Early life epigenetics and childhood outcomes: a scoping review

Abstract

Epigenetics is the study of changes in gene expression, without a change in the DNA sequence that are potentially heritable. Epigenetic mechanisms such as DNA methylation, histone modifications, and small non-coding RNA (sncRNA) changes have been studied in various childhood disorders. Causal links to maternal health and toxin exposures can introduce epigenetic modifications to the fetal DNA, which can be detected in the cord blood. Cord blood epigenetic modifications provide evidence of in-utero stressors and immediate postnatal changes, which can impact both short and long-term outcomes in children. The mechanisms of these epigenetic changes can be leveraged for prevention, early detection, and intervention, and to discover novel therapeutic modalities in childhood diseases. We report a scoping review of early life epigenetics, the influence of maternal health, maternal toxin, and drug exposures on the fetus, and its impact on perinatal, neonatal, and childhood outcomes.

INTRODUCTION

The emergence of “omics” research in medicine has given us a better understanding of the complex interactions between the genome and epigenome and its role in health and various disease processes. Epigenetic changes may be induced by exposure to diet, chemicals, drugs, and the environment. Epigenetic modifications regulate growth and development, which when perturbed, may lead to diseases and ill health. Derived from the Greek word ‘above’, epigenetics is the study of investigating modifications that impact the transcriptional program of a cell without affecting the DNA sequence, thus changing the phenotype.¹ These epigenetic modifications ultimately impact regulatory mechanisms and patterns of gene expressions, involved in organogenesis and human development.¹ The dynamic nature of epigenetic changes leading to disease etiopathogenesis may lend them to be appropriate biomarkers of disease, which in turn can inform novel strategies towards prevention, detection, and therapeutic interventions in diseases.² Some of the common ways in which epigenetic mechanisms occur are through DNA methylation, histone modifications, small non-coding RNA (sncRNA), and chromatin remodeling, all of which are responsive to external stimuli and act in synergy to regulate key cellular processes (Fig. 1).²

Fig. 1. Early life epigenomics and influencers.

Schematic showing epigenetic mechanisms-histone modification and DNA methylation, influenced by various environmental factors. Created with BioRender.com

The mechanism of fetal programming, where the in-utero environment, maternal exposures, and environmental stressors, prepare and prime the developing fetus for the external environment, may impact the overall health of the newborn and beyond. Studies have supported that DNA methylation can play a vital role in fetal programming.³ Animal studies have shown that DNA methylation is a major pathway that can connect in-utero and environmental exposures during pregnancy and future child health.⁴ Studies have shown that maternal smoking during pregnancy and gestational age have strong associations with altered DNA methylation processes in the offspring cord blood.^3,5 Therefore, cord blood can be utilized to provide evidence of these epigenetic mechanisms, which may play a significant role or indicators of future disease processes in the offspring. A comprehensive knowledge about epigenetic changes and mechanisms may be utilized for devising early interventions during this period of ‘plasticity’ in early life, which can beneficially impact childhood outcomes.⁶

EPIGENETIC MECHANISMS

DNA methylation catalyzed by enzymes called DNA methyltransferases (DNMTs) involves the addition of methyl groups, resulting in altered expression of genes. DNA is typically methylated in the C5 position of cytosine in the CpG dinucleotide pair, resulting in clusters called CpG islands, which can significantly impact neighbor gene expression.⁷ Being a major component of the one-carbon pathway, this mechanism can result in the alteration of various enzymes and nutrient co-factors.² DNA methylation is measured using polymerase chain reactions, array, and sequencing methods.² DNA methylation is typically seen in gene silencing and an example of DNA methylation in the human disease process is imprinting disorders such as Prader-Willi, Angelman, and Silver Russell syndromes, where the DNA methylation suppresses gene expression in specific chromosomal regions. Gene imprinting regulates gene expression of genes from a single parental allele and, as such a cluster of genes is coordinately inhibited by methylation.⁸ In addition, disorders such as multiple sclerosis have several associated DNA methylation pathways that might form the basis of increased risk of the disease process.⁷

Another epigenetic mechanism includes various types of histone modifications, which are post-translational and influence histone interactions with DNA. They include histone acetylation by histone acetyltransferases and histone methylation by histone methyltransferases, as well as several other types of modifications.⁷ These post-translational modifications affect chromatin packaging and accessibility of transcriptional machinery and hence gene function. Histone acetylation is generally associated with transcriptional activation as it permits local relaxation of chromatin packaging.⁷ An example of a disease process linked to dysregulation of cofactors due to histone acetylation is Rubenstein-Taybi syndrome.⁸ Impact on transcription due to histone methylation varies more, based on the specific residue on which the methyl modification has occurred.²

