Long-Term Neurodevelopmental, Mental, and Cardiometabolic Health in Individuals Conceived with Assisted Reproductive Technology: A Literature Review

Introduction

Assisted reproductive technology (ART) has transformed fertility treatment since the first successful live birth through in-vitro fertilisation (IVF) in 1978. Assisted reproductive techniques account for over 4% of all live births [1]. Glob- ally, ART has facilitated the birth of approxi- mately 9 million babies, providing hope to countless infertile and subfertile couples [2]. ART encompasses various procedures designed to assist conception, with IVF being the most widely practiced. IVF involves fertilising an egg outside the body and transferring the embryo to the uterus. Another ART procedure, introduced in 1992, is the intracytoplasmic sperm injection (ICSI), which utilises a micromanipulation technique to pick up a single spermatozoan un- der the microscope and inject it into the oocyte using a micropipette. ICSI is useful in couples struggling with male infertility factors and a

history of prior fertilisation failure or poor treatment outcome from previous IVF [3]. The World Health Organization’s global report, ‘Infertility Prevalence Estimates, 1990-2021’, reveals that approximately one in six individuals worldwide experience infertility during their lifetime [4]. Other research highlights the con- siderable negative impact of advanced maternal age on fertility outcomes [5]. Similarly, findings by Alharbi et al. indicate that advanced paternal age can moderately affect certain semen param- eters, further contributing to fertility challenges [6]. While assisted reproductive technologies have led to significant advancements in repro- ductive medicine, these procedures are associat- ed with various health risks that must be careful- ly considered. Research has linked ART with adverse perinatal outcomes, such as preterm birth, low birth weight, and pregnancy-related complications; however, the exact cause re- mains uncertain [7], [8], [9]. Similarly, ART has been associated with an elevated risk of imprint- ing disorders and major non-chromosomal birth defects [10], [11]. While the birth defect risk among ART children is declining [12], the un- derlying mechanism for these associations is not known. There are concerns about the potential long-term health risks in ART individuals; how- ever, the limited availability of data beyond ear- ly adulthood remains a challenge [13]. Despite extensive research into perinatal outcomes, sig- nificant gaps remain in our understanding of the long-term health risks, particularly regarding neurodevelopmental, mental, and cardiometa- bolic health in individuals conceived through ART. Although a substantial body of literature has examined its effects, the findings are often conflicting or inconclusive. This gap can signif- icantly impact treatment decisions for couples struggling with infertility, making it essential to synthesise and critically evaluate the existing evidence. This literature review aims to address

this knowledge gap in reproductive medicine by examining the topic and exploring the relevant research. The following sections of this review will explore and discuss the specific long-term health impacts associated with ART, focusing on neurodevelopmental, mental, and cardiomet- abolic health.

Methodology

This literature review conducted a detailed ex- amination of the neurodevelopmental, mental, and cardiometabolic health-related impacts on individuals conceived through assisted repro- ductive technologies (ART), with a focus on synthesising and analysing research evidence from studies published between 2016 and 2023. The primary method for data collection involved a comprehensive literature search using the PubMed electronic database, targeting studies on the long-term effects of ART on neurodevel- opmental, mental, and cardiometabolic health. The search strategy utilised MeSH terms com- bined with Boolean operators for precise filter- ing, applied as follows: for neurodevelopmental and mental health impacts, the MeSH terms included ‘reproductive techniques, assist- ed/adverse effects’, ‘neurodevelopmental disor- ders’, ‘mental health’, ‘risks’; for cardiometa- bolic health impacts, the MeSH terms were ‘re- productive techniques, assisted/adverse effects’, ‘cardiovascular diseases’, ‘metabolic syn- drome’, ‘risks’. Additional alternative search terms were em- ployed in PubMed’s Advanced Search Builder to broaden the scope of the search. Furthermore, reference lists from relevant studies published between 2016 and 2023 were meticulously re- viewed to identify further research not initially captured. The search was continuously updated, with the most recent update on May 29, 2023. The inclusion criteria focused strictly on re- search explicitly related to the long-term effects

of ART on neurodevelopmental, mental, and cardiometabolic health. Only studies published in English or those available in translated ver- sions were considered. The exclusion criteria eliminated publications related to intrauterine insemination and other fertility treatments not classified as ART, as well as duplicate studies.

