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

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.