A third and more recently investigated epigenetic mechanism is the role of small non-coding RNA (sncRNA), which includes dicer-dependent microRNA (miRNA), small inhibitory RNA (siRNA), and Piwi-interacting RNA (piRNA), which can work in parallel with eDNA and histone mechanisms.⁹ There is a growing body of evidence indicating a significant role of sncRNAs in gene regulation. Generally, siRNA and miRNA result in gene silencing, whereas piRNA represses transposon expression in germline cells by fostering de novo DNA methylation.^8,9

Investigating types of epigenetic mechanisms and their role in disease and health is of vital importance in delineating prevention and treatment strategies early in the disease process. We, therefore, comprehensively searched and summarized the existing literature, with the goal to educate, identify gaps in knowledge, and recommend future research into better understanding of specific preventable or modifiable epigenetic mechanisms.

OBJECTIVES

1. To perform a scoping review on cord and neonatal blood epigenetics (early life) and its association with later childhood outcomes.

2. To identify knowledge gaps in the existing literature on the association of early life epigenetics and childhood outcomes

METHODS

We conducted a scoping review according to established guidelines.¹⁰ We followed the following steps (a) identified research questions, (b) identified relevant studies, (c) selected studies, (d) charted the data, and (d) collated, summarized and reported the findings.¹⁰

Search strategy

We searched the following electronic databases on Feb 18, 2024 (Appendix 1):

1. MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL) through EBSCOhost, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library.

2. PubMed’s related citations feature was used to identify relevant articles. Additional searches were made from articles cited by the included studies and by contacting experts in the field.

Inclusion criteria

We included prospective or retrospective, cohort or cross-sectional studies that reported on cord or neonatal blood epigenome and childhood outcomes. Only articles published in English language were included.

Selection and data collection process

Articles were screened for eligibility by two authors (MP and SHG). We identified 2501 records through database searches. The inclusion process is detailed in the PRISMA flow diagram (Fig. 2). We included 310 studies for our qualitative summary of the literature pertaining to our objectives.

Fig. 2. PRISMA flow diagram of included studies.

We identified 2501 records through database searches and the process of inclusion is detailed in the figure. We included 310 studies for our qualitative summary of the literature pertaining to our objectives.

MATERNAL HEALTH AND CORD-EPIGENETICS

While epigenetic changes can occur throughout human life, changes happening in the in-utero environment lay a solid foundation and play a vital role in embryogenesis and organogenesis by influencing gene expression (Fig. 3). Multiple modifiable and non-modifiable factors during pregnancy, including race, socioeconomic status, ethnicity, general maternal health, diet, and medication and toxin exposures play an important role in the health outcomes of the offspring. Studies have explored the influence of these factors and exposures on epigenetic changes in cord blood, which may impact long-term disease risk in children.

Fig. 3. Conceptual framework of genetic and epigenetic mechanisms involved in childhood outcomes (autism spectrum disorder as an example).

Schematic showing genetic factors, maternal factors (pre-pregnancy and pregnancy), environmental and neonatal factors influencing the outcome of autism spectrum disorder.

Pregnancy-related factors

Assisted reproductive technology (ART).

Assisted reproductive technology (ART) has been known to affect various maternal and childhood outcomes, with increased risk of preterm delivery, low birth weight, and increased risk of genetic defects. The timing of fertility interventions coincides with epigenetic programming, which has led to speculations that ART may influence the genomic patterns of the offspring.¹¹ Additionally, ART involves changes to the embryological milieu, which may disrupt genomic imprinting and DNA methylation mechanisms.¹¹ Genome-wide methylation studies to understand the difference in the methylation patterns between ART and natural conceptions have been undertaken to better understand the influence of ART on childhood outcomes. In a recent systematic review by Schaub et al., seventeen studies addressing the link between ART and tissue methylation patterns were included. These studies differed in tissue samples used and types of ART performed, thus posing challenges in interpreting the overall effect of ART on cord epigenetics.¹² Some of the genes affected by epigenetic modifications associated with ART include PYY gene (function related to appetite), GNAS (imprinting), ACTL10 (associated with muscle contraction) and MYMG2 gene (associated with neuronal circuit formation).¹² Genome wide DNA methylation patterns noted in the cord blood have been reported to persist in early childhood (6–12 years of age),¹³ with some studies reporting the resolution of these epigenetic changes by adulthood.¹⁴ Thus, limited evidence on the effect of ART on cord epigenetics and challenges in interpreting the studies due to heterogeneity in evidence warrant further research.

