Abstract
Introduction
F
Continuous glucose monitoring (CGM) measures fetal exposure to maternal glucose in daily life and is likely to provide a better estimate of fetal exposure to maternal glucose than the current oral glucose tolerance test (OGTT). A pilot study examining the potential of CGM to diagnosis GDM found that CGM was a more acceptable alternative for pregnant women than the current OGTT screening (3). Larger studies in different populations are required to further explore CGM metrics in the diagnosis of GDM and their relationship to obstetric and neonatal complications. A pilot study of intermittently scanned CGM in pregnant women with type 2 diabetes (T2D) found that it was acceptable, but they highlighted important systemic barriers that need to be addressed in the care of people with T2D who are pregnant (4). While CGM is becoming increasingly used in pregnancies with T2D and GDM, data demonstrating the ideal time in range in these pregnancies are limited. A retrospective cohort study of individuals with GDM or T2D found that in those with time in range of 70–140 mg/dL (3.9–7.8 mmol/L) ≤ 70% had more frequent maternal and neonatal complications (5). More data are needed to understand the pregnancy glucose targets in GDM and T2D.
The type 1 diabetes (T1D) studies included this year explore the use of technology and therapeutics in pregnancy. Although CGM is generally recommended in T1D in pregnancy, a cohort study of women aged 15 to 45 years demonstrated a number of adverse social determinants of health were associated with lower odds of using CGM (6). Much more work needs to be done to ensure equitable access and use of CGM in people living with diabetes. The results were published of the insulin degludec versus insulin detemir trial (EXPECT), both in combination with insulin aspart, in the treatment of pregnant women with T1D (7). This noninferiority trial demonstrated that insulin degludec is likely a suitable alternative to detemir, but degludec use was associated with potential trends for increased preeclampsia, preterm births, caesarean delivery, and large-for-gestational-age neonates.
We continue to deepen our understanding of glucose physiology in pregnancy. A cohort of women with early, classic, and no GDM demonstrated that there is an increase in the insulin secretory response that is independent of insulin and describes a novel pregnancy insulin physiology (PIP) index that predicts GDM independent of clinical risk factors (8). Lastly, using CGM in early, middle, and late pregnancy and the postpartum period, a study including women with a previous Roux-en-Y gastric bypass and matched controls found that those with gastric bypass had different CGM profiles when compared with the matched controls (9). Future research is needed to examine whether these CGM measures are associated with pregnancy and neonatal outcomes.
Key Articles Reviewed
Crowther CA, Samuel D, McCowan LME, Edlin R, Tran T, McKinlay CJ, for the GEMS Trial Group
Simmons D, Immanuel J, Hague WM, Teede H, Nolan CJ, Peek MJ, Flack JR, McLean M, Wong V, Hibbert E, Kautzky-Willer A, Harreiter J, Backman H, Gianatti E, Sweeting A, Mohan V, Enticott J, Cheung NW; TOBOGM Research Group
Di Filippo D, Henry A, Bell C, Haynes S, Chang MHY, Darling J, Welsh A
McLean A, Sinha A, Barr E, Maple-Brown LJ
Bitar G, Cornthwaite JA, Sadek S, Ghorayeb T, Daye N, Nazeer S, Ghafir D, Cornthwaite J, Chauhan SP, Sibai BM, Fishel Bartal M
Venkatesh KK, Powe CE, Buschur E, Wu J, Landon MB, Gabbe S, Gandhi K, Grobman WA, Fareed N
Mathiesen ER, Alibegovic AC, Corcoy R, Dunne F, Feig DS, Hod M, Jia T, Kalyanam B, Kar S, Kautzky-Willer A, Marchesini C, Rea RD, Damm P, on behalf of the EXPECT Study Group
Thaweethai T, Soetan Z, James K, Florez JC, Powe CE
Stentebjerg LL, Madsen LR, Støving RK, Andersen LLT, Vinter CA, Juhl CB, Jensen DM
Lower versus Higher Glycemic Criteria for Diagnosis of Gestational Diabetes
Crowther CA1, Samuel D1, McCowan LME2, Edlin R3, Tran T4, McKinlay CJ1; for the GEMS Trial Group
1The Liggins Institute, University of Auckland, Auckland, New Zealand; Garvan Institute of Medical Research, Sydney, Australia; 2Department of Obstetrics and Gynaecology, University of Auckland, Auckland, New Zealand; Garvan Institute of Medical Research, Sydney, Australia; 3School of Population Health, University of Auckland, Auckland, New Zealand; Garvan Institute of Medical Research, Sydney, Australia; 4Osteoporosis and Bone Biology, Garvan Institute of Medical Research, Sydney, Australia
Controversy surrounding the diagnosis of gestational diabetes mellitus (GDM) has prevailed since the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study team evaluated 23,316 pregnant women from 2000 to 2006 and demonstrated continuous associations between maternal glucose and fetal hyperinsulinism (cord C-peptide) and neonatal birthweight, but no clear diagnostic threshold. The Gestational Diabetes Mellitus Trial of Diagnostic Detection Thresholds (GEMS) study group examined higher versus lower GDM cutoffs.
