Children Born From IVM-CAPA vs IVF or Natural Conception

Follow-up of Children Born From CAPA-IVM IVF or Natural Conception: a Prospective Cohort Study

CAPA-IVM is a new promising IVM technique involving the use of a new compound to facilitate the oocyte and embryo competence. CAPA-IVM preserved the maintenance of trans-zonal projections and significantly improved maturation rate and blastocyst yield. NGS analysis of 20 good quality CAPA-IVM blastocysts did not reveal increased aneuploidy compared to age-matched routine ICSI patients. The first CAPA-IVM baby was born in 2017 at My Duc Hospital, Vietnam and up to now, there are 33 babies born from this technique. There is no study to investigate the development of babies born from CAPA-IVM.

Study Overview

• Status: Completed
• Conditions: IVF; IVM
• Intervention / Treatment: Other: Developmental score according to The Ages & Stages Questionnaires®, Third Edition - ASQ®-3; Other: Physical development and General Health; Other: Developmental Red flags

Detailed Description

Assisted reproductive technologies (ART), such as in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI) and in vitro maturation (IVM), are widely used to solve human infertility, and have provided great benefits for millions of couples who have struggled with infertility disorders. The use of ART has been growing persistently and more than 8 million babies worldwide have been born via ART since the first IVF conceived child was born in 1978 (ESHRE monitoring).

During the last two decades, many studies have shown that children born following assisted reproductive techniques (ART) have an increased risk of adverse obstetric, perinatal and short-term follow-up outcomes when compared to naturally conceived (NC) infants (Jackson RA 2004, Helmerhorst et al., 2004; Pinborg et al., 2013; Adams et al., 2015). The etiologies of this association are mainly related to higher proportion of multiple pregnancies due to double embryo transfer option and greater rate of unfavorable comorbidities of infertile women (older age, high BMI, diabetes…). But with the trend toward single embryo transfer in current IVF practice, there are existing evidences supporting that the perinatal risks of singleton gestations following IVF treatment are still higher than those that result from a spontaneous conception (McDonald et al., 2009; Pandey et al., 2012).

Long-term development of children born by ART is also a concerned issue. It is evident that children born as a result of IVF treatment have an excess rate of congenital abnormalities, higher risk of developing metabolic, cardiovascular disorders and subclinical hyperthyroidism in later life (Roger Hart and Robert J. Norman, 2013, part I). Regarding mental health and development outcomes, cerebral palsy and slight neurodevelopmental delay are potential long-term associations with ART (Roger Hart and Robert J. Norman, 2013, part II). However, these adverse outcomes can be explained by obstetric factors (higher rate of prematurity and intrauterine growth restriction) rather than IVF. This leads to the concern about research biases in studies of long-term development of children born by ART where multiple gestations, prematurity, neonatal hospitalization and growth restriction were not well-controlled. Another concern about long-term follow-up studies of IVF children is the limitation of literatures and high-quality clinical trials that investigate the general health outcomes of children born by ART. The majority of valuable data only exist on the short-term outcome of infants born as a result of IVF treatment (Kalra and Barnhart, 2011) even though it is possible that some suspected disorders might only be identifiable beyond the first year of life (Oliver et al., 2012).

When studying about the long-term development of children following ART, a very important factor need to be considered is the medium of culture. There have been existing theories that proposed the mechanism of how epigenetic environment can up or down-regulate a set of genes which then results in the changes in embryonic growth or even the long-term development of children in later stage of life. Different ART methods may cause possible changes in DNA methylation patterns which in turn affect development of the placenta and fetus. This is the "developmental origins of health and disease hypothesis" (DOHaD) explaning why exposure to an adverse environment (possibly the culture medium) may result in unfavorable development and illnesses profiles in the ART offspring (Barker, 2007).

CAPA-IVM is a new promising IVM technique involving the use of a new compound to facilitate the oocyte and embryo competence. CAPA-IVM preserved the maintenance of trans-zonal projections and significantly improved maturation rate and blastocyst yield. NGS analysis of 20 good quality CAPA-IVM blastocysts did not reveal increased aneuploidy compared to age matched routine ICSI patients. The first CAPA-IVM baby was born in 2017 at My Duc Hospital, Vietnam and up to now, there are 33 babies born from this technique. There is no study to investigate the development of babies born from CAPA-IVM.

The investigators therefore conduct this study to investigate the physical and mental development of babies born from CAPA-IVM, IVF or natural conception.

