Child Follow-up in Women Treated With Conventional IVF or ICSI

Study Overview
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Brief Summary
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To compare the physical, mental and motor development of babies born from pregnancy using ICSI technique and and conventional IVF in non-male factor infertile couples. Based on our previous RCT (NCT03428919), the non-male factor couples were randomly assigned to IVF or ICSI, which leads to the similarity in characteristics of these two groups. Hence, the result of analyzing these offsprings would be preciously valuable.

Detailed Description
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Over the past two decades, intracytoplasmic sperm injection (ICSI) indications have been extended and routinely applied to all cases of assisted reproductive techniques: unexplained infertility, poor-quality oocytes, low oocyte yeild, advanced marternal age, prior failed fertilization with conventional insemination, after in-vitro maturation of oocytes and for cases of cryopreserved oocytes (Practice Committees of the American Society for Reproductive Medicine, 2020). In 2004, fertilization using ICSI accounted for nearly 60% of all aspirations globally. In the Middle East, the number of ICSI cycles increased rapidly from 2000 (47.6%) to 2007 (65.2%), and reached 97.8% in the Middle East in 2007 (Ishihara et al, 2015). Another survey recorded in Europe in 2011, out of a total of 437,510 cycles of fresh embryo transfer, 68% of cycles were performed using ICSI techniques. In male infertility cases, the rate of implementation of ICSI increased from 76.3% to 93.3%. In particular, in cases of non-male-factor infertility, the incidence of ICSI also increased from 15.4% to 66.9%. From 2008-2012, of 494 907 treatment cycles, 74.6% used ICSI. In which, ICSI accounts for 92.9% of the cycle of male infertility and 64.5% of the cycle of non-male-factor infertility (Boulet, 2015). However, ICSI is an invasive technique that bypasses the natural barriers of fertilization. This has led to concern about an increase in the incidence of anomalies in ICSI-born babies as this technique is increasingly being used in all cases of contraception. In contrast, there are studies that have also compared IVF with ICSI and show that in the ICSI cycle, the incidence of multiple pregnancies and low birth weight infants is lower than that of IVF, although there is no difference in infant survival between the two groups (Boulet et al, 2015). In addition to the short-term outcomes, the investigators also have to consider the long-term maternal and neonatal outcomes. There is still not much evidence comparing the effects of the above methods, if any, on the psychomotor development in children. Therefore, the investigators decide to conduct a study to compare the physical, mental and motor development of babies born from pregnancy using ICSI technique and and conventional IVF in non-male factor infertile couples.

Official Title
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Developmental Outcomes of Children Born Through Intracytoplasmic Sperm Injection (ICSI) Versus Conventional in Vitro Fertilization (IVF) in Couples With Non-male Factor Infertility

Conditions
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Conventional IVF, ICSI

Intervention / Treatment
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* Other: Developmental score according to The Ages & Stages Questionnaires®, Third Edition - ASQ®-3
* Other: Physical development and General Health
* Other: Developmental Red flags


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Live babies born from ICSI Versus Conventional IVF in Non-male Factor Couples (NCT03428919) Parents agree to participate in the study. Exclusion Criteria: Babies died after the perinatal period.

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 36 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| ICSI technique<br>In ICSI group, insemination will be performed by using ICSI, 3 - 4 hours after oocyte retrieval. OCCs will be stripped by using hyaluronidase. Only matured oocytes will be inseminated. | Other: Developmental score according to The Ages & Stages Questionnaires®, Third Edition - ASQ®-3<br>* 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.<br>Other: Physical development and General Health<br>* Physical development and General health examination<br>Other: Developmental Red flags<br>* Developmental Red flags Questionnaires<br>|
| Conventional IVF<br>In conventional IVF group, insemination will be performed by conventional IVF. Two hours after retrieval, collected OCCs will be inseminated for another 2 hours, at a concentration of 100,000 motile sperm/ml. Inseminated OCCs will be cultured overnight in culture medium. | Other: Developmental score according to The Ages & Stages Questionnaires®, Third Edition - ASQ®-3<br>* 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.<br>Other: Physical development and General Health<br>* Physical development and General health examination<br>Other: Developmental Red flags<br>* Developmental Red flags Questionnaires<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of patients having abnormal ASQ-3 scores in each aspect | ASQ-3 (Ages and Stages Questionaires®) has 5 aspects: Communication, Gross motor, Fine motor, Problem solving and Personal-Social Each aspect has 6 questions, if the answer is Yes, score = 10, Sometimes = 5 and Not yet = 0. Abnormal ASQ-3 score in an aspect = ASQ-3 score of 2 standard deviations below the mean of the aspect. | 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 rate of children who have at least one red flag sign | He or she has at least one red flag sign by age: From 12 to < 18 month-old: Doesn't crawl Can't stand when supported Doesn't search for things that he/she sees the participants hide Doesn't say single words (baba, mama...) Doesn't learn gestures like waving or shaking head Doesn't point to things Loses skills he/she once had From 18 to < 24 month-old: Doesn't point to show things to others Can't walk Doesn't know what familiar things are for Doesn't gain new words Doesn't have at least 6 words Doesn't notice or mind when a caregiver leaves or returns Lose skills he once had From 24 to < 36 month-old: Doesn't use 2-word phrases Doesn't know what to do with common things, like a brush, spoon Doesn't copy actions and words Doesn't follow simple instructions Doesn't walk steadily Loses skills he/she once had | From 2 to 5.5 years 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 | 
| Name of diseases that lead to hospital admission | Name of diseases that lead to hospital admission | Up to 66 months after birth | 
| Weight | Weight on the examination date | Through study completion, an average of 1.5 months | 
| Height | Height on the examination date | Through study completion, an average of 1.5 months |