Health of Children Born From ICSI With AOA (AOA-BABIES)

Infertility Clinical Trial

Official title:

Physical, Mental, and Motor Development of Children Born From Intracytoplasmic Sperm Injection With Assisted Oocyte Activation With Calcium Ionophore

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05578118
• Other study ID #: 10/22/DD-BVMD
• Status: Completed
• Start date: August 23, 2022
• Est. completion date: March 30, 2023

Study information

• Verified date: August 2023
• Source: M? Ð?c Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The investigators follow up on the development of children born from ICSI-AOA using the Developmental Red Flags and Ages & Stages Third Edition (ASQ-3) Questionnaires to give strong evidence about the safety of AOA in assisted reproductive technology.

Description:

Intracytoplasmic sperm injection (ICSI) is the most widely utilized assisted reproductive technique (ART) worldwide. Fertilization rates obtained after ICSI treatment are reported between 70 and 80%, representing the most efficient ART; however, complete post-ICSI fertilization failure still occurs in 3-5% of cases.

The leading cause of failed fertilization is failure to achieve oocyte activation, a crucial stage in the initiation of embryo development during fertilization. Assisted oocyte activation (AOA) using a calcium ionophore has been used for over a decade following ICSI fertilization failure. AOA is not considered a routine practice of ART yet, which is only suitable for patients with proper indications, including (i) total fertilization failure or low fertilization rate (<30%) in the previous IVF; (ii) severe male factor infertility; (iii) patients with a history of embryo arrest or poor embryo quality in previous IVF cycle.

Regarding technique, the artificial rise of induced calcium rises cannot precisely mimic the physiologically sperm-induced calcium oscillations. Little is known yet about the possible adverse effects of ionophores on post-implantation embryo development. Numerous studies have been conducted to compare the development of children born from ICSI - AOA versus non-AOA. Thus, the investigators performed this study to investigate the physical, mental, and motor development of children born following ICSI - AOA using the Developmental Red Flags and Ages & Stages Third Edition (ASQ-3) Questionnaires.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 63
• Est. completion date: March 30, 2023
• Est. primary completion date: March 30, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Months to 12 Months

Eligibility

Inclusion Criteria:

All single, live babies born following ICSI with AOA and ICSI without AOA from 08/2020 to 04/2021.

Parents consent to participate in the study. Group ICSI+AOA: Embryos from ICSI with AOA with calcium ionophore

In the ICSI+AOA group, indications of AOA are:

• Previous failed IVF treatment with no fertilization or poor fertilization rate (fertilized oocytes/pick-up oocytes<35%) or poor embryo result (number of embryos/pick-up oocytes<35%, <3 embryos, no good-quality embryo)

• Using sperm after retrieval technique, cryptozoospermia Group Control: Embryos from ICSI without AOA.

In the Control group, the indications of AOA for the next IVF cycle (if patients continue the next IVF cycle) are:

• Currently failed IVF treatment with no fertilization or poor fertilization rate (fertilized oocytes/pick-up oocytes<35%) or poor embryo result (number of embryos/pick-up oocytes<35%, <3 embryos, no good-quality embryo)

Exclusion Criteria:

Embryos with PGT. Oocyte donation

Related Conditions & MeSH terms

• Infertility
• Intracytoplasmic Sperm Injection

Locations

Country	Name	City	State
Vietnam	M? Ð?c Hospital	Ho Chi Minh City

Sponsors (1)

Lead Sponsor	Collaborator
M? Ð?c Hospital

Country where clinical trial is conducted

Vietnam, 

References & Publications (23)

Alberio R, Zakhartchenko V, Motlik J, Wolf E. Mammalian oocyte activation: lessons from the sperm and implications for nuclear transfer. Int J Dev Biol. 2001 Oct;45(7):797-809. — View Citation

Bos-Mikich A, Whittingham DG, Jones KT. Meiotic and mitotic Ca2+ oscillations affect cell composition in resulting blastocysts. Dev Biol. 1997 Feb 1;182(1):172-9. doi: 10.1006/dbio.1996.8468. — View Citation

Capalbo A, Ottolini CS, Griffin DK, Ubaldi FM, Handyside AH, Rienzi L. Artificial oocyte activation with calcium ionophore does not cause a widespread increase in chromosome segregation errors in the second meiotic division of the oocyte. Fertil Steril. 2 — View Citation

D'haeseleer E, Vanden Meerschaut F, Bettens K, Luyten A, Gysels H, Thienpont Y, De Witte G, Heindryckx B, Oostra A, Roeyers H, Sutter PD, van Lierde K. Language development of children born following intracytoplasmic sperm injection (ICSI) combined with a — View Citation

