Metabolomic and genetic architecture of gestational diabetes subtypes.

AIMS/HYPOTHESIS: Physiological gestational diabetes mellitus (GDM) subtypes that may confer different risks for adverse pregnancy outcomes have been defined. The aim of this study was to characterise the metabolome and genetic architecture of GDM subtypes to address the hypothesis that they differ between GDM subtypes. METHODS: This was a cross-sectional study of participants in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study who underwent an OGTT at approximately 28 weeks' gestation. GDM was defined retrospectively using International Association of Diabetes and Pregnancy Study Groups/WHO criteria, and classified as insulin-deficient GDM (insulin secretion <25th percentile with preserved insulin sensitivity) or insulin-resistant GDM (insulin sensitivity <25th percentile with preserved insulin secretion). Metabolomic analyses were performed on fasting and 1 h serum samples in 3463 individuals (576 with GDM). Genome-wide genotype data were obtained for 8067 individuals (1323 with GDM). RESULTS: Regression analyses demonstrated striking differences between the metabolomes for insulin-deficient or insulin-resistant GDM compared to those with normal glucose tolerance. After adjustment for covariates, 33 fasting metabolites, including 22 medium- and long-chain acylcarnitines, were uniquely associated with insulin-deficient GDM; 23 metabolites, including the branched-chain amino acids and their metabolites, were uniquely associated with insulin-resistant GDM; two metabolites (glycerol and 2-hydroxybutyrate) were associated with the same direction of association with both subtypes. Subtype differences were also observed 1 h after a glucose load. In genome-wide association studies, variants within MTNR1B (rs10830963, p=3.43×10-18, OR 1.55) and GCKR (rs1260326, p=5.17×10-13, OR 1.43) were associated with GDM. Variants in GCKR (rs1260326, p=1.36×10-13, OR 1.60) and MTNR1B (rs10830963, p=1.22×10-9, OR 1.49) demonstrated genome-wide significant association with insulin-resistant GDM; there were no significant associations with insulin-deficient GDM. The lead SNP in GCKR, rs1260326, was associated with the levels of eight of the 25 fasting metabolites that were associated with insulin-resistant GDM and ten of 41 1 h metabolites that were associated with insulin-resistant GDM. CONCLUSIONS/INTERPRETATION: This study demonstrates that physiological GDM subtypes differ in their metabolome and genetic architecture. These findings require replication in additional cohorts, but suggest that these differences may contribute to subtype-related adverse pregnancy outcomes.

The simultaneous occurrence of gestational diabetes and hypertensive disorders of pregnancy affects fetal growth and neonatal morbidity.

BACKGROUND: Gestational diabetes is associated with increased risk of hypertensive disorders of pregnancy, but there are limited data on fetal growth and neonatal outcomes when both conditions are present. OBJECTIVE: We evaluated the risk of abnormal fetal growth and neonatal morbidity in pregnancies with co-occurrence of gestational diabetes and hypertensive disorders of pregnancy. STUDY DESIGN: In a retrospective study of 47,093 singleton pregnancies, we compared the incidence of appropriate for gestational age birthweight in pregnancies affected by gestational diabetes alone, hypertensive disorders of pregnancy alone, or both gestational diabetes and hypertensive disorders of pregnancy with that in pregnancies affected by neither disorder using generalized estimating equations (covariates: maternal age, nulliparity, body mass index, insurance type, race, marital status, and prenatal care site). Secondary outcomes were large for gestational age birthweight, small for gestational age birthweight, and a neonatal morbidity composite outcome (stillbirth, hypoglycemia, hyperbilirubinemia, respiratory distress, encephalopathy, preterm delivery, neonatal death, and neonatal intensive care unit admission). RESULTS: The median (interquartile range) birthweight percentile in pregnancies with both gestational diabetes and hypertensive disorders of pregnancy (50 [24.0-78.0]; N=179) was similar to that of unaffected pregnancies (50 [27.0-73.0]; N=35,833). However, the absolute rate of appropriate for gestational age birthweight was lower for gestational diabetes/hypertensive disorders of pregnancy co-occurrence (78.2% vs 84.9% for unaffected pregnancies). Adjusted analyses showed decreased odds of appropriate for gestational age birthweight in pregnancies with both gestational diabetes and hypertensive disorders of pregnancy compared with unaffected pregnancies (adjusted odds ratio, 0.72 [95% confidence interval, 0.52-1.00]; P=.049), and in pregnancies complicated by gestational diabetes alone (adjusted odds ratio, 0.78 [0.68-0.89]; P<.001) or hypertensive disorders of pregnancy alone (adjusted odds ratio, 0.73 [0.66-0.81]; P<.001). The absolute risk of large for gestational age birthweight was greater in pregnancies with both gestational diabetes and hypertensive disorders of pregnancy (14.5%) than in unaffected pregnancies (8.2%), without apparent difference in the risk of small for gestational age birthweight (7.3% vs 6.9%). However, in adjusted models comparing pregnancies with gestational diabetes/hypertensive disorders of pregnancy co-occurrence with unaffected pregnancies, neither an association with large for gestational age birthweight (adjusted odds ratio, 1.33 [0.88-2.00]; P=.171) nor small for gestational age birthweight (adjusted odds ratio, 1.32 [0.80-2.19]; P=.293) reached statistical significance. Gestational diabetes/hypertensive disorders of pregnancy co-occurrence carried an increased risk of neonatal morbidity that was greater than that observed with either condition alone (gestational diabetes/hypertensive disorders of pregnancy: adjusted odds ratio, 3.13 [2.35-4.17]; P<.001; gestational diabetes alone: adjusted odds ratio, 2.01 [1.78-2.27]; P<.001; hypertensive disorders of pregnancy alone: adjusted odds ratio, 1.38 [1.26-1.50]; P<.001). CONCLUSION: Although pregnancies with both gestational diabetes and hypertensive disorders of pregnancy have a similar median birthweight percentile to those affected by neither condition, pregnancies concurrently affected by both conditions have a higher risk of abnormal fetal growth and neonatal morbidity.

