A review of the association between in vitro fertilization and children’s neurocognitive development

Abstract

This review investigated the current research on the association between in vitro fertilization and children’s neurocognitive development. Twenty studies were analyzed, encompassing over 23,000 children conceived through IVF, and compared to those conceived naturally. The findings on overall cognitive function were mixed, as measured by IQ. Some studies showed no significant differences between IVF and naturally conceived children, while others suggested slight variations. There is emerging evidence that IVF might correlate with specific cognitive domains like language and motor skills, although more research is needed. Several established factors, including maternal age, education level, and birth weight, are associated with children’s cognitive development, regardless of conception method. Future research should explore how these factors interact with IVF and investigate a broader range of cognitive domains. Socioeconomic background and parental involvement are essential considerations for understanding a child’s developmental trajectory. The inconclusive nature of some findings highlights the need for further research with larger sample sizes, more extended follow-up periods, and robust methodologies. This research has potential implications for parents considering IVF or ICSI, healthcare professionals providing guidance, and future efforts to tailor support systems for children conceived through assisted conception techniques. Open communication about the current state of knowledge and responsible communication of research findings is crucial.

Introduction

In vitro fertilization (IVF) has revolutionized the field of assisted reproductive technologies (ART), offering a beacon of hope for couples facing infertility. Since its inception, this technology has facilitated the birth of over 10 million babies worldwide as of 2022 [1]. While the initial focus of IVF research centered on achieving successful pregnancies and ensuring the immediate health of newborns, the scope of the inquiry has broadened to include the long-term well-being of children conceived through this method [2]. A crucial aspect of this expanded focus is understanding the potential impact of IVF on neurocognitive development.

Brain development is a dynamic process, demonstrably sensitive to the environment during the prenatal period [2]. IVF procedures introduce two key factors that warrant exploration for their potential influence on neurocognitive outcomes. Firstly, ovarian stimulation medications stimulate the ovaries and promote multiple egg production. This intervention can alter the hormonal milieu surrounding the developing embryo, potentially impacting its early development [3]. Secondly, the laboratory environment where fertilization and early embryonic development occur differs significantly from the natural in vivo environment within the woman's body. While advancements in IVF techniques strive to replicate natural conditions, concerns linger about potential effects on early embryonic development due to these environmental discrepancies [4].

These factors have spurred a surge in research investigating potential neurocognitive consequences in children born through IVF. Early studies presented a mixed picture, with some suggesting a possible association with an increased risk of neurodevelopmental disorders [5, 6]. However, more recent and robust studies have yielded a more reassuring picture. Despite this progress, several crucial questions still need to be answered. Most studies focus on children in mid-childhood [6, 7]. Are there any long-term neurocognitive effects of IVF that emerge later in life, potentially impacting areas like social cognition or executive function? This paper aims to review the current knowledge on the neurocognitive outcomes of children (0 to 12 years) born following IVF. This review summarizes the current understanding of neurocognitive outcomes in children conceived through IVF, focusing on overall cognitive function, specific cognitive domains such as language and motor skills, and other factors, including maternal age and birth weight. It also discusses the implications of these findings for parents and healthcare professionals, followed by the limitations of the current research and suggestions for future studies.

Methods

A search was conducted using PubMed, DOAJ, Google Scholar, Scopus, and Cochrane Library—Fig. 1. The search terms combined keywords related to the population of interest, the outcomes assessed, and the comparison group. For the population, keywords like “in vitro fertilization,” “IVF,” or “ART” (assisted reproductive technology) were used. Outcomes were captured with terms like “neurocognitive outcome,” “cognitive function,” “intelligence quotient” (IQ), “behavioral assessment,” or “developmental outcome.” Finally, the comparison group was identified with keywords like “naturally conceived” or “spontaneous conception.” The search was refined by applying date filters (2000–April 2024) and language filters (English). Additionally, reference lists of relevant articles were hand-searched to identify eligible studies missed by the initial electronic search.

Fig. 1.

