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As part of the American Diabetes Association Precision Medicine in Diabetes Initiative (PMDI) – a partnership with the European Association for the Study of Diabetes (EASD) – this systematic review is part of a comprehensive evidence evaluation in support of the 2 (nd) International Consensus Report on Precision Diabetes Medicine. Here, we sought to synthesize evidence from empirical research papers published through September 1 (st) , 2021 to evaluate and identify prognostic conditions, risk factors, and biomarkers among women and children affected by gestational diabetes mellitus (GDM), focusing on clinical endpoints of cardiovascular disease (CVD) and type 2 diabetes (T2D) among women with a history of GDM; and adiposity and cardiometabolic profile among offspring exposed to GDM in utero. We identified a total of 107 observational studies and 12 randomized controlled trials testing the effect of pharmaceutical and/or lifestyle interventions. Broadly, current literature indicates that greater GDM severity, higher maternal body mass index, belonging to racial/ethnic minority group; and unhealthy lifestyle behaviors would predict a woman’s risk of incident T2D and CVD, and an unfavorable cardiometabolic profile among offspring. However, the level of evidence is low (Level 4 according to the Diabetes Canada 2018 Clinical Practice Guidelines for diabetes prognosis) largely because most studies leveraged retrospective data from large registries that are vulnerable to residual confounding and reverse causation bias; and prospective cohort studies that may suffer selection and attrition bias. Moreover, for the offspring outcomes, we identified a relatively small body of literature on prognostic factors indicative of future adiposity and cardiometabolic risk. Future high-quality prospective cohort studies in diverse populations with granular data collection on prognostic factors, clinical and subclinical outcomes, high fidelity of follow-up, and appropriate analytical approaches to deal with structural biases are warranted.

Heterozygous mutations in GCK result in a persistent, mildly raised glucose from birth, but it is usually diagnosed in adulthood as maturity-onset diabetes of the young (MODY), where hyperglycemia is often an incidental finding. The hyperglycemia of GCK-MODY is benign and does not require treatment, but is important to be aware of, particularly in females where it has implications for managing pregnancy. We present three cases of neonatal hyperglycemia resulting from a heterozygous mutation in GCK, illustrating its clinical presentation and evolution in early life. In summary, as with adults, neonatal hyperglycemia is an incidental finding, does not require treatment and has no adverse consequences for health. Neonates and their parents should be referred for genetic testing to confirm the diagnosis, avoid a label of diabetes and enable pregnancy counselling for females found to be affected.

Additional file 2: Supplementary tables S2-S6. This file contains the supplementary tables for this paper.

Using genetic scores for fasting plasma glucose (FPG GS) and Type 2 diabetes (T2D GS), we investigated whether different diagnostic criteria for gestational diabetes (GDM) have different implications for genetic susceptibility to later T2D in women from the the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) and Atlantic Diabetes in Pregnancy (DIP) studies. To investigate different features of WHO (1999) and IADPSG (2010) criteria for diagnosing GDM, cases were divided into three subgroups: (i) FPG ≥5.1 mmol/L only, n=261; (ii) 2-hour glucose post 75 g oral glucose load ≥7.8 mmol/L only, n=305); and (iii) both FPG ≥5.1 mmol/L and 2-hour glucose ≥7.8 mmol/L, n=135. We compared the FPG and T2D genetic scores of these groups with controls (n=3,083). GDM as defined by fasting hyperglycemia was associated with a higher genetic score for both FPG and T2D, whether or not 2-hour glucose was also raised. GDM defined only by 2-hour hyperglycemia, was associated with a higher T2D GS, but not a higher FPG GS. The T2D GS was similar whether the fasting glucose alone, 2-hour glucose alone, or both fasting and 2-hour glucose were raised. Thus, the newest criteria identify women with a genetic predisposition to T2D who may not have been identified by previous criteria.

CONTEXT: Previous studies have shown reduced placental levels of 11-β-hydroxysteroid dehydrogenase type 2 (11βHSD2) in preeclampsia (PE). However, it is unknown if the maternal cortisol-to-cortisone ratio is predictive of placental complications of pregnancy. OBJECTIVE: To determine the relationship between the maternal serum cortisol-to-cortisone ratio at different stages of pregnancy and the risk of PE or fetal growth restriction (FGR). DESIGN: Women from the Pregnancy Outcome Prediction Study experiencing PE (n = 194) or FGR (n = 185), plus a random sample of healthy controls (n = 279), were studied. Steroids were measured at ∼12, ∼20, ∼28, and ∼36 weeks of gestational age (wkGA). Separate analyses were performed for outcomes with term or preterm delivery. Associations were modeled using logistic regression. RESULTS: At 28 wkGA, the cortisol-to-cortisone ratio was negatively associated (OR per 1 SD increase, 95% CI)] with preterm PE (OR 0.33, 95% CI 0.19 to 0.57), term PE (OR 0.61, 95% CI 0.49 to 0.76), and preterm FGR (OR 0.50, 95% CI 0.29 to 0.85). At 36 wkGA, the cortisol-to-cortisone ratio was negatively associated with term PE (OR 0.42, 95% CI 0.32 to 0.55) but not term FGR (OR 1.07, 95% CI 0.87 to 1.31). Associations were not materially affected by adjustment for maternal characteristics. CONCLUSIONS: A lower maternal serum cortisol-to-cortisone ratio precedes clinical manifestation of PE and preterm FGR by many weeks, despite previous reports of reduced levels of placental 11βHSD2 in these conditions. Our observations implicate enhanced maternal 11βHSD2 activity or reduced 11βHSD type 1 activity in the pathophysiology of PE.

CONTEXT: Previous studies have shown reduced placental levels of 11-β-hydroxysteroid dehydrogenase type 2 (11βHSD2) in preeclampsia (PE). However, it is unknown if the maternal cortisol-to-cortisone ratio is predictive of placental complications of pregnancy. OBJECTIVE: To determine the relationship between the maternal serum cortisol-to-cortisone ratio at different stages of pregnancy and the risk of PE or fetal growth restriction (FGR). DESIGN: Women from the Pregnancy Outcome Prediction Study experiencing PE (n = 194) or FGR (n = 185), plus a random sample of healthy controls (n = 279), were studied. Steroids were measured at ∼12, ∼20, ∼28, and ∼36 weeks of gestational age (wkGA). Separate analyses were performed for outcomes with term or preterm delivery. Associations were modeled using logistic regression. RESULTS: At 28 wkGA, the cortisol-to-cortisone ratio was negatively associated (OR per 1 SD increase, 95% CI)] with preterm PE (OR 0.33, 95% CI 0.19 to 0.57), term PE (OR 0.61, 95% CI 0.49 to 0.76), and preterm FGR (OR 0.50, 95% CI 0.29 to 0.85). At 36 wkGA, the cortisol-to-cortisone ratio was negatively associated with term PE (OR 0.42, 95% CI 0.32 to 0.55) but not term FGR (OR 1.07, 95% CI 0.87 to 1.31). Associations were not materially affected by adjustment for maternal characteristics. CONCLUSIONS: A lower maternal serum cortisol-to-cortisone ratio precedes clinical manifestation of PE and preterm FGR by many weeks, despite previous reports of reduced levels of placental 11βHSD2 in these conditions. Our observations implicate enhanced maternal 11βHSD2 activity or reduced 11βHSD type 1 activity in the pathophysiology of PE.