ABSTRACT
Objective:
This meta-analysis aimed to investigate the risk of neurodevelopmental disorders in children conceived through assisted reproductive technology (ART), focusing on comparisons of neurodevelopment outcomes in children conceived using intracytoplasmic sperm injection (ICSI) and conventional in vitro fertilization (IVF), as well as using frozen and fresh embryo transfers.
Methods:
A systematic literature search of PubMed, Web of Science, Scopus and Embase databases was done for studies focusing on singleton pregnancies, published in the last two decades (from year 2004 onwards to 31st May 2024) and reporting confounder-adjusted effect sizes. Pooled effect sizes were expressed as relative risk (RR) with 95% confidence intervals (CIs). Egger’s test and funnel plots were used to assess publication bias. The certainty of the pooled evidence was assessed using the GRADE approach.
Results:
Analysis of the 13 included studies showed that ICSI correlated with a higher incidence of autism spectrum disorder (ASD) in offspring compared to IVF ART (RR 1.36, 95% CI: 1.05, 1.75). However, the risks of attention-deficit/hyperactivity disorder (ADHD), intellectual disability, cerebral palsy and “any” developmental disorder were similar between the groups. There was no significant difference in neurodevelopmental outcomes, such as ASD, intellectual disability and cerebral palsy, in children conceived after frozen or fresh embryo transfer. The overall quality of evidence for these outcomes was judged to be “Low” according to the GRADE assessment criteria.
Conclusion:
Based on the low-quality evidence, children conceived through ICSI may be at higher risk of ASD compared to children conceived through IVF, while risks of other neurodevelopmental disorders appear similar. Frozen embryo transfer does not seem to increase the risk of neurodevelopmental disorders in offspring compared to fresh transfer.
Registration: PROSPERO: CRD42024557480).
KEYWORDS: Assisted reproductive technology, In vitro fertilization, Neurodevelopmental disorders, Autism spectrum disorder, Intellectual disability
INTRODUCTION
Assisted reproductive technology (ART), such as in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI) and embryo cryopreservation, has become an integral part of infertility treatment.1-3 As ART procedures have become more refined and widespread, the focus of research has expanded beyond immediate pregnancy outcomes to include the long-term health and developmental outcomes of children conceived through these methods.4,5 However, while numerous studies focus on the ART-associated risks of multiple pregnancies, preterm birth and congenital anomalies, the potential impact of these technologies on neurodevelopmental outcomes in offspring remains less clear.6-8 Neurodevelopmental disorders, including cerebral palsy, intellectual impairment, autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD) and behavioral problems, can significantly affect the quality of life and long-term prognosis of affected children. Given the complexity and multifactorial nature of these disorders, it is crucial to understand whether different ART treatments contribute to varying risks.
Outcomes in children born through ART may be affected by several factors, including the specific technique used, the conditions of embryo culture and the stage at which embryos are transferred or cryopreserved.9-11 However, the research of possible links between various AST procedures and neurodevelopmental outcomes is complicated by the challenges in conducting long-term follow-up studies and delayed manifestation of some neurodevelopmental disorders. Several reviews attempted to summarize known data on these associations.12-15 A review conducted by Djuwantono et al. (2020) included six studies comparing ICSI with conventional IVF and frozen with fresh embryo transfer12 and revealed that children born through ICSI had a higher risk of intellectual disability and ASD compared to children born through conventional IVF.
However, the review did not find significant impact of embryo cryopreservation on the risk of neurodevelopmental disorders.12 In another review by Catford et al. (2017), twenty-four studies published between 1995 and 2016 were included, focusing on neurodevelopmental outcomes in children conceived through ICSI compared to IVF.13 However, no formal meta-analysis was conducted and findings were presented narratively. While studies suggested comparable neurodevelopment in children, conceived by IVF and ICSI, ICSI was associated with an increased risk of autism and intellectual impairment.13 This review did not include a comparison between frozen and fresh embryo transfers.
