Glycemia in early pregnancy and pregnancy outcomes

Detecting and managing mild hyperglycemiain early pregnancy is a research priority. Currently, there is no solid evidence for suitable diagnostic criteria, screening methods, and approaches for treating mild hyperglycemiain early pregnancy. Despite the absence of universally accepted guidelines, women who develop dysglycemia in early pregnancy have been diagnosed and treated as having early gestational diabetes mellitus (GDM)using the standard (24–28-week) criteria, which varies globally. That many women diagnosed with GDM in early pregnancy using the standard criteria do not have hyperglycemia in late gestation calls into question the suitability of this approach. Regardless, in my meta-analysis, women who developed GDM in early pregnancy were found to have a higher risk of perinatal mortality and neonatal hypoglycemia and were more likely to receive insulin therapy than those with late GDM. This urgently necessitates addressing GDM not just in late gestation but from the beginning of pregnancy. This thesis includes a range of research objectives, including investigating the utility of early pregnancy HbA1c for detecting GDM, defining and characterizing metabolic phenotypes of early GDM, comparing pregnancy outcomes among women with different degrees of hyperglycemia during pregnancy, and evaluating the accuracy of blood glucose meters in pregnancy. The analysis of the early pregnancy data of women enrolled in the Vitamin D and lifestyle intervention for GDM prevention (DALI) trial showed that HbA1c measured before 20 weeks of gestation had limited value for identifying GDM and predicting adverse pregnancy outcomes. This thesis refutes the current practice of using HbA1c to identify and treat GDM in early pregnancy. Apart from identifying major gaps in the knowledge of women with early hyperglycemia, this research provides insight into the metabolic heterogeneity of early GDM and highlights the need for a new model of care for women with early dysglycemia. This research provides future direction in GDM care by including insulin resistance screening for high-risk women and emphasizes the importance of using glucose meters that adjust for hematocrit interferences during pregnancy. This thesis has also shown the significance of early GDM and suggests that it should be considered as a separate but related clinical entity to GDM diagnosed later in pregnancy

Differences in newborn screening results among women with gestational diabetes mellitus

Multiple studies undertaken on cord blood demonstrate analyte perturbations in infants exposed to gestational diabetes mellitus (GDM). Cord blood as a sample is influenced by maternal and placental metabolism. Newborn screening (NBS), performed after the first 24 hours of life reflects ea rly neonatal metabolism. We compared NBS analytes between women wi th and wi thout GDM with different management approaches in the Treatment of Booking of Gestational Diabetes (TOBOGM) pilot randomised controlled trial. Pregnant women with GDM risk factors were randomised to early or deferred GDM treatment following an oral glucose tolerance test (<20 weeks gestation). Women without GDM served as “decoys”. From the decoy group 11 developed GDM (screened at 26-28 weeks), were analysed separately; their results were compared with the other groups. De-identified controls were chosen from NBS results from the same analytic run matched for sex, birthweight and gestational age. Results were available for 73/78 women participating in the pilot and 358 de-identified controls. Tyrosine levels (μmol/l; whole blood)were higher in the late GDM group vs early, deferred treatment, and decoy groups (medians:106.28; IQR: 96.73-151.11) (76.33; 64.64-97.90) (75.68; 66.59-110.88)(73.74; 58.32-90.36) (p=0.009) and remained elevated when compared to normal, age-matched controls (106.28; 96.73-151.11) (87.26; 68.55-111.26) (p value=0.01) Immunoreactive trypsinogen (μgm/l; whole blood)was highest in the early treatment group when compared with group-specific controls (22.30; 13.90–29.90 vs 14.00, 10.60–21.10) (p=0.02). These results provide evidence of biochemical perturbations detectable on NBS of in-utero exposure to hyperglycemia and treatment and provide data for hypothesis building

Effectiveness of integrated diabetes care interventions involving diabetes specialists working in primary and community care settings : systematic review and meta-analysis

