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Cited by 0Birth, Development, and HealthGestational Diabetes Research and ManagementPregnancy and preeclampsia studies

Maternal Obesity, Metabolic Syndrome, and Long-Term Effects on Offspring: A Developmental Origins of Health and Disease (DOHaD) Perspective

Open access
Tsaqifah, Nabila Aulia, Hanifah, Rifdah, Husna, Firda Asma'ul, Hidayati, Mailani Dwi, Widyawati, Dwi, Putri, Ghea Farmaning Thias, Al Shadrina, Ainina·2025·Nusantara Medical Science Journal
DOI 10.20956/nmsj.v10i2.47907
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Abstract

Introduction: The global prevalence of obesity among women of reproductive age has increased markedly over the past two decades, reaching 24% in high-income and 16% in low- and middle-income countries. This trend contributes to adverse maternal and neonatal outcomes, including a 2–4-fold higher risk of gestational diabetes, a threefold increase in preeclampsia, and up to a 50% higher caesarean delivery rate. Maternal metabolic disorders also have long-term consequences for offspring metabolic and cardiovascular health. Objective: To synthesize current biological and epidemiological evidence linking maternal metabolic status to offspring health within the Developmental Origins of Health and Disease (DOHaD) framework. Methods: A comprehensive search was conducted in PubMed, Scopus, and Web of Science from January 2015 to September 2025 using keywords related to maternal obesity, metabolic syndrome, DOHaD, offspring health, and epigenetics. Included studies comprised human and animal research with follow-up beyond two years, while case reports, editorials, and studies without long-term outcomes were excluded. Findings: From 22 eligible studies, consistent evidence indicates that maternal obesity and metabolic syndrome affect offspring through placental dysfunction, systemic inflammation, and epigenetic reprogramming. Offspring of obese mothers show a 1.5–2.8-fold increased risk of obesity and insulin resistance during adolescence and adulthood. Epigenome-wide analyses reveal altered methylation of genes regulating lipid metabolism (LEP, IGF2) and inflammatory pathways, supporting the DOHaD hypothesis. Conclusion: Maternal metabolic health critically shapes offspring developmental and metabolic outcomes. Preconception and antenatal interventions targeting metabolic optimization provide key opportunities to prevent intergenerational transmission of metabolic risk and promote healthier future generations.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review synthesizes evidence that maternal obesity and metabolic syndrome program long-term offspring cardiometabolic risk through placental, epigenetic, inflammatory, oxidative-stress, and microbiome-related mechanisms within the DOHaD framework. It concludes that preconception and antenatal metabolic optimization may help interrupt intergenerational transmission of metabolic disease.

Key findings

  • Offspring of obese mothers show a 1.5–2.8-fold increased risk of obesity and insulin resistance during adolescence and adulthood; pooled analyses report adjusted odds ratios of 1.8–2.5 for childhood obesity and 1.6–2.0 for metabolic syndrome.
  • Meta-analyses cited in the review indicate maternal prepregnancy obesity increases offspring risk of obesity by 2.3-fold and type 2 diabetes by 1.8-fold, independent of postnatal weight gain.
  • Mechanistic evidence links maternal obesity/MetS to placental dysfunction (e.g., TNF-α, IL-6, mTOR/AMPK dysregulation), epigenetic changes (e.g., altered methylation at IGF2, LEP, PPARγ), oxidative stress, inflammation, and maternal gut microbiota alterations.
  • Sex-specific vulnerability is reported: male offspring tend to show greater insulin resistance and hepatic steatosis, while females show higher adiposity and altered leptin regulation.

Methods

  • A comprehensive search of PubMed, Scopus, and Web of Science was conducted for studies published January 2015–September 2025 using keywords related to maternal obesity, metabolic syndrome, DOHaD, offspring health, and epigenetics.
  • Inclusion criteria were human and animal studies on maternal obesity/MetS and offspring health outcomes with follow-up beyond 2 years; exclusions included case reports, editorials, conference abstracts, and studies without long-term outcomes.
  • From 1,247 records, 312 duplicates were removed, 935 abstracts screened, 104 full texts assessed, and 22 studies included; two reviewers independently screened and extracted data, and findings were synthesized narratively rather than quantitatively.

