Risk of neurodevelopmental disorders in children born from different ART treatments: a systematic review and meta-analysis

Abstract

Background Various techniques in assisted reproductive technology (ART) have been developed as solutions for specific infertility problems. It is important to gain consensual conclusions on the actual risks of neurodevelopmental disorders among children who are born from ART. This study aimed to quantify the relative risks of cerebral palsy, intellectual disability, autism spectrum disorder (ASD), and behavioral problems in children from different ART methods by using systematic review and meta-analysis. Healthcare providers could use the results of this study to suggest the suitable ART technique and plan optimum postnatal care. Methods Pubmed, Google Scholar, and Scopus databases were used to search for studies up to January 2020. Of the 181 screened full manuscripts, 17 studies (9.39%) fulfilled the selection criteria. Based on the Newcastle-Ottawa scale ratings, 7 studies were excluded, resulting in 10 studies that were eventually included in the meta-analyses. Mantel-Haenszel risk ratio model was used in the meta-analysis, and the results are described using forest plot with 95% confidence interval. Heterogeneity was assessed using the I2 value. Results Pooled evaluation of 10 studies showed that the risk of cerebral palsy in children from assisted reproductive technology (ART) is higher than children from natural conceptions (risk ratio [RR] 1.82, [1.41, 2.34]; P = 0.00001). Risk of intellectual disability (RR 1.46, [1.03, 2.08]; P = 0.03) and ASD (RR 1.49 [1.05, 2.11]; P = 0.03) are higher in intracytoplasmic sperm injection (ICSI) children compared to conventional in vitro fertilization (IVF) children. The differences in the risk of neurodevelopmental disorders in children born after frozen and fresh embryo transfers are not significant. Analysis on potential cofounder effects, including multiple birth, preterm birth, and low birth body weight highlight possibilities of significant correlation to the risks of neurodevelopmental disorders. Conclusions Pooled estimates suggest that children born after ART are at higher risk of acquiring cerebral palsy. ICSI treatment causes higher risk of intellectual disability and ASD. These findings suggest the importance of the availability of intensive care unit at the time of delivery and long-term developmental evaluation particularly in children from ICSI.

Association between maternal infertility treatment and child neurodevelopment: findings from the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study in Miyagi and Iwate Prefectures, Japan

“…We also performed analysis adjusted for birth weight and the similar result was obtained ( online supplemental table S7 ). A systematic review of neurodevelopmental disorders, 5 neuromotor, cognitive, language, and behavioural outcomes of children born after ART showed that ART had no significant effect on children’s neuromotor and cognitive development. 6 A previous study showed no significant difference in the neurodevelopmental scores between children conceived through ART and those conceived naturally; however, it showed a decrease in the score units of each scale among children conceived through ART.…”

“… 3 4 Therefore, many studies have investigated the association between ART and neurodevelopmental outcomes. 5–8 …”

DNA Methylation Differences Between Zona Pellucida-Bound and Manually Selected Spermatozoa Are Associated With Autism Susceptibility

“…Several studies have suggested that children born through ICSI have an increased risk of autism and intellectual disability, which may be influenced by paternal characteristics linked to male infertility or the processes of ICSI treatment (4,5,29,30). Kissin et al ( 5) reported a higher incidence of autism in children conceived after ICSI compared with those conceived via conventional IVF in a cohort study of 42,383 children conceived with assisted reproductive technology (1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006).…”

“…Several studies have suggested that children born through ICSI have an increased risk of autism and intellectual disability, which may be influenced by paternal characteristics linked to male infertility or the processes of ICSI treatment ( 4 , 5 , 29 , 30 ). Kissin et al.…”

“…A meta-analysis has reported a higher incidence of intellectual disability and autism, a set of heterogeneous neurodevelopmental conditions characterized by early-onset difficulties in social communication and unusually restricted, repetitive behavior and interests, in children conceived with ICSI ( 4 ). Importantly, the association between autism and ICSI is stronger among children conceived with ICSI for non-male factors, suggesting that autism may be associated with factors besides male infertility factors ( 5 ).During ICSI, the direct injection of a single spermatozoon into the egg bypasses the processes of natural sperm selection that occur during normal fertilization, which may increase the risk of transmission of genetic or epigenetic mutations in spermatozoa that are naturally unable to bind and enter eggs.…”