Open research questions in Birth, Development, and Health

What the literature leaves open

• ABSTRACT Background Leptin integrates metabolic and reproductive signaling later in life; however, whether maternal metabolic cues influence early neonatal hypothalamic–pituitary–gonadal (HPG) axis activity remains unclear.

  Maternal–Neonatal Metabolic Continuity and Early Postnatal HPG Axis Activity in Healthy Term Neonates · 2026 · DOI

• Epigenomic mechanisms, including DNA methylation (DNAm), offer insight into the biological embedding of metabolic risk, yet protective family-level factors remain understudied.

  The Role of Parenting in Mitigating Epigenetic Cardiometabolic Risk in a Sample of Predominantly Latino Preschoolers · 2026 · DOI

• Conclusions: These exploratory findings highlight the need for further research into prenatal GLY exposure, its impact on neurodevelopment, and potential exposure through breastmilk.

  Assessment of effect modification in associations between biomarkers of prenatal glyphosate exposure and child neurodevelopment in Puerto Rico · 2026 · DOI

• Despite substantial advances in understanding the developmental origins of metabolic disease, several important questions remain unan- swered. Future research should move beyond establishing associations between maternal hyperglycemia and offspring outcomes toward eluci- dating the molecular mechanisms underlying developmental program- ming. Integrative multi-omics approaches—including epigenomics, transcriptomics, proteomics, metabolomics, and microbiome profiling —combined with advanced bioinformatics and systems biology are expected to provide a more comprehensive understanding of the complex interactions between placental function, fetal metabolism, endocrine regulation, and postnatal environmental influences (58–60). Large, prospective longitudinal birth cohorts incorporating stan- dardized diagnostic criteria for gestational diabetes mellitus (GDM), detailed maternal metabolic phenotyping, and long-term follow-up of offspring are needed to identify critical windows of susceptibility and validate biomarkers predictive of future cardiometabolic disease. Future studies should also address current knowledge gaps regarding sex-specific responses, the reversibility of hyperglycemia-induced programming, and the interaction between prenatal metabolic expo- sures and postnatal lifestyle factors, including nutrition, breastfeed- ing, physical activity, and the gut microbiome (29, 61). The translation of mechanistic discoveries into clinical practice represents another important priority. Continuous glucose monitor- ing, individualized nutritional interventions, optimization of gesta- tional weight gain, breastfeeding promotion, and microbiome- targeted strategies have shown promise in improving maternal metabolic control; however, their long-term effects on offspring health remain incompletely understood. Integrating clinical charac- teristics with molecular biomarkers may facilitate precision preven- tion strategies that enable early identification of pregnancies at increased risk for adverse developmental programming and allow timely intervention during the first 1000 days (62, 63). Although maternal hyperglycemia remains the primary deter- minant of the intrauterine metabolic environment, increasing evidence suggests that paternal metabolic health may also influence offspring metabolic programming. Paternal obesity, diabetes, and other metabolic disturbances before conception have been associ- ated with alterations in the sperm epigenome, including changes in DNA methylation, histone modifications, and small non-coding RNAs, which may influence early embryonic development and increase susceptibility to obesity, insulin resistance, and impaired glucose metabolism in the offspring (64, 65). While these findings are supported predominantly by experimental models and emerg- ing human studies, they highlight the importance of considering parental metabolic health as a shared determinant of developmental programming and warrant further investigation into the contribu- tion of paternal factors to intergenerational cardiometabolic risk.

  Hyperglycemia during the first 1000 days as a driver of metabolic programming · 2026 · DOI

• The current findings also align with the few studies on ado- lescents and adults demonstrating links between SNS hypo- activity and CU traits (de Vries-Bouw et al.

  Using Machine Learning to Identify Infant and Child Environmental and Biological Predictors of Callous-Unemotional Traits · 2026 · DOI

• Although histologic chorioamnionitis (HCA) and placental vascular abnormalities are frequently observed in sPTB, the molecular cascades linking these lesions to labor initiation remain poorly understood.

