Metabolic outcomes

Metabolic outcomes in ART-conceived children have been a subject of study, with findings highlighting elevated risks for various conditions such as foetal hypertrophy, preterm birth, and congenital malformations, which are more likely to affect ART-conceived twins, as discussed by Faa and others.2 There has also been evidence of premature vascular aging, which further contributes to increasing the risk of arterial hypertension in adulthood.3

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Pinborg et al. also reported potential long-term cardiovascular problems such as ischemic heart disease, cardiomyopathy, heart failure, and cerebrovascular diseases.4 Additionally, elevated BMI, BP, fasting blood glucose, fasting insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) values specifically in children LGA from 0.4 to 9.9 years of age were observed by Zhang in their extensive prospective cohort study, including over 14,000 ART-conceived children.5  A decreased level of ApoA, which may further increase carotid intima-media thickness—a marker for early atherosclerosis—was also noted by Cui.6

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Conversely, some suggested no significant differences in BP, heart rate, triglycerides, or insulin resistance between ART and naturally conceived children. However, slightly elevated levels of total HDL and LDL cholesterol were noted in ART offspring, particularly in adulthood, Elhakeem.7  

 

Collectively, these studies indicate that ART-conceived children may face various cardiometabolic conditions, although whether they are caused by underlying parental factors or the specific ART procedures remains unclear.
 

Neurodevelopmental outcomes 

Following metabolic outcomes, neurodevelopmental outcomes in these children are another significant challenge. Although widely studied, there have been varied and conflicting results. Faa and colleagues2 highlight developmental delays chiefly in language and motor abilities. The risk is more pronounced in cases of multiple or premature births. Mild cognitive impairments and behavioural issues were observed in children conceived via ICSI by Pinborg and others.4 These concerns may be reinforced by the findings of Lo,8 which suggest a potential mechanism by which ICSI may bypass natural sperm selection and increase the risk of transmitting fragmented DNA. In a cohort study by Rönö,9 the increased risk of learning or motor disorders, ASD, ADHD, and conduction disorders was highlighted. Nonetheless, no significant difference was stated between the types of procedures used, such as IVF, ICSI, or FET. It is also worth mentioning that this risk was found to be amplified by anovulatory infertility or endometriosis.

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In contrast, according to Farhi and others,10 there is no substantial difference in the long-term neurodevelopmental effects between ART and naturally conceived children. Zhu and colleagues11 suggest that these outcomes may be more closely linked to perinatal and parental factors. Studies conducted by Balayla12 indicate that children born via ART at two years of age had similar cognitive, motor, and language development as naturally conceived peers. Likewise, Wagenaar13 predicted no significant differences in information processing, attention, and visual-motor skills.

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Overall, while some studies suggest potential neurodevelopmental challenges associated with ART, the evidence remains inconclusive. In the future, longitudinal research is needed to distinguish the consequences of ART procedures from the underlying parental or perinatal factors. Follow-up studies on ART technique-specific effects can emphasize this.

Birth outcomes

Birth outcomes in children represent a significant category of discussion in children conceived via ART. Findings from Faa2 highlight an elevated incidence of preterm birth and low birth weight, particularly among twins and multiple births from ART. Pinborg and others4 have highlighted the risks of being born large for gestational age (LGA) following frozen embryo transfers (FET). They added that even singletons born after ART carry higher obstetric and perinatal risks than spontaneously conceived ones. They further mention that both fresh and frozen embryo transfer singletons are more likely to be small for gestational age (SGA), have low birth weight, and be born preterm.

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On the other hand, FET singletons are more often large for gestational age (LGA). Regarding childhood malignancies, conflicting evidence stating a possibly high risk in children born after FET vs spontaneous conception is noted. Moreover, as stated by them, ART offspring may face an increased risk of early onset puberty; in boys, the risk of late puberty also prevails.

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According to Maheshwari et al.,14 Frozen embryo transfers (FETs) pose a lower risk of low birth weight (LBW) and very low birth weight (VLBW) compared to fresh transfers. However, FET was associated with an increased risk of high birth weight (>4 kg). Their study did not cite a significant difference in preterm or very preterm delivery rates between FET and fresh transfers.