Methods
Participants were randomized to a higher or lower glycemic criteria after oral glucose tolerance test results at 24–32 weeks' gestation. Higher was defined as fasting plasma glucose (FPG) of ≥ 99 mg/dL (≥ 5.5 mmol/L) or 2-hour measure of ≥ 162 mg/dL (≥ 9.0 mmol/L). Lower was FPG of ≥ 92 mg/dL (≥ 5.1 mmol/L), 1-hour measure of ≥ 180 mg/dL (≥ 10.0 mmol/L), or a 2-hour measure of ≥ 153 mg/dL (≥ 8.5 mmol/L). The primary outcome was a large-for-gestational-age (LGA) birthweight. Secondary outcomes were obstetric and neonatal health measures.
Results
From 4061 randomized participants, 124 of 2039 (6.1%) had a diagnosis of GDM based on the higher criteria, and 310 of 2022 (15.3%) based on the lower criteria. Birthweights at 39 + 3 weeks' gestation (3402 vs 3389 g) and LGA rates (8.9% vs 8.8%) were similar using the higher versus lower criteria. Medical interventions (induced labor, health-care contacts, glucose-lowering therapy, and neonatal hypoglycemia) were more common using the lower criteria with no between-group differences in serious adverse pregnancy outcomes. Approximately 34% versus 30% of women had induced labor, and 35% versus 38% had caesarean deliveries.
Conclusions
The Gestational Diabetes Mellitus Trial of Diagnostic Detection Thresholds (GEMS) study did not find lower rates of LGA associated with use of lower glycemic criteria for GDM.
Comments
The pregnancy outcomes of women with a GDM diagnosis by either criterion were good, with overall low rates of preterm birth (5%), neonatal hypoglycemia (∼10%), neonatal care unit admission (5%), or serious adverse composite outcomes such as shoulder dystocia, birth injury, or perinatal death (2.5%). Women with GDM have good pregnancy outcomes, but more attention is needed on reducing T2D for both mother and child.
Treatment of Gestational Diabetes Mellitus Diagnosed Early in Pregnancy
Simmons D1, Immanuel J1, Hague WM2, Teede H3, Nolan CJ4, Peek MJ5, Flack JR6, McLean M7, Wong V8, Hibbert E9, Kautzky-Willer A10, Harreiter J10, Backman H11, Gianatti E12, Sweeting A13, Mohan V14, Enticott J3, Cheung NW15; TOBOGM Research Group
1Western Sydney University, Campbelltown, NSW, Australia; Sydney, Australia; 2Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia; Sydney, Australia; 3Monash University, Melbourne, VIC, Australia; Sydney, Australia; 4Canberra Hospital and Australian National University, Canberra, ACT, Australia; Sydney, Australia; 5Australian National University, Canberra, ACT, Australia; Sydney, Australia; 6Bankstown-Lidcombe Hospital, Bankstown NSW, Australia; Sydney, Australia; 7Blacktown Hospital, Blacktown NSW, Australia; Sydney, Australia; 8Liverpool Hospital and University of New South Wales, Liverpool NSW, Australia; Sydney, Australia; 9Nepean Clinical School, University of Sydney and Nepean Hospital, Sydney, Australia; Sydney, Australia; 10Gender Medicine Unit, Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Sydney, Australia; 11Department of Obstetrics and Gynecology, Faculty of Medicine and Health, Örebro University, Orebro, Sweden; Sydney, Australia; 12Department of Endocrinology, Fiona Stanley Hospital, Murdoch, WA, Australia; Sydney, Australia; 13Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, Australia; Sydney, Australia; 14Dr. Mohan's Diabetes Specialities Centre and Madras Diabetes Research Foundation, Chennai, India; Sydney, Australia; 15Westmead Hospital, Sydney, Australia
There are limited data on the risks and benefits of treating gestational diabetes mellitus (GDM) when diagnosed early in pregnancy.