Results

A total of 49 studies met the inclusion criteria and were included in the review, with 31 studies examining the neurodevelopmental and mental

health-related impacts of ART, and 18 studies exploring the cardiometabolic health-related impacts.

Impact of ART on neurodevelopmental and men- tal health in ART-conceived individuals: A total of 31 research studies included in this literature review explored the impact of ART on neurodevelopmental and mental health in ART- conceived individuals. The findings from the relevant studies have been organised into fa- vourable findings, presented in Table 1, and adverse findings, in Table 2.

Table 2. Adverse Research Findings on Neurodevelopmental and Mental Health in ART-

SN Author, Ref. &

Adverse Research Findings on Neurodevelopmental and Mental Health in ART-Conceived Individuals

Year of Publi- cation

1 Acharyya et al.[31] (2023)

Delayed growth and neurodevelopment in early infancy in term singleton babies conceived through ART compared with naturally conceived babies, but no statistically significant difference in outcomes at 24 months. 2 Rönö et al.[32] (2022)

Higher adjusted risk of learning and motor functioning disorders, and a tendency for higher risk of ASD, ADHD, and conduct disorders in ART singletons compared to non-ART singletons; only small differences in neu-

Conceived Individuals.

rodevelopment between ART and non-ART singletons; no difference in tic disorders risk after adjustment. 3 Fine et al.[15] (2022)

Children conceived via IVF/ICSI exhibited slightly higher adjusted hazard ratios for ADHD. 4 Wang et al.[33] (2021)

More than a two-fold increased risk of CP in ART children (mostly medi- ated by multiple and preterm births). 5 Sánchez-Soler et al.[20] (2020)

Association between language delay and FET observed in ART-conceived children (further research warranted).

6 Djuwantono et al.[34] (2020)

Higher CP risk in ART children than naturally conceived children, influ- enced by preterm birth and low birth weight; ICSI children face higher risks of intellectual disability and ASD than those conceived via conven- tional IVF; no significant difference in neurodevelopmental disorder risk between children born after frozen versus fresh embryo transfer. 7 Robinson et al.[35] (2020)

Toddlers conceived through ART may have increased chances of failing an ASD screening compared with those born without infertility treatment, though results remain inconclusive. 8 Rissanen et al.[36] (2020)

Slightly elevated risk of psychiatric diagnosis in children conceived through ART until young adulthood, compared with the control group.

9 Rumbold et al.[37] (2019)

A small increase in the risk of mental retardation and autism in ICSI- conceived offspring, suggesting that both severe male factor infertility and the use of ICSI may contribute, with inconsistent findings about the rela- tive contribution of these factors. 10 Briana and Mal- amitsi- Puchner[38] (2019)

Neurodevelopmental outcomes in IVF-conceived twins are influenced by foetal growth restriction, prematurity, and zygosity, with higher CP in term infants, those with growth restrictions, prematurity, and twins surviving co- twin intrauterine death. The impact of IVF on these outcomes has not been documented, therefore warranting further research. 11 Esteves et al.[39] (2018)

Higher risk of delayed psychological and neurological development in in- fants born through ICSI than in children conceived naturally.

12 Goldsmith et al.[40] (2018)

A two-fold increase in the birth prevalence of CP after ART (mostly medi- ated by multiple and preterm births).

13 Liu et al.[41] (2017)

ART associated with a significantly higher risk of ASD in offspring, sug- gesting ART as an independent risk factor for ASD. (Caution is advised when interpreting the findings of this study.) 14 Kuiper et al.[42] (2017)

Less favourable health and development (lower total IQ, body weight, and height) in 4-year-old IVF twins than in 4-year-old IVF singletons, and not altered by IVF per se. 15 Xu et al.[43] (2017)

Reduced IQ in young children of OHSS IVF women compared with non- OHSS IVF children, potentially due to prenatal estradiol exposure. ART: Assisted Reproductive Technology; ASD: Autism Spectrum Disorder; ADHD: Attention-Deficit/Hyperactivity Disorder; CP: Cerebral Palsy; IQ: Intelligence Quotient; OHSS: Ovarian Hyperstimulation Syndrome; FET: Frozen Embryo Transfer.