Glycated Albumin and Glycemia in Pregnancy and Postpartum: A Pilot Study.

OBJECTIVE: Percent glycated albumin (%GAlb) is a marker of glycemia over the past 2 to 3 weeks in nonpregnant individuals. Longitudinal changes in %GAlb extending throughout pregnancy and postpartum (PP) have not been described. We aimed to describe levels of %GAlb throughout pregnancy and PP and relationships with glycemia. STUDY DESIGN: Fifty women among those in the Study of Pregnancy Regulation of INsulin and Glucose cohort underwent 75-g oral glucose tolerance tests (OGTTs) at a mean of 13 weeks (V1) and 26 weeks (V2) of gestation and 11 weeks' PP. %GAlb was measured on frozen plasma samples. RESULTS: Total albumin decreased from V1 to V2 and increased PP to levels higher than at V1. %GAlb declined between V1 and V2 (ß = - 0.63% 95% CI [-0.8, -0.6] p < 0.001) and remained stable between V2 and PP (ß = - 0.04% [-0.3, 0.2] p = 0.78). Body mass index (BMI) was inversely related to %GAlb in pregnancy (V1: rho = - 0.5, p = 0.0001; V2 rho = - 0.4, p = 0.006), but not PP (rho = - 0.15, p = 0.31). The longitudinal changes in %GAlb persisted after adjusting for BMI. Neither glycemia measurements nor hemoglobin A1c were associated with %GAlb at any time point, and adjustments for BMI did not reveal additional associations. CONCLUSION: %GAlb decreases between early and late gestation and remains decreased PP, despite a PP increase in total albumin above early pregnancy values. Given the lack of correlation with OGTT values or A1c, %GAlb is unlikely to be useful in assessing glycemia in pregnant or PP women. KEY POINTS: · Changes in %GAlb extending to the postpartum period have not been described.. · %GAlb decreases in pregnancy and remains decreased postpartum, despite a postpartum increase in total albumin above early pregnancy values.. · Glycemia measurements nor A1c were associated with %GAlb at any time point, therefore, %GAlb is unlikely to be useful in assessing glycemia in pregnant or postpartum women..

Pregnancy- and birth-related risk factors for the development of childhood celiac disease.

AIM: To evaluate whether pregnancy and birth-related factors are associated with celiac disease (CD) in a large, United States (US)-based mother-child cohort. METHODS: We analysed data gathering from the Massachusetts General Hospital Maternal Child Cohort (MMCC) of children born between 1998 and 2016. Data included the mode of delivery, maternal pregnancy and their offspring characteristics. We searched for CD cases by using diagnosis billing codes. Cox proportional hazard regression models were created to identify variables associated with CD. RESULTS: We identified 44 539 mother-child pairs who had at least one encounter by 5 years old and identified 173 children (0.4%) with CD diagnosis; median age at the diagnosis was 6 years. Overall, the adjusted hazard ratio (aHR) of caesarean delivery for CD was 1.39 (95% CI: 0.99, 1.96, p = 0.06) when compared to children born vaginally. After stratifying for the presence of labour, children born by Caesarean delivery without labour had a higher risk of CD (aHR 1.56; 95%CI: 1.01, 2.41; p = 0.046) while infants born by Caesarean delivery with labour did not (aHR 1.26; 95% CI: 0.83, 1.93; p = 0.28). CONCLUSION: Being born by Caesarean delivery without labour may be associated with an increased risk for CD in the US children.