Methods
This randomized controlled trial recruited women between 4 and 19 + 6 weeks' gestation with at least one risk factor for GDM. Participants completed a 75 g oral glucose tolerance test (OGTT) before 20 weeks' gestation, and GDM was diagnosed using the World Health Organization diagnostic criteria. Those who received a diagnosis of GDM were randomized to receive immediate treatment (intervention) or no immediate treatment (control). Participants assigned to the no immediate treatment group were rescreened with a 75 g OGTT at 24–28 weeks and treated if a diagnosis of GDM was made. The three prespecified outcomes included a composite of adverse neonatal outcomes, pregnancy-related hypertension, and neonatal lean body mass. A gatekeeping approach was used to examine the primary outcomes. The analyses were performed using a prespecified plan and an intention-to-treat analysis.
Results
A total of 802 women received a diagnosis of GDM in early pregnancy and were randomized to the early treatment group (n = 404) or control group (n = 396). The participants who were randomized to the immediate treatment group were less likely to have an adverse neonatal outcome event compared with the control group (24.9% vs 30.5%; P = 0.02) with an adjusted relative risk of 0.82 (95% CI, 0.68–0.98). This difference was mostly driven by neonatal respiratory distress, which occurred in 9.8% versus 17.0% in the invention and control arms, respectively. There was no difference in pregnancy-related hypertension between the treatment and control groups (10.6% and 9.9%, respectively), so the third primary outcome, neonatal lean body mass, was changed to a secondary outcome. Severe perineal injury was lower in the treatment group compared with the control group (0.8% vs 3.6%, respectively [95% CI, −4.1 to −1.5]). There were no significant differences in secondary neonatal outcomes.
Conclusions
Participants randomized to early treatment of GDM had fewer adverse neonatal outcomes compared with those who had deferred or no treatment of GDM.
Comments
This randomized controlled trial addresses an important clinical question in GDM management: should we screen and treat people for GDM early in pregnancy? This high-quality trial enrolled 802 women after screening a massive 43,721 women for possible inclusion, with 4537 providing consent and 3681 undergoing early GDM screening. It demonstrated some benefits in the composite of adverse neonatal outcomes, which was primarily driven by a difference in neonatal respiratory distress. International guidelines will need to balance the negative results of the Early Gestational Diabetes Screening in the Gravid Obese Women (EGGO) and the modest benefits seen in the Treatment of Booking Gestational Diabetes Mellitus (TOBOGM) study with the resource utilization required to screen and treat early GDM when they re-evaluate the recommendations on early screening for and treatment of GDM in women with risk factors. Importantly, TOBOGM excluded people with higher degrees of hyperglycemia (fasting > 6.1 mmol/L or 2-hour ≥ 11.1 mmol/L) because they were already considered to warrant treatment, so these results should not be applied to this likely higher risk group.