Although the majority of research findings on neurodevelopmental and mental health out- comes in ART-conceived individuals are reas-

suring, as evidenced by the studies listed in Ta- ble 1, certain specific neurodevelopmental and

mental health conditions still require further investigation, as outlined in Table 2. ART-conceived children generally exhibit lan- guage, motor, and adaptive behaviour skills comparable to those of naturally conceived chil- dren, with some studies noting slightly en- hanced social development, particularly in male ART offspring [14]. No significant differences between ART-conceived and spontaneously conceived children have been observed in verbal skills, cognitive function, visual-motor ability, or attention during early school age [19]. Addi- tionally, there are no disparities in neurodevel- opment, growth, vision, or hearing between children conceived via ICSI and those con- ceived naturally [25]. Another study found no statistically significant differences in neurode- velopmental or physical health between children conceived via in-vitro procedure of assisted re- production and natural conception at a mean age of 5.5 years, although limitations in the study’s power and attrition may have masked subtle effects [24]. Furthermore, no heightened risk of neurocognitive development issues or ASD have been identified in children born after ART, particularly after adjusting for multiple births [22] and neurodevelopmental outcomes at age 2 are similar between ART-conceived children and those conceived naturally [28]. Additional- ly, mental health and social or cognitive devel- opmental problems at ages 7–8 are generally comparable between ART and naturally con- ceived children, with some gender-specific dif- ferences noted [30]. Preterm infants born before 29 weeks of gestation and conceived via ART have been found to have lower odds of adverse neurodevelopmental outcomes, particularly in cognitive and language development, when as- sessed at 18 to 24 months of corrected age [18]. Moreover, ART-conceived children, such as term singletons, who may experience delayed growth and neurodevelopment in early infancy, typically catch up to their naturally conceived peers by 24 months of age [31]. Importantly, no

increased risk of hospitalisation for cognitive and motor development issues has been identi- fied in ART-conceived children after adjusting for shared genetic, environmental, and familial factors up to 11 years of age [17]. Studies indicate that there is no increased risk of neurodevelopmental disorders such as ASD, language delay, or global developmental delay in children conceived by ART, although an as- sociation between frozen embryo transfer (FET) and language delay has been noted in another study; however, further studies are required [20]. Another research study reported no signif- icant difference in neurodevelopmental disorder risk between children born after frozen and fresh embryo transfer [34]. However, one study found an increased adjusted risk of learning and motor functioning disorders and conduct disor- ders in ART-conceived singletons compared with non-ART singletons, albeit with only small differences observed in neurodevelopment be- tween the two groups [32]. A modest link was observed between parental subfecundity and neurodevelopmental delays in ART-conceived children [16], while another study showed a higher risk of delayed neurological development in ICSI-born infants than in naturally conceived children [39]. A review study highlighted the factors affecting neurodevelopmental outcomes in IVF-conceived twins, including foe- tal/intrauterine growth restriction, prematurity, and zygosity [38]. The study observed no doc- umented impact of IVF itself on neurodevelop- mental outcomes in IVF-conceived twins; how- ever, the research highlighted the need for fur- ther research on this topic [38]. It is noteworthy that most literature shows no association be- tween ART and poorer neurodevelopmental outcomes in ART-conceived offspring; howev- er, research reporting such associations should be interpreted cautiously in the presence of con- founders, as mentioned in a literature review by Perros et al. [1].

The research shows no increased risk of hospi- talisation for cerebral palsy (CP) in ART- conceived children after adjusting for shared genetic, environmental, and familial factors up to 11 years of age [17]. Nonetheless, an in- creased risk of CP has been observed in ART- conceived children, particularly those born pre- term or as multiples, highlighting the heightened vulnerability of these groups [33], [40]. A re- view study relating to IVF-conceived twins ob- served a higher CP risk in term infants, those with growth restrictions, premature infants, and twins surviving co-twin intrauterine death, while emphasising the influence of certain confound- ing factors on neurodevelopmental outcomes in IVF twins [38]. The increased CP risk, com- pared with naturally conceived children, under- scores the importance of considering the rele- vant confounders such as preterm birth and low birth weight in ART pregnancies [34].

