Precision stratification of prognostic risk factors associated with outcomes in gestational diabetes mellitus: a systematic review.

BACKGROUND: The objective of this systematic review is to identify prognostic factors among women and their offspring affected by gestational diabetes mellitus (GDM), focusing on endpoints of cardiovascular disease (CVD) and type 2 diabetes (T2D) for women, and cardiometabolic profile for offspring. METHODS: This review included studies published in English language from January 1st, 1990, through September 30th, 2021, that focused on the above outcomes of interest with respect to sociodemographic factors, lifestyle and behavioral characteristics, traditional clinical traits, and 'omics biomarkers in the mothers and offspring during the perinatal/postpartum periods and across the lifecourse. Studies that did not report associations of prognostic factors with outcomes of interest among GDM-exposed women or children were excluded. RESULTS: Here, we identified 109 publications comprising 98 observational studies and 11 randomized-controlled trials. Findings indicate that GDM severity, maternal obesity, race/ethnicity, and unhealthy diet and physical activity levels predict T2D and CVD in women, and greater cardiometabolic risk in offspring. However, using the Diabetes Canada 2018 Clinical Practice Guidelines for studies, the level of evidence was low due to potential for confounding, reverse causation, and selection biases. CONCLUSIONS: GDM pregnancies with greater severity, as well as those accompanied by maternal obesity, unhealthy diet, and low physical activity, as well as cases that occur among women who identify as racial/ethnic minorities are associated with worse cardiometabolic prognosis in mothers and offspring. However, given the low quality of evidence, prospective studies with detailed covariate data collection and high fidelity of follow-up are warranted.

Gestational diabetes mellitus (GDM) occurs when levels of sugar in the blood are high during pregnancy. We sought to identify factors associated with short- and long-term cardiometabolic disease risk, health conditions that involve heart-related issues and complications in bodily function, among women with GDM and their offspring. We reviewed publications on factors related to type 2 diabetes (T2D) and cardiovascular disease (CVD) risk among women with GDM, and additionally assessed body composition in offspring of women with GDM. We found that GDM severity, maternal obesity, self-identified race/ethnicity, poor diet, and low physical activity levels predict postpartum T2D and CVD in the women, and unfavorable long-term cardiometabolic disease risk in offspring. The quality of evidence was poor, emphasizing a need for high-quality research capturing detailed short- and long-term outcome data to facilitate preventative interventions to improve health of women and children.

Bringing precision medicine to the management of pregnancy in women with glucokinase-MODY: a study of diagnostic accuracy and feasibility of non-invasive prenatal testing.

AIMS/HYPOTHESIS: In pregnancies where the mother has glucokinase-MODY (GCK-MODY), fetal growth is determined by fetal genotype. When the fetus inherits a maternal pathogenic GCK variant, normal fetal growth is anticipated, and insulin treatment of maternal hyperglycaemia is not recommended. At present, fetal genotype is estimated from measurement of fetal abdominal circumference on ultrasound. Non-invasive prenatal testing of fetal GCK genotype (NIPT-GCK) using cell-free DNA in maternal blood has recently been developed. We aimed to compare the diagnostic accuracy of NIPT-GCK with that of ultrasound, and determine the feasibility of using NIPT-GCK to guide pregnancy management. METHODS: We studied an international cohort of pregnant women with hyperglycaemia due to GCK-MODY. We compared the diagnostic accuracy of NIPT-GCK with that of measurement of fetal abdominal circumference at 28 weeks' gestation (n=38) using a directly genotyped offspring sample as the reference standard. In a feasibility study, we assessed the time to result given to clinicians in 43 consecutive pregnancies affected by GCK-MODY between July 2019 and September 2021. RESULTS: In terms of diagnostic accuracy, NIPT-GCK was more sensitive and specific than ultrasound in predicting fetal genotype (sensitivity 100% and specificity 96% for NIPT-GCK vs sensitivity 53% and specificity 61% for fetal abdominal circumference 75th percentile). In terms of feasibility, a valid NIPT-GCK fetal genotype (≥95% probability) was reported in all 38 pregnancies with an amenable variant and repeated samples when needed. The median time to report was 5 weeks (IQR 3-8 weeks). For the 25 samples received before 20 weeks' gestation, results were reported at a median gestational age of 20 weeks (IQR 18-24), with 23/25 (92%) reported before 28 weeks. CONCLUSIONS/INTERPRETATION: Non-invasive prenatal testing of fetal genotype in GCK-MODY pregnancies is highly accurate and is capable of providing a result before the last trimester for most patients. This means that non-invasive prenatal testing of fetal genotype is the optimal approach to management of GCK-MODY pregnancies.