• Study Type: Observational
• Enrollment (Actual): 66

Contacts and Locations

Study Locations

• Vietnam
  • Tan Binh
    • Ho Chi Minh City, Tan Binh, Vietnam
      • Mỹ Đức Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 4 years (Child)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Live babies born from CAPA-IVM, IVF or natural conception

Description

Inclusion Criteria:

• Live babies born from CAPA-IVM
• Live babies born from IVF
• Live babies born from natural conception
• Parents agree to participate

Exclusion Criteria:

• Babies born from oocyte donation cycles
• Babies born from sperm donation cycles
• Babies born from PGT cycles

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
CAPA-IVM; Live babies born from CAPA-IVM	Other: Developmental score according to The Ages & Stages Questionnaires®, Third Edition - ASQ®-3; Ages & Stages Questionnaires®, Third Edition (ASQ®-3) is a developmental screening tool designed for use by early educators and health care professionals. It relies on parents as experts, is easy-to-use, family-friendly and creates the snapshot needed to catch delays and celebrate milestones.; Other: Physical development and General Health; Physical development and General health examination; Other: Developmental Red flags; Developmental Red flags Questionnaires
IVF/ICSI; Live babies born from IVF/ICSI
Natural conception; Live babies born from natural conception	Other: Developmental score according to The Ages & Stages Questionnaires®, Third Edition - ASQ®-3; Ages & Stages Questionnaires®, Third Edition (ASQ®-3) is a developmental screening tool designed for use by early educators and health care professionals. It relies on parents as experts, is easy-to-use, family-friendly and creates the snapshot needed to catch delays and celebrate milestones.; Other: Physical development and General Health; Physical development and General health examination; Other: Developmental Red flags; Developmental Red flags Questionnaires

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The average total ASQ-3 score	ASQ-3 (Ages and Stages Questionares®) has 5 aspects: Communication, Gross motor, Fine motor, Problem solving and Personal-Social; Each aspesct has 6 questions, if the answer is Yes, score = 10, Sometimes = 5 and Not yet = 0.; ASQ-3 average = average score of 5 aspects.	Up to 66 months after birth

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 aspects in each stages has alternative threshold	Up to 66 months after birth
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 aspects in each stages has alternative threshold	Up to 66 months after birth
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 aspects in each stages has alternative threshold	Up to 66 months after birth
Score of Problem solving	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 aspects in each stages has alternative threshold	Up to 66 months after birth
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 aspects in each stages has alternative threshold	Up to 66 months after birth
The presence of red flag signs by age	For children less than 4 monthsRolling prior to 3 monthsPersistent fisting at 3 monthsFailure to alert to environmental stimuli; For children from 4 to 6 monthsPoor head controlFailure to reach for objects by 5 monthsAbsent smile; For children from 6 to 12 monthsAbsent babbling by 6 monthsW-sitting at 7 monthsInability to localize sound by 10 monthsPersistent mouthing of objects at 12 monthsLack of consonant production by 15 months; For children from 12 to 24 monthsLack of imitation by 16 monthsLack of protodeclarative pointing by 18 monthsHand dominance prior to 18 monthsInability to walk up and down stairs at 24 monthsAdvanced non-communicative speech (meaningless communication repertoires)Delayed Language Development milestone (50 single words at 24 months)	Up to 24 months after birth
Duration of breast-feeding	Duration of breast-feeding	Up to 24 months after birth
Infant age at which weaning starts	Infant age at which weaning starts	Up to 24 months after birth
Diseases that lead to hospital admission	Diseases that lead to hospital admission	Up to 24 months after birth
Number of hospital admission	Number of hospital admission	Up to 24 months after birth
Weight	Weight at 3, 6, 12, 18, 24 months and on the examination date	At 3, 6, 12, 18, 24 months and on the examination date
Height	Height at 3, 6, 12, 18, 24 months and on the examination date	At 3, 6, 12, 18, 24 months and on the examination date