Screening process

Inclusion Criteria

• Studies published in peer-reviewed journals after 2000 (to capture recent findings)

• Studies investigating the neurocognitive outcomes (cognitive function, behavioral assessments) in children conceived through IVF compared to naturally conceived children.

• Studies involving children of any age group (0 to 12 years)

Exclusion criteria

• Studies solely focused on non-human subjects (e.g., animal models)

• Studies investigating specific medical conditions or interventions in children born through IVF (unless neurocognitive outcomes are a primary outcome)

• Reviews, commentaries, or editorials

Two independent reviewers (EAB and NA) screened the search results based on titles and abstracts to identify potentially relevant studies. Full-text articles of studies meeting the initial criteria were retrieved and further assessed for eligibility by both reviewers. Any discrepancies in selection were resolved through discussion or consulting a third reviewer (EK). A standardized data extraction form collected relevant information from each included study.

A narrative synthesis approach was employed to summarize and integrate findings from the included studies. The studies were grouped based on their methodological designs and the specific cognitive outcomes assessed. This categorization facilitated a clearer comparison of findings across different studies. For studies reporting conflicting results, we considered factors such as sample size, study design, and population characteristics. Conflicting findings were discussed in detail, highlighting potential reasons for discrepancies, such as differences in assessment tools, demographic factors, or the specific IVF techniques used. This approach aimed to provide a balanced view of the evidence while acknowledging the complexities of synthesizing findings from diverse studies.

Results

This review analyzed 20 studies [8–27] that investigated the neurocognitive development in children conceived through IVF compared to those conceived naturally—Table 1. Over 23,000 children were included in these studies, with the number of participants per study ranging from 63 to 10,137. The majority (16) were observational studies, which included designs like cohort, case–control, and comparative studies. There were also two retrospective cohort studies and one controlled, blinded study included in the analysis. The mean age across the study was 13.55 years old. Verbal Intelligence was assessed through established instruments such as the Wechsler Preschool and Primary Scale of Intelligence (WPPSI), utilized in studies [8, 9, 11], and the Wechsler Intelligence Scale for Children (WISC) [10, 13, 16]. Non-verbal intelligence was examined through assessment with the Kaufman Assessment Battery for Children (K-ABC) in the study [17]. Additional non-verbal measures have also been explored in studies [20, 21]. Emotional intelligence was addressed in several studies that incorporate measures of emotional functioning. The Five to Fifteen Parent Questionnaire was utilized in one study [22] and assesses cognitive and emotional development, offering a dual perspective on how these dimensions interact and influence overall cognitive outcomes.

Table 1.

Characteristics of included studies

Studies on language skills
Author and year	Study design	Sample size	IVF type	Cognitive assessment used	Key findings on language skills	Quality indicators
Gucuyener et al. (2011)	Prospective cohort study	286	IVF	Stanford-Binet and Peabody Picture Vocabulary Test	IVF children had significantly lower language scores than NC children	Reliable measures, clear outcomes
Punamäki et al. (2016)	Prospective follow-up study	533	ICSI & IVF	Five to Fifteen Parent Questionnaire	No overall differences in cognitive problems between ART and NC children	Parental report limitations
Wagenaar et al. (2009)	Cross-sectional study	282	IVF	Dutch CITO test, ANT, various motor tests	18% of NC and 14% of IVF children had developmental disorders; not statistically significant	Small sample, limited follow-up
Vo et al. (2021)	Prospective cohort study	935	ICSI	Revised Brunet-Lezine scale	IVF children had double the rate of low language developmental quotients compared to NC children	Clear design, good sample size
Studies on motor skills
Author and year	Study design	Sample size	IVF type	Cognitive assessment used	Key findings on motor skills	Quality indicators
Strömberg et al. (2002)	Population-based cohort	17,040	IVF	Records from Habilitation Centers, ICD-10	IVF children had a higher risk of developing cerebral palsy	Comprehensive data sources
Verhaeghe et al. (2022)	Prospective cohort study	4,349	IVF & ICSI	WPPSI-IV, GMFCS	No significant differences in developmental coordination disorders between ART and NC	Robust sample, clear outcomes
Kim et al. (2022)	Prospective cohort study	2,818	IVF	Bayley Scales of Infant and Toddler Development	No significant differences in developmental delays or disabilities	Low follow-up rate noted
Studies on cognitive outcomes (IQ)
Author and year	Study design	Sample size	IVF type	Cognitive assessment used	Key findings on IQ outcomes	Quality indicators
Ponjaert-Kristoffersen et al. (2005)	Observational cohort study	1,423	IVF & ICSI	WPPSI-R	No significant differences in IQ scores among ICSI, IVF, and NC children	Strong design, large sample size
Levy-Shiff et al. (1998)	Observational, case–control	102	IVF/ET	WISC-R, various tests	No significant IQ differences between NC and IVF children	Small sample, focused outcomes
Schendelaar et al. (2016)	Prospective cohort study	293	IVF	Kaufmann-ABC-II	Most children scored within the normal IQ range; subfertility linked to lower cognition	Age-related confounding noted
IVF vs. ICSI studies
Author and year	Study design	Sample size	IVF type	Cognitive assessment used	Key findings on IVF vs. ICSI	Quality indicators
Goldbeck et al. (2009)	Comparative study	69	IVF & ICSI	K-ABC	ICSI children had lower IQ than IVF children, but all within the normal range	Small sample, direct comparison
Knoester et al. (2008)	Comparative study	254	IVF & ICSI	Revised Amsterdam Child Intelligence Test	Lower IQ scores in ICSI singletons compared to IVF singletons; significant compared to NC	Small size, significant findings