Introduction: Evidence that integrated diabetes care interventions can substantially improve clinical outcomes is mixed. However, previous systematic reviews have not focussed on clinical effectiveness where the endocrinologist was actively involved in guiding diabetes management. Methods: We searched EMBASE, COCHRANE, MEDLINE, SCOPUS, CINAHL, Google Scholar databases and grey literature published in English language up to 25 January 2021. Reviewed articles included Randomised Controlled Trials (RCTs) and pre-post studies testing the effectiveness on clinical outcomes after ≥6 months intervention in non-pregnant adults (age ≥ 18 years) with type 1 or type 2 diabetes mellitus. Two reviewers independently extracted data and completed a risk of bias assessment. Appropriate meta-analyses for each outcome from RCTs and pre-post studies were performed. Heterogeneity was assessed using the I2 statistic and Cochran’s Q and publication bias assessed using Doi plots. Studies were not pooled to estimate the cost-effectiveness as the cost outcomes were not comparable across trials/studies. Results: We reviewed 4 RCTs and 12 pre-post studies. The integrated care model of diabetes specialists working with primary care health professionals had a positive impact on HbA1c in both RCTs and pre-post studies and on systolic blood pressure, diastolic blood pressure, total cholesterol and weight in pre-post studies. In the RCTs, interventions reduced HbA1c (–0.10% [–0.15 to –0.05]) (–1.1 mmol/mol [–1.6 to –0.5]), versus control. Pre-post studies demonstrated improvements in HbA1c (–0.77% [–1.12 to –0.42]) (–8.4 mmol/mol [–12.2 to –4.6]), systolic blood pressure (–3.30 mmHg [–5.16 to –1.44]), diastolic blood pressure (–3.61 mmHg [–4.82 to –2.39]), total cholesterol (–0.33 mmol/L [–0.52 to –0.14]) and weight (–2.53 kg [–3.86 to –1.19]). In a pre-post study with no control group only 4% patients experienced hypoglycaemia after one year of intervention compared to baseline. Conclusions: Integrated interventions with an active endocrinologist involvement can result in modest improvements in HbA1c, blood pressure and weight management. Although the improvements per clinical outcome are modest, there is possible net improvements at a holistic level

Placental abnormalities in type 1 and type 2 diabetes mellitus : a systematic review and metaanalysis of shear wave elastography

OBJECTIVE: This study aimed to describe the placental changes occurring in women with preexisting diabetes mellitus and to determine if elastography can detect placental changes in vivo. DATA SOURCES: PubMed, Embase, Medline, and Cochrane were searched to identify English language studies published until July 2020. STUDY ELIGIBILITY CRITERIA: 1) For key question 1, studies that described histopathologic changes in placentas from women with known diabetes mellitus and 2) for key question 2, those that described structural–placental changes detectable by elastography in high-risk pregnancies (eg, those complicated by preeclampsia and/or fetal growth restriction), were included. METHODS: For key question 1, we grouped placental pathologies using the Amsterdam International Consensus Group definitions. For key question 2, we conducted a metaanalysis including all data from studies reporting placental stiffness in meters per second (m/s) or kilopascals (kPa). The mean difference (95% confidence interval) was calculated using a random effects model. RESULTS: Data were extracted from 14 studies of placental histopathology in women with known diabetes. In this group, a wide variety of placental histopathologic changes are described, though none are considered pathognomonic. The histopathologic changes including maternal vascular malperfusion, fetal vascular malperfusion, and/or infectious/inflammatory/other changes were divided into 3 broad categories on the basis of presumed etiology. A total of 15 studies reported the placental stiffness scores in women with a high-risk pregnancy vs those with a normal pregnancy. Only 1 reported stiffness scores for placentas in women with preexisting diabetes mellitus (N<10 women). Pooled analysis of 14 studies with available data included 478 “high-risk pregnancies” and 828 control or healthy pregnancies. Maternal-derived pathologies resulted in higher placental stiffness (mean difference 4.5 kPa [95% confidence interval, 3.16–5.87]) compared with control or healthy pregnancies. Fetal-derived pathologies also resulted in higher placental stiffness (mean difference of 6.5 kPa [95% confidence interval, 1.08–11.86]) compared with control or healthy pregnancies. CONCLUSION: Shear wave elastography may provide an in vivo approximation of placental histopathology in women with certain kinds of high-risk pregnancies. A high-risk pregnancy may involve maternal- and fetal-derived pathologies. Further studies, particularly in women with preexisting diabetes, are needed to confirm this observation