First Trimester Cardiac Biomarkers among Women with Peripartum Cardiomyopathy: Are There Early Clues to This Late-Pregnancy Phenomenon?

OBJECTIVE: Whether biomarkers may enable early identification of women who develop peripartum cardiomyopathy (PPCM) prior to disease onset remains a question of interest. STUDY DESIGN: A retrospective nested case-control study was conducted to determine whether first trimester N-terminal pro-B type natriuretic peptide (NT-proBNP) or high sensitivity cardiac troponin I (hs-cTnI) differed among women who developed PPCM versus unaffected pregnancies. Cases were matched to unaffected women by age, race, parity, and gestational age of sample (control A) and then further by blood pressure and pregnancy weight gain (control B). RESULTS: First trimester NT-proBNP concentrations were numerically higher among women who subsequently developed PPCM (116 pg/mL [83-177]) as compared with women in control A (56.1 pg/mL [38.7-118.7], p = 0.3) or control B (37.6 [23.3 - 53.8], p <0.05). A higher proportion of women who subsequently developed PPCM (50%) had detectable levels of hs-cTnI as compared with control A (0%, p = 0.03) or control B (18.8%, p = 0.52). Among both cases and controls, hs-cTnI values were low and often below the limit of detection. CONCLUSION: There were differences in first trimester NT-proBNP and hs-cTnI concentrations between women who subsequently developed PPCM and those who did not, raising the possibility the early pregnancy subclinical myocardial dysfunction may be associated with this late-pregnancy disease. KEY POINTS: · First trimester NT-proBNP is numerically higher among women who subsequently develop PPCM.. · First trimester hs-cTnI was nominally higher among women who developed PPCM versus those who did not.. · A significant proportion of normal pregnant women have undetectable hs-cTnI..

Patient Priorities, Decisional Comfort, and Satisfaction with Metformin versus Insulin for the Treatment of Gestational Diabetes Mellitus.

OBJECTIVE: We compared patient priorities, decisional comfort, and satisfaction with treating gestational diabetes mellitus (GDM) with metformin versus insulin among pregnant individuals with GDM requiring pharmacotherapy. STUDY DESIGN: We conducted a cross-sectional study of patients' perspectives about GDM pharmacotherapy in an integrated prenatal and diabetes care program from October 19, 2022, to August 24, 2023. The exposure was metformin versus insulin as the initial medication decision. Outcomes included standardized measures of patient priorities, decisional comfort, and satisfaction about their medication decision. RESULTS: Among 144 assessed individuals, 60.4% were prescribed metformin and 39.6% were prescribed insulin. Minoritized individuals were more likely to receive metformin compared with non-Hispanic White individuals (34.9 vs. 17.5%; p = 0.03). Individuals who were willing to participate in a GDM pharmacotherapy clinical trial were more likely to receive insulin than those who were unwilling (30.4 vs. 19.5%; p = 0.02). Individuals receiving metformin were more likely to report prioritizing avoiding injections (62.4 vs. 19.3%; adjusted odds ratio [aOR]: 2.83; 95% confidence interval [CI]: 1.10-7.31), wanting to take a medication no more than twice daily (56.0 vs. 30.4%; aOR: 3.67; 95% CI: 1.56-8.67), and believing that both medications can equally prevent adverse pregnancy outcomes (70.9 vs. 52.6%; aOR: 2.67; 95% CI: 1.19-6.03). Conversely, they were less likely to report prioritizing a medication that crosses the placenta (39.1 vs. 82.5%; aOR: 0.09; 95% CI: 0.03-0.25) and needing supplemental insulin to achieve glycemic control (21.2 vs. 47.4%; aOR: 0.36; 95% CI: 0.15-0.90). Individuals reported similarly high (mean score > 80%) levels of decisional comfort, personal satisfaction with medication decision-making, and satisfaction about their conversation with their provider about their medication decision with metformin and insulin (p ≥ 0.05 for all). CONCLUSION: Individuals with GDM requiring pharmacotherapy reported high levels of decision comfort and satisfaction with both metformin and insulin, although they expressed different priorities in medication decision-making. These results can inform future patient-centered GDM treatment strategies. KEY POINTS: · Pregnant individuals with GDM requiring pharmacotherapy expressed a high level of decisional comfort and satisfaction with medication decision making.. · Individuals placed different priorities on deciding to take metformin versus insulin.. · These results can inform interventions aimed at delivering person-centered diabetes care in pregnancy that integrates patient autonomy and knowledge about treatment options..