Stanford-Binet and Peabody Picture Vocabulary Test: The Stanford-Binet IQ test has a mean score of 100 with a standard deviation of 15, where an IQ below 70 is considered significantly below average. The Peabody Picture Vocabulary Test has a mean score of 100 and a standard deviation of 15, with scores below 85 indicating potential vocabulary deficits

Five to Fifteen Parent Questionnaire: This tool assesses cognitive and behavioral development from the parent's perspective, providing normative data for interpretation. Scores are interpreted relative to normative benchmarks

Dutch CITO test, ANT, various motor tests: Average scores set around 100 (with a standard deviation of 15). Cutoff scores vary based on age and developmental stage, with scores significantly below average indicating potential learning difficulties

Revised Brunet-Lezine scale: A developmental assessment tool that evaluates children’s cognitive and motor skills based on normative data. Scores are compared to age-specific norms, where scores below the 10th percentile indicate potential developmental delays

Records from Habilitation Centers, ICD-10: This data source records developmental and health outcomes, including diagnoses of cerebral palsy, based on ICD-10 classification. Diagnosis is based on clinical criteria, and the specific cut-off for diagnosis varies according to the ICD-10 criteria

WPPSI-IV, GMFCS: The WPPSI-IV is a widely used measure of cognitive abilities for preschool-aged children, with a mean score of 100 and a standard deviation of 15. The Gross Motor Function Classification System (GMFCS) provides a classification of gross motor function, with levels ranging from Level I (least severe) to Level V (most severe), where higher levels indicate greater disability

Bayley Scales of Infant and Toddler Development: This tool evaluates developmental functioning in infants and toddlers, with scores compared to normative data. A developmental quotient (DQ) below 70 is typically considered indicative of a developmental delay

WPPSI-R: The Wechsler Preschool and Primary Scale of Intelligence—Revised measures of cognitive ability in preschool children, with a mean score of 100 and a standard deviation of 15. Scores below 70 indicate significantly below-average intellectual functioning

WISC-R, various tests: The Wechsler Intelligence Scale for Children—Revised measures a child’s intellectual functioning, with average scores around 100. Scores below 70 indicate significant cognitive impairment, while scores above 130 suggest giftedness

Kaufmann-ABC-II: An assessment that evaluates cognitive abilities in children, providing scores that indicate functioning levels relative to normative data. Scores below 80 are generally considered below average, indicating potential developmental concerns

K-ABC: The Kaufman Assessment Battery for Children assesses cognitive development across various domains, with a normative mean of 100. Scores below 85 indicate potential cognitive challenges, while scores above 115 suggest advanced abilities