Ducibella T, Huneau D, Angelichio E, Xu Z, Schultz RM, Kopf GS, Fissore R, Madoux S, Ozil JP. Egg-to-embryo transition is driven by differential responses to Ca(2+) oscillation number. Dev Biol. 2002 Oct 15;250(2):280-91. — View Citation

Ebner T, Oppelt P, Wober M, Staples P, Mayer RB, Sonnleitner U, Bulfon-Vogl S, Gruber I, Haid AE, Shebl O. Treatment with Ca2+ ionophore improves embryo development and outcome in cases with previous developmental problems: a prospective multicenter study — View Citation

Eftekhar M, Janati S, Rahsepar M, Aflatoonian A. Effect of oocyte activation with calcium ionophore on ICSI outcomes in teratospermia: A randomized clinical trial. Iran J Reprod Med. 2013 Nov;11(11):875-82. — View Citation

Fawzy M, Emad M, Mahran A, Sabry M, Fetih AN, Abdelghafar H, Rasheed S. Artificial oocyte activation with SrCl2 or calcimycin after ICSI improves clinical and embryological outcomes compared with ICSI alone: results of a randomized clinical trial. Hum Rep — View Citation

Heytens E, Soleimani R, Lierman S, De Meester S, Gerris J, Dhont M, Van der Elst J, De Sutter P. Effect of ionomycin on oocyte activation and embryo development in mouse. Reprod Biomed Online. 2008 Dec;17(6):764-71. doi: 10.1016/s1472-6483(10)60403-8. — View Citation

Hirata, K., Nakamura, Y., Hattori, H., Kuchiki, M., Sakamoto, E., & Kyono, K. (2013). Follow-up child growth regarding new technologies: Testicular sperm extraction (TESE), in vitro maturation (IVM), and assisted oocyte activation (AOA). Fertility and Ste

Kashir J, Nomikos M, Lai FA, Swann K. Sperm-induced Ca2+ release during egg activation in mammals. Biochem Biophys Res Commun. 2014 Aug 1;450(3):1204-11. doi: 10.1016/j.bbrc.2014.04.078. Epub 2014 Apr 21. — View Citation

Kim BY, Yoon SY, Cha SK, Kwak KH, Fissore RA, Parys JB, Yoon TK, Lee DR. Alterations in calcium oscillatory activity in vitrified mouse eggs impact on egg quality and subsequent embryonic development. Pflugers Arch. 2011 May;461(5):515-26. doi: 10.1007/s0 — View Citation

Koo OJ, Jang G, Kwon DK, Kang JT, Kwon OS, Park HJ, Kang SK, Lee BC. Electrical activation induces reactive oxygen species in porcine embryos. Theriogenology. 2008 Oct 15;70(7):1111-8. doi: 10.1016/j.theriogenology.2008.06.031. — View Citation

Miller N, Biron-Shental T, Sukenik-Halevy R, Klement AH, Sharony R, Berkovitz A. Oocyte activation by calcium ionophore and congenital birth defects: a retrospective cohort study. Fertil Steril. 2016 Sep 1;106(3):590-596.e2. doi: 10.1016/j.fertnstert.2016 — View Citation

Ozil JP, Banrezes B, Toth S, Pan H, Schultz RM. Ca2+ oscillatory pattern in fertilized mouse eggs affects gene expression and development to term. Dev Biol. 2006 Dec 15;300(2):534-44. doi: 10.1016/j.ydbio.2006.08.041. Epub 2006 Aug 25. — View Citation

Ozil JP, Huneau D. Activation of rabbit oocytes: the impact of the Ca2+ signal regime on development. Development. 2001 Mar;128(6):917-28. doi: 10.1242/dev.128.6.917. — View Citation

Swann K, Ozil JP. Dynamics of the calcium signal that triggers mammalian egg activation. Int Rev Cytol. 1994;152:183-222. doi: 10.1016/s0074-7696(08)62557-7. No abstract available. — View Citation

Tesarik J, Sousa M. Key elements of a highly efficient intracytoplasmic sperm injection technique: Ca2+ fluxes and oocyte cytoplasmic dislocation. Fertil Steril. 1995 Oct;64(4):770-6. doi: 10.1016/s0015-0282(16)57853-4. — View Citation

Vanden Meerschaut F, Leybaert L, Nikiforaki D, Qian C, Heindryckx B, De Sutter P. Diagnostic and prognostic value of calcium oscillatory pattern analysis for patients with ICSI fertilization failure. Hum Reprod. 2013 Jan;28(1):87-98. doi: 10.1093/humrep/d — View Citation

Vanden Meerschaut F, Nikiforaki D, De Roo C, Lierman S, Qian C, Schmitt-John T, De Sutter P, Heindryckx B. Comparison of pre- and post-implantation development following the application of three artificial activating stimuli in a mouse model with round-he — View Citation

