From womb to world: scientists reveal how maternal stress programs infant development
Chongqing Medical University
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Flowchart depicts the interconnected nature of the proposed factors influencing maternal stress and fetal development.
view moreCredit: Pediatric Discovery
Maternal stress during pregnancy profoundly affects fetal growth and long-term health. This comprehensive review synthesizes evidence showing that elevated cortisol, disrupted brain connectivity, and stress-induced inflammation can alter fetal brain structure, immune function, and developmental programming. The timing and type of stress exposure—ranging from natural disasters to chronic anxiety—determine specific outcomes such as preterm birth, low birth weight, and emotional dysregulation. These effects, often mediated through the hypothalamic–pituitary–adrenal (HPA) axis and epigenetic mechanisms, may extend into adulthood, predisposing offspring to mental health and metabolic disorders. The findings underscore the urgent need for stress-reduction interventions and equitable maternal healthcare to safeguard the next generation.
Maternal stress, encompassing physical, emotional, and psychological distress, remains a widespread yet underestimated risk during pregnancy. Previous research has linked stress to increased cortisol levels and abnormal neurotransmitter signaling, which may interfere with fetal brain development. However, inconsistencies persist in understanding how prenatal stress translates into measurable cognitive and emotional outcomes in children. Environmental crises, socioeconomic inequities, and access to healthcare further compound these risks, particularly in resource-limited regions. Due to these challenges, in-depth investigations are needed to clarify how maternal stress disrupts developmental pathways and to identify strategies that can mitigate its lifelong effects.
Researchers from the Georgia Institute of Technology have published (DOI: 10.1002/pdi3.70004) a comprehensive review in Pediatric Discovery (September 2025), revealing how maternal stress reshapes fetal growth and brain development through complex biological and environmental interactions. Drawing on data from major disasters such as the 1998 Ice Storm, 2010 Chile Earthquake, and 2008 Iowa Floods, the team integrates molecular, physiological, and sociocultural evidence. Their findings demonstrate that maternal stress activates hormonal and epigenetic changes that can persist across generations, emphasizing the urgent need for maternal mental health interventions.
The review identifies the hypothalamic–pituitary–adrenal (HPA) axis as the central stress-response system, where elevated cortisol and glucocorticoids cross the placenta and disrupt fetal brain regions such as the hippocampus and amygdala. These disruptions can impair cognitive function, emotional regulation, and later stress resilience. Imaging studies revealed reduced left hippocampal volume and altered neural connectivity in infants exposed to high prenatal anxiety. Environmental events such as the Chile Earthquake and Project Ice Storm further demonstrate how acute and chronic stressors reshape development—leading to lower birth weights, smaller head circumferences, and increased emotional reactivity. On a molecular level, chronic stress modifies DNA methylation patterns in glucocorticoid receptor genes (NR3C1), predisposing offspring to anxiety and depression. Data from Georgia's OASIS platform also linked maternal stress with fluctuating fetal mortality rates between 2013 and 2023, reinforcing the public health dimension of prenatal stress. Together, these findings portray maternal stress as both a biological and societal issue requiring targeted interventions.
"Maternal stress is not merely an emotional experience—it is a physiological signal that directly shapes the developing brain," said Divya Tadanki, lead author of the review. "Our analysis highlights that the timing, intensity, and type of stress exposure can leave molecular imprints on the fetus, some of which persist throughout life. Recognizing these effects calls for systemic support—mental health care, equitable access to prenatal services, and policies that protect expectant mothers, especially during crises."
The study reinforces that reducing maternal stress is vital for improving both maternal and child health outcomes. Integrating mindfulness-based stress reduction, cognitive behavioral therapy, and trauma-informed counseling into prenatal care could mitigate adverse outcomes. Policymakers are urged to prioritize structural solutions—such as paid parental leave, affordable housing, and access to mental healthcare—to alleviate socioeconomic drivers of maternal distress. Future longitudinal studies are essential to trace how prenatal stress affects adolescence and adulthood. Ultimately, promoting maternal well-being is an investment in healthier, more resilient future generations.
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References
DOI
Original Source URL
https://doi.org/10.1002/pdi3.70004
About Pediatric Discovery
Pediatric Discovery is a Gold Open Access publication and officially sponsored by The National Clinical Research Center for Child Health and Disorders of China, and Children's Hospital of Chongqing Medical University. The journal does not charge any submission fees. The Article Publication Charge (APC) is currently waived for accepted manuscripts. Pediatric Discovery is an open access and peer-reviewed international journal. The journal aims to advance the health and well-being of infants, children, and adolescents by disseminating cutting-edge discovery and knowledge in the field. It provides a platform for publishing and discussing the most important and state-of-the-art basic, translational and clinical discoveries affecting child and adolescent health and disorders in all aspects of pediatric medicine. Currently, this journal has been indexed by Pubmed Central and Directory of Open Access Journals (DOAJ).