Performance of early pregnancy HbA1c for predicting gestational diabetes mellitus and adverse pregnancy outcomes in obese European women

Aims: To investigate the performance of early pregnancy HbA1c for predicting gestational diabetes mellitus (GDM) and adverse pregnancy outcomes in obese women. Methods: Post hoc analysis using data from the Vitamin D And Lifestyle Intervention for GDM prevention trials conducted across 9 European countries (2012–2014). Pregnant women (BMI ≥ 29 kg/m2) underwent a baseline HbA1c and oral glucose tolerance tests at \u3c 20 weeks, 24–28 weeks, and 35–37 weeks. Women with GDM were referred for treatment. Results: Among the 869 women tested, the prevalence of GDM was 25.9% before 20 weeks, with a further 8.6% at 24–28 weeks. The areas under the curves for HbA1c at the two time points were 0.55 (0.50–0.59) and 0.54 (0.47–0.61), respectively. An early HbA1c ≥ 5.7% (39 mmol/mol) (N = 111) showed low sensitivity (18.2%) with 89.1% specificity for GDM before 20 weeks, at 24–28 weeks (sensitivity of 8.0% and specificity of 88.6% after excluding early GDM), and throughout gestation (sensitivity of 15.9% and specificity of 89.4%). The ≥ 5.7% (39 mmol/mol) threshold was significantly associated with concurrent GDM before 20 weeks (adjusted OR (aOR) 2.77(1.39–5.51)) and throughout gestation (aOR 1.72 (1.02–2.89)), but not adverse pregnancy outcomes. Conclusions: Early pregnancy HbA1c is of limited use for predicting either GDM or adverse outcomes in overweight/obese European women

Corrigendum to “Performance of early pregnancy HbA1c for predicting gestational diabetes mellitus and adverse pregnancy outcomes in obese European women” [Diab. Res. Clin. Pract. 168 (2020) 108378](S0168822720306318)(10.1016/j.diabres.2020.108378)

The authors regret that a few lines in Tables 1 and 2 were formatted incorrectly in the published version of the article with numbers all appearing in one line instead of being in separate lines. The correctly formatted tables are shown below. The authors would like to apologise for any inconvenience caused

The ADIPS pilot national diabetes in pregnancy benchmarking programme

Background: To test the feasibility of benchmarking the care of women with pregnancies complicated by hyperglycaemia. Methods: A retrospective audit of volunteer diabetes services in Australia and New Zealand involving singleton pregnancies resulting in live births between 2014 and 2020. Ranges are shown and compared across services. Results: The audit included 10,144 pregnancies (gestational diabetes mellitus (GDM) = 8696; type 1 diabetes (T1D) = 435; type 2 diabetes (T2D) = 1013) from 11 diabetes services. Among women with GDM, diet alone was used in 39.4% (ranging among centres from 28.8-57.3%), metformin alone in 18.8% (0.4-43.7%), and metformin and insulin in 10.1% (1.5-23.4%); when compared between sites, all p 6.5% (48 mmol/mol)), 78.4% and 54.6%, respectively (p < 0.001). Conclusion: Management of maternal hyperglycaemia and pregnancy outcomes varied significantly. The maintenance and extension of this benchmarking service provides opportunities to identify policy and clinical approaches to improve pregnancy outcomes among women with hyperglycaemia in pregnancy

Screening and treatment for early-onset gestational diabetes mellitus : a systematic review and meta-analysis