Longitudinal changes in glucose during pregnancy in women with gestational diabetes risk factors.

AIMS/HYPOTHESIS: Despite recommendations to screen women with diabetes risk factors for hyperglycaemia in the first trimester, criteria for normal glucose values in early pregnancy have not been firmly established. We aimed to compare glucose levels in early pregnancy with those later in gestation and outside of pregnancy in women with diabetes risk factors. METHODS: In pregnant women (N = 123) followed longitudinally through the postpartum period, and a separate cohort of non-pregnant women (N = 65), we performed 75 g oral glucose tolerance tests. All participants had one or more risk factors for diabetes. Using linear regression, we tested for differences in glucose levels between non-pregnant and pregnant women at early (7-15 weeks) and mid-late (24-32 weeks) gestation as well as postpartum, with adjustment for maternal age, parity, marital status and BMI. In a longitudinal analysis using mixed-effects models, we tested for differences in glucose levels across early and mid-late pregnancy compared with postpartum. Differences are expressed as ß (95% CI). RESULTS: Fasting glucose was lower in pregnant compared with non-pregnant women by 0.34 (0.18, 0.51) mmol/l (p < 0.0001) in early pregnancy and by 0.45 (0.29, 0.61) mmol/l (p < 0.0001) in mid-late pregnancy. In longitudinal models, fasting glucose was lower by 0.13 (0.04, 0.21) mmol/l (p = 0.003) in early pregnancy and by 0.16 (0.08, 0.25) mmol/l (p = 0.0003) in mid-late pregnancy compared with the same women postpartum. Early pregnancy post-load glucose levels did not differ from those in non-pregnant women or the same women postpartum. In mid-late pregnancy, compared with non-pregnant women, elevations in 1 h post-load glucose level (0.60 [-0.12, 1.33] mmol/l, p = 0.10) and 2 h post-load glucose (0.49 [-0.21, 1.19] mmol/l, p = 0.17) were not statistically significant. However, in longitudinal analyses, 1 h and 2 h post-load glucose levels were higher in mid-late pregnancy (by 0.78 [0.35, 1.21] mmol/l, p = 0.0004, and 0.67 [0.30, 1.04] mmol/l, p = 0.0005, respectively) when compared with postpartum. CONCLUSIONS/INTERPRETATION: In women with diabetes risk factors, fasting glucose declines in the first trimester. Post-load glucose increases later in pregnancy. These findings may inform criteria for diagnosing hyperglycaemia early in pregnancy.

Sex-Based Role Misidentification and Burnout of Resident Physicians: An Observational Study.

OBJECTIVE: This cross-sectional study characterized associations between sex, role misidentification, and burnout among surgical and nonsurgical residents. SUMMARY BACKGROUND DATA: Limited evidence suggests that female resident physicians are more likely to be misidentified as nonphysician team members, with potential negative implications for wellbeing. The prevalence and impact of role misidentification on the trainee experience in surgical as compared to nonsurgical specialties is unknown. METHODS: An anonymous electronic survey was distributed to fourteen different residency programs at 2 academic medical centers in August 2018. The survey included questions about demographics, symptoms of burnout, the frequency of misidentification as another member of the care team, and the effect of misidentification on respondents' well-being. Results: Two-hundred sixty out of 419 (62.1% response rate) resident physicians completed the survey, of whom 184 (77.3%) reported being misidentified as a nonphysician at least weekly. Female sex was associated with a significantly increased odds of being misidentified at least weekly (adjusted OR 23.7, 95% CI 10.9-51.5; P < 0.001), as was training in a surgical program (adjusted OR 3.7, 95% CI 1.7-8.0; P = 0.001). Frequent role misidentification was associated with burnout (OR 2.6, 95% CI 1.2-5.5; P = 0.01). In free-text responses, residents reported that being misidentified invoked a sense of not belonging, caused emotional exhaustion, and interfered with patient communication. CONCLUSIONS: Role misidentification is more prevalent among female residents and surgical residents, compared to male residents and nonsurgical residents, respectively. Physician role misidentification is associated with burnout and has negative implications for resident wellbeing; interventions to reduce role misidentification are needed.