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gestational age at delivery	Gestational age at delivery	At birth
Rate of congenital anomalies	Any congenital anomalies detected in baby born	At birth
Mode of delivery	Vaginal birth or C-section	At birth
Birth weight	Weight of baby born	At birth
Length circumference	Length circumference after birth	At birth
Head circumference	Head circumference after birth	At birth
5-min Apgar score	The Apgar score is determined by evaluating the newborn baby on five simple criteria on a scale from zero to two, then summing up the five values thus obtained. The resulting Apgar score ranges from zero to 10. The five criteria are summarized using words chosen to form a backronym (Appearance, Pulse, Grimace, Activity, Respiration).	At 5 minute after birth
Rate of 5-min Apgar score <7	Rate of Apgar score at 5 minute after birth <7	At 5 minute after birth
Rate of Admission to neonatal intensive care unit	Admission to neonatal intensive care unit of baby	Within 7 days after birth
Length of NICU admission	Number of admission days to NICU	Up to 28 days after birth
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
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
Rate of Necrotizing enterocolitis	Necrotizing enterocolitis (NEC) will be diagnosed according to Bell.	Up to 28 days after birth
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
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

Collaborators and Investigators

• Sponsor: Mỹ Đức Hospital

Publications and helpful links

General Publications

• Stephens SM, Arnett DM, Meacham RB. The use of in vitro fertilization in the management of male infertility: what the urologist needs to know. Rev Urol. 2013;15(4):154-60.
• Helmerhorst FM, Perquin DA, Donker D, Keirse MJ. Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies. BMJ. 2004 Jan 31;328(7434):261. doi: 10.1136/bmj.37957.560278.EE. Epub 2004 Jan 23.
• Pinborg A, Wennerholm UB, Romundstad LB, Loft A, Aittomaki K, Soderstrom-Anttila V, Nygren KG, Hazekamp J, Bergh C. Why do singletons conceived after assisted reproduction technology have adverse perinatal outcome? Systematic review and meta-analysis. Hum Reprod Update. 2013 Mar-Apr;19(2):87-104. doi: 10.1093/humupd/dms044. Epub 2012 Nov 14.
• McDonald SD, Han Z, Mulla S, Murphy KE, Beyene J, Ohlsson A; Knowledge Synthesis Group. Preterm birth and low birth weight among in vitro fertilization singletons: a systematic review and meta-analyses. Eur J Obstet Gynecol Reprod Biol. 2009 Oct;146(2):138-48. doi: 10.1016/j.ejogrb.2009.05.035. Epub 2009 Jul 4.
• Pandey S, Shetty A, Hamilton M, Bhattacharya S, Maheshwari A. Obstetric and perinatal outcomes in singleton pregnancies resulting from IVF/ICSI: a systematic review and meta-analysis. Hum Reprod Update. 2012 Sep-Oct;18(5):485-503. doi: 10.1093/humupd/dms018. Epub 2012 May 19.
• Hart R, Norman RJ. The longer-term health outcomes for children born as a result of IVF treatment: Part I--General health outcomes. Hum Reprod Update. 2013 May-Jun;19(3):232-43. doi: 10.1093/humupd/dms062. Epub 2013 Feb 28.
• Hart R, Norman RJ. The longer-term health outcomes for children born as a result of IVF treatment. Part II--Mental health and development outcomes. Hum Reprod Update. 2013 May-Jun;19(3):244-50. doi: 10.1093/humupd/dmt002. Epub 2013 Feb 28.
• Kalra SK, Barnhart KT. In vitro fertilization and adverse childhood outcomes: what we know, where we are going, and how we will get there. A glimpse into what lies behind and beckons ahead. Fertil Steril. 2011 May;95(6):1887-9. doi: 10.1016/j.fertnstert.2011.02.044. Epub 2011 Mar 16.
• Oliver VF, Miles HL, Cutfield WS, Hofman PL, Ludgate JL, Morison IM. Defects in imprinting and genome-wide DNA methylation are not common in the in vitro fertilization population. Fertil Steril. 2012 Jan;97(1):147-53.e7. doi: 10.1016/j.fertnstert.2011.10.027. Epub 2011 Nov 23.
• Barker DJ. The origins of the developmental origins theory. J Intern Med. 2007 May;261(5):412-7. doi: 10.1111/j.1365-2796.2007.01809.x.

Helpful Links

• De Geyter
• Adams: A meta-analysis of neonatal health outcomes

Study record dates

Study Major Dates

• Study Start (Actual): August 7, 2019
• Primary Completion (Actual): September 30, 2019
• Study Completion (Actual): December 15, 2019

Study Registration Dates

• First Submitted: August 2, 2019
• First Submitted That Met QC Criteria: August 6, 2019
• First Posted (Actual): August 7, 2019

Study Record Updates

• Last Update Posted (Actual): October 12, 2020
• Last Update Submitted That Met QC Criteria: October 8, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Other Study ID Numbers: CS/BVMĐ/19/07

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No