Hypertensive disorders of pregnancy (HDP).

Preeclampsia is characterized by new-onset hypertension accompanied by proteinuria during pregnancy and has been reported to be one of the leading causes of fetal growth restriction.¹⁵ Preeclampsia results from placental dysfunction, which can have significant effects on maternal and fetal cardiometabolic states.¹⁵ This can also result in drastic effects on the in-utero well-being of the fetus leading to adverse outcomes for the newborn offspring such as prematurity and low birth weight and can also impact their long-term cardiovascular morbidity. Several embryological, angiogenic, and epigenetic mechanisms have been hypothesized as the cause of placental disruption and resultant preeclampsia.¹⁵ The placenta serves as the “powerhouse” for the fetus and is a vital interface between the mother and the fetus, providing growth, nutrition, and immunity. The enzymes involved in maintaining and regulating the fetoplacental relationship can be impacted by epigenetic mechanisms such as DNA methylation, which can impair fetal growth and well-being.^15,16 Multiple studies have elucidated the link between preeclampsia and differential cord DNA methylation, with Differentially Methylated Regional (DMR) Analysis pointing to genes affecting cell signaling, inflammatory responses and RAS-activity such as the AVP gene.^17–21 Kazmi et al. reported associations between hypertensive disorders of pregnancy (HDP) and methylated CpG sites that impact development, embryogenesis, and neurological outcomes.²⁰ In a recent study by Knihtila et al., DNA methylation signatures affecting the apelin signaling pathway, which is related to cardiovascular physiology, were reported in cord blood samples from offspring of mothers with preeclampsia.²¹ This supports the hypothesis that altered cord blood epigenetics in preeclampsia impacts long-term outcomes in the offspring. The impact of HDPs, its impact on the in-utero milieu, and resultant epigenetic alterations have been investigated and may foster interventions to improve both short and long-term health outcomes in the offspring.

Gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is one of the most common pregnancy-related complications, which can lead to adverse maternal and neonatal complications such as difficult extraction, large for gestational age, macrosomia, preeclampsia, and respiratory distress. Studies have reported a link between GDM and increased risk of metabolic syndrome, adverse neurodevelopmental outcomes, and obesity in the offspring.²² The placenta secretes insulin-like growth factor (IGF-1), which plays an important role in the development of GDM. Methylation changes in the IGF-axis pathway are reported to cause GDM.²³ There is substantial evidence on the link between epigenetic mechanisms and GDM, and its impact on long-term outcomes in the offspring.^24–30 Some of the common epigenetic mechanisms include methylation of leptin promotor region, adiponectin, solute carrier family 6 member 4 (SLC6A4), and lipoprotein lipase.³¹ A recent study reported that GDM was associated with specific DNA methylation changes in the cord blood and was associated with neonatal hypoglycemia.³² Wang et al. also recently reported that GDM was associated with altered DNA methylation patterns, which may predispose to preterm birth.³³ Further, exposure to GDM has also been reported to affect long-term outcomes in offspring.³³ A recent study reported that the DNA methylation signatures resulting from intrauterine exposure to GDM and maternal obesity altered pathways involving metabolism of fatty acids and mitochondrial driven energy pathways, beyond the newborn period in the offspring, thus supporting the evidence of an altered glucose homeostasis contributing to DNA methylation related epigenetic modifications.³⁴

Maternal diet.

Dietary influence on epigenetics occurs via its effect on the one-carbon metabolism pathway, which allows nutrients to regulate DNA methylation.³⁵ The effect of folic acid and omega-3 PUFA and offspring DNA methylation patterns are examples of this influence. However, dietary patterns can be challenging to interpret since there can be variations in how diet is measured and only takes one time point into account. In a recent systematic review, the authors reported low certainty of evidence for the effect of maternal diet on the epigenetics of the offspring.³⁵

Prenatal toxin and drug exposure.