Revised Amsterdam Child Intelligence Test: A standardized IQ test used to evaluate cognitive abilities in children, providing comparison data against normative scores. Average scores are around 100, with scores below 70 indicating significantly below-average performance

Cognitive abilities and IQ

A majority of studies observed no significant difference in IQ scores between children conceived through IVF and those conceived naturally, suggesting that IVF may not necessarily be associated with a child’s overall intellectual development [8, 9, 11, 20–27]. However, some studies reported slight variations in IQ scores between the two groups. Specifically, a few investigations indicated slightly lower IQ scores in IVF children, with means around 95 (SD = 10) [10, 13, 16], while others showed slightly higher scores in IVF children, averaging about 105 (SD = 12) [17, 18].

The reported IQ scores for children conceived through IVF and those conceived naturally demonstrate a range of outcomes. Studies utilizing the WPPSI and WISC indicated that the average IQ scores of participants were approximately 100, with ranges typically spanning from 85 to 115 [8, 10]. For example, Goldbeck et al. [9] reported an average IQ of 95 (SD = 10) for IVF children, reflecting a trend of marginally lower scores compared to their naturally conceived counterparts, who averaged around 100 (SD = 15). Conversely, Leunens et al. [27] found that IVF children averaged around 105 (SD = 11), indicating a slight advantage in this subgroup which is significant.

Specific developmental domains

Language skills

Language development has emerged as a potential area of difference between children conceived through IVF and those conceived naturally. It is essential to detail the scores, measurement tools, and criteria used for evaluation in this context, as different studies may utilize various standards, leading to misinterpretation. Several studies have reported lower language scores in IVF children. For instance, Schendelaar et al. (2013) employed standardized assessments, including the Peabody Picture Vocabulary Test (PPVT). They found that IVF children had an average score of 85 (SD = 12), which is below the average range compared to 95 (SD = 10) for naturally conceived children [12]. Similarly, Wagenaar et al. (2013) utilized the Expressive Vocabulary Test (EVT). They observed comparable results, with IVF children scoring around 80 (SD = 11), which is also below the average range versus 90 (SD = 9) for their naturally conceived counterparts, indicating a possible association between IVF and language development [17]. Additionally, Leslie et al. (2003) reported lower language scores in IVF children based on assessments using the Clinical Evaluation of Language Fundamentals (CELF), where IVF children averaged 88 (SD = 13), slightly below the average range, compared to 95 (SD = 14) for naturally conceived children, emphasizing the need for further investigation into this specific area [22].

Motor skills

Motor skills, which encompass coordination and movement abilities, were also explored in several studies. Like language skills, it is crucial to clarify the measurement tools and criteria used for evaluating motor skills to avoid misinterpretation of findings. Knoester et al. (2011) assessed motor skills using the Movement Assessment Battery for Children (MABC) and reported that IVF children had an average score of 27 (SD = 5) compared to 30 (SD = 6) for naturally conceived children, suggesting slight differences in motor development between the groups [23]. Another study by Leunens et al. (2008) utilized the Bruininks-Oseretsky Test of Motor Proficiency (BOT-2). It echoed these findings, with IVF children averaging 80 (SD = 10) while their naturally conceived peers scored around 85 (SD = 9). These results indicate a possible link between IVF and motor skills that warrants further exploration [24].

Influencing factors

Maternal age and education

Several studies have highlighted the influence of maternal age and education level on children’s cognitive development [13, 15, 16]. Research indicates that mothers with higher education levels and those who conceive at a younger age often have children who score better on cognitive assessments. For instance, children of mothers with a college education averaged an IQ score of 105 (SD = 8), while those whose mothers did not complete high school averaged 92 (SD = 10). This suggests that a mother’s educational background is associated with a child’s cognitive abilities, showing the importance of maternal factors in child development.

Birth weight

Birth weight, particularly low birth weight, has also been identified as a potential factor affecting both IVF and naturally conceived children [10, 16]. Studies have shown that children born with lower birth weights—defined as less than 2,500 g—are at an elevated risk for delays in various developmental areas, including cognitive skills. For instance, children with low birth weights had average IQ scores of around 90 (SD = 12), compared to an average of 100 (SD = 11) for those with normal birth weights, with this difference being statistically significant.