Predictors and risk factors of short-term and long-term outcomes among women with gestational diabetes mellitus (GDM) and their offspring: Moving toward precision prognosis?

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.

Assessing whether genetic scores explain extra variation in birthweight, when added to clinical and anthropometric measures.

BACKGROUND: Human birthweight is a complex, multifactorial trait. Maternal characteristics contribute to birthweight variation by influencing the intrauterine environment. Variation explained by genetic effects is also important, but their contributions have not been assessed alongside other key determinants. We aimed to investigate variance in birthweight explained by genetic scores in addition to easily-measurable clinical and anthropometric variables. METHODS: We analysed 549 European-ancestry parent-offspring trios from a UK community-based birth cohort. We investigated variance explained in birthweight (adjusted for sex and gestational age) in multivariable linear regression models including genetic scores, routinely-measured maternal characteristics, and parental anthropometric variables. We used R-Squared (R2) to estimate variance explained, adjusted R-squared (Adj-R2) to assess improvement in model fit from added predictors, and F-tests to compare nested models. RESULTS: Maternal and fetal genetic scores together explained 6.0% variance in birthweight. A model containing maternal age, weight, smoking, parity and 28-week fasting glucose explained 21.7% variance. Maternal genetic score explained additional variance when added to maternal characteristics (Adj-R2 = 0.233 vs Adj-R2 = 0.210, p < 0.001). Fetal genetic score improved variance explained (Adj-R2 = 0.264 vs 0.248, p < 0.001) when added to maternal characteristics and parental heights. CONCLUSIONS: Genetic scores account for variance explained in birthweight in addition to easily measurable clinical variables. Parental heights partially capture fetal genotype and its contribution to birthweight, but genetic scores explain additional variance. While the genetic contribution is modest, it is comparable to that of individual clinical characteristics such as parity, which suggests that genetics could be included in tools aiming to predict risk of high or low birthweights.

Identification of GCK-maturity-onset diabetes of the young in cases of neonatal hyperglycemia: A case series and review of clinical features.

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 counseling for females found to be affected.

Two decades since the fetal insulin hypothesis: what have we learned from genetics?

In 1998 the fetal insulin hypothesis proposed that lower birthweight and adult-onset type 2 diabetes are two phenotypes of the same genotype. Since then, advances in research investigating the role of genetics affecting insulin secretion and action have furthered knowledge of fetal insulin-mediated growth and the biology of type 2 diabetes. In this review, we discuss the historical research context from which the fetal insulin hypothesis originated and consider the position of the hypothesis in light of recent evidence. In summary, there is now ample evidence to support the idea that variants of certain genes which result in impaired pancreatic beta cell function and reduced insulin secretion contribute to both lower birthweight and higher type 2 diabetes risk in later life when inherited by the fetus. There is also evidence to support genetic links between type 2 diabetes secondary to reduced insulin action and lower birthweight but this applies only to loci implicated in body fat distribution and not those influencing insulin resistance via obesity or lipid metabolism by the liver. Finally, we also consider how advances in genetics are being used to explore alternative hypotheses, namely the role of the maternal intrauterine environment, in the relationship between lower birthweight and adult cardiometabolic disease.

All thresholds of maternal hyperglycaemia from the WHO 2013 criteria for gestational diabetes identify women with a higher genetic risk for type 2 diabetes.

