Publications by authors named "Denice S Feig"

76 Publications

Can placental growth factors explain birthweight variation in offspring of women with type 1 diabetes?

Diabetologia 2021 Apr 10. Epub 2021 Apr 10.

Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada.

Aims/hypothesis: Maternal hyperglycaemia alone does not explain the incidence of large offspring amongst women with type 1 diabetes. The objective of the study was to determine if there is an association between placental function, as measured by angiogenic factors, and offspring birthweight z score in women with type 1 diabetes.

Methods: This cohort study included samples from 157 Continuous Glucose Monitoring in Pregnant Women with Type 1 Diabetes (CONCEPTT) trial participants. Correlations were estimated between birthweight z score and placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt-1) levels measured at baseline and at 24 and 34 weeks of gestation. Linear regression was used to assess the relationship between birthweight z score and placental health, as measured by PlGF and sFlt-1/PlGF ratio, stratified by glycaemic status (continuous glucose monitoring and HbA measures) and adjusted for potential confounders of maternal BMI, smoking and weight gain. Higher PlGF levels and lower sFlt-1/PlGF ratios represent healthy placentas, while lower PlGF levels and higher sFlt-1/PlGF ratios represent unhealthy placentas.

Results: Among CONCEPTT participants, the slopes relating PlGF levels to birthweight z scores differed according to maternal glycaemia at 34 weeks of gestation (p = 0.003). With optimal maternal glycaemia (HbA < 48 mmol/mol [6.5%]/ or continuous glucose monitoring time above range ≤ 30%), birthweight z scores were reduced towards zero (normal weight) with increasing PlGF values (representing a healthy placenta), and increased with decreasing PlGF values. With suboptimal glycaemic status (HbA ≥ 48 mmol/mol [6.5%] or time above range > 30%), increasing PlGF values were associated with heavier infants. Those with a healthy placenta (PlGF > 100) and suboptimal glycaemic control had a higher mean z score (2.45) than those with an unhealthy placenta (mean z score = 1.86). Similar relationships were seen when using sFlt-1/PlGF ratio as a marker for a healthy vs unhealthy placenta.

Conclusions/interpretation: In women with type 1 diabetes, infant birthweight is influenced by both glycaemic status and placental function. In women with suboptimal glycaemia, infant birthweight was heavier when placentas were healthy. Suboptimal placental function should be considered in the setting of suboptimal glycaemia and apparently 'normal' birthweight.
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http://dx.doi.org/10.1007/s00125-021-05438-yDOI Listing
April 2021

Increased risk of major congenital malformations in early pregnancy use of angiotensin-converting-enzyme inhibitors and angiotensin-receptor-blockers: a meta-analysis.

Diabetes Metab Res Rev 2021 Mar 29:e3453. Epub 2021 Mar 29.

Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

Aims: To evaluate the risk of adverse fetal outcomes after exposure to angiotensin converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) in first trimester of pregnancy, by conducting a systematic review and meta-analysis.

Materials And Methods: A systematic literature search was conducted using Medline, Embase, Cochrane and PubMed from inception to 25 November 2019. Studies were included if they evaluated pregnancies exposed to ACE-Is or ARBs, reported fetal outcomes, and compared these outcomes with a control group. Pooled odds ratios (ORs) were estimated using inverse variance-weighted random effects model. The protocol was registered with the PROSPERO International Prospective Register of Systematic Reviews (CRD42020160566).

Results: Studies reporting on 6234 pregnancies exposed to ACE-Is or ARBs, 4104 pregnancies exposed to other oral antihypertensives, and 1,872,733 pregnancies without exposure were included in the meta-analysis. ACE-I or ARB exposed pregnancies, compared to non-exposed controls, had higher risk of major congenital malformations (OR 1.82; 95% confidence interval [CI]: 1.42-2.34), cardiovascular malformations (OR 2.50; 95% CI: 1.62-3.87) and stillbirths (OR 1.75; 95% CI: 1.21-2.53). There was no difference in congenital malformations observed between pregnancies exposed to other antihypertensives compared to non-exposed controls (OR 0.96; 95% CI: 0.69-1.33).

Conclusions: Women exposed to ACE-Is or ARBs during early pregnancy had higher risk of adverse fetal outcomes, including malformations and stillbirths, than non-exposed controls. This increased risk was independent of underlying maternal hypertension, as those exposed to other antihypertensives did not exhibit a higher risk than healthy controls. Women planning for pregnancy using these medications, including those with diabetic nephropathy, should be counselled appropriately.
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http://dx.doi.org/10.1002/dmrr.3453DOI Listing
March 2021

Diabetes after pregnancy: a study protocol for the derivation and validation of a risk prediction model for 5-year risk of diabetes following pregnancy.

Diagn Progn Res 2021 Mar 8;5(1). Epub 2021 Mar 8.

Women's College Research Institute, Women's College Hospital, 76 Grenville Street, Toronto, Ontario, M5S 1B2, Canada.

Background: Pregnancy offers a unique opportunity to identify women at higher future risk of type 2 diabetes mellitus (DM). In pregnancy, a woman has greater engagement with the healthcare system, and certain conditions are more apt to manifest, such as gestational DM (GDM) that are important markers for future DM risk. This study protocol describes the development and validation of a risk prediction model (RPM) for estimating a woman's 5-year risk of developing type 2 DM after pregnancy.