Importantly, current available synthesized evidence is presented mostly in form of narrative reviews and utilizes findings from studies, irrespective of whether they were adjusted for potential confounders or not. Given heterogeneous and sometimes contradictory findings of available studies, there is a need for a comprehensive updated review to draw more definitive conclusions. The current meta-analysis aimed to systematically evaluate the existing literature on neurodevelopmental outcomes in children conceived through different ART procedures and to compare the risks associated with ICSI versus conventional IVF and frozen versus fresh embryo transfer.
METHODS
Search strategy:
A systematic search of PubMed, Web of Science, Scopus and Embase was done to identify studies published until 31st May 2024. Search keywords used were: (reproductive techniques, assisted[mh] OR assisted reproduc*[tw] OR in vitro fertilization[tw] OR in vitro fertilization[tw] OR Intracytoplasmic Sperm Injection (tw) OR frozen embryo transfer [tw] OR frozen embryo transfer[mh] OR fresh embryo transfer[tw] OR fresh embryo transfer[mh]) AND (Child development[mh] OR Child development[tw] OR Cognition[mh] OR Cognition[tw] OR Cognition disorders[mh] OR Developmental disabilities[mh] OR Developmental disabilit*[tw] OR Language disorders[mh] OR Language disorder*[tw] OR Learning disorders[mh] OR Learning disorder* [tw] OR Intelligence[mh] OR Intelligence[tw] OR Intelligence tests[mh] OR child behav*[tw] OR neurobehavioral manifestations[tw] OR neurobehavioral manifestation*[tw]). The search strategy was customized as per the needs of each of the databases. The PRISMA guidelines were followed. Study protocol was pre-registered in PROSPERO; (https://www.crd.york.ac.uk/prospero/),16 (reference number: CRD42024557480).
Screening and selection of the studies:
The initial pool of studies, identified by the search across databases, was deduplicated. Subsequently, unique studies underwent screening of titles and abstracts for relevance by two reviewers (HL & FQ). Full texts of relevant reports were read and eligible studies were included in the final review. To ensure the reliability and accuracy of this selection process, each step was conducted independently by the two authors. Any differences were resolved by consultation with third reviewer (DC).
Inclusion Criteria:
Original research articles that investigated neurodevelopmental outcomes in children conceived through ART and studies focusing on singleton pregnancies were included. The research had to compare either IVF and ICSI techniques or fresh versus frozen embryo transfers. We included studies published in the last two decades (from 2004 onwards) to ensure that the evidence reflected recent advancements in ART, including improvements in scientific rigor, standardized protocols and technological development.17 Additionally, the studies needed to report on outcomes of interest, i.e., cerebral palsy, intellectual impairment, ASD and behavioural problems. Only studies that reported confounder-adjusted effect sizes were included, to minimize bias and ensure the reliability of associations. We also included studies that reported outcomes as mean differences in neurodevelopmental scores between groups, provided these were confounder-adjusted. The studies had to be published in peer-reviewed journals and have a follow-up period extending into early childhood or beyond. There were no language restrictions, although we found no relevant non-English language papers.
Exclusion Criteria:
Review articles, meta-analyses, case reports, editorials, or conference abstracts were excluded. Studies that did not differentiate between various ART techniques or lacked comparative data on neurodevelopmental outcomes were also excluded. Research focusing exclusively on non-neurodevelopmental outcomes, such as immediate birth outcomes or physical growth metrics, was not considered.
Data extraction, quality assessment:
Data were extracted independently by the two authors using a structured extraction form, developed collaboratively after thorough discussions. This form captured critical details such as study identifiers (author and year of publication), study design, child’s age at assessment, methods of assessment and diagnosis, adjusted confounders, sample size and key findings. Any disagreements or discrepancies encountered during the extraction process were resolved through consensus discussions, ensuring consistency and accuracy in the collected data. Newcastle-Ottawa Scale (NOS), with a maximum attainable score of 9, was employed to assess study quality.18 Studies with scores of ≤6, 7-8 and 9 were considered to be low, moderate and high quality respectively.