  Placental pathology, circadian biology, and pathogenesis of spontaneous preterm birth: a pilot study of human placental gene expression profiling using a targeted HTG transcriptome panel · 2026 · DOI

• The causal relationships and potential pathways between birth weight (BW) and various cardiovascular diseases (CVDs) remain unclear, particularly when discriminating maternal and fetal contributions of BW to CVDs.

  The causal relationships and potential pathways between birth weight and cardiovascular diseases: A human genomics study · 2026 · DOI

• In this regard, cardiac fitness after delivery (with or without breastfeeding) has been poorly explored, studies are limited to the characterization in blood flow increase and cardiac output (36), condition probably expected for milk production. So far, only a few reports have described post-partum reversibility of gestational cardiac hypertrophy, but the impact of the lactation period has been poorly analyzed (5, 11, 12).

  Meteorin-like controls metabolic adaptations and physiological myocardial remodeling in pregnancy and lactation · 2026 · DOI

• Despite their central role, the physiological and behavioral consequences of repeated reproductive cycles have been poorly characterized, in part because breeding animals fall outside the primary focus of laboratory animal welfare efforts, and in part because meaningful welfare readouts for laboratory rodents remain an active area of research.

  Evidence of maternal resilience in two mouse strains in the context of permanent mouse breeding strategies · 2026 · DOI

• Conclusions: Adolescents with early-onset hypogonadism show evidence of EVA, with associated oxidative stress and epigenetic alterations warranting further investigation.

  Vascular Ageing in Conditions Associated With Early Onset Hypogonadism · 2026 · DOI

• We recognize that our study has several limitations. First, the N value was relatively low (sample size= 26). However, although our study included only 26 partici- pants, we adopted several strategies to enhance statistical robustness. Stringent FDR and effect size thresholds were applied, and a leave-one-out cross-validation framework was implemented, requiring consensus across 26 models. Jackknife resampling was also used to confirm the stabil- ity of the model. These steps reduce the likelihood of false positives and provide robustness to our study. However, larger studies will be required to further validate the pre- dictive capacity of the identified CpGs and ensure their translational applicability. Secondly, here, we lack an independent validation cohort. We acknowledge that replication in independent samples will be essential to confirm the generalizability of our findings. Despite an active search, we were unable to identify a comparable weight loss intervention cohort that matches the specific characteristics of this study. Nonetheless, despite this limitation, our findings pro- vide extremely useful insights and lay the groundwork for future studies aimed at evaluating epigenetic markers as predictive tools. Finally, physical activity was not objectively or sub- jectively monitored (e.g. questionnaires, pedometers, or accelerometers) during the intervention, which would have provided valuable information on the response to the intervention and the compliance of the participants. Consequently, we were unable to assess the adherence to this component of the lifestyle intervention or evaluate its independent contribution to the observed results.

  Predictive epigenetic biomarkers of successful weight-loss intervention in pre-pubertal children with obesity · 2026 · DOI

• This narrative review examined the impact of restrictive and exacerbated diets, with a primary focus on the roles of macronutrients - proteins and lipids, respectively. We iden- tified significant effects while also highlighting important gaps in the literature. Among the limitations, the PRISMA methodology was not applied, as we aimed was to specifi- cally review studies addressing the maternal–offspring–thy- roid axis, avoiding exclusions that might overlook critical contexts for our discussion. Another limitation was the exclusion of other adverse maternal dietary conditions (e.g., caloric or micronutrient restriction, or excessive protein or carbohydrate intake). Nonetheless, we emphasized two major scenarios currently relevant: (1) limited access to food with insufficient protein intake, a condition frequently observed in socioeconomically vulnerable populations; and (2) excessive lipid intake, which encompasses the previ- ous context but also reflects modern dietary patterns, even within economically advantaged groups, largely driven by the consumption of ultra-processed, nutrient-poor foods. Finally, while this review focused specifically on thyroid outcomes, we acknowledge that similar maternal dietary manipulations have been associated with broader metabolic alterations. However, these findings were not included here, as they lack direct methodological evidence demonstrating effects on the thyroid gland itself. Despite all the limitations, this narrative is important for establishing the risks of maternal malnutrition in offspring, particularly in terms of metabolic programming and basal metabolism - strengthening the themes of metabolic pro- gramming and DOHaD. We also raise pressing questions about the need for studies that evaluate molecular aspects and biomarkers of these conditions, in addition to the evident Page 9 of 11 74 gap in the scientific knowledge regarding epidemiological data, necessary to compile public and interventionist poli- cies regarding maternal dietary risks to maternal-fetal health in the short, medium, and long term. Finally, this review fulfills its role in bringing clear, objective, and important insights into panoramas that plague humanity today, out- lining a detailed view of the thyroid, but also generating hypotheses and perspectives for future studies, character- izing in a holistic manner the maternal-descendant-thyroid nutrition interface.