Methods: Data will be obtained from existing Ontario population-based administrative datasets. The derivation cohort will consist of all women who gave birth in Ontario, Canada between April 2006 and March 2014. Pre-specified predictors will include socio-demographic factors (age at delivery, ethnicity), maternal clinical factors (e.g., body mass index), pregnancy-related events (gestational DM, hypertensive disorders of pregnancy), and newborn factors (birthweight percentile). Incident type 2 DM will be identified by linkage to the Ontario Diabetes Database. Weibull accelerated failure time models will be developed to predict 5-year risk of type 2 DM. Measures of predictive accuracy (Nagelkerke's R), discrimination (C-statistics), and calibration plots will be generated. Internal validation will be conducted using a bootstrapping approach in 500 samples with replacement, and an optimism-corrected C-statistic will be calculated. External validation of the RPM will be conducted by applying the model in a large population-based pregnancy cohort in Alberta, and estimating the above measures of model performance. The model will be re-calibrated by adjusting baseline hazards and coefficients where appropriate.

Discussion: The derived RPM may help identify women at high risk of developing DM in a 5-year period after pregnancy, thus facilitate lifestyle changes for women at higher risk, as well as more frequent screening for type 2 DM after pregnancy.
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http://dx.doi.org/10.1186/s41512-021-00095-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938478PMC
March 2021

Which growth standards should be used to identify large- and small-for-gestational age infants of mothers with type 1 diabetes? A pre-specified analysis of the CONCEPTT trial.

BMC Pregnancy Childbirth 2021 Jan 29;21(1):96. Epub 2021 Jan 29.

Cambridge Universities NHS Foundation Trust, Cambridge, UK.

Background: Offspring of women with type 1 diabetes are at increased risk of fetal growth patterns which are associated with perinatal morbidity. Our aim was to compare rates of large- and small-for-gestational age (LGA; SGA) defined according to different criteria, using data from the Continuous Glucose Monitoring in Type 1 Diabetes Pregnancy Trial (CONCEPTT).

Methods: This was a pre-specified analysis of CONCEPTT involving 225 pregnant women and liveborn infants from 31 international centres ( ClinicalTrials.gov NCT01788527; registered 11/2/2013). Infants were weighed immediately at birth and GROW, INTERGROWTH and WHO centiles were calculated. Relative risk ratios, sensitivity and specificity were used to assess the different growth standards with respect to perinatal outcomes, including neonatal hypoglycaemia, hyperbilirubinaemia, respiratory distress, neonatal intensive care unit (NICU) admission and a composite neonatal outcome.

Results: Accelerated fetal growth was common, with mean birthweight percentiles of 82.1, 85.7 and 63.9 and LGA rates of 62, 67 and 30% using GROW, INTERGROWTH and WHO standards respectively. Corresponding rates of SGA were 2.2, 1.3 and 8.9% respectively. LGA defined according to GROW centiles showed stronger associations with preterm delivery, neonatal hypoglycaemia, hyperbilirubinaemia and NICU admission. Infants born > 97.7th centile were at highest risk of complications. SGA defined according to INTERGROWTH centiles showed slightly stronger associations with perinatal outcomes.

Conclusions: GROW and INTERGROWTH standards performed similarly and identified similar numbers of neonates with LGA and SGA. GROW-defined LGA and INTERGROWTH-defined SGA had slightly stronger associations with neonatal complications. WHO standards underestimated size in preterm infants and are less applicable for use in type 1 diabetes.

Trial Registration: This trial is registered with ClinicalTrials.gov . number NCT01788527 . Trial registered 11/2/2013.
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http://dx.doi.org/10.1186/s12884-021-03554-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845036PMC
January 2021

Novel Biochemical Markers of Glycemia to Predict Pregnancy Outcomes in Women With Type 1 Diabetes.

Diabetes Care 2021 Mar 25;44(3):681-689. Epub 2021 Jan 25.

Norwich Medical School, University of East Anglia, Norwich, U.K.

Objective: The optimal method of monitoring glycemia in pregnant women with type 1 diabetes remains controversial. This study aimed to assess the predictive performance of HbA, continuous glucose monitoring (CGM) metrics, and alternative biochemical markers of glycemia to predict obstetric and neonatal outcomes.

Research Design And Methods: One hundred fifty-seven women from the Continuous Glucose Monitoring in Women With Type 1 Diabetes in Pregnancy Trial (CONCEPTT) were included in this prespecified secondary analysis. HbA, CGM data, and alternative biochemical markers (glycated CD59, 1,5-anhydroglucitol, fructosamine, glycated albumin) were compared at ∼12, 24, and 34 weeks' gestation using logistic regression and receiver operating characteristic (ROC) curves to predict pregnancy complications (preeclampsia, preterm delivery, large for gestational age, neonatal hypoglycemia, admission to neonatal intensive care unit).

Results: HbA, CGM metrics, and alternative laboratory markers were all significantly associated with obstetric and neonatal outcomes at 24 weeks' gestation. More outcomes were associated with CGM metrics during the first trimester and with laboratory markers (area under the ROC curve generally <0.7) during the third trimester. Time in range (TIR) (63-140 mg/dL [3.5-7.8 mmol/L]) and time above range (TAR) (>140 mg/dL [>7.8 mmol/L]) were the most consistently predictive CGM metrics. HbA was also a consistent predictor of suboptimal pregnancy outcomes. Some alternative laboratory markers showed promise, but overall, they had lower predictive ability than HbA.

Conclusions: HbA is still an important biomarker for obstetric and neonatal outcomes in type 1 diabetes pregnancy. Alternative biochemical markers of glycemia and other CGM metrics did not substantially increase the prediction of pregnancy outcomes compared with widely available HbA and increasingly available CGM metrics (TIR and TAR).
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http://dx.doi.org/10.2337/dc20-2360DOI Listing
March 2021

BMI and risk of gestational diabetes among women of South Asian and Chinese ethnicity: a population-based study.

