is proven to help, become more common as women get older, not less. For an older woman whose eggs haven't fertilised well, this is a proven, one-off laboratory step, not a speculative one.

Put together, calcium ionophore is on solid ground for the fertilisation problems that grow with age, and on hopeful but unproven ground for the euploidy problem that defines it. The safety data is reassuring and it's a single lab step rather than another full cycle, so for an older woman with fertilisation or development problems, or one weighing the euploidy question, it's a reasonable thing to raise with a clinic rather than rule out.

Evidence strength

The efficacy for fertilisation failure rests on 22 studies, though only five are randomised, so the headline is solid and the quality is mixed. The development and euploidy findings are newer, same-patient and preliminary. The safety data is reassuring but comes from small samples. It's strong enough to treat fertilisation failure with confidence and to take the development question seriously, but not strong enough to promise a euploidy benefit for women who fertilise normally.

Things you can discuss with your doctor

• Find out why your fertilisation or development failed. Calcium ionophore fixes a specific problem, oocyte activation, so the reason matters.
• If you've had failed or very low fertilisation after ICSI, ask your clinic about assisted oocyte activation. It's a one-off laboratory add-on, not another whole cycle.
• If the sperm issue is teratozoospermia, raise the sibling-egg finding that AOA may not help and may lower top-quality embryos.
• If you fertilise normally but have a euploidy problem, know that this use is untested. It's reasonable to discuss it as an option with your clinic, understanding the evidence isn't there yet.

Source: Shan Y, Zhao H, Zhao D, et al. Assisted Oocyte Activation With Calcium Ionophore Improves Pregnancy Outcomes and Offspring Safety in Infertile Patients. Front Physiol, 2022;12:751905.

Written by

Michelle Bourke

Founder of Better IVF. I went through IVF over 38 myself, and I write these guides to be the clear, properly-sourced resource I wish I'd had, more honest than the forums and deeper than the clinic pages.