Journal
Pediatric Discovery
Subject of Research
Not applicable
Article Title
Comprehensive Review of the Impact of Maternal Stress on Fetal Development
m⁶A methylation: A master regulator of female fertility and reproductive health
New review uncovers how m⁶A RNA modifications shape female reproductive physiology
Compuscript Ltd
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Successful pregnancy requires coordinated physiological processes, with m⁶A participating in critical stages: i) Folliculogenesis: m⁶A dynamically regulates oocyte-granulosa cell crosstalk during follicular maturation from primordial follicles to metaphase II (MII) oocytes, mediated by key regulators including METTL3, METTL14, KIAA1429, FTO, YTHDC1, YTHDC2, and IGF2BP1. ii) Embryogenesis: Following fertilization, m⁶A governs epigenetic modulation of zygotic development from the 2-cell stage through blastocyst formation. iii) Embryo implantation: Endometrial receptivity, a pivotal determinant of implantation success, is enhanced by m⁶A-mediated homeostatic control of hormonal metabolic signaling, involving METTL3, METTL14, METTL16, WTAP, and IGF2BP2. iv) Immune microenvironment: Embryo-derived immunomodulatory factors recruit immune cells to coordinate developmental processes. m⁶A regulators such as METTL3, METTL14, IGF2BP2, ALKBH5, and YTHDF2 modulate T cell/NK cell activities during immune adaptation. METTL3/14/16, methyltransferase 3/14/16; ALKBH5, ALKB homologue 5; FTO, fat mass and obesity-associated protein; YTHDC1/2, YTH domain containing 1/2; WTAP, Wilms tumor 1-associated protein; KIAA1429, also called VIRMA, vir-Like m⁶A methyltransferase associated, VIRILIZER; IGF2BP1/2, insulin-like growth factor-2 mRNA-binding protein 1/2; YTHDF2, YTH domain family 2; NK, natural killer.
view moreCredit: Jie Ding, Yalun He, Yangshuo Li, Shuai Sun, Wen Cheng, Jiami Huang, Chaoqin Yu
N⁶-methyladenosine (m⁶A) is the most abundant internal RNA modification in eukaryotes, regulating RNA splicing, translation, stability, and degradation. This reversible modification is dynamically controlled by three groups of proteins—“writers,” “erasers,” and “readers.” The writers (e.g., METTL3, METTL14, and WTAP) install methyl groups onto RNA, the erasers (such as FTO and ALKBH5) remove them to maintain epigenetic balance, and the readers (YTH and IGF2BP family proteins) interpret these methylation marks to fine-tune gene expression. Together, they form a central regulatory network essential for normal reproductive physiology and fertility.
A recent review published in Genes & Diseases by researchers at The First Affiliated Hospital of Naval Medical University, Fudan University, and Shanghai University of Traditional Chinese Medicine provides a comprehensive overview of how m⁶A RNA methylation governs female reproductive physiology and contributes to infertility-associated disorders.
The review systematically analyzes the influence of m⁶A across multiple dimensions of female reproduction, including oocyte maturation, granulosa cell function, endometrial receptivity, immune modulation, and systemic metabolic balance. The authors describe m⁶A as a dynamic molecular switch, coordinated by writers, erasers, and readers to fine-tune stage-specific gene expression throughout the reproductive cycle.
Notably, the review highlights that dysregulation of m⁶A-related mechanisms underlies key pathologies including endometriosis, polycystic ovary syndrome (PCOS), and recurrent miscarriage, linking aberrant RNA methylation to disrupted fertility networks. Moreover, m⁶A modifications bridge reproductive and metabolic processes, affecting energy regulation, inflammation, and stress responses, all of which are critical for successful conception and pregnancy maintenance.
The authors emphasize the clinical potential of m⁶A-modifying enzymes as diagnostic biomarkers and therapeutic targets. Given its reversible nature, m⁶A methylation represents a promising avenue for developing epigenetic interventions aimed at restoring reproductive homeostasis and treating infertility-related conditions.
Despite these advances, challenges remain, including limited clinical validation, unresolved mechanistic details of specific m⁶A sites, and an insufficient exploration of m⁶A–immune interactions in reproductive contexts. The review calls for multi-omics and organoid-based approaches to map the spatiotemporal dynamics of m⁶A regulation in human reproductive tissues.
Ultimately, the authors advocate for translational research to harness m⁶A pathways for clinical benefit, alongside deeper mechanistic studies investigating cell-type-specific roles and interactions with epigenetic and metabolic networks that shape female fertility.