Diabetologia 2021 Apr 24;64(4):805-813. Epub 2021 Jan 24.

Women's College Research Institute, Women's College Hospital, Toronto, ON, Canada.

Aims/hypothesis: The aim of this study was to examine how BMI influences the association between Asian ethnicity and risk of gestational diabetes (GDM).

Methods: This population-based cohort study included pregnant women without pre-existing diabetes mellitus in Ontario, Canada between 2012 and 2014. Women of Chinese and South Asian ethnicity were identified using a validated surname algorithm. GDM was ascertained using hospitalisation codes. The relationship between ethnicity and GDM was modelled using modified Poisson regression, adjusted for maternal age, pre-pregnancy BMI, parity, previous GDM, long-term residency status, income quintile and smoking status. An interaction term between ethnicity and pre-pregnancy BMI was tested.

Results: Of 231,618 pregnant women, 9289 (4.0%) were of South Asian ethnicity and 12,240 (5.3%) were of Chinese ethnicity. Relative to women from the general population, in whom prevalence of GDM was 4.3%, the adjusted RR of GDM was higher among those of South Asian ethnicity (1.81 [95% CI 1.64, 1.99]) and Chinese ethnicity (1.66 [95% CI 1.53, 1.80]). The association between GDM and Asian ethnicity remained significant across BMI categories but differed according to BMI. The prevalence of GDM exceeded 5% at an estimated BMI of 21.5 kg/m among South Asian women, 23.0 kg/m among Chinese women and 29.5 kg/m among the general population.

Conclusions/interpretation: The risk of GDM is significantly higher in South Asian and Chinese women, whose BMI is lower than that of women in the general population. Accordingly, targeted GDM prevention strategies may need to consider lower BMI cut-points for Asian populations.
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http://dx.doi.org/10.1007/s00125-020-05356-5DOI Listing
April 2021

Metformin in women with type 2 diabetes in pregnancy (MiTy): a multicentre, international, randomised, placebo-controlled trial.

Lancet Diabetes Endocrinol 2020 10;8(10):834-844

Department of Medicine, University of Toronto, Toronto, ON, Canada; Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada; Sinai Health System, Mount Sinai Hospital, Toronto, ON, Canada; Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON, Canada.

Background: Although metformin is increasingly being used in women with type 2 diabetes during pregnancy, little data exist on the benefits and harms of metformin use on pregnancy outcomes in these women. We aimed to investigate the effects of the addition of metformin to a standard regimen of insulin on neonatal morbidity and mortality in pregnant women with type 2 diabetes.

Methods: In this prospective, multicentre, international, randomised, parallel, double-masked, placebo-controlled trial, women with type 2 diabetes during pregnancy were randomly assigned from 25 centres in Canada and four in Australia to receive either metformin 1000 mg twice daily or placebo, added to insulin. Randomisation was done via a web-based computerised randomisation service and stratified by centre and pre-pregnancy BMI (<30 kg/m or ≥30 kg/m) in a ratio of 1:1 using random block sizes of 4 and 6. Women were eligible if they had type 2 diabetes, were on insulin, had a singleton viable pregnancy, and were between 6 and 22 weeks plus 6 days' gestation. Participants were asked to check their fasting blood glucose level before the first meal of the day, before the last meal of the day, and 2 h after each meal. Insulin doses were adjusted aiming for identical glucose targets (fasting glucose <5·3 mmol/L [95 mg/dL], 2-h postprandial glucose <6·7 mmol/L [120 mg/dL]). Study visits were done monthly and patients were seen every 1-4 weeks as was needed for standard clinical care. At study visits blood pressure and bodyweight were measured; patients were asked about tolerance to their pills, any hospitalisations, insulin doses, and severe hypoglycaemia events; and glucometer readings were downloaded to the central coordinating centre. Participants, caregivers, and outcome assessors were masked to the intervention. The primary outcome was a composite of fetal and neonatal outcomes, for which we calculated the relative risk and 95% CI between groups, stratifying by site and BMI using a log-binomial regression model with an intention-to-treat analysis. Secondary outcomes included several relevant maternal and neonatal outcomes. The trial was registered with ClinicalTrials.gov, NCT01353391.