Physiological subtypes of gestational glucose intolerance and risk of adverse pregnancy outcomes.

BACKGROUND: Women with gestational glucose intolerance, defined as an abnormal initial gestational diabetes mellitus screening test, are at risk of adverse pregnancy outcomes even if they do not have gestational diabetes mellitus. Previously, we defined the physiological subtypes of gestational diabetes mellitus based on the primary underlying physiology leading to hyperglycemia and found that women with different subtypes had differential risks of adverse outcomes. Physiological subclassification has not yet been applied to women with gestational glucose intolerance. OBJECTIVE: We defined the physiological subtypes of gestational glucose intolerance based on the presence of insulin resistance, insulin deficiency, or mixed pathophysiology and aimed to determine whether these subtypes are at differential risks of adverse outcomes. We hypothesized that women with the insulin-resistant subtype of gestational glucose intolerance would have the greatest risk of adverse pregnancy outcomes. STUDY DESIGN: In a hospital-based cohort study, we studied women with gestational glucose intolerance (glucose loading test 1-hour glucose, ≥140 mg/dL; n=236) and normal glucose tolerance (glucose loading test 1-hour glucose, <140 mg/dL; n=1472). We applied homeostasis model assessment to fasting glucose and insulin levels at 16 to 20 weeks' gestation to assess insulin resistance and deficiency and used these measures to classify women with gestational glucose intolerance into subtypes. We compared odds of adverse outcomes (large for gestational age birthweight, neonatal intensive care unit admission, pregnancy-related hypertension, and cesarean delivery) in each subtype to odds in women with normal glucose tolerance using logistic regression with adjustment for age, race and ethnicity, marital status, and body mass index. RESULTS: Of women with gestational glucose intolerance (12% with gestational diabetes mellitus), 115 (49%) had the insulin-resistant subtype, 70 (27%) had the insulin-deficient subtype, 40 (17%) had the mixed pathophysiology subtype, and 11 (5%) were uncategorized. We found increased odds of large for gestational age birthweight (primary outcome) in women with the insulin-resistant subtype compared with women with normal glucose tolerance (odds ratio, 2.35; 95% confidence interval, 1.43-3.88; P=.001; adjusted odds ratio, 1.74; 95% confidence interval, 1.02-3.48; P=.04). The odds of large for gestational age birthweight in women with the insulin-deficient subtype were increased only after adjustment for covariates (odds ratio, 1.69; 95% confidence interval, 0.84-3.38; P=.14; adjusted odds ratio, 2.05; 95% confidence interval, 1.01-4.19; P=.048). Among secondary outcomes, there was a trend toward increased odds of neonatal intensive care unit admission in the insulin-resistant subtype in an unadjusted model (odds ratio, 2.09; 95% confidence interval, 0.99-4.40; P=.05); this finding was driven by an increased risk of neonatal intensive care unit admission in women with the insulin-resistant subtype and a body mass index of <25 kg/m2. Infants of women with other subtypes did not have increased odds of neonatal intensive care unit admission. The odds of pregnancy-related hypertension in women with the insulin-resistant subtype were increased (odds ratio, 2.09; 95% confidence interval, 1.31-3.33; P=.002; adjusted odds ratio, 1.77; 95% confidence interval, 1.07-2.92; P=.03) compared with women with normal glucose tolerance; other subtypes did not have increased odds of pregnancy-related hypertension. There was no difference in cesarean delivery rates in nulliparous women across subtypes. CONCLUSION: Insulin-resistant gestational glucose intolerance is a high-risk subtype for adverse pregnancy outcomes. Delineating physiological subtypes may provide opportunities for a more personalized approach to gestational glucose intolerance.

Risk of Adverse Pregnancy Outcomes Among Pregnant Individuals With Gestational Diabetes by Race and Ethnicity in the United States, 2014-2020.