A New Continuous Glucose Monitor for the Diagnosis of Gestational Diabetes Mellitus: A Pilot Study
Di Filippo D1, Henry A1,2, Bell C1, Haynes S1, Chang MHY1, Darling J3, Welsh A1,4
1Discipline of Women's Health, School of Clinical Medicine, University of New South Wales Sydney, Randwick, NSW, Australia; Royal Hospital for Women, Randwick, NSW, Australia; 2Department of Women's and Children's Health, St George Hospital, Kogarah, NSW, Australia; Royal Hospital for Women, Randwick, NSW, Australia; 3Diabetes Clinic Royal Hospital for Women, Randwick, NSW Australia; Royal Hospital for Women, Randwick, NSW, Australia; 4Department of Maternal-Fetal Medicine, Royal Hospital for Women, Randwick, NSW, Australia
The validity of the oral glucose tolerance test (OGTT) for gestational diabetes mellitus (GDM) diagnosis has long been questioned, and the OGTT is no longer commonly used outside of pregnancy. This study assessed the acceptability of continuous glucose monitoring (CGM) as a diagnostic test to replace the OGTT for pregnant women undergoing screening for GDM.
Methods
The participants wore a masked CGM device (FreeStyle Libre Pro 2) for 7 days while undergoing the OGTT at 24–28 weeks' gestation. CGM metrics and acceptability were examined in comparison with the OGTT results, a GDM risk factor score (total risk score), and a subgroup who provided antenatal ultrasound data (modified ultrasound GDM score).
Results
Participation rates were high (81%) and included 74 women (85%) with normal glucose tolerance and 13 (15%) with GDM. Pregnant women found CGM far more acceptable than the OGTT (81% vs 27% rating 5/5 for CGM, P < 0.001). Fifty-five participants with normal glucose tolerance had simultaneous CGM data, showing 28 true negatives (no GDM on OGTT or CGM), and most of those (four of five) had normal ultrasound features. Five participants had false-negative results (no GDM on OGTT but CGM glucose values that were consistent with GDM), and six were false positive (positive OGTT but normal CGM glucose values and low GDM total risk score).
Conclusions
For GDM diagnosis, CGM is a more acceptable alternative for pregnant women than the current OGTT screening test, which resulted in both false-positive and false-negative results.
Comments
CGM can measure fetal exposure to maternal glucose in daily life, and it is likely to provide a better estimate of fetal exposure to maternal glucose than the current OGTT screening test. Larger studies in representative patient samples are needed to better understand the relationship between CGM and OGTT metrics, and to relate CGM glucose profiles to obstetric and neonatal complications.
Feasibility and Acceptability of Intermittently Scanned Continuous Glucose Monitoring for Women with Type 2 Diabetes in Pregnancy
McLean A1,2, Sinha A2, Barr E1, Maple-Brown LJ1,3
1Wellbeing and Preventable Chronic Diseases Division, Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia; Royal Darwin Hospital, Darwin, NT, Australia; 2Endocrinology Department, Cairns Hospital, North Cairns, QLD, Australia; Royal Darwin Hospital, Darwin, NT, Australia; 3Endocrinology Department, Royal Darwin Hospital, Darwin, NT, Australia
Intermittently scanned continuous glucose monitoring (isCGM) has not been widely studied in women with type 2 diabetes (T2D) and pregnancy, who have high rates of obstetric and neonatal morbidity and mortality. This study assessed the feasibility and acceptability of isCGM in pregnancy for women with T2D.
Methods
In a single-arm prospective pilot study between 2019 and 2021, pregnant women before 30 weeks' gestation were given the option to use isCGM (flash monitoring) for the remaining duration of their T2D pregnancy. Participants' characteristics, enrollment, and retention rates, sensor usage, and satisfaction were evaluated.
Results
Fifty-seven participants were enrolled (75% Aboriginal and Torres Strait Islander, and 30% from remote areas), of whom 88% completed the satisfaction questionnaire, 79% used isCGM for ≥ 2 weeks, and 21% discontinued. Mean sensor use was 12 weeks (range: 0–32), and mean sensor activity time was 60% (range: 12%–98%); the proportion of participants with sensor activity of > 75% was 27%. Only 40% commenced isCGM use at < 14 weeks' gestation. The self-reported frequency of capillary blood glucose testing four times per day increased from 36% to 68% (P = 0.001) compared with before isCGM use. Diabetes educators (nurses/dietitians) gave the most useful user support and training (compared with physicians). The majority of participants reported isCGM was worthwhile, and 94% would recommend isCGM use to others.