Findings: Between May 25, 2011, and Oct 11, 2018, we randomly assigned 502 women, 253 (50%) to metformin and 249 (50%) to placebo. Complete data were available for 233 (92%) participants in the metformin group and 240 (96%) in the placebo group for the primary outcome. We found no significant difference in the primary composite neonatal outcome between the two groups (40% vs 40%; p=0·86; relative risk [RR] 1·02 [0·83 to 1·26]). Compared with women in the placebo group, metformin-treated women achieved better glycaemic control (HbA at 34 weeks' gestation 41·0 mmol/mol [SD 8·5] vs 43·2 mmol/mol [-10]; 5·90% vs 6·10%; p=0·015; mean glucose 6·05 [0·93] vs 6·27 [0·90]; difference -0·2 [-0·4 to 0·0]), required less insulin (1·1 units per kg per day vs 1·5 units per kg per day; difference -0·4 [95% CI -0·5 to -0·2]; p<0·0001), gained less weight (7·2 kg vs 9·0 kg; difference -1·8 [-2·7 to -0·9]; p<0·0001) and had fewer caesarean births (125 [53%] of 234 in the metformin group vs 148 [63%] of 236 in the placebo group; relative risk [RR] 0·85 [95% CI 0·73 to 0·99]; p=0·031). We found no significant difference between the groups in hypertensive disorders (55 [23%] in the metformin group vs 56 [23%] in the placebo group; p=0·93; RR 0·99 [0·72 to 1·35]). Compared with those in the placebo group, metformin-exposed infants weighed less (mean birthweight 3156 g [SD 742] vs 3375 g [742]; difference -218 [-353 to -82]; p=0·002), fewer were above the 97th centile for birthweight (20 [9%] in the metformin group vs 34 [15%] in the placebo group; RR 0·58 [0·34 to 0·97]; p=0·041), fewer weighed 4000 g or more at birth (28 [12%] in the metformin group vs 44 [19%] in the placebo group; RR 0·65 [0·43 to 0·99]; p=0·046), and metformin-exposed infants had reduced adiposity measures (mean sum of skinfolds 16·0 mm [SD 5·0] vs 17·4 [6·2] mm; difference -1·41 [-2·6 to -0·2]; p=0·024; mean neonatal fat mass 13·2 [SD 6·2] vs 14·6 [5·0]; p=0·017). 30 (13%) infants in the metformin group and 15 (7%) in the placebo group were small for gestational age (RR 1·96 [1·10 to 3·64]; p=0·026). We found no significant difference in the cord c-peptide between groups (673 pmol/L [435] in the metformin group vs 758 pmol/L [595] in the placebo group; p=0·10; ratio of means 0·88 [0·72 to 1·02]). The most common adverse event reported was gastrointestinal (38 events in the metformin group and 38 events in the placebo group).

Interpretation: We found several maternal glycaemic and neonatal adiposity benefits in the metformin group. Along with reduced maternal weight gain and insulin dosage and improved glycaemic control, the lower adiposity and infant size measurements resulted in fewer large infants but a higher proportion of small-for-gestational-age infants. Understanding the implications of these effects on infants will be important to properly advise patients who are contemplating the use of metformin during pregnancy.

Funding: Canadian Institutes of Health Research, Lunenfeld-Tanenbaum Research Institute, University of Toronto.
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http://dx.doi.org/10.1016/S2213-8587(20)30310-7DOI Listing
October 2020

Continuous Glucose Monitoring in Pregnancy: Importance of Analyzing Temporal Profiles to Understand Clinical Outcomes.

Diabetes Care 2020 06 24;43(6):1178-1184. Epub 2020 Mar 24.

Division of Maternal Health, St Thomas' Hospital, King's College London, London, U.K.

Objective: To determine if temporal glucose profiles differed between ) women who were randomized to real-time continuous glucose monitoring (RT-CGM) or self-monitored blood glucose (SMBG), ) women who used insulin pumps or multiple daily insulin injections (MDIs), and ) women whose infants were born large for gestational age (LGA) or not, by assessing CGM data obtained from the Continuous Glucose Monitoring in Women With Type 1 Diabetes in Pregnancy Trial (CONCEPTT).

Research Design And Methods: Standard summary metrics and functional data analysis (FDA) were applied to CGM data from the CONCEPTT trial (RT-CGM, = 100; SMBG, = 100) taken at baseline and at 24- and 34-weeks' gestation. Multivariable regression analysis determined if temporal differences in 24-h glucose profiles occurred between comparators in each of the three groups.

Results: FDA revealed that women using RT-CGM had significantly lower glucose (0.4-0.8 mmol/L [7-14 mg/dL]) for 7 h/day (0800 h to 1200 h and 1600 h to 1900 h) compared with those with SMBG. Women using pumps had significantly higher glucose (0.4-0.9 mmol/L [7-16 mg/dL]) for 12 h/day (0300 h to 0600 h, 1300 h to 1800 h, and 2030 h to 0030 h) at 24 weeks with no difference at 34 weeks compared with MDI. Women who had an LGA infant ran a significantly higher glucose by 0.4-0.7 mmol/L (7-13 mg/dL) for 4.5 h/day at baseline, by 0.4-0.9 mmol/L (7-16 mg/dL) for 16 h/day at 24 weeks, and by 0.4-0.7 mmol/L (7-13 mg/dL) for 14 h/day at 34 weeks.

Conclusions: FDA of temporal glucose profiles gives important information about differences in glucose control and its timing, which are undetectable by standard summary metrics. Women using RT-CGM were able to achieve better daytime glucose control, reducing fetal exposure to maternal glucose.
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http://dx.doi.org/10.2337/dc19-2527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245356PMC
June 2020

Maternal thyroid disease and its effects on the fetus and perinatal outcomes.

Prenat Diagn 2020 08 26;40(9):1077-1084. Epub 2020 Mar 26.

Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

Thyroid disease is common in women of childbearing age and can have significant effects on the development of the fetus and perinatal outcomes. Maternal thyroid hormone is critical for proper fetal neurodevelopment, and the fetus relies on thyroid hormone from its mother for the first half of pregnancy. Both overt maternal hypothyroidism and overt maternal hyperthyroidism have been shown to be associated with adverse effects on central nervous system gray matter and neurocognitive development of offspring as well as increased obstetrical risks. Treatment of overt thyroid conditions improves outcomes. Subclinical maternal hypothyroidism may increase adverse neurocognitive and obstetrical outcomes although data are conflicting. To date, treatment of subclinical hypothyroidism has not shown benefit. Subclinical hyperthyroidism is well tolerated in pregnancy. Thyroid autoantibodies alone may also affect neurodevelopment and obstetrical outcomes; however, recent data have shown no improvement with levothyroxine treatment. Several rare maternal genetic thyroid conditions can affect the fetus including a thyroid-stimulating hormone receptor mutation leading to hypersensitivity to human chorionic gonadotropin and thyroid hormone resistance. The thyroid plays a crucial role in fetal health and understanding it is important for optimal care.
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http://dx.doi.org/10.1002/pd.5684DOI Listing
August 2020

Diagnosis of Gestational Diabetes: More Questions Than Answers.