Importance: Gestational diabetes, which increases the risk of adverse pregnancy outcomes, has been increasing in frequency across all racial and ethnic subgroups in the US. Objective: To assess whether the frequency of adverse pregnancy outcomes among those in the US with gestational diabetes changed over time and whether the risk of these outcomes differed by maternal race and ethnicity. Design, Setting, and Participants: Exploratory serial, cross-sectional, descriptive study using US National Center for Health Statistics natality data for 1 560 822 individuals with gestational diabetes aged 15 to 44 years with singleton nonanomalous live births from 2014 to 2020 in the US. Exposures: Year of delivery and race and ethnicity, as reported on the birth certificate, stratified as non-Hispanic American Indian, non-Hispanic Asian/Pacific Islander, non-Hispanic Black, Hispanic/Latina, and non-Hispanic White (reference group). Main Outcomes and Measures: Maternal outcomes of interest included cesarean delivery, primary cesarean delivery, preeclampsia or gestational hypertension, intensive care unit (ICU) admission, and transfusion; neonatal outcomes included large for gestational age (LGA), macrosomia (>4000 g at birth), small for gestational age (SGA), preterm birth, and neonatal ICU (NICU) admission, as measured by the frequency (per 1000 live births) with estimation of mean annual percentage change (APC), disparity ratios, and adjusted risk ratios. Results: Of 1 560 822 included pregnant individuals with gestational diabetes (mean [SD] age, 31 [5.5] years), 1% were American Indian, 13% were Asian/Pacific Islander, 12% were Black, 27% were Hispanic/Latina, and 48% were White. From 2014 to 2020, there was a statistically significant increase in the overall frequency (mean APC per year) of preeclampsia or gestational hypertension (4.2% [95% CI, 3.3% to 5.2%]), transfusion (8.0% [95% CI, 3.8% to 12.4%]), preterm birth at less than 37 weeks (0.9% [95% CI, 0.3% to 1.5%]), and NICU admission (1.0% [95% CI, 0.3% to 1.7%]). There was a significant decrease in cesarean delivery (-1.4% [95% CI, -1.7% to -1.1%]), primary cesarean delivery (-1.2% [95% CI, -1.5% to -0.9%]), LGA (-2.3% [95% CI, -2.8% to -1.8%]), and macrosomia (-4.7% [95% CI, -5.3% to -4.0%]). There was no significant change in maternal ICU admission and SGA. In comparison with White individuals, Black individuals were at significantly increased risk of all assessed outcomes, except LGA and macrosomia; American Indian individuals were at significantly increased risk of all assessed outcomes except cesarean delivery and SGA; and Hispanic/Latina and Asian/Pacific Islander individuals were at significantly increased risk of maternal ICU admission, preterm birth, NICU admission, and SGA. Differences in adverse outcomes by race and ethnicity persisted through these years. Conclusions and Relevance: From 2014 through 2020, the frequency of multiple adverse pregnancy outcomes in the US increased among pregnant individuals with gestational diabetes. Differences in adverse outcomes by race and ethnicity persisted.

Genetic Studies of Gestational Diabetes and Glucose Metabolism in Pregnancy.

PURPOSE OF REVIEW: In this review, we summarize studies investigating genetics of gestational diabetes mellitus (GDM) and glucose metabolism in pregnancy. We describe these studies in the context of the larger body of literature on type 2 diabetes (T2D) and glycemic trait genomics. RECENT FINDINGS: We reviewed 23 genetic association studies for GDM and performed a meta-analysis, which revealed variants at eight T2D loci significantly associated with GDM after the Bonferroni correction. These studies suggest that GDM and T2D share a number of genetic risk loci. Only two unbiased genome-wide association studies (GWASs) have successfully revealed genetic associations for GDM and related glycemic traits in pregnancy. A GWAS for GDM in Korean women identified two loci (near CDKAL1 and MTNR1B) known to be associated with T2D, though the association of the MTNR1B locus with GDM appears to be stronger than that for T2D. A multi-ethnic GWAS for glycemic traits in pregnancy identified two novel loci (near HKDC1 and BACE2) which appear to be associated with post-load glucose and fasting c-peptide specifically in pregnant women. There are ongoing efforts to use this genetic information, in the form of polygenic scores, to predict risk of GDM and postpartum T2D. The body of literature examining genetic associations with GDM is limited, especially when compared to the available literature on T2D and glycemic trait genomics. Additional genetic discovery for glucose metabolism in pregnant women will require larger pregnancy cohorts and international collaborative efforts. Studies on the clinical implications of these findings are also warranted.

Augmented insulin secretory response in early pregnancy.