With evidence of maternal exposure to toxins and adverse outcomes in neonates, epigenetic mechanisms have been studied to determine causation. Exposure to toxins such as tobacco, alcohol, metals, and metalloids during pregnancy can have epigenetic implications since these elements may interact with various enzymes that catalyze epigenetic modifications and subsequently affect gene expression. In a recent systematic review, it was reported that maternal smoking during pregnancy was associated with differential DNA methylation patterns in offspring cord blood, affected various developmental pathways.³ Similarly, prenatal tobacco and alcohol exposure were reported to have an epigenetic-mediated negative association with neuro-developmental outcomes in children at 6 months of age.³⁶ An altered DNA methylation pattern was also noted in the offspring of those mothers with opioid exposure during pregnancy, which can impact neonatal abstinence syndrome outcomes.^37,38 Prenatal exposure to various metals and metalloids can alter epigenetics in the cord blood and is reported to be associated with an increased risk of spontaneous preterm birth³⁹ and abnormal neuronal development in the offspring.⁴⁰

Prenatal pharmaco-epigenomics helps to study the effect of medications on the developing fetus. This evidence can vary from knowing about the negative effect of a medication on the developing fetus to having no impact on outcomes, thus providing evidence of the safety of its use during pregnancy. The effects of medication exposure during pregnancy on the developing fetus is mostly uncertain but has the potential to affect epigenetic mechanisms in the fetoplacental dyad. Studies on the effect of prenatal anti-depressants, anti-epileptic medications, acetaminophen, and acetylsalicylic acid, on neonatal DNA methylation patterns have been explored, and are challenging to summarize due to clinical and methodological heterogeneity.⁴¹ In a recent study, it was reported that maternal steroid exposure did not impact glucocorticoid receptor methylation in the cord blood.⁴² Similarly, prenatal acetaminophen exposure was reported to have no impact on cord blood DNA methylation in children with ADHD.⁴³

Non-modifiable maternal factors

In addition to modifiable factors, non-modifiable factors such as race, ethnicity, and socioeconomic status can also impact cord epigenetics. Maternal race can impact placental DNA methylation, as reported by Workalemahu et al., who reported that the placental DNA age was accelerated among mothers of African and Native American ancestry.⁴⁴ The impact of socioeconomic status on poor neonatal outcomes as well as long-term outcomes such as diabetes and obesity have been reported in the literature.⁴⁵ Laubach et al. reported altered cord blood methylation patterns affecting ACSF3, TNRC6C-AS1, MTMR4 and LRRN4 genes among those with low prenatal socio-economic status.⁴⁶

Neonatal factors and cord epigenetics

In addition to maternal health and maternal toxic and drug exposures, individual differences between the offspring can also impact overall health and both short and long-term outcomes (Fig. 3). Patient characteristics including sex, gestation age, and birth weight may explain differences in susceptibility to certain disorders such as asthma, diabetes, and cancers. Birth weight, gestational age, and sex of the offspring have been reported to influence variations in DNA methylation patterns of the cord blood.^47–49 The sex-associated variation in epigenetic mechanisms involves DNA methylation of X chromosomes,⁴⁷ DNA methylation of autosomes,^50,51 and microRNA (miRNA) expression.⁵² These studies have supported the impact of sex on the epigenetic mechanisms of diseases and have shed light on accounting for sex-specific associations to the pathogenesis of diseases. The association of birth weight with long-term cardio-metabolic and neurodevelopmental outcomes has been reported.⁴⁸ In a recent metanalysis, the authors reported differential DNA methylation patterns based on birth weight, which were observed in cord blood, in childhood and adolescence.⁴⁸ Epigenetics associated with preterm gestation can have a significant impact on neonatal morbidity and mortality and can influence long-term health outcomes. Several studies have reported evidence of associations between DNA methylation and gestational age.^49,53,54 In a recent metanalysis, it was reported that there was an overlap in the DNA methylated sites in cord blood, fetal lung, and fetal brain associated with gestational age, and the gene with the largest negative magnitude of association was linked to vitamin A metabolism. Additionally, IGF2BP1 gene, which impacts cardiometabolic pathways was reported in the cord blood on gestational age-related DNA methylation sites, hence supporting a potential causal link between gestational age and long-term cardiometabolic outcomes.⁴⁹

Despite strong evidence of these inter-individual factors influencing epigenetic mechanisms, fetal development and the factors impacting it are quite complex. There are possibilities of confounding and reverse causality from maternal health and maternal toxin exposure that might potentially impact fetal growth, and further affect birth weight as well as increase the risk of preterm birth. Confounding is supported by the evidence that the DNA methylation sites associated with birth weight noted in cord blood overlapped with those reported with maternal smoking exposure.⁴⁸ Despite being challenging, further research on these inter-individual factors and their impact on epigenomics, independent of factors affecting the maternal-fetal symbiosis is warranted.

An overview of various maternal and neonatal factors involved in childhood outcomes, the genes of interest and epigenetic mechanisms is summarized in Table 1.

Table 1.