Can J Diabetes 2019 Dec;43(8):547-548

Winnipeg Children's Hospital, Shared Health; University of Manitoba, Department of Pediatrics and Child Health; Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, Canada.

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http://dx.doi.org/10.1016/j.jcjd.2019.09.006DOI Listing
December 2019

Dietary Patterns of Insulin Pump and Multiple Daily Injection Users During Type 1 Diabetes Pregnancy.

Diabetes Care 2020 01 6;43(1):e5-e7. Epub 2019 Nov 6.

Mount Sinai Hospital, Toronto, Ontario, Canada.

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http://dx.doi.org/10.2337/dc19-1908DOI Listing
January 2020

Characteristics of Women With Gestational Diabetes From Non-Caucasian Compared With Caucasian Ethnic Groups.

Can J Diabetes 2019 Dec 27;43(8):600-605. Epub 2019 Sep 27.

Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada.

Objectives: Short- and long-term outcomes in women after gestational diabetes mellitus (GDM) vary by ethnicity. Understanding differences in baseline diabetes risk factors is important for informing choice of risk-reducing interventions. We aimed to compare maternal and pregnancy-related characteristics in Caucasian and non-Caucasian women with GDM.

Methods: Using a large multicentre Canadian cohort of women diagnosed with GDM and recruited between 2009 and 2013, we compared demographic, clinical and behavioural characteristics in women with GDM across 7 ethnic groups. Data were obtained from chart reviews and surveys, and logistic and linear regression models were used to compare binary and continuous variables, respectively, between Caucasian and non-Caucasian ethnic groups.

Results: Of the 1,332 women with GDM, 911 were eligible for inclusion. Of these, 41.4% were white Caucasian, 17.1% were South Asian, 18.4% were East Asian, 5.8% were black, 8.8% were Filipina, 5.2% were Middle Eastern and 3.3% were Hispanic. Non-Caucasian women were diagnosed with GDM at a younger age and were more likely to have a family history of diabetes compared with Caucasian women. With the exception of East Asians, non-Caucasian women were more likely to be overweight using ethnicity-specific body mass index cutoffs and have higher oral glucose tolerance test values than Caucasian women. Prepregnancy smoking and alcohol consumption prevalence were highest in Caucasian women.

Conclusions: Several important ethnicity-specific differences in clinical and behavioural characteristics of women with GDM were identified. These differences need to be considered when offering interventions for reducing risk of adverse perinatal outcomes and subsequent type 2 diabetes.
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http://dx.doi.org/10.1016/j.jcjd.2019.09.005DOI Listing
December 2019

Predictors of Large-for-Gestational-Age Birthweight Among Pregnant Women With Type 1 and Type 2 Diabetes: A Retrospective Cohort Study.

Can J Diabetes 2019 Dec 4;43(8):560-566. Epub 2019 Sep 4.

Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada; Division of Endocrinology & Metabolism and the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. Electronic address:

Objective: Our aim in this study was to compare the effects of risk factors for large-for-gestational-age (LGA) birthweight between women with type 1 and type 2 diabetes mellitus (TIDM and T2DM, respectively).

Methods: A retrospective cohort study was conducted for women with T1DM (n=152) and T2DM (n=255) attending a diabetes/pregnancy clinic during the period from 2009 to 2016. Multiple logistic regression analysis was used to identify variables associated with LGA birthweight.

Results: LGA was significantly higher in those with T1DM (39%) than T2DM (17%) (p<0.001). Among those with T1DM, there was a nonsignificant association between LGA and continuous subcutaneous insulin infusion (odds ratio, 1.17; 95% confidence interval, 0.99 to 1.39; p=0.06) and excess maternal weight gain (T1DM odds ratio, 1.19; 95% confidence interval, 0.99 to 1.43; p=0.069). In those with T2DM, there was an association between LGA and glycated hemoglobin at delivery (T2DM odds ratio, 1.10; 95% confidence interval, 1.02 to 1.19; p=0.01).

Conclusions: In the study population, glycemic control at delivery was predictive of LGA in women with T2DM, and there was a trend toward an association of maternal weight gain and continuous subcutaneous insulin infusion with LGA infants in T1DM. Further study is warranted to better guide targeted interventions to reduce high rates of LGA birthweight in T1DM/T2DM.
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http://dx.doi.org/10.1016/j.jcjd.2019.08.015DOI Listing
December 2019

Perinatal Outcomes Among Different Asian Groups With Gestational Diabetes Mellitus in Ontario: A Cohort Study.

Can J Diabetes 2019 Dec 26;43(8):606-612. Epub 2019 Jun 26.

Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada; Women's College Research Institute, Women's College Hospital, Toronto, Ontario, Canada. Electronic address:

Objective: The aim of this study was to determine whether perinatal outcomes differ between Caucasian and Asian subgroups of women with gestational diabetes mellitus (GDM) through use of standard vs ethnicity-specific birthweight curves.

Methods: This retrospective cohort study included 537 women with GDM, within the ethnically diverse province of Ontario, Canada. Study outcomes included large-for-gestational-age (LGA) and small-for-gestational-age (SGA) birthweights in newborns of women from prevalent Asian ethnic groups compared with newborns of Caucasian women. Odds ratios were adjusted for maternal age, parity, prepregnancy body mass index, gestational weight gain and insulin use in pregnancy.

