Gestational diabetes doubles a child’s odds of glucose intolerance, major meta-analysis finds

A sweeping systematic review and meta-analysis published in BMC Medicine has found that the metabolic seeds of future cardiometabolic disease are planted well before a child takes a single step. The study, led by Marco Brandimonte-Hernández of the University of Granada and a multinational team of pediatricians, nutrition scientists, and epidemiologists, screened 18,765 research records and distilled them into 70 studies that tracked children from preconception, pregnancy, and birth through infancy and into childhood and adolescence. Its central finding is stark: children and adolescents whose mothers developed gestational diabetes mellitus during pregnancy face more than double the odds of developing glucose intolerance themselves, with a pooled odds ratio of 2.13 and a 95 percent confidence interval of 1.58 to 2.86. The analysis also revealed that the same early-life exposures are linked to a broader constellation of cardiometabolic risks, including dyslipidemia, hypertension, metabolic syndrome, and type 2 diabetes, suggesting that the developmental origins of adult disease reach back to the earliest moments of life.

The research team, which included investigators from Erasmus MC in Rotterdam, the Institute of Agrochemistry and Food Technology in Valencia, and Helmholtz Munich, among other institutions, set out to answer a deceptively simple question: which exposures occurring before conception, during pregnancy and birth, and in infancy up to two years of age are associated with cardiometabolic outcomes in later childhood and adolescence? The outcomes they examined were the five canonical precursors of adult cardiovascular disease: glucose intolerance, dyslipidemia, hypertension, metabolic syndrome, and type 2 diabetes. The review was prospectively registered with PROSPERO under registration number CRD42022355152, and the authors followed PRISMA reporting guidelines to ensure methodological transparency. The 70 studies that met the inclusion criteria comprised 65 longitudinal observational studies, four case-control studies, and one randomized controlled trial, a distribution that reflects the ethical and practical constraints of studying developmental exposures in human populations.

What distinguishes this meta-analysis from previous efforts is its rigorous handling of statistical dependency. Because many large birth cohorts contribute multiple overlapping publications, naive pooling can artificially inflate the precision of an estimate by counting the same children more than once. The authors addressed this by revising their meta-analyses to retain only one independent estimate per source cohort, a correction that materially changed the precision of the pooled results. The gestational diabetes finding survived this scrutiny with remarkably low heterogeneity, an I-squared value of just 12.7 percent, indicating that the underlying studies were unusually consistent in the direction and magnitude of the association. The team also classified any meta-analysis based on fewer than five independent studies as exploratory, a conservative decision that separates robust conclusions from preliminary signals and provides a template for how future reviews in this field should handle sparse evidence.

Gestational diabetes mellitus emerged as the most consequential early-life exposure in the entire analysis. It was positively associated with every cardiometabolic risk outcome examined, with glucose intolerance being the most frequently reported. This finding carries particular biological plausibility. During a pregnancy complicated by gestational diabetes, the fetus is exposed to elevated maternal glucose, which crosses the placenta and stimulates fetal insulin production. Chronic hyperinsulinemia in the developing fetus can alter pancreatic beta-cell function, adipose tissue development, and hypothalamic programming of appetite and metabolism. Animal models have shown that such developmental exposures can permanently reprogram metabolic homeostasis, a phenomenon known as metabolic imprinting or fetal programming. The human evidence now assembled in this meta-analysis suggests that the same mechanisms operate in real-world populations, producing measurable cardiometabolic consequences that persist into adolescence.

Maternal body mass index during pregnancy was another exposure with broad reach across the cardiometabolic spectrum. Higher maternal pregnancy BMI was positively associated with glucose intolerance, dyslipidemia, hypertension, and metabolic syndrome in offspring. The biological pathways here are multifaceted. Maternal obesity is accompanied by elevated circulating free fatty acids, inflammatory cytokines, and leptin, all of which can cross the placenta and influence fetal development. Maternal insulin resistance, a hallmark of obesity, can also alter nutrient delivery to the fetus and modify the intrauterine metabolic environment. The consistency of the association across four distinct cardiometabolic outcomes suggests that maternal obesity acts through a general developmental perturbation rather than through a single organ-specific pathway, a conclusion that aligns with the developmental origins of health and disease framework that has gained prominence over the past three decades.

The analysis also examined birth characteristics and found that being born small for gestational age was associated with higher odds of hypertension in later childhood and adolescence, though this finding was classified as exploratory because it was based on fewer than five independent studies. The corresponding exploratory analysis for preterm birth and elevated systolic blood pressure did not reach statistical significance and is presented for methodological illustration only. The authors also found that low or high birth weight, and being born large for gestational age, were associated with cardiometabolic outcomes in childhood and adolescence. The link between restricted fetal growth and later hypertension is biologically coherent. Fetuses that experience intrauterine growth restriction often develop a preferential blood flow pattern that shunts oxygen and nutrients toward the brain at the expense of other organs, including the kidneys. Reduced nephron number in the developing kidney is a well-established mechanism for later hypertension, because a smaller nephron complement increases sodium retention and raises blood pressure throughout life.