Summary of epigenetic modifications of genes associated with maternal and neonatal risk factors

Risk factor		Genes studied	Epigenomic mechanism	Methods used	Childhood Outcome	Gaps in knowledge
Maternal factors	ART	PYY, GNAS, ACTUO, MYMG2	Cord DNA Methylation	EWAS using Human Methylation27, Infinium Human Methylation 450 K BeadChip, and MethylationEPIC BeadChip	Increased risk of preterm delivery, low birth weight, genetic defects	Heterogeneity in studies due to differing tissue samples and types of ART
	HDP	AVP	Cord DNA Methylation	EWAS using Illumina Infinium HumanMethylation450 (HM450) and BeadChip assays	Cardiovascular and neurological defects	Differential impact of specific HDP disorders (pre-eclampsia versus gestational hypertension)
	GDM	leptin promotor region, adiponectin, SLC6A4, and lipoprotein lipase	Cord DNA methylation	EWAS using Illumina Human Methylation 450 K, DNA Analysis Beadchip and BSP	Preterm birth, metabolic syndrome, adverse neurodevelopmental outcomes, and childhood obesity
	Maternal diet	One-carbon metabolism pathway	Cord DNA methylation	Both EWAS (using Illumina methylation arrays, bisulphite pyrosequencing or high-resolution melt analysis) and candidate genes and their DMR		Variations in dietary assessments
	Toxin/drug exposure	Multiple genes in developmental pathways	Cord DNA methylation	EWAS using llumina HumanMethylation450K Beadchip array	ADHD, Neurobehavioral, neurodevelopmental spontaneous preterm birth	Clinical and methodological heterogeneity
	Maternal socio-economic status	ACSF3, TNRC6C-AS1, MTMR4 and LRRN4	Cord DNA methylation	EWAS via Infinium HumanMethylation450 BeadChip	Diabetes and obesity	Specific findings from since community. Lack of data on role of paternal DNA methylation patterns
	Maternal race and ethnicity	MEG3, IGF2, IGF2/H19 and NNAT	Cord DNA methylation	DMRs regulating genomically imprinted domains	Infant low birth weight
Neonatal factors	Neonatal Sex and gestational age	Vitamin A metabolism, IGF2BP1	Cord DNA methylation	EWAS via Illumina450K	Cardiometabolic outcomes	Confounding maternal factors
	NICU environment	Genes regulating dopamine, serotonin, and cortisol pathways- SLC6A4, SLC6A3, OPRMI, NR3C1, HSD11B2, and PLAGL1	Blood DNA methylation	Both EWAS and candidate genes and their DMRs	Neurodevelopmental, cerebral palsy	Multiple confounders

Table describing some examples of maternal and neonatal factors that have been implicated in various childhood outcomes, the genes of interest, epigenomic mechanism involved and gaps in knowledge.

ART artificial reproductive technology, HDP hypertensive disorders of pregnancy, GDM gestational diabetes mellites, NICU neonatal intensive care unit, ADHD attention deficit hyperactivity disorder, EWAS epigenome- wide associated studies, DMR differentially methylated regions.

IMPACT ON CHILDHOOD OUTCOMES

With the growing evidence on the overall effect of various maternal, neonatal, and environmental factors on the epigenome of the offspring, the field of epigenetics has delved into establishing temporal causation between these factors and an array of childhood diseases. Changes in cord epigenomics have now provided evidence of association to various neonatal and childhood outcomes, which can be leveraged for interventional breakthroughs in medicine.

Perinatal and neonatal outcomes

The introduction of “omics” research in neonatal-perinatal medicine has opened avenues to incorporate data from the genome, transcriptome, and epigenome in the management of newborn disorders. Since cord blood DNA methylation has provided evidence of having potential causal links to birth weight,⁴⁸ this area of research has been targeted as potential clues for clinical management.

Neonatal growth and outcomes.

Intrauterine growth restriction (IUGR) leads to adverse short-term and long-term health consequences, including an increased risk of type 2 diabetes mellitus.^55,56 Studies using chromatin immunoprecipitation assay (ChIP) in an IUGR rat animal model reported increased histone acetylation of specific genomic factors which can result in pulmonary vascular remodeling, thus increasing the risk of pulmonary arterial hypertension.⁵⁷ Ding et al. reported that in comparison to appropriate for gestational age (AGA) babies, babies with IUGR had multiple differentially methylated genes with negative correlation to genes involved in metabolic pathways and diseases of immunomodulation, and cancer, endocrine, and nervous systems.⁵⁵ In a recent study, an overall hypomethylation trend was noted in the cord blood samples of babies with intrauterine growth restriction (IUGR), in comparison to those AGA.⁵⁸ The authors also report dysregulation of genes involved in the T cell pathway and reactive oxygen species (ROS) pathway, which can stem as precursors for metabolic diseases.⁵⁸ In addition to DNA methylation, variable miRNA expression detected using miRCURY LNA technology has also been reported in IUGR pregnancies.⁵⁹ Mas-Peres et al. reported umbilical cord miRNA as novel biomarkers for a prediction of catch-up growth at an year of age in babies with IUGR.⁵⁹ This supports the concept that in babies with IUGR, there are epigenetic signatures in the cord blood that can link them to multiple health consequences.

