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Hyperglycemia and Adverse Pregnancy Outcome Follow-up Study (HAPO FUS): Maternal Gestational Diabetes Mellitus and Childhood Glucose Metabolism
Open accessAbstract
OBJECTIVE: Whether hyperglycemia in utero less than overt diabetes is associated with altered childhood glucose metabolism is unknown. We examined associations of gestational diabetes mellitus (GDM) not confounded by treatment with childhood glycemia in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort. RESEARCH DESIGN AND METHODS: HAPO Follow-up Study (FUS) included 4,160 children ages 10–14 years who completed all or part of an oral glucose tolerance test (OGTT) and whose mothers had a 75-g OGTT at ∼28 weeks of gestation with blinded glucose values. The primary predictor was GDM by World Health Organization criteria. Child outcomes were impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and type 2 diabetes. Additional measures included insulin sensitivity and secretion and oral disposition index. RESULTS: For mothers with GDM, 10.6% of children had IGT compared with 5.0% of children of mothers without GDM; IFG frequencies were 9.2% and 7.4%, respectively. Type 2 diabetes cases were too few for analysis. Odds ratios (95% CI) adjusted for family history of diabetes, maternal BMI, and child BMI z score were 1.09 (0.78–1.52) for IFG and 1.96 (1.41–2.73) for IGT. GDM was positively associated with child’s 30-min, 1-h, and 2-h but not fasting glucose and inversely associated with insulin sensitivity and oral disposition index (adjusted mean difference −76.3 [95% CI −130.3 to −22.4] and −0.12 [−0.17 to −0.064]), respectively, but not insulinogenic index. CONCLUSIONS: Offspring exposed to untreated GDM in utero are insulin resistant with limited β-cell compensation compared with offspring of mothers without GDM. GDM is significantly and independently associated with childhood IGT.
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In the citing paper
“The higher diagnosis of GDM in the one-step approach can lead to more resource utilization for subsequent maternal treatment and fetal monitoring.55,59,66”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [55]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Consistent with obesity parameters, offspring glucose levels from the 75 g OGTT and glycosylated hemoglobin were linearly associated with maternal glucose levels during pregnancy independent of maternal and child BMI [34,35].”
From Gestational Diabetes Mellitus: Diagnostic Approaches and Maternal-Offspring Complications (2022) · cites this paper as [34]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The results clearly demonstrate that maternal glycemia is associated with immediate and long-term adverse outcomes for both mother and offspring.”
From Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus (2023) · cites this paper as [269]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The HAPO FUS documented in both groups that risk of disorders of glucose metabolism at follow-up were associated with GDM and continuously with maternal glucose concentrations (268,269).”
From Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus (2023) · cites this paper as [269]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Associations of mother ' s fasting, 1h, and 2-h values on the 75-g OGTT were continuous with a comprehensive panel of offspring metabolic outcomes (216, 217).”
From 2. Diagnosis and Classification of Diabetes: Standards of Care in Diabetes—2024 (2024) · cites this paper as [216]
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Associations of mother's fasting, 1-h, and 2-h values on the 75-g OGTT were continuous with a comprehensive panel of offspring metabolic outcomes (198,199).”
From 2. Diagnosis and classification of diabetes: standards of care in diabetes-2025 (2025) · cites this paper as [198]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“A dose-dependent relationship emerged between maternal antenatal glycemia and offspring metabolic parameters across the continuum of glucose concentrations.”
From Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences (2026) · cites this paper as [60]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Findings revealed persistent metabolic consequences of maternal hyperglycemia on long-term offspring glucose homeostasis, notably extending to glycemic levels below current GDM diagnostic thresholds.”
From Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences (2026) · cites this paper as [60]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Maternal glycemic dysregulation correlated with increased prevalence of impaired fasting glucose, glucose intolerance, elevated glycated hemoglobin, and pediatric obesity in adolescent offspring.”
From Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences (2026) · cites this paper as [60]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Furthermore, recent evidence shows that there is increased glucose-linked hypothalamic activation in offspring who were previously exposed to maternal obesity and GDM in utero, which represents one possible mechanism for this increased childhood obesity risk [31,32,60,61].”
From Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences (2026) · cites this paper as [60]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Conversely, maternal glucose elevation demonstrated inverse associations with offspring insulin sensitivity and homeostatic model assessment (HOMA) indices at 14 years, with these relationships persisting after statistical adjustment for maternal body mass index, offspring BMI, and familial diabetes predisposition.”