Background: Using genetic scores for fasting plasma glucose (FPG GS) and type 2 diabetes (T2D GS), we investigated whether the fasting, 1-hour and 2-hour glucose thresholds from the WHO 2013 criteria for gestational diabetes (GDM) have different implications for genetic susceptibility to raised fasting glucose and type 2 diabetes in women from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) and Atlantic Diabetes in Pregnancy (DIP) studies. Methods: Cases were divided into three subgroups: (i) FPG ≥5.1 mmol/L only, n=222; (ii) 1-hour glucose post 75 g oral glucose load ≥10 mmol/L only, n=154 (iii) 2-hour glucose ≥8.5 mmol/L only, n=73; and (iv) both FPG ≥5.1 mmol/L and either of a 1-hour glucose ≥10 mmol/L or 2-hour glucose ≥8.5 mmol/L, n=172. We compared the FPG and T2D GS of these groups with controls (n=3,091) in HAPO and DIP separately. Results: In HAPO and DIP, the mean FPG GS in women with a FPG ≥5.1 mmol/L, either on its own or with 1-hour glucose ≥10 mmol/L or 2-hour glucose ≥8.5 mmol/L, was higher than controls (all P <0.01). Mean T2D GS in women with a raised FPG alone or with either a raised 1-hour or 2-hour glucose was higher than controls (all P <0.05). GDM defined by 1-hour or 2-hour hyperglycaemia only was also associated with a higher T2D GS than controls (all P <0.05). Conclusions: The different diagnostic categories that are part of the WHO 2013 criteria for GDM identify women with a genetic predisposition to type 2 diabetes as well as a risk for adverse pregnancy outcomes.

The association between first trimester AFP to PAPP-A ratio and placentally-related adverse pregnancy outcome.

INTRODUCTION: Low maternal serum levels of pregnancy-associated plasma protein A (PAPP-A) measured in the first trimester and high levels of alpha fetoprotein (AFP) measured in the second trimester have been associated with adverse pregnancy outcomes reflective of placental insufficiency, and there is a synergistic relationship between the two. We investigated the utility as a screening test of a simple ratio of maternal serum AFP to PAPP-A (AFP:PAPP-A) measured in the first trimester. METHODS: We studied 4057 nulliparous women with a singleton pregnancy from the Pregnancy Outcome Prediction (POP) study. We studied the predictive ability for adverse outcome of the AFP:PAPP-A ratio measured in the first trimester with and without correction for maternal weight and gestational age at measurement. We compared the AFP:PAPP-A ratio with corrected AFP and PAPP-A on their own and in combination. RESULTS: An AFP:PAPP-A ratio >10 was associated with placentally-related adverse outcomes, including fetal growth restriction (risk ratio (RR) 3.74, 95% confidence interval (CI) 2.30-6.09), severe preeclampsia (RR 2.12, 95% CI 1.39-3.25) and stillbirth (RR 5.05, 95% CI 1.48-17.18). The ratio performed favorably in predicting adverse pregnancy outcomes when compared with corrected measurements of either AFP or PAPP-A, and was equivalent to a model combining the two. Its predictive ability was not affected by correction for maternal weight or gestational age at measurement. DISCUSSION: An elevated maternal AFP:PAPP-A ratio in the first trimester is associated with placentally-related adverse outcomes in a cohort of unselected nulliparous women.

A Lower Maternal Cortisol-to-Cortisone Ratio Precedes Clinical Diagnosis of Preterm and Term Preeclampsia by Many Weeks.

CONTEXT: Previous studies have shown reduced placental levels of 11-ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2) 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 11ßHSD2 in these conditions. Our observations implicate enhanced maternal 11ßHSD2 activity or reduced 11ßHSD type 1 activity in the pathophysiology of PE.

Fetal Genotype and Maternal Glucose Have Independent and Additive Effects on Birth Weight.

Maternal glycemia is a key determinant of birth weight, but recent large-scale genome-wide association studies demonstrated an important contribution of fetal genetics. It is not known whether fetal genotype modifies the impact of maternal glycemia or whether it acts through insulin-mediated growth. We tested the effects of maternal fasting plasma glucose (FPG) and a fetal genetic score for birth weight on birth weight and fetal insulin in 2,051 European mother-child pairs from the Exeter Family Study of Childhood Health (EFSOCH) and the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study. The fetal genetic score influenced birth weight independently of maternal FPG and impacted growth at all levels of maternal glycemia. For mothers with FPG in the top tertile, the frequency of large for gestational age (birth weight ≥90th centile) was 31.1% for offspring with the highest tertile genetic score and only 14.0% for those with the lowest tertile genetic score. Unlike maternal glucose, the fetal genetic score was not associated with cord insulin or C-peptide. Similar results were seen for HAPO participants of non-European ancestry (n = 2,842 pairs). This work demonstrates that for any level of maternal FPG, fetal genetics has a major impact on fetal growth and acts predominantly through independent mechanisms.