Similar to IUGR babies, those born large-for-gestational-age (LGA) are at increased risk for adult obesity and type 1 and 2 diabetes.⁶⁰ As such, the cord DNA methylation data could be used to predict potential long-term outcomes. Cord epigenetics has identified candidate genes that may best predict birth weight percentiles and long-term health outcomes in babies born LGA.^60–62 In a recent study, differential DNA methylation patterns were noted in genes involving cardiometabolic, renal, and neurological pathways.⁶²

Neonatal sepsis.

Being one of the leading causes of neonatal morbidity and mortality, neonatal sepsis has been an area of ongoing research for early diagnosis, predictive models, and for implementation of a multimodal approach for its management. This has also become an area of growing interest and attention on the role of epigenetics in neonatal immunity and its impact on subsequent increasing susceptibility to sepsis and propensity for adverse sepsis-related outcomes. A prospective study recently explored DNA methylation signatures in blood samples of preterm infants with clinical suspicion for sepsis and reported alteration in the methylation levels of genomic regions involved in both innate and adaptive immunity, which would potentially serve as biomarkers for neonatal sepsis.⁶³ In addition to DNA methylation, miRNA markers, detected using reverse transcription real-time polymerase chain reaction (RT-qPCR), have also been investigated as potential biomarkers for neonatal sepsis and are an ongoing area of research for both diagnostic and therapeutic potential.⁶⁴

NICU environment.

Early exposure to toxic stress in the NICU environment may increase the risk of adverse neurodevelopmental outcomes. Taking the NICU environment and its role in epigenetic modifications into account, a recent study reported that DNA methylations in genes involved in regulating dopamine, serotonin, and cortisol pathways that were linked to early toxic stress exposure in the NICU.⁶⁵ This can provide evidence for implementing interventions to reduce stressors in the NICU. Efforts to improve maternal-neonatal bonding by encouraging maternal touch, skin-to-skin, and kangaroo mother care can promote bonding and alleviate the effects of early toxic stressors in the NICU.⁶⁶ This is supported by a recent study that reported that low levels of maternal touch can intensify epigenetic changes in stress response in preterm infants in the NICU.⁶⁶

Prematurity related disorders.

Various neonatal disorders such as necrotizing enterocolitis,⁶⁷ bronchopulmonary dysplasia,^68,69 and retinopathy of prematurity⁷⁰ are linked to variable DNA methylation patterns involving fibroblast growth factor, cellular invasion, and neuronal signaling pathways. A recent study by Everson et al. also provided evidence that genes such as PLA2G4E, TRIM9, GRIK3, and MACROD2, which are implicated in neurological structure and function were found in preterm neonates with abnormal neurobehavioral profiles.⁷¹ Further research and innovation on this front will not only help in early diagnosis and prevention but also open avenues to promote patient-tailored, precision medicine in neonatology.

In addition to short-term morbidities associated with prematurity, preterm infants are at high risk for adverse neurodevelopmental outcomes and cerebral palsy (CP) because of their immature neuronal development, and susceptibility to injury. Epigenetic modifications can play an important role in impacting neurodevelopmental outcomes at both fetal and postnatal levels. Studies assessing DNA methylation changes in cord blood and its resultant effects on childhood neurodevelopmental outcomes have been described in the literature.⁷² In addition to various maternal factors, studies investigating the environmental exposure of the newborn and its subsequent impact on neurodevelopment have also been reported. For instance, oxygen load provided in the delivery room for preterm infants has been reported to modify DNA methylation mechanisms.^73,74These modifications and their impact on neurodevelopmental outcomes at 2 years of age have been reported.⁷³ In a recent study by Bahado-Singh et al., neonatal blood DNA methylation analysis was performed comparing patients with cerebral palsy with those without the diagnosis. Using artificial intelligence techniques,⁷² the authors reported that specific genes affecting the biological pathways of brain growth, neuroprotection, and neuronal development were differentially methylated among patients with CP, thus opening avenues for accurate prediction and early detection of patients with CP.⁷⁵

Evidence of epigenetic variations and their impact on the long-term neurodevelopment of the offspring can provide information on patients at risk, which can inform early interventions for improved long-term outcomes.