From Maternal Overnutrition and Fetal Programming: Long-Term Metabolic, Cognitive, and Epigenetic Consequences (2026) · cites this paper as [60]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In utero exposure to hyperglycaemia is also associated with long term cardiometabolic risks in the baby, including diabetes and obesity. 8 , 9 , 10”
From Australasian Diabetes in Pregnancy Society ( ADIPS ) 2025 consensus recommendations for the screening, diagnosis and classification of gestational diabetes (2025) · cites this paper as [8]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In utero exposure to hyperglycaemia is also associated with long term cardiometabolic risks in the baby, including diabetes and obesity. 8 , 9 , 10”
From Australasian Diabetes in Pregnancy Society ( ADIPS ) 2025 consensus recommendations for the screening, diagnosis and classification of gestational diabetes (2025) · cites this paper as [10]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“However, raising the POGTT diagnostic thresholds at 24–28 weeks’ gestation means that women (and their offspring) at risk of adverse perinatal and long term cardiometabolic outcomes previously diagnosed at HAPO OR 1.75 thresholds 3 , 8 , 10 will no longer be identified as having gestational diabetes mellitus.”
From Australasian Diabetes in Pregnancy Society ( ADIPS ) 2025 consensus recommendations for the screening, diagnosis and classification of gestational diabetes (2025) · cites this paper as [8]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“However, raising the POGTT diagnostic thresholds at 24–28 weeks’ gestation means that women (and their offspring) at risk of adverse perinatal and long term cardiometabolic outcomes previously diagnosed at HAPO OR 1.75 thresholds 3 , 8 , 10 will no longer be identified as having gestational diabetes mellitus.”
From Australasian Diabetes in Pregnancy Society ( ADIPS ) 2025 consensus recommendations for the screening, diagnosis and classification of gestational diabetes (2025) · cites this paper as [10]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“The International Association for Diabetes and Pregnancy Study Groups criteria result in overall higher percentages of women diagnosed with GDM.”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [55]
The cited source says what the claim attributes to it.
In the citing paper
“Offspring with exposure to untreated GDM have reduced insulin sensitivity and b-cell compensation and are more likely to have impaired glucose tolerance in childhood (57).”
From 15. Management of Diabetes in Pregnancy: Standards of Care in Diabetes—2024 (2024) · cites this paper as [57]
The cited source says what the claim attributes to it.
In the citing paper
“Post hoc GDM in individuals diagnosed with this method in the HAPO cohort was associated with higher prevalence of IGT; higher 30-min, 1-h, and 2-h glucose levels during the OGTT; and reduced insulin sensitivity and oral disposition index in their offspring at 10-14 years of age compared with offspring of mothers without GDM.”
From 2. Diagnosis and classification of diabetes: standards of care in diabetes-2025 (2025) · cites this paper as [198]
The cited source says what the claim attributes to it.
In the citing paper
“The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study 1 and subsequently follow‐up studies 2 , 3 , 4 have reported that gestational diabetes mellitus (GDM) is associated with various adverse pregnancy outcomes, which increases the mother's susceptibility to developing type 2 diabetes, and the child's susceptibility to developing obesity and impaired glucose tolerance in the future 3 , 4 , 5”
From Clinical challenges in early pregnancy in Japan: An update on gestational diabetes (2024) · cites this paper as [4]
The cited source says what the claim attributes to it.
In the citing paper
“The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study 1 and subsequently follow‐up studies 2 , 3 , 4 have reported that gestational diabetes mellitus (GDM) is associated with various adverse pregnancy outcomes, which increases the mother's susceptibility to developing type 2 diabetes, and the child's susceptibility to developing obesity and impaired glucose tolerance in the future 3 , 4 , 5”
From Clinical challenges in early pregnancy in Japan: An update on gestational diabetes (2024) · cites this paper as [4]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Universal screening is recommended, as selective screening (only in women with risk factors) would miss a significant number of women with GDM and universal screening has been shown to be cost-effective compared with selective screening.”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [55]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Universal screening is recommended, as selective screening (only in women with risk factors) would miss a significant number of women with GDM and universal screening has been shown to be cost-effective compared with selective screening.9,50–55”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [55]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Universal screening is recommended, as selective screening (only in women with risk factors) would miss a significant number of women with GDM and universal screening has been shown to be cost-effective compared with selective screening.9,50–55”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [55]
Experimental — accuracy not yet measuredIn the citing paper
“Measurements of insulin sensitivity and oral disposition demonstrated that offspring exposed to untreated IADPSG GDM in utero are insulin resistant with limited beta cell compensation compared with offspring of mothers without GDM.”
From One-step or 2-step testing for gestational diabetes: which is better? (2021) · cites this paper as [34]
In the citing paper
“Rates of impaired glucose tolerance and impaired fasting glucose were 10.6% and 9.2% in offspring of IADPSG GDMs vs 5.0% and 7.4% in offspring of non-GDMs”
From One-step or 2-step testing for gestational diabetes: which is better? (2021) · cites this paper as [34]
In the citing paper
“adjusted odds ratios were 1.96 (CI, 1.41e2.73)and 1.09 (CI, 0.78e1.52),respectively.”