Reference
Title of Original Paper: The role of m⁶A methylation in female reproductive physiology and pathology
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101755
Pregnancy requires the support of a healthy physiological state, and dysregulation of m⁶A methylation can lead to abnormalities in the body's condition, including depression (FTO), Hashimoto's thyroiditis (hnRNPC), diabetes (METTL3, YTHDC1), obesity (FTO, YTHDF2, METTL3, IGF2BP2), thereby affecting conception. METTL3, methyltransferase 3; FTO, fat mass and obesity-associated protein; YTHDC1/2, YTH domain containing 1/2; hnRNPC, heterogeneous nuclear ribonucleoprotein C; IGF2BP2, insulin-like growth factor-2 mRNA-binding protein 2; YTHDF2, YTH domain family 2.
m⁶A modification plays a key role in multiple female reproductive diseases, such as endometriosis (METTL3, FTO, YTHDF2, IGF2BP2), polycystic ovary syndrome (FTO, METTL3), and recurrent spontaneous abortion (METTL3, METTL14, ALKBH5). METTL3/14, methyltransferase 3/14; ALKBH5, ALKB homologue 5; FTO, fat mass and obesity-associated protein; YTHDC2, YTH domain containing 2; IGF2BP2, insulin-like growth factor-2 mRNA-binding protein 2; YTHDF2, YTH domain family 2.
Credit
Jie Ding, Yalun He, Yangshuo Li, Shuai Sun, Wen Cheng, Jiami Huang, Chaoqin Yu
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Journal
Genes & Diseases
DOI
A study involving UPF analyses explores how having a partner determines changes in fertility desires in Japan
The research, which involved Ryohei Mogi, a researcher at the University’s Department of Political and Social Sciences, shows that people without a romantic partner are more likely to revise their fertility desires downwards.
Universitat Pompeu Fabra - Barcelona
Research involving Pompeu Fabra University studies the relationship between having or not having a romantic partner with changes in fertility desires in Japan. The study, which involved Ryohei Mogi, a researcher at the University’s Department of Political and Social Sciences, together with Ryota Mugiyama (Gakushuin University, Japan) and Alyce Raybould (University College London, UK), shows that people without a romantic partner are more likely to revise their fertility desires downwards, especially from “wanting children” to “unsure”. These findings underscore the importance of romantic relationships in shaping fertility desires and highlight that many people may remain unintentionally childless.
In Japan, nearly 70% of unmarried people are not in a romantic relationship
Japan has the world’s highest percentage of childless individuals, cohabitation is not widespread, and nearly 70% of unmarried people are not in a romantic relationship. Furthermore, nearly all childbearing happens within married partnerships. These conditions make the Asian country a particularly interesting context for examining the links between romantic relationship and fertility desires, with broader implications for understanding the country’s low fertility rate.
Not having a partner lowers fertility desires
The study uses data from the Japanese Life Course Panel Survey (JLPS), conducted between 2009 and 2023, focusing on men and women aged 20-49 who have never had children. Relationship status was classified into four groups: “married”, “cohabiting”, “in a relationship but not cohabiting”, and “not in a relationship”. Fertility desires were assessed using three categories: “want children”, “unsure”, and “do not want children”. Applying a fixed-effects model, a statistical method that tracks the same individuals over time, the researchers examined how changes in relationship status influenced changes in fertility desires.
The results revealed that among childless people, those who do not have a partner are more likely than those who are married, cohabiting, or in a relationship to shift their fertility desires from “wanting children” to “unsure” or “not wanting children”. The change from “wanting” to “unsure” was especially pronounced. Crucially, this shift appeared soon after individuals became unpartnered, rather than growing steadily with longer periods of non-partnership.
Among those who remained single throughout the survey period, 28% of women and 21% of men consistently expressed a desire to have children, whereas only 10% of women and 7% of men consistently reported not wanting children.
According to the authors: “The study reveals how the presence or absence of a romantic partner affects changes in fertility desires, and that not having a partner increases the uncertainty surrounding people’s desire to have children. At the same time, many people without children still wish to become parents.”
Towards More Nuanced Support Strategies
These findings provide valuable insight into the psychological and social barriers that single people may face in realising their fertility desires. They suggest that romantic relationships function as a key life event in the formation of the desire to have children.
For policymakers, the results highlight the need for more nuanced support strategies. Instead of treating “unmarried individuals” as a homogeneous group, it is important to recognise the differences between those in a relationship and those who are not. In particular, it is crucial to better understand dating behaviour itself. Many individuals without partners still express a clear desire to have children, yet remain unpartnered. Analysing why people with fertility desires do not have partners—whether due to economic insecurity, work–life balance issues, or limited opportunities for social interaction—can provide valuable insight into the social barriers they face. If such factors are more systematically studied and reflected in policy, support measures could more effectively help individuals achieve their fertility desires.
Reference article: Mogi, R., Mugiyama, R. I Raybould, A. (August 2025) “Exposure to non-partnership and fertility desires among childless population in Japan”. Social Forces
https://doi.org/10.1093/sf/soaf123
https://academic.oup.com/sf/advance-article-abstract/doi/10.1093/sf/soaf123/8222480
Journal
Social Forces
Method of Research
Survey
Subject of Research
People
Article Title
Exposure to non-partnership and fertility desires among childless population in Japan
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