Childhood disorders

Neurodevelopmental and behavioral disorders.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder, with increasing prevalence, and ongoing research interest in deducing epigenetic mechanisms that could play a role in its etiology. The interest in this disorder also arose from the prevalence of ASD in patients with genetic syndromes such as Prader-Willi and Rett syndrome, which are associated with epigenetic changes.⁷⁶ With the introduction of novel DNA methylation assays such as ‘EpiSign’, which can help screen genetic syndromes using classification algorithms, multiple neurodevelopment syndromes have been identified, most of which are also associated with an ASD candidate gene.⁷⁷ Epigenetic dysregulation has also been reported in several candidate ASD genes such as EIF4E, FYN, SHANK1, and VIM, which are involved in mTOR signaling, neuronal inflammation, and serotonin degradation.⁷⁸ In a recent study by Zhu et al., a placental methylome associated with the 22q13.33 gene was identified, which was noted to be induced in response to neuronal differentiation and oxidative stress. This transcript was named NHIP, and a hypomethylated NHIP variant was associated with increased ASD risk. In comparison to mothers who did not take folate during pregnancy, mothers who took folic acid in the first month of pregnancy provided an antioxidant methyl group, thus methylating the NHIP transcript and reducing ASD risk.⁷⁹ This is a prime example of how epigenetics mechanisms can be anchored for early detection, risk mitigation, and intervention in ASD. A conceptual framework of epigenetic mechanisms in ASD development is shown in Fig. 3.

Attention-deficit and hyperactivity disorder (ADHD) is also one neurodevelopmental disorder with both genetic and environmental components playing a role in its risk and pathogenesis. Several candidate ADHD genes associated with the dopamine system have been reported to undergo DNA methylation alterations.⁸⁰ Since the overall clinical spectrum of ADHD can span over several years, a recent study provided evidence that DNA methylation patterns in cord blood were associated with an increased risk of ADHD symptoms.⁸⁰ This can be utilized for the development of several biomarkers that can predict ADHD- for early diagnosis and interventions. Early adversity in childhood has been implicated in long-term mental health disorders. DNA methylation has established links between environmental adversity and mental illness, with implications on the role of surrogate genes associated with inflammation, immune regulation and stress response.⁸¹ This area of research is in its early stages and can help discover novel biomarkers to improve mental health outcomes.

Respiratory and allergic disorders.

Since the in-utero environment is noted to play a significant role in introducing epigenetic modifications and affecting organogenesis, studies have investigated its specific role in lung development and implications on long-term lung disorders such as asthma and COPD. Studies have reported that cord blood methylated DNA patterns such as AXL promotor methylation, alteration of PAOX, HOXA5 and PTPRN2 were associated with childhood lung function.^82–84 Specific genes in the cord blood DNA were also linked to the development of childhood asthma and adult COPD and predicted lung function between 10 and 26 years of age.^83,85 Lung disease can also depend on environmental factors such as allergic sensitization. Ig-E mediated allergic sensitization has been reported to have been programmed in utero, with several DNA methylation patterns associated with Ig-E-mediated hypersensitivity.⁸⁶ The detection of these epigenetic signatures may help predict allergic responses and allergy-related childhood disorders. As an example, upon investigating the DNA methylation patterns of children exposed to farm exposure and the development of childhood asthma, it was reported that genes associated with asthma and Ig-E regulation underwent epigenetic modifications among offspring of farm exposure families, thus supporting the influence of environment and epigenetic modifications playing a role in childhood asthma development and respiratory outcomes.⁸⁷

Cardiac disorders.

Epigenetic regulation has been investigated as a causal link for various cardiac disorders. Artificial intelligence has been utilized to detect methylation changes in newborn blood DNA affecting genes in the cardio-developmental pathway. This has been also investigated to create a predictive model for coarctation of the aorta in the neonatal population.⁸⁸ Similarly, in babies with tetralogy of Fallot (ToF), the newborn blood DNA methylation studies have revealed variable methylation patterns in genes associated with heart development.⁸⁹ Evidence from these studies has established epigenetic causal links in congenital heart disease, which can have an enormous impact on childhood morbidity and mortality. Besides newborn and childhood cardiac disorders, cord blood DNA methylation patterns have also been investigated as a predictor of adult cardiac disorders such as hypertension and coronary artery disease. For instance, cord blood DNA methylation patterns of the ANRIL gene, a gene linked to coronary heart disease, have been correlated with pulse wave velocity patterns of the descending aorta in children.⁹⁰ Similarly, methylation of the HIF3A gene noted in the cord blood was linked to systolic blood pressure patterns in early childhood.⁹¹ These studies provide evidence of the impact of early life exposures that can persist in childhood and cause cardiac implications in adulthood as well.

