Health of Frozen Transferred Versus Fresh Transferred Children

Study Overview
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Brief Summary
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In order to give strong recommendation on the efficacy and safety of fresh versus frozen embryo transfer, we conduct this study in order to investigate the physical and mental development of children from fresh versus frozen embryo transfer. Based on our Freeze-only study (Vuong et al., 2018), the women without polycystic ovary syndrome undergoing the first or second IVF were randomly assigned to receive either fresh or frozen embryos on day 3 after oocyte retrieval, which leads to the similarity in characteristics of these two groups. Hence, the result from analysing these offsprings would be preciously valuable.

Detailed Description
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Since the first live birth after the transfer of a frozen-thawed embryo reported in 1984, cryopreservation has been considered as an enormous revolution in assisted reproductive technology (ART). It is observed that the trend of ART cycles using frozen embryo transfer is on the increase, which leads to a great deal number of children born from frozen embryos. This is the commencement of 2 embryo transfer strategies, the first one is transferring the fresh embryos, the other is freezing all the embryos and transfer them in the next cycle. Comparing these two strategies, up till now, there are 4 published randomized control trials (RCTs) indicating different methods for certain groups of patients (Chen et al., 2016; Shi et al., 2018; Vuong et al., 2018; Wei et al., 2019). Regarding the efficacy, the freeze-all strategy outweighs the fresh embryo transfer in women with polycystic ovary syndrome (PCOS). While that efficacy gets a controversy in non-PCOS or ovulatory patients; two groups of authors indicated that these 2 strategies are equally effective, while the other group claims that the better result goes to cycles with frozen embryos. In term of safety, the rate of ovarian hyperstimulation syndrome (OHSS) is the equivalent or lower in the freeze-all group, which implies the important role of embryo-freezing in avoiding maternal risk. The question that whether freezing the embryos exerts effect on offspring is not thoroughly understood. The mostly used parameter in evaluating the safety of children is the perinatal status of infants, not the development of these children. Searching literature, in 2010, S. Pelkonen published a large cohort study indicating that freezing the embryos do not change the rate of prematurity, low birthweight and being small for gestational age (Pelkonen et al., 2010). Looking further in our freeze-only study, our sub-analysis indicates that the livebirth weight of infants born from frozen embryos is 300 gram heavier than that from fresh embryos (Vuong et al., 2018). Following 4 studies comparing fresh and frozen embryo transfer, children from frozen embryos are similar or higher in term of newborn weight, and there is no study investigate the onward development of childrens born from these two strategies. The only proof on the development of children born from fresh verus frozen embryo is from one study with no randomization which states that children from fresh and frozen embryos share similar academic performance at the age 15-16 (Spangmose et al., 2019). We found no study investigate the impact of different embryo transfer strategies on the growth of children resulting from either fresh or frozen embryos. In order to give strong recommendation on the efficacy and safety of fresh versus frozen embryo transfer, we conduct this study in order to investigate the physical and mental development of children from fresh versus frozen embryo transfer. Based on our Freeze-only study (Vuong et al., 2018), the women without polycystic ovary syndrome undergoing the first or second IVF were randomly assigned to receive either fresh or frozen embryos on day 3 after oocyte retrieval, which leads to the similarity in characteristics of these two groups. Hence, the result from analysing these offsprings would be preciously valuable.

Official Title
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Follow-up of Children Born From Freeze-only Versus Fresh Embryo Transfer: a Follow-up of a Randomized Controlled Trial

Conditions
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IVF, Infertility

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 the first transfer of both freeze-only and fresh embryo transfer group from our Freeze-only study. Parents agree to participate in the study. Exclusion Criteria: Babies died after perinatal period.

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 66 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Freeze-only<br>Children born from freeze-only group and frozen embryo transfer | 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>|
| Fresh<br>Children born from fresh embryo transfer | 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 average total ASQ-3 score | 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. 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. | 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. | 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. | 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. | 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 2 to < 3 year-old: Has very unclear speech Doesn't understand simple instruction • Doesn't speak in sentences Doesn't make eye contact Loses skills he/she once had From 3 to < 4 year-old: Can't jump in place Doesn't play pretend or make-believe • Speaks unclearly Can't retell a favorite story Doesn't use me and you correctly Loses skills he/she once had From 4 to < 5.5 year-old: Is easily distracted, has trouble focusing on one activity for more than 5 minutes • Doesn't talk about daily activities or experiences Shows extreme behavior 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 | 
| Number of hospital admission | Number of 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fresh transfer, freeze-only, ASQ-3, health of children