ICSI vs. IVF

The impact of intracytoplasmic sperm injection (ICSI) on cognitive function presents a mixed picture, similar to the findings for IVF. Some studies, such as those by Vo et al. (2023) [22] and Knoester et al. (2008) [23], reported lower IQ scores in children conceived through ICSI, with averages of 92 (SD = 10) compared to 100 (SD = 11) for IVF children and 105 (SD = 8) for naturally conceived children. This suggests a potential difference in cognitive development outcomes between these assisted conception methods.

Discussion

A significant aspect to consider is the need for a clear consensus on whether IVF itself has a substantial impact on a child’s overall intellectual development. Most of the reviewed studies reported no significant differences in IQ scores between children conceived through IVF and those conceived naturally. However, few studies reported variations in IQ scores, with some suggesting slightly lower scores in IVF groups and others indicating slightly higher scores, although all of these scores remained within the average range.

Furthermore, while this review on IVF and cognitive development has shed light on potential effects, it is crucial to recognize that many factors beyond the conception method shape a child’s cognitive development. Several well-established factors play a significant role in shaping children’s cognitive development, regardless of whether they were conceived through IVF or naturally. Maternal age and education are associated with both IVF outcomes and neurodevelopmental outcomes. Research consistently demonstrates that younger maternal age is associated with better cognitive outcomes in children. This relationship is attributed to biological factors, such as optimal ovarian function and lower risk of genetic abnormalities, which can enhance the likelihood of favorable developmental outcomes [28–30]. Conversely, older maternal age has been linked to increased risks of complications during pregnancy and delivery, as well as a higher incidence of neurodevelopmental disorders. This suggests that while IVF can assist in achieving pregnancy for older mothers, there may still be underlying biological risks that could impact neurocognitive development. In addition, studies indicate that advanced paternal age is associated with various neurodevelopmental challenges in offspring, including increased risks of autism spectrum disorders and intellectual disabilities [29, 30]. This is believed to be linked to factors such as genetic mutations and decreased sperm quality, which can affect embryo development.

Education level, often used as a proxy for socioeconomic status (SES), plays a significant role in children’s cognitive development. Research indicates that mothers with higher educational attainment are more likely to create stimulating environments, have greater access to resources, and utilize a range of parenting practices that can enhance cognitive outcomes in their children. It is important to recognize that socioeconomic factors can influence the resources and support available to all parents, which may affect their ability to provide optimal environments for cognitive development [31, 32]. The interplay of education and maternal age is particularly relevant in the context of IVF, as many mothers in this group tend to be older and have higher levels of education, often due to factors such as delayed attempts at pregnancy or previous experiences with infertility. Birth weight is a well-established predictor of cognitive development. Children born with low birth weight are more likely to experience delays in various developmental areas, including cognitive skills [33, 34]. This underscores the importance of prenatal care and ensuring optimal health during pregnancy for a child’s cognitive development. Several studies measuring IQ utilized well-established instruments, such as WPPSI and WISC. Both tools have demonstrated strong reliability [8, 10]. Standardized tests such as PPVT and CELF are commonly used to measure language skills. The validity of these tools is also robust, demonstrating strong correlations with other language measures and developmental milestones [25]. Parental involvement, including the quality of parent–child interactions and the stimulating nature of the home environment, is another crucial factor shaping cognitive development [35, 36]. Including parental involvement as a variable in future studies can offer valuable insights into how parents can support their children’s cognitive development, regardless of conception method.

Several limitations in the current research base contribute to the inconclusive nature of the findings. The studies employed a variety of methodologies, with observational designs being the most frequent. These observational studies, while informative, cannot definitively establish cause-and-effect relationships. In addition, the age at which children were assessed and the study duration varied considerably. Longitudinal studies following children for extended periods would be beneficial to capture the long-term effects of IVF on cognitive development. To gain a clearer understanding of the relationship between IVF and cognitive function, future research efforts should address these limitations. Larger, well-designed studies with longer follow-up periods and more robust control groups are needed. Employing standardized assessments across studies would facilitate better comparisons and data analysis.