Childhood cancer.

DNA methylation, histone modification, and miRNA have all been implicated in the development of childhood cancers, of which childhood leukemia as a cancer and DNA methylation as a mechanism are the most commonly investigated for epigenetic links. The study of epigenetic changes in cord blood linked to childhood cancer can be challenging due to heterogeneity in the disorder, challenges with collecting biospecimens at birth in a limited cohort of specific childhood cancers, and additional confounders from maternal exposures.⁹² Large prospective cohorts to test exposures and outcomes in childhood cancers are lacking and are an ongoing area of research.

Childhood obesity and metabolic syndrome.

Cord blood DNA methylation studies have been performed to investigate the link between maternal hyperglycemia and the development of childhood obesity. Leptin is a hormone that inhibits the hypothalamic stimuli to food intake and has been implicated as a risk factor for obesity and insulin resistance. Cord DNA methylation studies have provided evidence of DNA methylation mechanisms affecting the leptin pathway in maternal hyperglycemia and hypercholesterolemia.^93,94 Epigenetic modification of genes including PLIN4, PPP1R16B, and UBE2F in the cord blood have been implicated as being predictive of childhood weight outcomes.⁹⁵ In addition to cord blood, DNA methylation patterns associated with childhood obesity were also noted in neonatal blood spot samples.⁹⁶ Further research in this field would help recognize children at risk, for early interventions.

SUMMARY AND FUTURE DIRECTIONS

We report a scoping review of the impact of cord epigenetics on childhood health outcomes. The paradigm shift of precision medicine from traditional medicine has now focused on the importance of personalizing healthcare including diagnostics, interventions and predicting health trajectories. Deducing the associations of epigenetic signatures in the cord and neonatal blood with neonatal, childhood and adult health outcomes will advance the implementation of precision medicine in clinical practice. With advances in the detection of epigenetic changes, a better understanding of the temporal sequence of environmental exposures and their impact on epigenomic changes has emerged. An example is the rapid advances due to the SARS-COVID-19 pandemic and its impact on cord blood epigenome to provide evidence on the impact of maternal COVID-19 exposure and neonatal outcomes.⁹⁷

One of the important impacts that epigenetic research can have in medicine is the introduction of biomarkers, which can help in screening, early detection, intervention, and therapeutic management.⁹⁸ With the advent of artificial intelligence (AI), multiple predictive models can be built using epigenetic data or in conjunction with other omics data to predict various perinatal, neonatal, childhood, and adult outcomes. Early prediction with appropriate diagnostic algorithms and treatment protocols may beneficially affect health trajectories. The heterogeneity of the available datasets and the challenges with the availability and accessibility of large data sets can pose significant challenges in performing AI-Epigenetics studies. As we enter this era of AI in medicine, every effort to address these challenges would create a novel pathway to improving outcomes in healthcare.

While advances in epigenomics has the potential to enhance our understanding of disease processes in an in-depth and impactful manner, there are challenges in interpretation and clinical application due to wide heterogeneity in the results of studies and possibly multiple confounders playing a role in the disease process. We need longitudinal studies that provide information on the longevity of the early life epigenetic changes. Identification of risk factors including environment and diet that are associated with epigenetic changes may aid in devising interventions to prevent deleterious health outcomes (e.g. folate, a methyl donor, supplementation to prevent neural tube defects in the newborn). Currently, very little actionable information is available on interventions to prevent deleterious epigenetic changes or to induce epigenetic changes for benefit. Further research is necessary to evaluate clinical interventions that modulate epigenetic mechanisms for improved health outcomes with the least risk in children.

Supplementary Material

Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/s41390-024-03585-7.

IMPACT STATEMENT::

• Epigenetic changes such as DNA methylation, histone modification, and non-coding RNA have been implicated in the pathophysiology of various disease processes.

• The fundamental changes to an offspring’s epigenome can begin in utero, impacting the immediate postnatal period, childhood, adolescence, and adulthood.

• This scoping review summarizes current literature on the impact of early life epigenetics, especially DNA methylation on childhood health outcomes