Results: Of the 537 women participing in the study, 228 (35.8%) were Caucasian, 109 (17.1%) South Asian, 141 (22.1%) East Asian and 59 (9.3%) Filipino. Using standard birthweight curves, compared with Caucasian women, the risk of LGA was lower among South Asian (adjusted odds ratio [aOR], 0.065; 95% confidence interval [CI], 0.01 to 0.49) and East Asian (aOR, 0.36; 95% CI, 0.14 to 0.95) women. The aOR for SGA was notably higher among South Asian women (aOR, 2.96; 95% CI, 1.24 to 7.09). Significant effects were not seen among Filipino women. Use of ethnicity-specific birthweight curves largely attenuated these associations, except for LGA in South Asian mothers (aOR, 0.27; 95% CI, 0.09 to 0.81).

Conclusion: South Asian women with GDM are at lower risk of having an LGA newborn, even after accounting for maternal risk factors or the use of an ethnicity-specific birthweight curve.
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http://dx.doi.org/10.1016/j.jcjd.2019.06.006DOI Listing
December 2019

Neurocognitive and behavioural outcomes in offspring exposed to maternal pre-existing diabetes: a systematic review and meta-analysis.

Diabetologia 2019 09 5;62(9):1561-1574. Epub 2019 Jul 5.

Department of Medicine, Cumming School of Medicine, University of Calgary, Richmond Road Diagnostic and Treatment Centre, 1820 Richmond Road SW, Calgary, AB, T2T 5C7, Canada.

Aims/hypothesis: We performed a systematic review and meta-analysis to determine whether exposure to maternal pre-existing diabetes in pregnancy is associated with neurocognitive or behavioural outcomes in offspring.

Methods: We searched MEDLINE, EMBASE, PsychINFO, the Cochrane Database of Systematic Reviews and Scopus for studies that examined any neurocognitive or behavioural outcomes in offspring of mothers with pre-existing diabetes in pregnancy in accordance with a published protocol (PROSPERO CRD42018109038). Title and abstract review, full-text review and data extraction were performed independently and in duplicate. Risk of bias was assessed using the Newcastle-Ottawa scale. Meta-analyses of summary measures were performed using random-effects models.

Results: Nineteen articles including at least 18,681 exposed and 2,856,688 control participants were identified for inclusion. Exposure to maternal pre-existing diabetes in pregnancy was associated with a lower pooled intelligence quotient in the offspring (pooled weighted mean difference -3.07 [95% CI -4.59, -1.55]; I = 0%) and an increased risk of autism spectrum disorders (effect estimate 1.98 [95% CI 1.46, 2.68]; I = 0%). There was also an increased risk of attention deficit/hyperactivity disorder (pooled HR 1.36 [95% CI 1.19, 1.55]; I = 0%), though this was based on only two studies. Although most studies were found to be high quality in terms of participant selection, in many studies, comparability of cohorts and adequacy of follow-up were sources of bias.

Conclusions/interpretation: There is evidence to suggest that in utero exposure to maternal pre-existing diabetes is associated with some adverse neurocognitive and behavioural outcomes. It remains unclear what the role of perinatal factors is and the degree to which other environmental factors contribute to these findings.
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http://dx.doi.org/10.1007/s00125-019-4923-0DOI Listing
September 2019

Response to Comment on Barbour and Feig. Metformin for Gestational Diabetes Mellitus: Progeny, Perspective, and a Personalized Approach. Diabetes Care 2019;42:396-399.

Diabetes Care 2019 07;42(7):e131-e132

Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Lunenfeld-Tanenbaum Research Institute, Toronto, Canada.

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http://dx.doi.org/10.2337/dci19-0025DOI Listing
July 2019

Impact of Socioeconomic Status on Incidence of End-Stage Renal Disease and Mortality After Dialysis in Adults With Diabetes.

Can J Diabetes 2019 Oct 17;43(7):483-489.e4. Epub 2019 Apr 17.

Department of Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Objectives: To determine whether low socioeconomic status (SES), with or without universal drug coverage, predicts end-stage renal disease (ESRD) and survival after dialysis in patients with diabetes.

Methods: We conducted a population-based retrospective cohort study in Ontario, Canada. We used ≥65 years of age as a surrogate for universal drug coverage. Adults with diabetes were followed from March 31, 1997 to March 31, 2011 for occurrence of the composite primary outcome (acute kidney injury, ESRD requiring dialysis or kidney transplantation). Patients on dialysis with diabetes were followed from April 1, 1994 to March 31, 2011 for occurrence of death or transplantation.

Results: SES quintile (Q) was inversely associated with the primary outcome in both age groups; however, the gradient was higher in those <65 years of age (Q1:Q5 hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.37-1.49) compared with ≥65 years of age (HR, 1.19; 95% CI, 1.15-1.24). Low SES was associated with a lower likelihood of kidney transplantation among those <65 years of age (HR, 0.77; 95% CI, 0.65-0.92). In patients on dialysis, low SES was associated with higher mortality (HR, 1.09; 95% CI, 1.02-1.16) in both age groups. This association was eliminated after accounting for the decreased rates of kidney transplantation in lower SES groups.

Conclusions: SES is inversely associated with ESRD outcomes in individuals with diabetes, and this disparity is reduced in those ≥65 years of age who universally receive prescription drug coverage. Low SES is associated with a higher mortality after dialysis, largely explained by lower kidney transplantation rates in poorer populations.
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http://dx.doi.org/10.1016/j.jcjd.2019.04.006DOI Listing
October 2019

Effect of postpartum glucose tolerance results on subsequent weight retention in women with recent gestational diabetes: A retrospective cohort study.