AIMS/HYPOTHESIS: This study aimed to examine changes in the insulin secretory response in early pregnancy, while accounting for changes in insulin sensitivity. METHODS: This is a secondary analysis of a previously conducted longitudinal physiological study. In 34 women, insulin secretory response (by IVGTT) and insulin sensitivity (by euglycaemic clamp) were assessed prior to pregnancy, in early pregnancy (12-14 weeks gestation) and in late pregnancy (34-36 weeks gestation). Using mixed-effects models, we compared insulin secretory response and sensitivity in early pregnancy to the same variables prior to pregnancy and in late pregnancy, with adjustment for age, obesity status and gestational diabetes mellitus (GDM). We examined changes in insulin secretory response after adjustment for insulin sensitivity using both multivariate modelling and the disposition index (DI). We explored the relationship between insulin secretory response and circulating hormones. RESULTS: The insulin secretory response increased from prior to pregnancy to early pregnancy (unadjusted mean [SD] first-phase insulin response 465.1 [268.5] to 720 [358.2], p < 0.0001) and from early pregnancy to late pregnancy (to 924 [494.6], p = 0.01). Insulin sensitivity increased from prior to pregnancy to early pregnancy (insulin sensitivity index 0.10 [0.04] to 0.12 [0.05], p = 0.001) and decreased in late pregnancy (to 0.06 [0.03], p < 0.0001). Accounting for changes in insulin sensitivity, using either multivariate modelling or the DI, did not attenuate the early-pregnancy augmentation of insulin secretory response. Leptin was positively associated with insulin secretory response, independent of insulin sensitivity and adiposity (p = 0.004). Adjustment for leptin attenuated the observed augmentation of insulin secretory response in early pregnancy (adjusted mean change 121.5, p = 0.13). CONCLUSIONS/INTERPRETATION: The insulin secretory response increases markedly in early pregnancy, prior to and independent of changes in insulin sensitivity. Circulating hormones may mediate this metabolic adaptation. Identifying mediators of this physiological effect could have therapeutic implications for treating hyperglycaemia during and outside of pregnancy.

Pregnancy Outcomes after Clinical Recovery from AKI.

The effect of clinically recovered AKI (r-AKI) on future pregnancy outcomes is unknown. We retrospectively studied all women who delivered infants between 1998 and 2007 at Massachusetts General Hospital to assess whether a previous episode of r-AKI associated with subsequent adverse maternal and fetal outcomes, including preeclampsia. AKI was defined as rise in serum creatinine concentration to 1.5-fold above baseline. We compared pregnancy outcomes in women with r-AKI without history of CKD (eGFR>90 ml/min per 1.73 m2 before conception; n=105) with outcomes in women without kidney disease (controls; n=24,640). The r-AKI and control groups had similar prepregnancy serum creatinine measurements (0.70±0.20 versus 0.69±0.10 mg/dl; P=0.36). However, women with r-AKI had increased rates of preeclampsia compared with controls (23% versus 4%; P<0.001). Infants of women with r-AKI were born earlier than infants of controls (37.6±3.6 versus 39.2±2.2 weeks; P<0.001), with increased rates of small for gestational age births (15% versus 8%; P=0.03). After multivariate adjustment, r-AKI associated with increased risk for preeclampsia (adjusted odds ratio [aOR], 5.9; 95% confidence interval [95% CI], 3.6 to 9.7) and adverse fetal outcomes (aOR, 2.4; 95% CI, 1.6 to 3.7). When women with r-AKI and controls were matched 1:2 by age, race, body mass index, diastolic BP, parity, and diabetes status, r-AKI remained associated with preeclampsia (OR, 4.7; 95% CI, 2.1 to 10.1) and adverse fetal outcomes (OR, 2.1; 95% CI, 1.2 to 3.7). Thus, a past episode of AKI, despite return to normal renal function before pregnancy, associated with adverse outcomes in pregnancy.

Gestational Diabetes and Long-Term Cardiometabolic Health.

This JAMA Insights discusses adverse long-term effects of gestational diabetes on the pregnant individual and the exposed fetus.

Early Pregnancy Biochemical Predictors of Gestational Diabetes Mellitus.

PURPOSE OF REVIEW: Universal oral glucose tolerance-based screening is employed to identify pregnant women with gestational diabetes mellitus (GDM), as treatment of this condition decreases the risk of associated complications. A simple and accurate blood test which identifies women at low or high risk for GDM in the first trimester would have the potential to decrease costs and improve outcomes through prevention or treatment. This review summarizes published data on early pregnancy biomarkers which have been tested as predictors of GDM. RECENT FINDINGS: A large number of first-trimester biochemical predictors of GDM have been reported, mostly in small case-control studies. These include glycemic markers (fasting glucose, post-load glucose, hemoglobin A1C), inflammatory markers (C-reactive protein, tumor necrosis factor-alpha), insulin resistance markers (fasting insulin, sex hormone-binding globulin), adipocyte-derived markers (adiponectin, leptin), placenta-derived markers (follistatin-like-3, placental growth factor, placental exosomes), and others (e.g., glycosylated fibronectin, soluble (pro)renin receptor, alanine aminotransferase, ferritin). A few large studies suggest that first-trimester fasting glucose or hemoglobin A1C may be useful for identifying women who would benefit from early GDM treatment. To translate the findings from observational studies of first-trimester biomarkers for GDM to clinical practice, trials or cost-effectiveness analyses of screening and treatment strategies based on these novel biomarkers are needed.