From One-step or 2-step testing for gestational diabetes: which is better? (2021) · cites this paper as [34]
In the citing paper
“animal and human studies have shown that intrauterine exposure to maternal preexisting diabetes or gestational diabetes mellitus (GDM) is associated with higher risk for altered offspring glucose metabolism (7–11).”
From Hyperglycemia and Adverse Pregnancy Outcome Follow-up Study (HAPO FUS): Maternal Glycemia and Childhood Glucose Metabolism (2019) · cites this paper as [11]
In the citing paper
“We recently demonstrated an inverse association of GDM, using IADPSG criteria, with insulin sensitivity and the disposition index and positive association with impaired glucose tolerance (IGT) in HAPO FUS children at ages 10–14 years (11).”
From Hyperglycemia and Adverse Pregnancy Outcome Follow-up Study (HAPO FUS): Maternal Glycemia and Childhood Glucose Metabolism (2019) · cites this paper as [11]
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Metadata
- Authors
- Lowe, W. L., Scholtens, D. M., Kuang, A., Linder, B., Lawrence, J. M., Lebenthal, Y., McCance, D., Hamilton, J., Nodzenski, M., Talbot, O., Brickman, W. J., Clayton, P., Ma, R. C., Tam, W. H., Dyer, A. R., Catalano, P. M., Lowe, L. P., Metzger, B. E., HAPO Follow-up Study Cooperative Research Group, Deerochanawong, C., Tanaphonpoonsuk, T., Chotigeat, S. B. U., Manyam, W., Forde, M., Greenidge, A., Neblett, K., Lashley, P. M., Walcott, D., Corry, K., Francis, L., Irwin, J.-A., Langan, A., McCance, D. R., Mousavi, M., Young, I., Gutierrez, J., Jimenez, J., Lawrence, J. M., Sacks, D. A., Takhar, H. S., Tanton, E., Brickman, W. J., Howard, J., Josefson, J. L., Miller, L., Bjaloncik, J., Catalano, P. M., Davis, A., Koontz, M., Presley, L., Smith, S., Tyhulski, A., Li, A. M., Ma, R. C., Ozaki, R., Tam, W. H., Wong, M., Yuen, C. S. M., Clayton, P. E., Khan, A., Vyas, A., Maresh, M., Benzaquen, H., Glickman, N., Hamou, A., Hermon, O., Horesh, O., Keren, Y., Lebenthal, Y., Shalitin, S., Cordeiro, K., Hamilton, J., Nguyen, H. Y., Steele, S., Chen, F., Dyer, A. R., Huang, W., Kuang, A., Jimenez, M., Lowe, L. P., Lowe, W. L., Metzger, B. E., Nodzenski, M., Reisetter, A., Scholtens, D., Talbot, O., Yim, P., Dunger, D., Thomas, A., Horlick, M., Linder, B., Unalp-Arida, A., & Grave, G.
- Affiliations
- Northwestern University Feinberg School of Medicine, Chicago, IL
- Royal Victoria Hospital, Belfast, U.K.
- Royal Manchester Children’s Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Healthy Sciences Centre, School of Medical Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester, U.K.
- ORCID
- Venue
- Diabetes Care
- Publisher
- American Diabetes Association
- Published
- 2019-01-17
- Volume
- 42
- Issue
- 3
- Pages
- 372-380
- ISSN
- 0149-5992 (ISSN-L)
- 1935-5548
- PMC
- PMC6385693
- OpenAlex
- W2910413249
- Semantic Scholar
- 0e85ef4750638fcff236e574ff240ce018f79007
- Cited by
- 574
- References
- 47
- Citations by year
- 2026: 51 · 2025: 81 · 2024: 88 · 2023: 86 · 2022: 95 · 2021: 86 · 2020: 65 · 2019: 22
- FWCI
- 72.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Diabetes Care (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, other-oa)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (1U01-DK-094830)
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Gestational Diabetes Research and Management
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Keywords
- gestational diabetes mellitus, impaired glucose tolerance, impaired fasting glucose, type 2 diabetes, insulin resistance, beta-cell compensation, oral disposition index, insulin sensitivity, insulinogenic index, maternal hyperglycemia, offspring of diabetic mothers
- MeSH terms
- Adolescent, Adult, Blood Glucose, Child, Diabetes Mellitus, Type 2, Female, Follow-Up Studies, Glucose, Glucose Tolerance Test, Humans, Hyperglycemia, Insulin Resistance, Male, Prediabetic State, Pregnancy, Pregnancy Outcome, Prenatal Exposure Delayed Effects, Risk Factors, Diabetes, Gestational, Glucose Intolerance
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