Purpose of Review: We conducted a systematic review to evaluate the current evidence for screening and treatment for early-onset gestational diabetes mellitus (GDM) Recent Findings: Many of the women with early GDM in the first trimester do not have evidence of hyperglycemia at 24–28 weeks’ gestation. Summary: A high proportion (15–70%) of women with GDM can be detected early in pregnancy depending on the setting, criteria used and screening strategy. However, there remains no good evidence for any of the diagnostic criteria for early-onset GDM. In a meta-analysis of 13 cohort studies, perinatal mortality (relative risk (RR) 3.58 [1.91, 6.71]), neonatal hypoglycemia (RR 1.61 [1.02, 2.55]), and insulin use (RR 1.71 [1.45, 2.03]) were greater among early-onset GDM women compared to late-onset GDM women, despite treatment. Considering the high likelihood of benefit from treatment, there is an urgent need for randomized controlled trials that investigate any benefits and possible harms of treatment of early-onset GDM

A perspective on the accuracy of blood glucose meters during pregnancy

Blood glucose monitoring is fundamental for hyperglycemia management during pregnancy, but are the devices up to the job? Studies assessing the accuracy of 10 commercially available glucose meters during pregnancy showed that although >98–99% of the meter values were in the acceptable zones of the error grid for the majority of the meters, the meter performance varied, with the majority showing positive bias and a few showing minimal negative bias. The mean difference between meter and laboratory plasma values varied between −0.33 and 0.73 mmol/L. Three meters showed deviations from laboratory results with a change in maternal hematocrit levels. No meters had a total analytical error 24 h), and a lower incidence of neonatal hypoglycemia. The flash glucose monitoring system shows good accuracy in pregnant women but has not been marketed widely in the U.S. We suggest that meters cannot be assumed to be sufficiently accurate during pregnancy and that manufacturers should ensure a total error <5%, with bias and imprecision <2% during pregnancy. Large studies are needed to evaluate the usefulness of CGMS among pregnant women with type 2 diabetes and gestational diabetes mellitus

Pregnancy outcomes among multi-ethnic women with different degrees of hyperglycaemia during pregnancy in an urban New Zealand population and their association with postnatal HbA1c uptake

Background: Adverse pregnancy outcomes are more common in women with hyperglycaemia. Many women have suboptimal uptake of HbA1c testing postdelivery. Aims: To compare pregnancy outcomes among multi-ethnic women with different degrees of hyperglycaemia during pregnancy, and their association with postnatal HbA1c uptake after the introduction of email reminders. Materials and Methods: A retrospective and prospective single-centre study was conducted in South Auckland in 2639 women with early gestational diabetes mellitus (GDM) (diagnosed < 20 weeks), late GDM (diagnosed ≥ 20 weeks), overt diabetes in pregnancy, or known type 2 diabetes (T2DM) during pregnancy. Automated email reminders were sent to general practitioners to increase postnatal HbA1c screening. Results: HbA1c during pregnancy increased across the late GDM (n = 1425), early GDM (n = 148), overt diabetes (n = 573) and T2DM (n = 493) groups (P < 0.001). Stillbirth was least common in the late GDM group (0, 0.7, 0.5, and 1.9%, respectively, P < 0.001), as were caesarean delivery (32.7, 45.1, 39.4, and 53.5%, respectively P < 0.001), large for gestational age (LGA) (14.7, 18.2, 22.3, and 30.5%, respectively, P < 0.001), small for gestational age (8.8, 16.7, 11.0, and 11.1%, respectively, P = 0.02), and preeclampsia/eclampsia (7.7, 9.2, 13.0, and 14.8%, respectively, P < 0.001). LGA and preeclampsia/eclampsia were more common among Pacific and Māori women than European women (LGA, 30.1, 22.7, 10.3%, respectively, P < 0.001; preeclampsia/eclampsia, 13.5, 14.0, and 8.1%, respectively, P < 0.001). Postpartum HbA1c screening increased among women with GDM/overt diabetes after the introduction of the reminder emails (39.6% vs 34.0%, P = 0.03). Conclusions: Women with late GDM are least likely to experience adverse outcomes. Email reminders to improve postpartum HbA1c screening warrant further investigation