Statistical analysis:
STATA version 15.0. was used for analyses. The pooled effect sizes were reported as relative risk (RR) with 95% confidence intervals (CIs). A random-effects model was used for the analysis to account for potential variations in participant characteristics and methodological differences across the included studies.19 Funnel plots and Egger’s test20 were used to assess publication biases. Heterogeneity was assessed using I2 statistic with values >50% indicating high heterogeneity. P<0.05 was considered significant. We evaluated the certainty of the evidence using the standard GRADE approach and GRADE Pro software.21
RESULTS
The database search yielded 1687 papers. Of them, 287 duplicate records were removed. Screening of titles and abstracts (Fig.1) eliminated an additional 1357 studies. The full texts of the remaining 43 studies were then reviewed. Ultimately, 13 eligible studies were included in the final meta-analysis (Fig.1).22-34 The important characteristics of the studies have been presented in Table-I. Most studies were retrospective cohort in design (n=10) and the remaining three reports were matched case-control studies. Three studies were from the USA, three from Netherlands and two from Denmark. One study each was from Canada, Taiwan, Australia and Sweden. One study was multicentric. Most studies reported on neurodevelopment outcomes based on the medical records/ICD-based coding (n=8). The remaining five studies used objective assessment or caregiver’s report (Table-I). Studies included a total of 91,589 children conceived by ICSI and 131,746 children conceived by IVF; 32,173 children conceived after frozen and 155,692 after fresh embryo transfer. All studies were of good quality (mean NOS score of 7.31), with seven studies having an NOS score of 8, three studies having a score of 7 and three studies having a score of 6 (Table-II).
Fig.1.
PRISMA flowchart to show process of study selection.
Table-I.
Summary of included studies.
| Author | Study design; location | Comparison between ART techniques | Sample size | Age at assessment | Adjusted for | Diagnosis based on |
|---|---|---|---|---|---|---|
| Velez et al (2023) | RC; Canada | ICSI vs. IVF | ICSI: 2551 IVF: 20968 | Mean 3.9 years | Maternal age, parity, income quintile, rurality, immigration status, smoking, obesity, any drug or alcohol use, maternal history of mental illness or ASD, pre-pregnancy diabetes mellitus or chronic hypertension and infant sex | 2 or more outpatient diagnoses, by either a pediatrician or psychiatrist and/or 1 or more diagnoses during a hospitalization |
| Lo et al (2022) | RC; Taiwan | ICSI vs. IVF | ICSI: 3825 IVF: 3889 | Mean 5.8 years | Maternal age, paternal age, gestation status (full-term or preterm) and offspring sex | ICD-9 or 10 |
| Rönö et al (2022) | RC; Multicentric (Denmark, Finland, Norway and Sweden) | ICSI vs. IVF Frozen vs. Fresh embryo transfer | ICSI: 37,504 IVF: 52,160 | Mean 7.8 years | Offspring sex, mother’s age at delivery, parity, smoking during pregnancy and maternal psychiatric morbidity. | ICD-10 |
| Diop et al (2019) | RC; USA | ICSI vs. IVF | ICSI: 3904 IVF: 4834 | 0 to 3 years | Maternal age, race, education, marital status, nativity), insurance, smoking, prenatal care, parity, gender, method of delivery, chronic and pregnancy hypertension, gestational and chronic diabetes, breech | ICD-9 |