Diabetes Res Clin Pract 2019 May 18;151:169-176. Epub 2019 Apr 18.

Women's College Research Institute, Women's College Hospital, Toronto, Canada; Institute of Health Policy, Management and Evaluation/Dalla Lana School of Public Health, University of Toronto, Toronto, Canada; Department of Medicine, University of Toronto, Toronto, Canada; Institute for Clinical Evaluative Sciences, Toronto, Canada; Sunnybrook Health Sciences Centre, Toronto, Canada. Electronic address:

Aims: Glucose tolerance normalizes postpartum in most women with gestational diabetes (GDM), which may provide false reassurance and decrease weight-reducing behaviours. We evaluated whether awareness of normal postpartum glucose tolerance was associated with higher weight retention than being unaware of glucose tolerance.

Methods: This cohort study of women with GDM collected survey data during pregnancy and in the first and second postpartum year. We compared women who reported normal glucose tolerance ('aware, normal') in the first year to those reporting no testing or unsure of results ('unaware'). The primary outcome was self-reported weight in the second year compared between groups using multivariable linear regression.

Results: Among 319 women, 110 (34.5%) were 'aware, normal'; 183 (57.4%) were 'unaware'; and 26 (8.2%) were 'aware, abnormal'. After adjusting for baseline weight and covariates, women with normal results had a mean 3.66 kg higher weight (CI 1.08-6.24 kg, p = 0.0056) by the second year than those unaware of results.

Conclusions: Women with GDM with normal postpartum glucose tolerance had significantly higher weight by the second year than those unaware of their results. Normal glucose tolerance after pregnancy may be misinterpreted as resolution of diabetes risk and decrease risk-reducing behaviours.
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http://dx.doi.org/10.1016/j.diabres.2019.04.016DOI Listing
May 2019

Metformin for Gestational Diabetes Mellitus: Progeny, Perspective, and a Personalized Approach.

Diabetes Care 2019 03;42(3):396-399

Department of Medicine, Division of Endocrinology and Metabolism, University of Toronto, Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada.

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http://dx.doi.org/10.2337/dci18-0055DOI Listing
March 2019

Pumps or Multiple Daily Injections in Pregnancy Involving Type 1 Diabetes: A Prespecified Analysis of the CONCEPTT Randomized Trial.

Diabetes Care 2018 12 16;41(12):2471-2479. Epub 2018 Oct 16.

Objective: To compare glycemic control, quality of life, and pregnancy outcomes of women using insulin pumps and multiple daily injection therapy (MDI) during the Continuous Glucose Monitoring in Women With Type 1 Diabetes in Pregnancy Trial (CONCEPTT).

Research Design And Methods: This was a prespecified analysis of CONCEPTT involving 248 pregnant women from 31 centers. Randomization was stratified for pump versus MDI and HbA. The primary outcome was change in HbA from randomization to 34 weeks' gestation. Key secondary outcomes were continuous glucose monitoring (CGM) measures, maternal-infant health, and patient-reported outcomes.

Results: At baseline, pump users were more often in stable relationships ( = 0.003), more likely to take preconception vitamins ( = 0.03), and less likely to smoke ( = 0.02). Pump and MDI users had comparable first-trimester glycemia: HbA 6.84 ± 0.71 vs. 6.95 ± 0.58% (51 ± 7.8 vs. 52 ± 6.3 mmol/mol) ( = 0.31) and CGM time in target (51 ± 14 vs. 50 ± 13%) ( = 0.40). At 34 weeks, MDI users had a greater decrease in HbA (-0.55 ± 0.59 vs. -0.32 ± 0.65%, = 0.001). At 24 and 34 weeks, MDI users were more likely to achieve target HbA ( = 0.009 and = 0.001, respectively). Pump users had more hypertensive disorders ( = 0.011), mainly driven by increased gestational hypertension (14.4 vs. 5.2%; = 0.025), and more neonatal hypoglycemia (31.8 vs. 19.1%, = 0.05) and neonatal intensive care unit (NICU) admissions >24 h (44.5 vs. 29.6%; = 0.02). Pump users had a larger reduction in hypoglycemia-related anxiety ( = 0.05) but greater decline in health/well-being ( = 0.02).

Conclusions: In CONCEPTT, MDI users were more likely to have better glycemic outcomes and less likely to have gestational hypertension, neonatal hypoglycemia, and NICU admissions than pump users. These data suggest that implementation of insulin pump therapy is potentially suboptimal during pregnancy.
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http://dx.doi.org/10.2337/dc18-1437DOI Listing
December 2018

New Diabetes Canada Clinical Practice Guidelines for Diabetes and Pregnancy - What's Changed?

J Obstet Gynaecol Can 2018 11 28;40(11):1484-1489. Epub 2018 Sep 28.

Department of Medicine, University of Toronto, Toronto, On, Canada; Mount Sinai Hospital, Toronto, ON.

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http://dx.doi.org/10.1016/j.jogc.2018.06.024DOI Listing
November 2018

Glucose Targets and Insulin Choice in Pregnancy: What Has Changed in the Last Decade?

Curr Diab Rep 2018 08 16;18(10):77. Epub 2018 Aug 16.

Mount Sinai Hospital, 60 Murray St, #5027, Toronto, Ontario, M5T 3L9, Canada.

Purpose Of Review: To review current glycaemic targets and the potential use of newer insulin formulations in pregnancy.