Limitations

  • The paper states that most available studies are observational, subject to recall and selection bias, often rely on self-reported maternal weight or non-standardized MetS definitions, have modest sample sizes, and have follow-up durations insufficient to capture long-term or multi-generational effects.
  • It also states that few studies adequately account for confounding by shared genetic, socioeconomic, or environmental factors, and that this review did not conduct a formal risk of bias assessment.
  • Evident from the text: the review uses narrative synthesis because of heterogeneity in study designs and outcome measures, so it does not provide pooled quantitative estimates; it also notes that most studies are concentrated in high-income countries, limiting generalizability to low- and middle-income settings.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.20956/nmsj.v10i2.47907

Cites

26 of 26 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 48 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Altered methylation of LEP, PPARγ, and IGF2 genes has been identified in placental and cord blood samples of infants born to mothers with obesity or gestational diabetes, influencing pathways of adipogenesis and glucose metabolism.

    “Altered methylation of LEP, PPARγ, and IGF2 genes has been identified in placental and cord blood samples of infants born to mothers with obesity or gestational diabetes, influencing pathways of adipogenesis and glucose metabolism.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [26]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [24]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Findingcitation

    The Generation R cohort identified a moderate increase in child systolic blood pressure with higher maternal BMI.

    “For example, the Generation R cohort identified a moderate increase in child systolic BP with higher maternal BMI 4 ,”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Findingcitation

    Several studies reported associations between maternal obesity or metabolic syndrome and neurodevelopmental delays, suggesting broader developmental consequences beyond metabolic health.

    “Additionally, several studies reported associations with neurodevelopmental delays, suggesting broader developmental consequences beyond metabolic health [10][11][12] .”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [10]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [11]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [12]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Findingcitation

    These epigenetic modifications may be sex dependent.

    “Importantly, these modifications may be sex dependent.”
    Quote in the paperSubstantial claim
  • Findingcitation

    Hypermethylation at IGF2, LEP, and PPARγ loci has been associated with higher maternal BMI and subsequent offspring adiposity.

    “Hypermethylation at IGF2, LEP, and PPARγ loci has been associated with higher maternal BMI and subsequent offspring adiposity 10,18 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [10]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [18]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims. 23
  • Classified as probably not a substantial claim. 6

  • May combine two claims.

    Findingcitation

    Evidence from recent cohorts (2022-2025) indicates that methylation changes in metabolic and inflammatory loci such as NR3C1 and H19 are more pronounced in male fetuses, potentially explaining their higher cardiometabolic vulnerability in later life.

    “Evidence from recent cohorts (2022-2025) indicates that methylation changes in metabolic and inflammatory loci-such as NR3C1 and H19-are more pronounced in male fetuses, potentially explaining their higher cardiometabolic vulnerability in later life 27,28 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [28]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation

    Recent meta-analyses demonstrate that maternal prepregnancy obesity increases offspring risk of obesity by 2.3-fold and type 2 diabetes by 1.8-fold, independent of postnatal weight gain.

    “Recent meta-analyses, including one published in The Lancet Diabetes & Endocrinology (2023), reinforce these associations, demonstrating that maternal prepregnancy obesity increases offspring risk of obesity by 2.3-fold and type 2 diabetes by 1.8-fold, independent of postnatal weight gain 25,26 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [25]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [26]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingcitation

    These studies reveal sex-specific vulnerability: male offspring tend to exhibit greater insulin resistance and hepatic steatosis, while females show higher adiposity and altered leptin regulation.

    “Notably, these studies also reveal sex-specific vulnerability: male offspring tend to exhibit greater insulin resistance and hepatic steatosis, while females show higher adiposity and altered leptin regulation 27,28 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [28]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingreasoning

    Although most studies converge on the positive relationship between maternal obesity and offspring metabolic risk, the magnitude of association varies across populations and exposure definitions.

    “Although most studies converge on the positive relationship between maternal obesity and offspring metabolic risk, the magnitude of association varies across populations and exposure definitions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Complementary animal studies demonstrate that maternal high-fat diets alter hypothalamic appetite regulation, gut microbiota composition, and hepatic lipid metabolism in offspring.

    “Complementary animal studies further demonstrate that maternal high-fat diets alter hypothalamic appetite regulation, gut microbiota composition, and hepatic lipid metabolism in offspring 24,27 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [24]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [27]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    These processes foster adipocyte hypertrophy, β-cell dysfunction, and endothelial impairment, establishing a pro-inflammatory and insulin-resistant phenotype early in life.

    “These processes foster adipocyte hypertrophy, β-cell dysfunction, and endothelial impairment, establishing a pro-inflammatory and insulin-resistant phenotype early in life.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationreasoning

    These influences operate through intertwined biological, molecular, and environmental mechanisms, aligning with the DOHaD framework.