Conclusions
The use of isCGM was acceptable for pregnant women with T2D, but late referrals, discontinuation, and variable use meant that very few participants used isCGM throughout their pregnancy. Ensuring culturally appropriate education and T2D pregnancy care pathways are needed to support optimal use.
Comments
This study suggests that CGM could be a useful and well-received tool for improving maternal glucose levels during T2D pregnancy. However, it identifies important barriers among women from minority ethnic groups, including the need for culturally appropriate education and care. It is interesting that the women found their consultations with diabetes educators (nurses/dietitians) more supportive than those with physicians.
Continuous Glucose Monitoring and Time in Range: Association with Adverse Outcomes among People with Type 2 or Gestational Diabetes Mellitus
Bitar G1, Cornthwaite JA1, Sadek S1, Ghorayeb T1, Daye N1, Nazeer S1, Ghafir D1, Cornthwaite J2, Chauhan SP1, Sibai BM1, Fishel Bartal M1,3
1Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, and Reproductive Sciences, McGovern Medical School, The University of Texas Health Science Center, Houston, TX; Sheba Medical Center at Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; 2Department of Earth, Environmental and Planetary Science, Rice University, Houston, TX; Sheba Medical Center at Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; 3Department of Obstetrics and Gynecology, Sheba Medical Center at Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Continuous glucose monitoring (CGM) is increasingly used in pregnancies complicated by gestational diabetes mellitus (GDM) and type 2 diabetes (T2D), but the recommended CGM time-in-range (TIR) targets and their associations with obstetric and neonatal outcomes are unclear in this population.
Methods
This retrospective cohort study of CGM use with GDM and T2D pregnancies compared maternal and neonatal outcomes in the patients with TIR of > 70% and ≤ 70%: 70–140 mg/dL (3.9–7.8 mmol/L). The neonatal composite outcome included large-for-gestational-age neonates, neonatal intensive care unit admission, hypoglycemia with intravenous glucose, neonatal respiratory support, or neonatal death.
Results
A total of 65 of 114 pregnant women (46%) were included. In this cohort, 37 women (57%) had a TIR of ≤ 70%, and 28 (43%) had a TIR of > 70%. The neonatal composite outcome occurred more frequently in those with a TIR of ≤ 70% (71.4% vs 37.8%; adjusted odds ratio, 4.8 [95% CI, 1.6–15.7]). Those with a TIR ≤ 70% were more likely to have hypertensive disorders of pregnancy (43% vs 16%), preterm births (54% vs 27%), and caesarean delivery (96% vs 51%).
Conclusions
In pregnancies complicated by T2D and GDM, women with TIR ≤ 70% had more frequent maternal and neonatal complications.
Comments
Aiming for at least 70% time in range of 70–140 mg/dL seems sensible for those with GDM and T2D, although a time in range of 80%–90% may be optimal. Tighter time-in-range targets, such as 63–120 mg/dL, may be more applicable for GDM. However, more data are needed to understand the pregnancy glucose targets in GDM and T2D pregnancy.
Disparities in Continuous Glucose Monitoring Use among Women of Reproductive Age with Type 1 Diabetes in the T1D Exchange
Venkatesh KK1, Powe CE2, Buschur E3, Wu J1, Landon MB1, Gabbe S1, Gandhi K4, Grobman WA1, Fareed N5
1Department of Obstetrics and Gynecology, The Ohio State University, Columbus, OH; The Ohio State University, Columbus, OH; 2Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA; The Ohio State University, Columbus, OH; 3Department of Medicine, The Ohio State University, Columbus, OH; The Ohio State University, Columbus, OH; 4Department of Pediatrics, The Ohio State University, Columbus, OH; The Ohio State University, Columbus, OH; 5Department of Biomedical Informatics, The Ohio State University, Columbus, OH
When used during pregnancy, continuous glucose monitoring (CGM) has been shown to improve outcomes for women with type 1 diabetes (T1D) and their babies, but little is known about whether these disparities exist in women of reproductive age.