Infant BMI and weight changes during the first two years of life were positively associated with dyslipidemia, hypertension, and metabolic syndrome in later childhood and adolescence. This finding is notable because it extends the window of cardiometabolic vulnerability beyond the intrauterine period and into postnatal development. Rapid weight gain in infancy, sometimes called catch-up growth, has been proposed as a mechanism that can alter body composition, insulin sensitivity, and lipid metabolism. The developmental logic is that infants who experience early growth restriction and then rapid postnatal weight gain may accumulate visceral adipose tissue preferentially, a pattern that is strongly associated with insulin resistance and dyslipidemia. The finding that infant BMI and weight trajectories are linked to three distinct cardiometabolic outcomes suggests that the first two years of life represent a critical period for metabolic programming, one that may be as consequential as the intrauterine environment itself.

The analysis also examined breastfeeding and found limited evidence suggesting a possible inverse association between breastfeeding and cardiometabolic risk in childhood and adolescence, though the authors characterized this evidence as limited and inconclusive because it was based on few studies per outcome. This finding is important because breastfeeding is a modifiable exposure with enormous public health implications. Human milk contains bioactive compounds, including long-chain polyunsaturated fatty acids, hormones, and growth factors, that could theoretically influence metabolic development. Breastfed infants also tend to have different growth trajectories than formula-fed infants, with slower early weight gain that may reduce the risk of later adiposity. However, the observational nature of the evidence means that confounding by socioeconomic status, maternal education, and other factors cannot be excluded, and the authors were appropriately cautious in their interpretation, noting that the evidence was limited and inconclusive rather than definitive.

The authors emphasize that their findings may support closer cardiometabolic monitoring of children with relevant early-life exposures and may inform future prevention research. This is a significant shift in clinical thinking. Traditionally, cardiometabolic risk assessment has been reserved for adults with established risk factors, but this meta-analysis suggests that children and adolescents with specific developmental exposures, such as maternal gestational diabetes, maternal obesity during pregnancy, or being born small or large for gestational age, may warrant earlier surveillance. The identification of modifiable early-life risk factors also opens the door to targeted interventions during pregnancy and infancy that could reduce the burden of cardiometabolic disease in future generations. The research was conducted by an expert group of the European branch of the International Life Sciences Institute and coordinated by the Early Nutrition and Long-term Health Task Force, with the scientific work carried out solely by the authors and ILSI Europe having no role in the definition of research questions, study design, data collection, statistical analysis, interpretation of results, or approval of the submitted manuscript.

The implications of this meta-analysis extend far beyond the clinic and into public health policy. With gestational diabetes affecting a growing proportion of pregnancies worldwide, and maternal obesity reaching epidemic levels, the developmental exposures identified in this study are becoming increasingly common. The finding that these exposures are associated with cardiometabolic outcomes in childhood and adolescence, rather than only in adulthood, suggests that the window for prevention may need to shift earlier. The authors’ rigorous methodology, including the correction for overlapping cohorts and the conservative classification of sparse evidence, provides a model for how future reviews in this field should be conducted. As the global burden of type 2 diabetes and cardiovascular disease continues to rise, understanding the developmental origins of these conditions has never been more urgent, and this meta-analysis represents a major step forward in that effort, offering a comprehensive map of the early-life risk factors that shape cardiometabolic health across the lifespan.

Subject of Research: Early-life risk factors and cardiometabolic outcomes in children and adolescents: a systematic review and meta-analysis

Article Title: Early-life risk factors and cardiometabolic outcomes in children and adolescents: a systematic review and meta-analysis

Article References: Brandimonte-Hernández, M., Ruiz-Ojeda, F. J., Blaauwendraad, S. M., Kamphuis, A. S., Flores-Ventura, E., Abrahamse-Berkeveld, M., Collado, M. C., van Diepen, J. A., Iozzo, P., Knipping, K., van Loo-Bouwman, C. A., Gaillard, R., & Gil, Á. (2026). Early-life risk factors and cardiometabolic outcomes in children and adolescents: a systematic review and meta-analysis. BMC Medicine. https://doi.org/10.1186/s12916-026-05316-7

Image Credits: AI Generated

DOI: 10.1186/s12916-026-05316-7

Keywords: gestational diabetes, glucose intolerance, cardiometabolic risk, early-life risk factors, meta-analysis, BMC Medicine, pediatrics, developmental origins, maternal BMI, hypertension, Early-life, risk