| Hansen et al (2018) | RC; Australia | ICSI vs. IVF Frozen vs. Fresh embryo transfer | ICSI: 618 IVF: 1291 | Median 12.6 years | Offspring sex, year of birth group, parity group, maternal age group, delivery mode and private health insurance | Record based |
| Kissin et al (2015) | RC; USA | ICSI vs. IVF Frozen vs. Fresh embryo transfer | ICSI: 27901 IVF: 13753 | Up to 5 years of age | Infant sex, gestational age, birthweight, maternal and paternal age at delivery, number of previous births, mode of delivery and birth year | Record based (diagnosis based on DSM-IV) |
| Sandin et al (2013) | RC; Sweden | ICSI vs. IVF Frozen vs. Fresh embryo transfer | ICSI: 9241 IVF: 19445 | Mean 10 years | Offspring sex, paternal age, maternal age, maternal psychiatric history at offspring birth, paternal psychiatric history at offspring birth | ICD-9/10 |
| Pinborg et al (2010) | RC; Denmark | ICSI vs. IVF Frozen vs. Fresh embryo transfer | ICSI: 3649 IVF: 7564 | Mean 5.4 years | Maternal age, parity, child year of birth and child gender | Hospital records |
| Zhu et al (2009) | RC; Denmark | ICSI vs. IVF | ICSI: 309 IVF: 1153 | Mean 19.5 months | Maternal age, parity, parental occupational status and child’s age | Caregiver reported responses |
| Knoester et al (2008) | CC; Netherlands | ICSI vs. IVF | ICSI: 83 IVF: 83 | 5 to 8 years | Paternal education, pregnancy complications | Assessment of the child using Revised Amsterdam Child Intelligence Test (RAKIT) |
| Knoester et al (2007) | CC; Netherlands | ICSI vs. IVF | ICSI: 81 IVF: 81 | 5 to 8 years | Paternal smoking during pregnancy, paternal educational level and socio-economic status | Assessment using Child Behaviour Checklist |
| Knoester et al (2007a) | CC; Netherlands | ICSI vs. IVF | ICSI: 81 IVF: 81 | 5 to 8 years | Maternal age, parity and low birthweight | Standardized neuromotor examination |
| Hvidtjørn et al (2006) | RC; Denmark | ICSI vs. IVF Frozen vs. Fresh embryo transfer | ICSI: 1842 IVF: 6444 | 1 to 7 years of age | Maternal educational level, age, parity, gender, multiplicity and preterm delivery. | ICD-10 |
ICSI: intracytoplasmic sperm injection; IVF: in vitro fertilization; RC: retrospective cohort; CC: case-control; ICD- International Classification of Diseases.
Table II.
Risk of bias analysis
| Author | Selection of cohort | Comparability | Outcome assessment | Quality score |
|---|---|---|---|---|
| Velez et al (2023) | 4 | 2 | 2 | 8 |
| Lo et al (2022) | 4 | 2 | 2 | 8 |
| Rönö et al (2022) | 4 | 2 | 2 | 8 |
| Diop et al (2019) | 4 | 2 | 2 | 8 |
| Hansen et al (2018) | 4 | - | 2 | 6 |
| Kissin et al (2015) | 4 | 2 | 2 | 8 |
| Sandin et al (2013) | 4 | 2 | 2 | 8 |
| Pinborg et al (2010) | 4 | 2 | 1 | 7 |
| Zhu et al (2009) | 4 | 2 | 2 | 8 |
| Knoester et al (2008) | 4 | 2 | 1 | 7 |
| Knoester et al (2007) | 4 | - | 2 | 6 |
| Knoester et al (2007a) | 4 | - | 2 | 6 |
| Hvidtjørn et al (2006) | 4 | 2 | 1 | 7 |
Neurodevelopmental outcomes in children conceived by ICSI compared to IVF:
Compared to offspring conceived through IVF, ICSI conception was associated with the increased risk of developing ASD (RR 1.36, 95% CI: 1.05, 1.75; n=6, I2=91.4%) (Fig.2).
Fig.2.
Risk of neurodevelopmental disorders in children born from ICSI compared to conventional IVF.