Vanden Meerschaut F, Nikiforaki D, Heindryckx B, De Sutter P. Assisted oocyte activation following ICSI fertilization failure. Reprod Biomed Online. 2014 May;28(5):560-71. doi: 10.1016/j.rbmo.2014.01.008. Epub 2014 Jan 31. — View Citation

WHO child growth standards: Length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass index-for-age: Methods and development. (n.d.). Retrieved June 10, 2022, from https://www.who.int/publications-detail-redirect/924154693X

Yoshida S, Plant S. Mechanism of release of Ca2+ from intracellular stores in response to ionomycin in oocytes of the frog Xenopus laevis. J Physiol. 1992 Dec;458:307-18. doi: 10.1113/jphysiol.1992.sp019419. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Gestational age at delivery	Gestational age at delivery	At birth
Other	Mode of delivery	Vaginal birth or C-section	At birth
Other	Birth weight	Weight of baby born	At birth
Other	Length circumference	Length circumference after birth	At birth
Other	Head circumference	Head circumference after birth	At birth
Other	Rate of congenital anomalies	Any congenital anomalies detected in baby born	At birth
Other	Length of neonatal intensive care unit (NICU) admission	Number of admission days to NICU	Up to 28 days after birth
Other	Rate of Respiratory distress syndrome	Respiratory distress syndrome (RDS), diagnosed as the presence of tachypnoea >60/minute, sternal recession and expiratory grunting, need for supplemental oxygen, and a radiological picture of diffuse reticulogranular shadowing with an air bronchogram	Up to 28 days after birth
Other	Rate of Periventricular haemorrhage	Periventricular haemorrhage II B or worse, will be diagnosed by repeated neonatal cranial ultrasound by the neonatologist according to the guidelines on neuro-imaging described by de Vries et al.	Up to 28 days after birth
Other	Rate of Necrotizing enterocolitis	Necrotizing enterocolitis (NEC) will be diagnosed according to Bell.	Up to 28 days after birth
Other	Rate of Proven sepsis	Proven sepsis, will be diagnosed on the combination of clinical signs and positive blood cultures.	Up to 28 days after birth
Other	Rate of Composite of poor perinatal outcomes	Composite of poor perinatal outcomes, defined as intraventricular haemorrhage, respiratory distress syndrome, necrotizing enterocolitis or neonatal sepsis.	Up to 28 days after birth
Other	Rate of long-term illness and chronic conditions	Any long-term illness and chronic condition appears in a child.	Up to 28 days after birth
Primary	The percentage of abnormal ASQ-3 score	ASQ-3 (Ages and Stages Questionaires®) has 5 aspects: Communication, Gross Motor, Fine Motor, Problem-solving, and Personal-Social Each element has 6 questions. If the answer is Yes, score = 10, Sometimes = 5, and Not yet = 0.; ASQ-3 average = average score of 5 aspects.	12 months after birth
Secondary	Score of Communication	6 questions, if the answer is Yes, score = 10, Sometimes = 5 and Not yet = 0. Total score will be used: minimum = 0 and maximum = 60. Each aspect in each stage has an alternative threshold.	12 months after birth
Secondary	Score of Gross motor	6 questions, if the answer is Yes, score = 10, Sometimes = 5 and Not yet = 0. Total score will be used: minimum = 0 and maximum = 60. Each aspect in each stage has an alternative threshold.	12 months after birth
Secondary	Score of Fine motor	6 questions, if the answer is Yes, score = 10, Sometimes = 5 and Not yet = 0. Total score will be used: minimum = 0 and maximum = 60. Each aspect in each stage has an alternative threshold.	12 months after birth
Secondary	Score of Problem-solving skill	6 questions, if the answer is Yes, score = 10, Sometimes = 5 and Not yet = 0. Total score will be used: minimum = 0 and maximum = 60. Each aspect in each stage has an alternative threshold.	12 months after birth
Secondary	Score of Personal-Social	6 questions, if the answer is Yes, score = 10, Sometimes = 5 and Not yet = 0. Total score will be used: minimum = 0 and maximum = 60. Each aspect in each stage has an alternative threshold.	12 months after birth
Secondary	The rate of children who have at least one red flag sign(s):	For children at 12 months: they; No response when being called by their name; Does not understand "no"; Can not stand even when being supported; Apathy or non-observance of the caregiver; Does not look at the point where the caregiver points	12 months after birth
Secondary	Duration of breastfeeding	Duration of breastfeeding	12 months after birth
Secondary	Infant age at which weaning starts	Infant age at which weaning starts	12 months after birth
Secondary	Name of diseases that lead to hospital admission	Name of diseases that lead to hospital admission	12 months after birth
Secondary	Number of hospital admission	Number of hospital admission	12 months after birth
Secondary	Weight	Weight on the examination date	12 months after birth
Secondary	Height	Height on the examination date	12 months after birth