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Certain studies cite preventive strategies, such as Single Embryo Transfer (SET), which can reduce preterm and multiple birth rates and lower the risk of neurological impairments.15

 

Epigenetic outcomes

Epigenetic changes refer to modifications that affect gene activity and expression without altering the DNA sequence itself- often influenced by environmental factors, including early developmental conditions. Faa and others2 highlight that their study raises concern about how ART techniques may interfere with normal epigenetic reprogramming. They also note several contributing factors, including hormonal stimulation and embryo freezing. Additionally, Frozen Embryo Transfer (FET) may affect epigenetic patterns, as suggested by Pinborg.4 These epigenetic alterations may contribute to the increased occurrence of large-for-gestational-age (LGA) births and macrosomia.

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Scioria and peers16 have observed that KvDMR1 (an imprinting control region regulating growth-related genes on chromosome 11) is atypically methylated in ART-related Beckwith-Wiedemann Syndrome (BWS) and exhibits hypomethylation in ART-derived Bovine Conceptuses with LOS. There was no direct link found between PCOS or Angelman Syndrome (AS) with IVF and ICSI, but rather with underlying infertility issues themselves. Additionally, ovarian stimulation is reported to be a key driver of epigenetic aberrations in oocytes and embryos. DNA methylation errors in PEG1, KCNQ1OT1, and ZAC were found to be elevated in oocytes collected following controlled ovarian stimulation as compared to naturally conceived ones. Altered methylation at the H19 ICR in embryos from superovulated oocytes also supports this finding. While some normal ICR (imprinting control region) methylation patterns were still maintained in some mature oocytes, aberrations were detected in genes involved in glucose metabolism, nervous system development, mRNA processing, cell cycle, and proliferation. Moreover, multiple superovulation cycles resulted in adverse ovarian and embryo outcomes, aberrant histone modifications, and reduced fertilization rates.

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Moreover, according to Lazaraviciute and others,17 there were no significant differences in cord blood DNA methylation of key genes (PEGs, IGF2, SNRPN, etc.), but in placentas, a lower DNA methylation at H19/IGF2, KCNQ1OT1, LINE1Hs, and ERVKRD1 in IVF/ ICSI than in control placentas. Additionally, placentas from ICSI (not IVF) have exhibited global differences in H3K4me3.  Their findings regarding paternal epigenetic contributions also focused on the association between male obesity and paternal diet, as well as the resulting changes in the sperm epigenome. These changes are considered to be transmissible, especially via ART/ICSI. Additionally, it has been reported that abnormal histone acetylation in sperm leads to poor chromatin compaction and alteration, which can be transmitted to future offspring. Their findings additionally described that altered methylation at Alu repeats and imprints in sperm of infertile men are linked to ART outcomes. It is important to note that IVF culture under low oxygen improves outcomes, but embryo manipulations must be minimized.

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A need for more rigorous evidence at the molecular level remains. Overall, while some studies focus on epigenetic changes, definitive conclusions remain to be drawn, as human evidence is limited, with most studies small-scale and short-term.

Perinatal and parental factors

Parental and perinatal characteristics majorly influence ART-related outcomes such as birth weight and preterm birth, suggesting an interplay of both ART procedures and these factors.2 Pinborg,4 in their studies, emphasize the impact of frozen embryo transfer (FET) and maternal characteristics such as BMI and infertility etiology on birth outcomes. They suggest that outcomes such as LGA (large for gestational age) and macrosomia may be more closely associated with maternal metabolic factors than with ART itself. They also noted that multiple embryo transfer increased the risk of preterm birth and perinatal mortality even in singletons. No independent associations were found between parental/ART treatment factors and congenital anomalies. Interestingly, although differences in follicular fluid composition (e.g., VEGF, IGFs, and their binding proteins) were noted between GnRH agonist and antagonist stimulation, their effect on birth weight remains unclear, though potential epigenetic alterations cannot be excluded.

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Pontesilli18 in their study mention that lower birth weight is associated with both parental characteristics (maternal hypertensive disease, diabetes, ethnicity, parity, and duration of subfertility) and ART treatment characteristics (HCG for luteal phase support, number of oocytes retrieved, and fresh vs. frozen embryo transfer). Maternal diabetes has been found to have the strongest association with low birth weight. Their study suggests that preterm birth is more common in South Asian mothers. These findings are further supported by recent comprehensive reviews highlighting increased preterm birth weight rates in ART-conceived children.

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Collectively, these findings strengthen the argument that underlying parental and perinatal variables may largely explain many risks previously attributed to ART.