Our study found that the full-scale scores were comparable between children born after IVF/ICSI and offspring conceived by AID. But the scores of block design and digit span were significantly lower in IVF/ICSI group.
Some studies have found that ART children perform better intellectual development. Aukje M et al. focused motor performance and physical development on 103 five-year-old children and found a better performance on ICSI children [14]. Likewise, Marco et al. also conducted a cohort study which included 396 children and reported a more positive cognitive development in ART children compared to normal population [17]. This specific phenomenon may associate with ART parents’ characteristics including higher education and income level, which are underlying confounders of these studies. We have adjusted the possible confounders related to economic education level, and found that there is no significant difference in full-scale scores between IVF/ICSI and AID offspring.
Our results are in line with some previous studies. Meijerink et al. accessed mental development in 103 younger ICSI children at the age of 5 years, with the use of the Dutch Wechsler Preschool and Primary Scale of Intelligence test [14]. Compared with general population, they did not detect abnormal condition in ICSI cohort. Punamäki et al. analyzed the mental developmental outcomes of 225 children 7–8 years old born after IVF/ICSI who were matched with 278 spontaneously conceived controls [18], and did not detect any differences between the two groups. Leunens et al. recruited 151 8-year-old children who were born after ICSI and compared their cognitive and motor development with control group. Wechsler Intelligence Scale for Children-Revised (WISC-R) and Movement Assessment Battery for Children (ABC) were used for assessing. And they also found a comparable outcome between two groups.
Although there is no obvious different in FSI, the score of digit span was still low in IVF/ICSI group. The possible mechanism may involve parental factor, metabolic disorders and epigenetic changes.
First, longer parental time-to-pregnancy (TTP) is proven to be associated with offspring neurodevelopmental delays and difficulties. Compared with naturally conceived parents, patients underwent ART mostly have a longer TTP. Maria C et al. conducted a national cohort study aimed to examined associations of parental TTP and conception by ART with neurodevelopmental traits up to 8 years of age. Their research have proven this link between long infertile time and impaired intellectual development. They have found that a longer time-to-pregnant could lead to impairment of language, motor and prosocial skills in children[19]. Second, compared with NC children, ART children are more susceptible to metabolic disorders, such as hyperlipemia [20]. Cui and Zhou et al. conducted a prospective study to investigate metabolic changes in offspring conceived by IVF or ICSI, and recruited 380 children born from IVF/ICSI and 380 naturally conceived children, all aged 6–10 years. The resulted showed that IVF/ICSI children has a worse cardiovascular metabolic condition. Rosenberg et al. reported that hyperlipidemia in children may have an adverse effect on psychology development [21].Another possible factor is epigenetic changes. Epigenetic changes refer to heritable changes in gene function, which ultimately lead to phenotypic changes, in the absence of changes in DNA sequence. The application of ART has been demonstrated a strong link with epigenetic changes in genes of offspring both in animals and humans. Animal studies have reported epigenetic alterations in imprinted genes after embryo culture or superovulation [22, 23]. Moreover, in human, ovulation stimulating drugs are proven to alter gene expression in human granulosa cells. Brannian et al. found differentially expressed genes in granulosa cells which was stimulated by recombinant FSH, including A kinase anchor protein 11 (AKAP11), bone morphogenetic protein receptor II (BMPR2), epidermal growth factor (EGF) and so on [24]. AKAP11 was proven to be associated with a higher risk of schizophrenia [25]. Thus, the change in AKAP11 may bring in varying degrees of brain development disorders. And EGF is a clinical biomarker of prognosis and diagnosis of psychology disorders [26]. Therefore, the changes in genes expression in ART children may be associated with poor intellectual performance. As well as, some ART processes such as manipulation of oocytes and embryo culture cause changes in gene expression patterns in early embryos [27]. The CX43 gene has been shown expressed differently between in-vivo and in-vitro embryo culture in the bovine. And the CX43 gene is the predominant gap junction protein and play a role in many aspects of brain development and physiology, such as intercellular communication and the release of neuroactive substances [28]. Therefore, the change of gene expression may affect the neurodevelopment of ART offspring.
Our study has several strengths. First, the sample size was larger than previous studies, so the results are more reliable. Second, it was elderly children that we focused on the intellectual development born after IVF and ICSI. In many countries, primary school begins from 6-year-old. At this age, children can perform some complex fine motoric tasks such as writing [29]. So the cognitive level of elderly children is more comparable to that of adults than infants, which enables us to evaluate intellectual development more accurately. Third, the WICS-IV questionnaire we used was a diagnose utility in clinic. It has accumulated a lot of data in clinical application and is most commonly administered standardized intelligence tests for children. Additionally, our study is a prospective cohort study and the baseline characteristics of parents and children we collected are more accurately. Therefore, we could adjust the possible confounders more comprehensive, making the results more convincing.
There were still some limitations. The patients undergoing AID other than naturally conceived population were selected for controls. This may lead to some possible biases. Women undergoing AID cannot completely represent the general population. The impact of AID operation such could not be eliminated. Although little research are available, sperm cryopreservation has been suggested to be related to sperm DNA methylation[30]. In the future, studies conducted in naturally conceived women are needed to verify our findings.
In conclusion, our study found that although the score of some items were unfavorable, the full-scale scores were comparable between IVF/ICSI group and control group. The prevalence of infertility is increasing and more and more children will be born after IVF/ICSI, their long-term intellectual development health still need to be evaluated in the future.