    “These influences operate through intertwined biological, molecular, and environmental mechanisms, aligning with the Developmental Origins of Health and Disease (DOHaD) framework.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Maternal obesity induces systemic oxidative stress, increasing reactive oxygen species and lipid peroxidation, which damage placental tissue and disturb foetal redox balance.

    “Maternal obesity induces systemic oxidative stress, increasing reactive oxygen species (ROS) and lipid peroxidation, which damage placental tissue and disturb foetal redox balance 19 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    These epigenetic alterations persist into childhood, suggesting stable metabolic reprogramming.

    “These alterations persist into childhood, suggesting stable metabolic reprogramming.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Maternal metabolic health before and during pregnancy constitutes a pivotal determinant of intergenerational wellbeing, shaping population-level patterns of noncommunicable disease risk.

    “Thus, maternal metabolic health before and during pregnancy constitutes a pivotal determinant of intergenerational wellbeing, shaping population-level patterns of noncommunicable disease risk.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Dysbiosis in obese mothers alters short-chain fatty acid profiles and increases lipopolysaccharide exposure, affecting foetal immune maturation and metabolic homeostasis.

    “Dysbiosis in obese mothers alters short-chain fatty acid (SCFA) profiles and increases lipopolysaccharide (LPS) exposure, affecting foetal immune maturation and metabolic homeostasis [21][22][23] .”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [21]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [22]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [23]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Elevated TNF-α and IL-6 concentrations in the placenta interfere with nutrient sensing via the mTOR and AMPK pathways, further amplifying metabolic stress.

    “Elevated TNF-α and IL-6 concentrations in the placenta interfere with nutrient sensing via the mTOR and AMPK pathways, further amplifying metabolic stress 17 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Obesity and metabolic syndrome impair placental angiogenesis and nutrient transport, leading to foetal hyperinsulinaemia and increased adipose deposition.

    “Obesity and MetS impair placental angiogenesis and nutrient transport, leading to foetal hyperinsulinaemia and increased adipose deposition 16 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    The overall trend supports the DOHaD hypothesis, indicating that maternal metabolic status shapes offspring physiology through intrauterine and early-life mechanisms.

    “Nonetheless, the overall trend supports the Developmental Origins of Health and Disease (DOHaD) hypothesis, indicating that maternal metabolic status shapes offspring physiology through intrauterine and early-life mechanisms.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Such dimorphic outcomes suggest differential epigenetic sensitivity to intrauterine metabolic stress, prompting a refinement of the classical DOHaD model to incorporate sex-dependent programming effects.

    “Such dimorphic outcomes suggest differential epigenetic sensitivity to intrauterine metabolic stress, prompting a refinement of the classical DOHaD model to incorporate sex-dependent programming effects 26,28 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [26]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [28]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Two reviewers independently screened titles and abstracts, extracted data, and resolved discrepancies through discussion or consultation with a third reviewer.

    “Two reviewers independently screened titles and abstracts, extracted data, and resolved discrepancies through discussion or consultation with a third reviewer.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Through intertwined physiological, molecular, and epigenetic pathways, maternal obesity and metabolic syndrome shape the developmental programming of offspring health and contribute to the global rise in metabolic diseases.

    “Through intertwined physiological, molecular, and epigenetic pathways, they shape the developmental programming of offspring health and contribute to the global rise in metabolic diseases.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Given heterogeneity in study designs and outcome measures, findings were synthesized narratively rather than quantitatively.

    “Given the heterogeneity in study designs and outcome measures, findings were synthesized narratively rather than quantitatively.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    A PRISMA-style flow diagram was constructed to illustrate the screening and selection process and was displayed as Figure 1 to enhance transparency.

    “A PRISMA-style flow diagram was constructed to illustrate the screening and selection process and was displayed as Figure 1 to enhance transparency.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    Although this review did not conduct a formal risk of bias assessment, the synthesis highlights consistent methodological weaknesses across the literature.

    “Although this review did not conduct a formal risk of bias assessment, the synthesis highlights consistent methodological weaknesses across the literature.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Such findings advance the DOHaD model by suggesting that maternal obesity-induced epigenetic reprogramming interacts with foetal sex hormones and placental signaling, creating divergent adaptive responses.

    “Such findings advance the DOHaD model by suggesting that maternal obesity-induced epigenetic reprogramming interacts with foetal sex hormones and placental signaling, creating divergent adaptive responses 26,28 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [26]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [28]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Study design and conductnone given

    Most available studies are observational, subject to recall and selection bias, and often rely on self-reported maternal weight or non-standardized definitions of metabolic syndrome.