Methods
This was a secondary analysis of the T1D Exchange Registry, which is a prospective cohort of people with T1D that includes over 80 clinics in the United States. Girls and women aged 14–45 years in the T1D Exchange from 2015–2018 were included. Logistic regression was used to examine the association of CGM use and a number of sociodemographic and clinical characteristics.
Results
A total of 6478 women and girls aged 15–45 were included in this analysis, of whom 1702 (26.3%) were using CGM. They had a median age of 20.0 years, median duration of diabetes of 11.5 years, and 67.3% were using insulin pump therapy. Of this cohort, 19.6% had Medicaid, and 5.9% and 9.3% self-identified as non-Hispanic Black and Hispanic, respectively. CGM use was associated with achieving target glycemia (adjusted odds ratio [aOR], 1.95 [95% CI, 1.57–2.44]). Several social determinants of health were associated with CGM use; specifically, self-identifying as non-Hispanic Black or Hispanic was associated with lower odds of using CGM (aOR 0.40 [95% CI, 0.28–0.56] and aOR 0.73 [95% CI, 0.57–0.92], respectively) compared with people who self-identified as non-Hispanic White. Lower income, lower levels of education, and enrollment in Medicaid were also associated with lower odds of CGM use.
Conclusions
In this cohort of women aged 15–45 years, CGM use was associated with achieving target hemoglobin A1c levels. Concerningly, a number of adverse social determinants of health were associated with lower odds of using CGM.
Comments
Although a number of international guidelines now recommend CGM for people with T1D both during and outside of pregnancy, there is a growing body of evidence demonstrating that people who are experiencing higher levels of social deprivation are less likely to use diabetes technologies. The findings in this study are consistent with those in the larger T1D population and suggest that, despite the benefits of CGM, people with adverse social determinants of health are less likely to be using these devices (10,11). Given that the period covered by this cohort included a number of years before the publication of landmark studies and trials demonstrating the benefits of CGM use in pregnancy and would be based on older CGM technology, additional research is needed to examine whether these trends persist.
Insulin Degludec versus Insulin Detemir, Both in Combination with Insulin Aspart, in the Treatment of Pregnant Women with Type 1 Diabetes (EXPECT): An Open Label, Multinational, Randomised, Controlled, Non-inferiority Trial
Mathiesen ER1,2, Alibegovic AC3, Corcoy R4,5,6, Dunne F7, Feig DS8, Hod M9, Jia T3, Kalyanam B10, Kar S10, Kautzky-Willer A11, Marchesini C3, Rea RD12, Damm P1,2, on behalf of the EXPECT Study Group
1Center for Pregnant Women with Diabetes, Departments of Endocrinology and Obstetrics, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Oxford, UK; 2Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; Oxford, UK; 3Novo Nordisk A/S, Søborg, Denmark; Oxford, UK; 4Servei d'Endocrinologia i Nutrició, Hospital de la Santa Creu i Sant Pau-Dos de Maig, Barcelona, Spain; Oxford, UK; 5CIBER-Bioengineering Biomaterials and Nanomedicine, (CIBER-BBN, ISCIII), Madrid, Spain; Oxford, UK; 6Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain; Oxford, UK; 7Clinical Research Facility (CRF), College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland; Oxford, UK; 8Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto and the Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada; Oxford, UK; 9Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Oxford, UK; 10Novo Nordisk Service Centre India Private Ltd, Bangalore, India; Oxford, UK; 11Division of Endocrinology & Metabolism, Medical University of Vienna, Vienna, Austria; Oxford, UK; 12Oxford Centre for Diabetes Endocrinology and Metabolism and NIHR Oxford Biomedical Research Centre, Oxford, UK
The EXPECT study group compared the safety and efficacy of two long-acting basal insulin analogues: first-generation insulin detemir and second-generation insulin degludec. Degludec has a longer half-life (∼24 vs 12 hours) and longer duration of action (42 vs 24 hours) than detemir, which means that degludec is taken once daily whereas detemir is usually taken twice daily.