The risk of ADHD (RR 1.17, 95% CI: 0.96, 1.41; n=2, I2=77.6%), intellectual disability (RR 1.23, 95% CI: 0.82, 1.85; n=4, I2=59.4%), cerebral palsy (RR 0.84, 95% CI: 0.49, 1.43; n=2, I2=0.0%) and “any” developmental disorder (RR 1.30, 95% CI: 0.98, 1.71; n=4, I2=94.0%) was similar between the two groups of children (Fig.2). Publication bias assessment by the Egger’s test and funnel plot was done only for ASD, intellectual disability and “any” developmental disorder because of the small number of studies reporting most outcomes. The Egger’s p-value was statistically non-significant for ASD (p=0.67) and intellectual disability (p=0.68) but significant (p=0.02) for “any” developmental disorder. The overall quality of evidence for the above outcomes was judged to be “Low” according to the GRADE assessment criteria (Table-II).
Frozen compared to fresh embryo transfer:
Frozen and fresh embryo transfer were linked to comparable rates of ASD (RR 0.93, 95% CI: 0.72, 1.22; n=3, I2=33.5%), intellectual disability (RR 0.88, 95% CI: 0.63, 1.23; n=3, I2=0.0%) and cerebral palsy (RR 1.16, 95% CI: 0.31, 4.35; n=2, I2=51.6%) in offspring (Fig.3). The overall quality of evidence was judged to be “Low” according to the GRADE assessment criteria (Table-III).
Fig.3.
Risk of neurodevelopmental disorders in children born from frozen compared to fresh embryo transfer.
Table-III.
Assessing the certainty of the evidence using GRADE approach.
| Outcomes | Number of studies (study design) | Certainty of the evidence (GRADE) | Relative effect (RR) (95% CI) |
|---|---|---|---|
| ICSI compared to IVF | |||
| Risk of ASD | 7 (All cohort) | ⨁⨁◯◯Lowa | RR 1.36 (1.05, 1.75) |
| Risk of ADHD | 2 (All cohort) | ⨁⨁◯◯Lowa | RR 1.17 (0.96 to 1.41) |
| Risk of intellectual disability | 4 (All cohort) | ⨁⨁◯◯Lowa | RR 1.23 (0.82 to 1.85) |
| Risk of cerebral palsy | 2 (All cohort) | ⨁⨁◯◯Low b | RR 0.84 (0.49 to 1.43) |
| Risk of “any” developmental disability | 4 (All cohort) | ⨁⨁◯◯Lowa | RR 1.30 (0.98 to 1.71) |
| Frozen compared to fresh embryo transfer | |||
| Risk of ASD | 3 (All cohort) | ⨁⨁◯◯Low b | RR 0.93 (0.72, 1.22) |
| Risk of intellectual disability | 3 (All cohort) | ⨁⨁◯◯Low b | RR 0.88 (0.63 to 1.23) |
| Risk of cerebral palsy | 2 (All cohort) | ⨁⨁◯◯Lowa | RR 1.16 (0.31 to 4.35) |
Explanations:
a) Downgraded two levels for: non-randomized studies; serious inconsistency (high heterogeneity)
b) Downgraded two levels for: non-randomized studies; imprecise results (wide confidence intervals).
Due to limited number of studies, publication bias using Egger’s test and funnel plot was done only for ASD and intellectual disability. The Egger’s p-value was statistically non-significant for ASD (p=0.90) and intellectual disability (p=0.99).
DISCUSSION
This meta-analysis showed that using ICSI to achieve pregnancy led to slightly higher risk of ASD in offspring compared to IVF. However, the risks of ADHD, intellectual disability, cerebral palsy and “any” developmental disorder were similar in the groups. Similarly, frozen and fresh embryo transfers were associated with a comparable incidence rate of neurodevelopmental disorders in offspring. Our results are consistent with previous reports and reviews12,13 that also showed that while ICSI conception may increase the incidence of ASD, it does not markedly impact the overall risk of other neurodevelopmental disorders compared to conventional IVF.