    “Most available studies are observational in nature, subject to recall and selection bias, and often rely on selfreported maternal weight or non-standardized definitions of metabolic syndrome (MetS).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductnone given

    Sample sizes are frequently modest, and follow-up durations are insufficient to capture long-term or multi-generational effects.

    “Sample sizes are frequently modest, and follow-up durations are insufficient to capture long-term or multi-generational effects.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    In total, 1,247 records were retrieved, 312 duplicates were removed, 935 abstracts were screened, 104 full-text articles were assessed for eligibility, and 22 studies meeting all inclusion criteria were included in the final synthesis.

    “In total, 1,247 records were retrieved across the three databases.After removing duplicates (n = 312), 935 abstracts were screened.Of these, 104 full-text articles were assessed for eligibility, and 22 studies meeting all inclusion criteria were included in the final synthesis.”
    Quote in the paperNot a substantial claim
24 of 24

  • The paper relies on this without support.

    Critical gaps remain in understanding how specific maternal metabolic profiles such as insulin resistance, lipid dysregulation, and inflammatory markers differentially affect offspring outcomes across populations and developmental stages.

    “However, despite growing evidence, critical gaps remain in understanding how specific maternal metabolic profiles-such as insulin resistance, lipid dysregulation, and inflammatory markers-differentially affect offspring outcomes across populations and developmental stages.”

  • The paper relies on this without support.

    Inconsistencies persist regarding the relative contribution of epigenetic mechanisms versus placental dysfunction in mediating long-term effects.

    “In addition, inconsistencies persist regarding the relative contribution of epigenetic mechanisms versus placental dysfunction in mediating these long-term effects.”

  • The paper relies on this without support.

    Most available studies are concentrated in high-income countries, limiting the generalizability of findings to low- and middle-income settings.

    “Furthermore, most available studies are concentrated in high-income countries, limiting the generalizability of findings to low-and middle-income settings, where the burden of maternal obesity is rapidly increasing.”
3 of 3

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Burton and Fowden study year differs from its reference

    Minor

    Table 2 dates the cited Burton and Fowden study to 2020, while reference 19 dates it to 2015.

  • Perrine study does not match reference 14

    Minor

    Table 1 labels reference 14 as a 2021 study by Perrine et al.; the reference list instead identifies a 2019 study by Nogues et al.

  • Catalano study year differs from its reference

    Minor

    Table 1 identifies the cited Catalano study as published in 2018, but reference 2 lists it as published in 2017.

  • Claimed 2023 Lancet meta-analysis does not match the cited references

    Minor

    The sentence attributes its conclusion-bearing risk estimates to meta-analyses including a 2023 Lancet Diabetes & Endocrinology publication, citing references 25 and 26. Reference 25 is instead a 2024 review in the International Journal of Obesity, and reference 26 is a 2025 article in the International Journal of Molecular Sciences.

4 of 4

Cites

Flagged first, then by citations

1 of the 27 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Morea M, Miu N, Morea VF, Cornean R. Maternal obesity -a risk factor for metabolic syndrome in children. Clujul Med [Internet]. 2013;86(3):259-65. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26527958%0Ahttp://www.pubmedcentral.ni h.gov/articlerender.fcgi?artid=PMC4462496

Authors
Tsaqifah, N. A., Hanifah, R., Husna, F. A., Hidayati, M. D., Widyawati, D., Putri, G. F. T., & Al Shadrina, A.
Affiliations
  • Sultan Ageng Tirtayasa University (ID)
  • University Sultan Ageng Tirtayasa
ORCID
Venue
Nusantara Medical Science Journal
Publisher
Hasanuddin University, Faculty of Law
Published
2025-12-15
Volume
10
Issue
2
Pages
34-44
ISSN
  • 2460-9757 (ISSN-L)
  • 2597-7288
DOI
10.20956/nmsj.v10i2.47907
OpenAlex
W7118066684
Semantic Scholar
8abb56586bf9496353711c4289180d1b469e4b0f
Cited by
0
References
27
FWCI
0.00
Type
journal article
Language
en
Open access
Licence
Locations
Nusantara Medical Science Journal (publishedVersion, cc-by)
Topics
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
  • Health Sciences › Medicine › Obstetrics and Gynecology › Gestational Diabetes Research and Management
  • Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
Keywords
maternal obesity, maternal metabolic syndrome, developmental origins of health and disease, offspring metabolic health, epigenetic reprogramming, DNA methylation, placental insufficiency, systemic inflammation, insulin resistance, gestational diabetes mellitus, preeclampsia, cesarean section, insulin-like growth factor II, LEP

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