  Maternal high-fat and protein-restricted diets during gestation and lactation: thyroid-mediated disruption of basal metabolism across the lifespan of offspring - a narrative review · 2026 · DOI

• Limited evidence necessitated the studying of additional adult post-term cohorts to accurately determine future risks to health and to investigate these potential metabolic alterations, as well as if the alterations in adiposity continue or get worse throughout adulthood, and how these correlations vary in adult born post-term in terms of pattern and amplitude.

  Review on Childhood Obesity: Discussing Effects of Gestational Age at Birth and Spotting Association of Postterm Birth with Childhood Obesity · 2024 · DOI

• Although the definitive timeframe remains unclear, childbirth may not have reached our present state of difficulty until fairly recently (<500,000 years ago) when body and brain sizes approximated what we have now, or perhaps not until even more recently because of agriculture's direct and indirect effects on the growth and development of both mother and fetus.

  The Evolution of Difficult Childbirth and Helpless Hominin Infants · 2015 · DOI

• In this article, we evaluate the utility of genetic variants in three genes that have unequivocal evidence of being related to three major risk factors-CHRNA3 for smoking, ADH1B for alcohol use, and FTO for obesity-as instrumental variables for identifying the causal effects of such factors during pregnancy.

  Genetic Instrumental Variable Studies of Effects of Prenatal Risk Factors · 2013 · DOI

• While taking into account this possibility and the fact that the findings were not consistently significant, it might still be possible to conclude, within the limitations of the present study, that a history of in- duced abortion might adversely affect fu- ture progeny, but spontaneous abortions do not. As mentioned above, in the pres- ent study it was found that babies born within twelve months of the previous de- livery were lighter even than firstborns, but unfortunately the data were insufficient to provide a meaningful conclusion.

  Birth weight in various population groups in Israel · 1973 · DOI

• The sharp fall in conception rate associated with amenorrhea resulted in so few pregnancies: t h a t data were inconclusive as to the relation between under- nutrition in early pregnancy and malformation Of the fetus: A slight but statistically insignificant increase in malformations did occur.

  Effects of maternal undernutrition upon thenewborn infant in Holland (1944–1945) · 1947 · DOI

• Although limited by the exploratory pilot nature and sample size of this study, the moderate-to-large effect sizes and consistent directional trends suggest that early-life nutritional environments critically influence offspring physiology.

  Maternal cafeteria diet intake influences offspring development in Wistar rats: a pilot study · 2026 · DOI

• However, how early-life overnutrition programs metabolism and immunity to influence CNS autoimmunity remains poorly defined.

  Early-Life Overnutrition Reprograms Metabolism and Immunity to Promote Sex-Biased CNS Autoimmunity 2333917 · 2026 · DOI

• These findings support further investigation of TAb+ as a thyroid hormone‐independent contributor to pregnancy complications, with placental function emerging as a potential mechanistic target.

  Thyroid antibody positivity in pregnancy is associated with altered reproductive hormone concentrations and placental growth in Lewis rats · 2026 · DOI

• Parental diet has emerged as a critical factor in programming offspring's metabolic health, yet the independent and combined effects of maternal and paternal obesogenic exposures remain largely underexplored (1, 2) .

  The impact of preconception parental obesogenic diets on offspring metabolic health in a rat model · 2026 · DOI

• Additionally, breastfeeding supports neurodevelopment, but limited research on GLY in human milk makes its role as an infant exposure source unclear.