Studies generally found no association between ART and an increased risk of ASD [21], [22], [26], or between IVF treatment and ASD risk compared with spontaneous conception [27]. Moreover, no increased risk of ASD diagnosis has been observed in ART-conceived singletons within their first three years of life [23], and there is no increased risk of hospitalisation for ASD in ART-conceived children up to 11 years of age after adjusting for certain factors [17]. However, some research findings indicate po- tential concerns. An association between FET and language delay has been reported, warrant- ing further research [20]. Additionally, a small, elevated risk of autism has been observed in ICSI-conceived children, suggesting that severe male factor infertility and/or the use of ICSI might contribute to this risk; however, further research is warranted [37]. Another research study found ICSI children to be at higher risk of ASD than conventional IVF children [34]. Fur- thermore, toddlers conceived through ART may have a higher likelihood of failing ASD screen-

ings, although these findings remain inconclu- sive [35]. The association between ART and ASD suggested in some studies highlights the need for further investigation [32], [41]. Children conceived via IVF/ICSI generally have lower rates of diagnosed ADHD compared with other conception groups. However, they exhib- ited slightly higher adjusted hazard ratios for ADHD [15]. Another study showed a higher tendency for increased risk of ADHD in ART- conceived singletons compared with non-ART singletons, although the differences in neurode- velopment between these two groups were small [32].

The research indicates that mental health or so- cial and cognitive developmental problems are not different overall in ART-conceived children at 7 to 8 years compared with their naturally conceived peers. However, some gender- specific differences have been observed [30]. Furthermore, no increased risk of hospitalisation for cognitive issues has been reported in ART- conceived children after adjusting for certain shared factors [17]. Conversely, a higher risk of intellectual disability has been noted in ICSI- conceived children compared with those con- ceived via conventional IVF [34], and research suggests that IVF twins at age 4 may exhibit less favourable health and development, includ- ing lower IQ, body weight, and height, than IVF singletons of the same age. However, IVF was not considered a direct contributing factor [42]. Moreover, a review study on IVF-conceived twins linked certain confounding factors to dif- ferences in cognitive ability between twins and singletons [38]. Concerns have also been raised about reduced IQ in young children of ovarian hyperstimulation syndrome (OHSS) IVF women compared with non-OHSS IVF children, with prenatal estradiol exposure suggested as a pos- sible underlying mechanism [43]. A Danish prospective nationwide cohort study did not find an overall increase in risk of ad-

verse mental health outcomes in children with ART exposure during follow-up in childhood, adolescence or early adulthood; however, the study lacked statistical power to exclude the possibility of an effect of ART on specific men- tal health disorders [29]. Another research study reported no overall differences in mental health or social and cognitive developmental problems in ART children at 7 to 8 years compared with naturally conceived peers [30]. Nevertheless, another study showed slightly elevated risk of psychiatric diagnoses extending into young adulthood in ART-conceived children compared with a control group [36]. Additionally, research reported a higher risk of delayed psychological development in infants born through ICSI than in children conceived naturally [39]. A review study on IVF-conceived twins reported limited evidence for differences in behavioural and psy- chiatric disorders between twins and singletons,

while highlighting the influence of certain con- founding factors on neurodevelopmental out- comes in IVF-conceived twins, as well as the need for further research on the impact of IVF on these outcomes [38]. Another study suggest- ed a small increase in the risk of mental retarda- tion in ICSI-conceived offspring, where severe male factor infertility and the use of ICSI may be the contributory factors [37]. However, fur- ther research is needed to clarify these findings. Impact of ART on Cardiometabolic Health in ART-Conceived Individuals:

This literature review included a total of 18 re- search studies on the impact of ART on cardi- ometabolic health in ART-conceived individu- als, the findings of which are categorised into favourable and adverse in this population (Ta- bles 3 and 4). These study results are further elaborated upon in the discussion section, which offers a more in-depth analysis of the findings.