The observed increased risk of ASD in children conceived through ICSI warrants further investigation into potential underlying mechanisms. One possible explanation could be related to the inherent differences in the patient populations undergoing ICSI versus IVF. ICSI is often used in cases of severe male factor infertility, where sperm quality may be compromised. Therefore, it is plausible that the underlying genetic or epigenetic factors may contribute to the increased risk of ASD in offspring.35,36 Additionally, the invasive nature of ICSI, involving direct injection of sperm into the egg, might potentially impact embryonic development and increase the risk of neurodevelopmental disorders.37 While ASD showed an increased risk with ICSI, the risks of other developmental disorder were similar between ICSI and IVF groups. This suggests that factors contributing to the risk of ASD may be specific to ICSI and may not influence other neurodevelopmental outcomes to the same extent. However, further research is needed to explore these associations comprehensively.
Importantly, our study suggests that the freezing and thawing process involved in frozen embryo transfer does not impact the risk of neurodevelopmental disorders in offspring compared to fresh transfer. This may be due to advances in cryopreservation techniques that minimize potential damage to embryos during freezing and thawing.38,39 Our results have an important clinical significance. Studies show that frozen embryo transfer lowers the risk of ovarian hyperstimulation syndrome.40 Additionally, fertility drugs were shown to negatively affect the lining of the womb and lower implantation rates.41-43 Therefore, frozen embryo transfer could be more beneficial than fresh embryo transfer in improving pregnancy rates. However, further high-quality research is needed.
Limitations.
A small number of studies for some outcomes may have led to the limited ability to detect any significant differences and also affected the robustness of our findings. This is reflected in the “Low” quality of evidence judged according to the GRADE assessment criteria Additionally, heterogeneity across studies and potential publication bias should be acknowledged. The included studies varied in their population characteristics, child age at assessment and method(s) of outcome measurement, which may have contributed to heterogeneity. Particularly, in most studies, assessment of neurodevelopmental disorder was based on medical records or ICD-9/10 coding, which in itself, is a key limitation.
Clinical utility and future research directions:
Medical professionals should acknowledge the possible increased risk of ASD in children conceived through ICSI and provide appropriate counselling to prospective parents. However, it’s important to note that the absolute risk remains relatively low. Moreover, the choice between frozen and fresh embryo transfer does not appear to impact neurodevelopmental outcomes, which is reassuring for couples undergoing ART procedures. Individualized counseling is essential and should consider specific fertility issues of the patients, risk factors and preferences to make informed decisions about the choice of ART technique. Future studies must also focus on understanding the underlying mechanisms behind the observed associations and identifying modifiable risk factors. Prospective longitudinal large-scale studies with longer follow-up periods need to confirm our findings and provide broader insights into neurodevelopmental outcomes. Comparative effectiveness research of different ART techniques and protocols is warranted to identify the safest and most effective approaches while minimizing the risk of neurodevelopmental disorders. Interventional studies aimed at mitigating potential risks associated with ART procedures should be considered, along with multidisciplinary approaches involving clinicians, embryologists, geneticists and neurodevelopmental specialists, to advance our understanding and guide clinical practice effectively.
CONCLUSION
Low-quality evidence suggests that while ICSI may be linked to an increased risk of ASD in offspring, overall risks of neurodevelopmental disorders appear similar between ICSI and IVF and between frozen and fresh embryo transfers. These findings should be further tested in methodologically robust high-quality studies.
Authors’ contributions:
HL: Literature search, study design and manuscript writing.
FQ and DC: Data collection, data analysis, interpretation and Critical Review.
HL: Manuscript revision and validation and is responsible for the integrity of the study.
All authors have read and approved the final manuscript.
Footnotes
Funding: Huzhou Science and Technology Bureau (2023GY39).
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