  Assessment of effect modification in associations between biomarkers of prenatal glyphosate exposure and child neurodevelopment in Puerto Rico · 2026 · DOI

• This dataset can serve as a reference for other groups considering the role of single molecules or molecular families in early intestinal and postnatal development, expanding the limited literature on postnatal gene expression in the developing intestine.

  Cataloguing the mouse small intestinal transcriptome in duodenum and ileum during the first postnatal month · 2026 · DOI

• Conclusion These findings support those found in previous experimental animal and epidemiological studies, highlighting the importance of further investigation into early-life antibiotic exposure, infection burden, and later obesity risk.

  The association between prenatal and early-life antibiotic use and obesity at 4–5 years in the Born in Bradford birth cohort · 2026 · DOI

• Despite advances in prenatal detection, surgical care and long-term follow-up, the aetiology of CHD remains incompletely understood.

  Causes of congenital heart disease: an integrative narrative review · 2026 · DOI

Most-cited papers in Birth, Development, and Health

• Transgenerational effects of prenatal exposure to the Dutch famine on neonatal adiposity and health in later life · BJOG An International Journal of Obstetrics & Gynaecology · 2008 · 542 citations
• First trimester phthalate exposure and anogenital distance in newborns · Human Reproduction · 2015 · 323 citations
• Prenatal Exposure to Perfluorooctanoate and Risk of Overweight at 20 Years of Age: A Prospective Cohort Study · Environmental Health Perspectives · 2012 · 320 citations
• Birth Weight and Prenatal Exposure to Polychlorinated Biphenyls (PCBs) and Dichlorodiphenyldichloroethylene (DDE): A Meta-analysis within 12 European Birth Cohorts · Environmental Health Perspectives · 2011 · 281 citations
• A new definition of maternal depletion syndrome. · American Journal of Public Health · 1992 · 240 citations
• The role of the Children of Twins design in elucidating causal relations between parent characteristics and child outcomes · Journal of Child Psychology and Psychiatry · 2003 · 173 citations
• Development of the murine and human immune system: differential effects of immunotoxicants depend on time of exposure. · Environmental Health Perspectives · 2000 · 152 citations
• Developmental trajectories of Body Mass Index from infancy to 18 years of age: prenatal determinants and health consequences · Journal of Epidemiology & Community Health · 2014 · 151 citations
• Paternal microbiome perturbations impact offspring fitness · Nature · 2024 · 137 citations
• Life course epidemiology and public health · The Lancet Public Health · 2024 · 129 citations

Most recent work

• Maternal high fat diet and acute viral mimic exposure impact placental inflammation, lipid peroxidation and cellular proliferation-to-death ratio across mouse pregnancy · bioRxiv · 2026
• Placental and juvenile immune responses to maternal immune activation are differentially regulated by sex chromosomes and gonads across gestation · Journal of Neuroinflammation · 2026
• Evidence of maternal resilience in two mouse strains in the context of permanent mouse breeding strategies · bioRxiv · 2026
• Epigenetic regulation in early embryogenesis: mechanisms, developmental programming, and transgenerational implications · Frontiers in Cell and Developmental Biology · 2026
• Disentangling the relationship between intrauterine exposures and offspring growth in mid-childhood · BMC Medicine · 2026
• Doppler Ultrasound Indices and Fetal Biometry as Prenatal Markers of SGA or Non-SGA Developmental Trajectories in Naturally Nutrient-Restricted Sheep Pregnancies from Patagonia · Animals · 2026
• Novel biomarkers of early-life cardiovascular health trajectories enabling biological understanding of primary prevention · European Journal of Preventive Cardiology · 2026
• Nutritional restriction during late gestation disrupts placental transcriptional programs related to metabolism, transport, and immune function in a sheep model · BMC Genomics · 2026
• Redefining Cardiovascular Risk in the Young: Integrating Longitudinal Evidence, Subclinical Endophenotypes, and the Imperative for Primordial Prevention · International Journal For Multidisciplinary Research · 2026
• The Potential Physiologic Mechanisms by Which Early-Life Nutrition May Influence Type 2 Diabetes Pathophysiology in Humans · Annual Review of Nutrition · 2026

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