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. 2022 Feb 7;2022(2):hoac003. doi: 10.1093/hropen/hoac003

Table I.

A comparative overview of study design and outcomes of AOA protocols using various chemical activators.

Endpoint type Study type (AOA stimulus) Fertilized oocytes (Total) Experimental group (Total) Control group Primary findings References
Efficacy

  • Retrospective

  • (Ionomycin)

 Undisclosed

  • History of severe teratozoospermia or previous ICSI failure

  • (50 couples)

 Standard ICSI Rates of fertilization and transferable embryos increased with AOA
Blastulation, pregnancy and implantation rates not improved.		 Li et al. (2019b)
Safety

  • Retrospective

  • (Ionomycin)

  • In vitro matured and transferred

  • (1228)

  • Matched with controls for:

  •  - Female/male age

  •  - Female BMI

  •  - Duration of infertility number of transferred embryos (total and per cycle)

  •  - Type of embryo transferred (cleavage embryo and blastocyst),

  •  - Endometrial thickness on embryo transfer day

  •  - Type of endometrial preparation

  •  - Causes of infertility

  • (676 women)

 Standard ICSI

  • Rates of:

  •  - Biochemical pregnancy

  •  - Clinical pregnancy,

  •  - Implantation

  •  - Miscarriage,

  •  - Ectopic pregnancy

  •  - Multiple pregnancy

  •  - live births

  • Not significantly increased

 Li et al. (2019a)
Safety

  • Retrospective

  • (Ionomycin)

  • In vivo matured

  • (Undisclosed)

  • History of teratozoospermia, severe male fertility or sperm obtained via testicular sperm extraction

  • (1681 couples)

 Standard ICSI

  • Rates of:

  •  - Abortion,

  •  - Major birth defects

  •  - Developmental retardation

  • Not significantly increased

 Deemeh et al. (2015)
Efficacy

  • Prospective, Multi-Centre

  • (Ionomycin)

  • In vivo matured

  • (193)

  • History of ICSI or low fertilization rate.

  • (14 couples)

 Standard ICSI—split by sibling oocytes Fertilization rates in patients with low fertilization history not always increased, even upon pre-screening for OAD. Vanden Meerschaut et al. (2012)
Safety

  • Retrospective

  • (Ionomycin with CaCl2 injection during ICSI)

  • In vivo matured

  • (undisclosed)

  • No fertility history

  • (undisclosed)

 Natural conception No intellectual or language disabilities identified in AOA children D’Haeseleer et al. (2014)
Safety

  • Retrospective

  • (Ionomycin with CaCl2 injection during ICSI)

  • In vivo matured

  • (Undisclosed)

  • History of total ICSI failure, near total ICSI failure, or globozoospermia

  • (14 couples)

 Natural conception Cognitive, language, motor development and behaviour within general population standards Vanden Meerschaut et al. (2014)
Safety

  • Prospective

  • (A23187 vs. Ionomycin)

  • In vitro matured

  • (231)

  • History of poor sperm quality, female factor infertility, or idiopathic infertility

  • (35 women)

 None Congenital malformations detected in 6.3% of children born following ionomycin treatment. Mateizel et al. (2018)
Safety and Efficacy

  • Prospective

  • (Ionomycin with CaCl2 injection during ICSI)

  • In vivo matured

  • (1110)

  • History of ICSI or low fertilization rate due to poor sperm quality.

  • (30 women)

 Standard ICSI from previous cycles

  • Fertilization and pregnancy rates back to normal.

  • No detectable minor or major congenital defects in babies.

 Heindryckx et al. (2008)
Efficacy

  • Prospective

  • (A23187 with GM-CSF vs. Ionomycin)

  • In vitro matured from humans and in vivo matured from mice

  • (69 human, 40 mouse, 420 mouse parthenotes)

  • No history of ICSI failure

  • (42 women)

 ICSI with activation- capable (control) or activation-deficient sperm

  • Mice and human oocytes responded differently to the two ionophores.

  • Mouse oocyte activation and blastulation higher using ionomycin compared to A23187.

  • Neither ionophore restored normal fertilization rates in human in vitro matured oocytes.

 Nikiforaki et al., (2016)
Safety and Efficacy

  • Prospective

  • (A23187 vs. SrCl2)

  • In vivo matured

  • (931)

  • History of ICSI failure or low fertilization rate

  • (50 women for calcimycin, 35 women on SrCl2, 530 women on ICSI without AOA)

 Standard ICSI

  • Both improved fertilization rates

  • Neither increased

  •  - Pregnancy

  •  - Implantation

  •  - Miscarriage

  • Children had no congenital/cognitive abnormalities compared to controls.

 Kyono et al. (2012)
Efficacy

  • Prospective

  • (Ionomycin vs. Ionomycin with SrCl2)

  • In vitro matured

  • (1170)

  • History of infertility with 99%-100% abnormal sperm morphology

  • (66 on ionomycin, 39 on ionomycin with SrCl2)

  • Standard AOA with Ionomycin

  • (no SrCl2)

  • Ionomycin alone gave higher rates of oocyte activation compared to Ionomycin and SrCl2

  • Treatment with SrCl2 improved embryo quality rather than with just Ionomycin.

 Norozi-Hafshejani et al. (2018)
Efficacy

  • Prospective

  • (7% ethanol)

  • In vitro matured, fresh, or vitrified

  • (810)

  • No fertility history

  • (325 women)

 Standard ICSI

  • No improvement in fertilization or cleavage rates

  • Increased rates of high-quality embryogenesis (from both fresh and vitrified oocytes).

 Zhang et al. (2017)
Efficacy

  • Prospective

  • (7% ethanol)

  • Originally failed to mature, were vitrified, and then matured in-vitro

  • (386)

  • No fertility history

  • (undisclosed)

 Standard ICSI Significantly improved high-quality embryo and blastocyst formation rates from vitrified oocytes to those comparable to fresh oocytes. Liu et al. (2013)

AOA, artificial oocyte activation; GM-CSF, granulocyte-macrophage colony stimulating factor; OAD, oocyte activation deficiency.