Methods
In this open-label, multicenter, randomized controlled trial at 56 sites from across 14 countries, women with type 1 diabetes (T1D) and glycated hemoglobin (HbA1c) levels of ≤ 8.0% (≤ 64 mmol/mol) were randomized to receive degludec or detemir, both in combination with insulin aspart. Randomization was stratified according to pregnancy status (pregnant or planning pregnancy) and CGM use. The primary outcome measure was the last HbA1c measure before delivery, based on a noninferiority margin of 0.4% for degludec versus detemir. The secondary outcomes included glycemic attainment (HbA1c ≤ 6.5 and 6.0% (≤ 48 and 42 mmol/mol) as well as fasting and postprandial glucose measures.
Results
The study randomized 225 participants, including 188 pregnant women, to degludec (n = 111 with 92 pregnant) or detemir (n = 114, with 96 pregnant). At trial entry, baseline HbA1c was 6.6% (∼ 49 mmol/mol) and 6.5% (∼ 48 mmol/mol) in the degludec and detemir groups, respectively, and 46 (20%) used CGM. The last HbA1c measure before delivery was 6.2% (45 mmol/mol) and 6.3% (46 mmol/mol) in the degludec and detemir groups, respectively, confirming the noninferiority of degludec. There were no between-group differences in the proportions of degludec versus detemir users achieving the target HbA1c before delivery; and no between-group differences in fasting or in postmeal glucose measures.
Conclusions
Degludec is probably a suitable alternative to detemir for use during T1D pregnancy.
Comments
Despite entering pregnancy with near-target HbA1c, the EXPECT participants struggled to achieve the pregnancy glucose targets, especially midpregnancy (∼16–24 weeks' gestation). Degludec use was associated with potential trends for increased preeclampsia, preterm births, caesarean delivery, and large-for-gestational-age infants. Neonatal birthweights were 3691 g and 3490 g, with large-for-gestational-age rates of 64% and 51% for degludec and detemir, respectively. These disappointing results may be attributed to switching insulin regimens during early pregnancy, or they may suggest that frequent precise adjustments to basal insulin delivery using hybrid closed-loop devices are needed.
Distinct Insulin Physiology Trajectories in Euglycemic Pregnancy and Gestational Diabetes Mellitus
Thaweethai T1,2, Soetan Z1, James K2,3, Florez JC2,4,5,6, Powe CE2,3,4,6
1Biostatistics, Massachusetts General Hospital, Boston, MA; Boston, MA; 2Harvard Medical School, Boston, MA; Boston, MA; 3Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA; Boston, MA; 4Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, MA; Boston, MA; 5Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA; Boston, MA; 6Broad Institute of MIT and Harvard, Boston, MA
Gestational diabetes is thought to occur when maternal β-cells cannot meet the increased insulin demands in pregnancy. This study evaluated insulin physiology in both euglycemic and gestational diabetes mellitus (GDM) pregnancies.
Methods
This prospective cohort study enrolled pregnant participants with at least one risk factor for GDM before 15 weeks' gestation. Study visits in early pregnancy, at 24–32 weeks' gestation and at 6–24 weeks postpartum included questionnaires, height and weight measurements, and glucose and insulin testing with a 75 g oral glucose tolerance test (OGTT). The participants were stratified using the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria to define GDM for an early GDM group, classic GDM group, or no GDM group. Insulin secretory response and sensitivity indexes were measured using the Strumvoll first-phase estimate and Matsuda index, respectively. Longitudinal changes in insulin secretory response and sensitivity were assessed using linear regression. To quantify β-cell compensation for insulin resistance, the pregnancy insulin physiology (PIP) index was derived.
Results
Of the 166 women included, 21 and 24 had a diagnosis of early and classic GDM, respectively. In the entire cohort, longitudinal models adjusted for participant characteristics and multiple imputation demonstrated the insulin secretory response was increased in early pregnancy and in mid-to-late pregnancy compared with the postpartum period. Insulin sensitivity was slightly lower in early pregnancy and in mid-to-late pregnancy compared with the postpartum period. When adjusted for insulin sensitivity, the insulin secretory response was higher in early and mid-to-late pregnancy than the postpartum period. A lower PIP index in early pregnancy was a significant predicator of GDM in both the unadjusted and adjusted models.