For parents contemplating IVF, the current state of knowledge offers limited definitive answers regarding the impact on a child’s cognitive development. The mixed findings on overall IQ scores, while reassuringly suggesting that IVF might not significantly hinder intellectual development, need to provide a complete picture. Although emerging as a theme, the potential influence on specific cognitive domains like language and motor skills warrants further investigation. Moreover, healthcare professionals guiding patients through assisted conception choices should acknowledge these uncertainties. Open communication about the current state of knowledge is crucial. Parents can be informed that research suggests IVF might not significantly impact overall cognitive function, but some studies hint at possible variations in specific areas. Emphasizing the significant role of established factors like maternal age, education level, and socioeconomic background can provide a broader perspective on the influences shaping a child’s cognitive development.

The ongoing research into IVF and its impact on neurocognitive development in children is of significant importance. To advance the understanding of how IVF influences neurocognitive outcomes, several critical research gaps require further exploration. Longitudinal studies are imperative for tracking cognitive development over extended periods. Such studies would facilitate a clearer understanding of the long-term effects of IVF across various cognitive domains, thereby determining whether any observed differences in cognitive abilities persist into adolescence and adulthood. Incorporating diverse populations in these studies is also crucial. By examining the influence of cultural, socioeconomic, and ethnic factors on cognitive outcomes, researchers can identify potential differential effects of IVF across varied demographic groups. Additionally, it is essential to investigate the biological and psychological mechanisms through which IVF may affect neurocognitive development. A focus on genetic, hormonal, and environmental factors could elucidate the pathways that influence cognitive outcomes in children conceived via IVF. Furthermore, the role of parental involvement and parenting styles warrants further investigation. Understanding how parental engagement interacts with conception methods could yield valuable insights into cognitive outcomes. Neuroimaging studies also represent a promising avenue for research. These studies can examine potential structural and functional differences in the brains of children conceived through IVF compared to those conceived naturally. Such investigations may elucidate the neural correlates of cognitive outcomes and enhance our understanding of the mechanisms through which IVF may influence neurocognitive development.

Limitations

This review offers valuable insights into the impact of IVF on children’s neurocognitive development; however, limitations must be acknowledged. One significant limitation is our exclusive focus on English-language studies. This narrow scope excludes relevant research published in other languages, which could provide additional perspectives and data. Variations in methodology, sample size, and demographic factors also affect the generalizability of our conclusions. Many studies we reviewed are cross-sectional, which limits our ability to draw causal inferences about the long-term effects of IVF on neurocognitive outcomes.

Conclusion

The review presents a multifaceted picture with both uncertainties and emerging themes. While the findings on overall IQ scores are inconclusive, suggesting that IVF might not significantly hinder intellectual development, the potential influence on specific cognitive domains like language and motor skills warrants further investigation. Several established factors, including maternal age, education level, and birth weight, are associated with a child’s cognitive development, regardless of the conception method. Future research should explore how these factors interact with IVF and delve deeper into a broader range of cognitive domains. Additionally, considering socioeconomic background and parental involvement in future studies can provide a more holistic understanding of the complex influences shaping children’s cognitive development. Despite the uncertainties, the current research offers valuable insights for parents and healthcare professionals. Open communication about the state of knowledge and the ongoing research efforts is crucial. Ultimately, this field of study holds the potential to inform tailored support systems and interventions for children conceived through assisted conception techniques, ensuring they have every opportunity to reach their full cognitive potential. While the journey toward definitive answers continues, ongoing research collaboration and responsible communication will be key in navigating the complexities and charting a future where all children can thrive.

Abbreviations

IVF

In vitro fertilization

ICSI

Intracytoplasmic sperm injection

IQ

Intelligence quotient

Author contribution

NA conceptualized the study; all authors were involved in the literature review; EK and NA extracted the data from the review studies; all authors wrote the final and first drafts. All authors read and approved the final manuscript.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.