Vitamin D-binding protein and vitamin D status of black Americans and white Americans.

BACKGROUND: Low levels of total 25-hydroxyvitamin D are common among black Americans. Vitamin D-binding protein has not been considered in the assessment of vitamin D deficiency. METHODS: In the Healthy Aging in Neighborhoods of Diversity across the Life Span cohort of blacks and whites (2085 participants), we measured levels of total 25-hydroxyvitamin D, vitamin D-binding protein, and parathyroid hormone as well as bone mineral density (BMD). We genotyped study participants for two common polymorphisms in the vitamin D-binding protein gene (rs7041 and rs4588). We estimated levels of bioavailable 25-hydroxyvitamin D in homozygous participants. RESULTS: Mean (±SE) levels of both total 25-hydroxyvitamin D and vitamin D-binding protein were lower in blacks than in whites (total 25-hydroxyvitamin D, 15.6±0.2 ng per milliliter vs. 25.8±0.4 ng per milliliter, P<0.001; vitamin D-binding protein, 168±3 µg per milliliter vs. 337±5 µg per milliliter, P<0.001). Genetic polymorphisms independently appeared to explain 79.4% and 9.9% of the variation in levels of vitamin D-binding protein and total 25-hydroxyvitamin D, respectively. BMD was higher in blacks than in whites (1.05±0.01 g per square centimeter vs. 0.94±0.01 g per square centimeter, P<0.001). Levels of parathyroid hormone increased with decreasing levels of total or bioavailable 25-hydroxyvitamin D (P<0.001 for both relationships), yet within each quintile of parathyroid hormone concentration, blacks had significantly lower levels of total 25-hydroxyvitamin D than whites. Among homozygous participants, blacks and whites had similar levels of bioavailable 25-hydroxyvitamin D overall (2.9±0.1 ng per milliliter and 3.1±0.1 ng per milliliter, respectively; P=0.71) and within quintiles of parathyroid hormone concentration. CONCLUSIONS: Community-dwelling black Americans, as compared with whites, had low levels of total 25-hydroxyvitamin D and vitamin D-binding protein, resulting in similar concentrations of estimated bioavailable 25-hydroxyvitamin D. Racial differences in the prevalence of common genetic polymorphisms provide a likely explanation for this observation. (Funded by the National Institute on Aging and others.).

24,25-Dihydroxyvitamin d3 and vitamin D status of community-dwelling black and white Americans.

BACKGROUND: 24,25-Dihydroxyvitamin D [24,25(OH)2D] is a metabolite of 25-hydroxyvitamin D (25D). Blacks frequently have low total 25D without manifestations of vitamin D deficiency, suggesting that total serum 25D may incorrectly reflect vitamin D status in different racial groups. The ratio of serum 24,25(OH)2D to 25D [vitamin D metabolite ratio (VMR)] represents a new candidate biomarker for vitamin D status. METHODS: We measured 24,25(OH)2D3 and 25D3 by mass spectrometry in a random community cohort of black (n = 212) and white (n = 164) Americans to evaluate VMR as a marker for vitamin D status. We measured parathyroid hormone concentrations by immunoassay to compare VMR and 25D3 against a physiological indicator of vitamin D deficiency. RESULTS: Serum 24,25(OH)2D3 strongly correlated with 25D3 in both black and white study participants (r = 0.90, P < 0.001 and r = 0.86, P < 0.001 respectively). Blacks had lower mean 25D3 than whites [17.0 (7.8) vs 27.5 (11.3) ng/mL; 42.4 (19.5) vs 68.6 (28.2) nmol/L, P < 0.001] and lower mean 24,25(OH)2D3 [2.1 (1.3) vs 3.6 (2.0) ng/mL; 5.1 (3.1) vs 8.7 (4.8) nmol/L, P < 0.001]. In contrast to total 25D3 concentrations, mean VMR values were similar in blacks and whites [11.9 (4.0) vs 12.5 (3.4), P = 0.16, respectively] and were negatively correlated with parathyroid hormone concentrations in both races (rs = -0.26, P < 0.001, and rs = -0.25, P < 0.001, respectively). CONCLUSIONS: Our results provide further evidence that measurement of total 25D for assessment of vitamin D status in patients of African descent deserves reevaluation and suggest that alternative measures such as VMR should be considered.