Conclusions
This cohort of women with early, classic, and no GDM demonstrated there is an increase in the insulin secretory response that is independent of insulin resistance. It also describes a novel PIP index that predicts GDM independent of clinical risk factors and postpartum PIP index.
Comments
This fascinating physiologic study adds to our understanding of the pathophysiology of GDM by characterizing the insulin secretory and sensitivity indexes in early pregnancy, mid-to-late pregnancy, and the postpartum period. Future research examining the role of hormonal mediators and other factors in these pregnancy-related insulin changes is warranted.
Roux-en-Y Gastric Bypass Increases Glycemic Excursions during Pregnancy and Postpartum: A Prospective Cohort Study
Stentebjerg LL1,2, Madsen LR3,4,5, Støving RK2,6, Andersen LLT2,7, Vinter CA1,2,7, Juhl CB1,8,9, Jensen DM1,2,7
1Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark; University of Southern Denmark, Odense, Denmark; 2Department of Clinical Research, University of Southern Denmark, Odense, Denmark; University of Southern Denmark, Odense, Denmark; 3Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark; University of Southern Denmark, Odense, Denmark; 4Department of Internal Medicine, Regional Hospital West Jutland, Herning, Denmark; University of Southern Denmark, Odense, Denmark; 5Danish Diabetes Academy, Odense University Hospital, Odense, Denmark; University of Southern Denmark, Odense, Denmark; 6Department of Endocrinology, Odense University Hospital, Odense, Denmark; University of Southern Denmark, Odense, Denmark; 7Department of Gynecology and Obstetrics, Odense University Hospital, Odense, Denmark; University of Southern Denmark, Odense, Denmark; 8Department of Endocrinology, Hospital of South West Jutland, Esbjerg, Denmark; University of Southern Denmark, Odense, Denmark; 9Department of Regional Health Research, University of Southern Denmark, Odense, Denmark
Despite the rise in pregnancies after metabolic surgery, little is known about how Roux-en-Y gastric bypass effects glycemic profiles throughout pregnancy.
Methods
This prospective cohort study of pregnant women included both women with a previous Roux-en-Y gastric bypass as well as a control group matched for age, parity, and prepregnancy body mass index (BMI). The participants used continuous glucose monitoring (CGM) for 10 days, worn at 12-, 14-, 24-, and 34-weeks' gestation as well as 4–6 weeks after delivery. CGM metrics were calculated using a target range of 63–140 mg/dL (3.5–7.8 mmol/L). Descriptive and inferential statistics were used to describe and compare the two groups, and logistic regression was used to examine for associations between clinical parameters and postbariatric surgery hypoglycemia.
Results
A total of 46 women were included in the cohort (23 with previous Roux-en-Y gastric bypass and 23 matched controls). The groups were similarly matched with the exception of age, in which the gastric bypass group was 4 years older (IQR, 0–7 years). The CGM metrics differed significantly between the groups. Specifically, women who had had previous gastric bypass surgery spent a lower time in range and higher time below and above range compared with the matched-controls for most of their pregnancy and during the postpartum period. Women with previous gastric bypass also had higher glycemic variability, measured using the coefficient of variation, throughout the pregnancy and postpartum periods. In the multivariable analysis, there were no significant predictors of post–bariatric surgery hypoglycemia.
Conclusions
This prospective cohort study demonstrated that people with previous Roux-en-Y gastric bypass had significantly different CGM profiles when compared with matched controls.
Comments
This study adds to our understanding of physiologic changes seen after metabolic surgery. Both groups spent a large amount of time in the target range defined for T1D (> 85% in both groups). Interestingly, the glycemic profiles between the women with gastric bypass and the matched controls were different throughout their pregnancies and into the postpartum period. Larger cohorts are required to further examine the relationship between CGM metrics and pregnancy outcomes in this population.
Footnotes
Author Disclosure Statement
HM is on the Medtronic (insulin pump and CGM manufacturer) European scientific advisory board. JY has received devices free of cost from Abbott for an investigator initiated and grant funded clinical study. There are no other competing financial interests.