Adverse Research Findings on Cardiometabolic Health in ART- Conceived Individuals

Higher total cholesterol, LDL cholesterol, and HDL cholesterol in ART- conceived offspring than in naturally conceived offspring. Lower blood pressure during childhood and subtle trajectories to nominally higher sys- tolic blood pressure and triglycerides in young adulthood with ART war- rant more extended follow-up studies. 2 Penova- Veselinovic et al. [45] (2022)

The observed increase in visceral adipose tissue in ART-conceived indi- viduals warrants further investigation.

Adverse cardiometabolic changes in offspring born after FET to over- weight/obese mothers. 4 Zhu et al.[54] (2022)

Association of early pregnancy OHSS with elevated blood pressure in sin- gletons aged 3-6 years conceived after IVF with or without ICSI. 5 Norrman et al.[50] (2021)

Significantly increased obesity risk in ART-conceived children.

Evidence of adverse metabolic alterations associated with ART at a young age that could lead to chronic adult-onset diseases like metabolic syn- drome, type 2 diabetes, and cardiovascular disease later in life. 7 Norrman et al. [56] (2020)

Concern for the association of FET with increased risk of type 1 diabetes in singleton ART children.

Accelerated postnatal growth in ICSI children and risk of increased adipos- ity, particularly in girls.

Greater risk of impaired cardiometabolic profile in infants born through ICSI than in those conceived naturally.

Association of ART with premature vascular aging in apparently healthy adolescents and young adults.

Greater susceptibility to adiposity and early insulin resistance in children conceived through ICSI than in spontaneously conceived peers; however, some inconsistent results warrant further research. 13 Belva et al.[58] (2018)

Lower mean HDL cholesterol in young adult men conceived by ICSI com- pared with the spontaneously conceived control group.

have been raised about the potential risk of car- diometabolic diseases later in life for individuals born via fresh embryo transfer [59].

The risk of diabetes and glucose regulation problems in ART-conceived individuals has been a focus of various studies, with mixed findings. On the positive side, one study ob- served that glucose measures in ART-conceived offspring were similar to those in naturally con- ceived offspring [44]. Another study found no increased risk of type 2 diabetes between chil- dren born after ART and those born through spontaneous conception [50]. Conversely, other studies suggest potential risks. Concerns have been raised about a potential association be- tween FET-conceived singletons and an elevat- ed risk of type 1 diabetes [56]. Moreover, epi- demiological evidence indicated that ART- conceived children exhibit cardiometabolic al- terations, including differences in glucose ho- meostasis [61]. Additional research found high- er fasting insulin levels in IVF-ICSI offspring than in naturally conceived offspring [60], while a further study reported increased susceptibility to early insulin resistance in children conceived through ICSI compared with spontaneously conceived peers, although some inconsistent results warrant further investigation [25]. There is also evidence from a review study that ART may be associated with adverse metabolic alter- ations at a young age, potentially leading to chronic adult-onset diseases such as metabolic syndrome, type 2 diabetes, and cardiovascular disease later in life [55]. Lastly, research has pointed to a higher risk of type 1 diabetes in children conceived through cryopreserved em- bryos [22].

Discussion

While most research on ART-conceived chil- dren reports reassuring neurodevelopmental and mental health, comparable to naturally con- ceived peers, particular concerns persist. ART children generally exhibit similar language, mo- tor, and adaptive behaviour skills, with no sig- nificant differences in verbal, cognitive, or visu-

al-motor abilities. However, specific subgroups, such as those conceived via ICSI, may have an elevated risk of intellectual disability and neu- rodevelopmental disorders, including autism spectrum disorder. Additionally, an association between FET and language delay has been ob- served, warranting further research. Children born prematurely or as multiples after ART are also at a higher risk for conditions like cerebral palsy. Although overall mental health in ART- conceived children is comparable to their peers, an increase in the risk of psychological and neu- rological development delays has been noted, particularly in ICSI cases. Continued research is crucial to fully understand the long-term neuro- developmental outcomes in ART-conceived children, especially as reproductive technologies evolve. Current research on cardiometabolic health in ART-conceived individuals presents a complex and evolving landscape. While many ART off spring exhibit a generally favourable impact of ART on cardiometabolic health, emerging con- cerns regarding elevated blood pressure, altered lipid profiles, obesity, and metabolic changes suggest potential long-term health risks. Evi- dence highlights the possibility of premature vascular aging and greater susceptibility to chronic conditions, including metabolic syn- drome and type 2 diabetes, in ART-conceived individuals. Specific subgroups, such as those conceived via ICSI, appear to be at a heightened risk, with increased susceptibility to adiposity and insulin resistance, warranting further inves- tigation. Additionally, a higher risk of type 1 diabetes has been reported in individuals con- ceived through FET. Continued monitoring and research are essential to understand and mitigate these potential long-term cardiometabolic risks in ART-conceived individuals. An essential caveat is the variability in method- ologies, sample sizes, and follow-up periods of the studies reviewed. This diversity can lead to inconsistent findings and make it challenging to

draw definitive conclusions. Inherent biases in the research, including selection and infor- mation bias, are possible. This review empha- sises observed associations rather than definitive causality. The intricate interplay of genetic, en- vironmental, and epigenetic factors in ART- related health outcomes underscores the com- plexity of establishing clear causal relationships.

The findings imply that while ART is generally safe and effective, specific subgroups of ART- conceived individuals may be at an increased risk for specific neurodevelopmental and cardi- ometabolic challenges. Children conceived via ICSI are at higher risk of intellectual disability, neurodevelopmental disorders such as autism spectrum disorder, and psychological and neuro- logical development delays, as well as metabol- ic concerns such as increased adiposity and in- sulin resistance. This highlights the importance of implementing long-term neurodevelopmental and metabolic monitoring for ICSI-conceived children to ensure optimal long-term health out- comes. Moreover, children conceived via FET have an elevated risk for language delay and type 1 diabetes, warranting further research in this area. To mitigate these risks, healthcare providers should prioritise early screening for language development and type 1 diabetes in FET-conceived children, ensuring timely and targeted interventions. The increased risk of cerebral palsy in children born as multiples or prematurely following ART requires careful consideration in both the medical management of ART and neonatal care. Additionally, cardi- ometabolic concerns in ART-conceived individ- uals, such as increased risks of high blood pres- sure, altered lipid profiles, obesity, insulin re- sistance, premature vascular aging, and adverse metabolic changes, underscore the importance of continuous monitoring and early interven- tions. These measures are essential to mitigate the potential development of chronic conditions later in life, including metabolic syndrome, type

2 diabetes, and cardiovascular disease. Robust research, including long-term follow-up studies on ART-conceived individuals, is essential to accurately determine the long-term health out- comes in this population.

Conclusion

The relationship between ART and specific long-term health impacts in ART-conceived individuals is complex, highlighting the need for ongoing research and careful consideration. While most neurodevelopmental and mental health outcomes are generally comparable to naturally conceived peers, specific subgroups face elevated risks. Children conceived via ICSI may have a higher risk of neurodevelopmental disorders, including autism spectrum disorder, intellectual disability, and psychological and neurological development delays. Additionally, frozen embryo transfer has been associated with an increased likelihood of language delay, and children born as multiples or prematurely after ART have a heightened risk of conditions like cerebral palsy. Further research is essential to clarify these risks and improve long-term out- comes.

Regarding cardiometabolic health, although many ART-conceived individuals demonstrate favourable profiles, emerging concerns include increased risks of high blood pressure, altered lipid levels, obesity, insulin resistance, prema- ture vascular aging, and adverse metabolic changes. ICSI-conceived individuals may be at higher risk for adiposity and early insulin re- sistance, while those conceived via frozen em- bryo transfer have shown associations with type 1 diabetes. These findings underscore the im- portance of continued monitoring, research, and targeted interventions to mitigate potential long- term risks as reproductive technologies evolve.

Funding: None. Conflict of Interest: None