Recent Findings: The impact of stricter glycaemic control on perinatal outcomes remains controversial, showing conflicting results. Current ongoing randomised trials investigating the role of tighter glucose targets in pregnancy should help clarify the benefit of tighter glucose control. Optimal timing for self-monitoring blood glucose (SMBG) remains debatable. Data suggest that post-prandial SMBG, particularly at 1 h, offers the best prediction of adverse perinatal outcome. To achieve these targets, insulin is the standard therapy. Novel insulin formulations offer benefits outside of pregnancy. Recent data on the use of new insulins in pregnancy (e.g. insulin degludec and glargine (U 300)) is limited to case reports. Glycaemic targets have remained unchanged in the last decade. Studies using stricter glycaemic targets may improve perinatal outcomes. Newer insulin formulations may offer increased flexibility and glycaemic control. Clinicians caring for women with diabetes striving to minimise adverse perinatal outcomes will find this review of interest.
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http://dx.doi.org/10.1007/s11892-018-1054-9DOI Listing
August 2018

Research Gaps in Gestational Diabetes Mellitus: Executive Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop.

Obstet Gynecol 2018 08;132(2):496-505

Diabetes Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; the Divisions of Endocrinology, Metabolism, and Diabetes and Maternal-Fetal Medicine, University of Colorado School of Medicine and Anschutz Medical Campus, Aurora, Colorado; the Division of Endocrinology and Diabetes, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California; Women & Infants Hospital of Rhode Island and Warren Alpert Medical School of Brown University, Providence, Rhode Island; the Diabetes Unit, Hospital de la Santa Creu I Sant Pau, Universitat Autonoma de Barcelona, Bellaterra, Barcelona, CIBER-BBN, Spain; the Center for Pregnant Women with Diabetes, Department of Obstetrics, Rigshospitalet, Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; College Medicine Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland; the Diabetes & Endocrine in Pregnancy Program, Mount Sinai Hospital and University of Toronto, Toronto, Canada; the Division of Research, Kaiser Permanente Northern California, Oakland, California; the Department of Maternal-Fetal Medicine, Center for Women's Reproductive Health, University of Alabama at Birmingham, Birmingham, Alabama; the Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, Ohio; the Departments of Medicine and Obstetrics and Gynecology, McGill University Health Centre, Montreal, Quebec, Canada; Northwestern University Feinberg School of Medicine, Chicago, Illinois; Kaiser Permanente Southern California, San Diego, California; National Women's Health, Auckland, New Zealand; the Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California; Campbelltown Hospital and Western Sydney University, Sydney, Australia; MedStar Health Research Institute, Hyattsville, Maryland; Georgetown-Howard Universities Center for Clinical and Translational Science, Washington, DC; and the Center for Reproductive Health, Case Western Reserve University at MetroHealth Medical Center, Cleveland, Ohio.

The National Institute of Diabetes and Digestive and Kidney Diseases convened a workshop on research gaps in gestational diabetes mellitus (GDM) with a focus on 1) early pregnancy diagnosis and treatment and 2) pharmacologic treatment strategies. This article summarizes the proceedings of the workshop. In early pregnancy, the appropriate diagnostic criteria for the diagnosis of GDM remain poorly defined, and an effect of early diagnosis and treatment on the risk of adverse outcomes has not been demonstrated. Despite many small randomized controlled trials of glucose-lowering medication treatment in GDM, our understanding of medication management of GDM is incomplete as evidenced by discrepancies among professional society treatment guidelines. The comparative effectiveness of insulin, metformin, and glyburide remains uncertain, particularly with respect to long-term outcomes. Additional topics in need of further research identified by workshop participants included phenotypic heterogeneity in GDM and novel and individualized treatment approaches. Further research on these topics is likely to improve our understanding of the pathophysiology and treatment of GDM to improve both short- and long-term outcomes for mothers and their children.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124493PMC
August 2018

Reply.

Am J Obstet Gynecol 2018 09 26;219(3):310-311. Epub 2018 Apr 26.

Department of Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.ajog.2018.04.033DOI Listing
September 2018

Maternal and neonatal outcomes after bariatric surgery; a systematic review and meta-analysis: do the benefits outweigh the risks?

Am J Obstet Gynecol 2018 06 15;218(6):573-580. Epub 2018 Feb 15.

Department of Medicine, University of Toronto, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Endocrinology and Metabolism and the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. Electronic address:

Objective Data: Obesity during pregnancy is associated with a number of adverse obstetric outcomes that include gestational diabetes mellitus, macrosomia, and preeclampsia. Increasing evidence shows that bariatric surgery may decrease the risk of these outcomes. Our aim was to evaluate the benefits and risks of bariatric surgery in obese women according to obstetric outcomes.

Study: We performed a systematic literature search using MEDLINE, Embase, Cochrane, Web of Science, and PubMed from inception up to December 12, 2016. Studies were included if they evaluated patients who underwent bariatric surgery, reported subsequent pregnancy outcomes, and compared these outcomes with a control group.

Study Appraisal And Synthesis Methods: Two reviewers extracted study outcomes independently, and risk of bias was assessed with the use of the Newcastle-Ottawa Quality Assessment Scale. Pooled odds ratios for each outcome were estimated with the Dersimonian and Laird random effects model.

Results: After a review of 2616 abstracts, 20 cohort studies and approximately 2.8 million subjects (8364 of whom had bariatric surgery) were included in the metaanalysis. In our primary analysis, patients who underwent bariatric surgery showed reduced rates of gestational diabetes mellitus (odds ratio, 0.20; 95% confidence interval, 0.11-0.37, number needed to benefit, 5), large-for-gestational-age infants (odds ratio, 0.31; 95% confidence interval, 0.17-0.59; number needed to benefit, 6), gestational hypertension (odds ratio, 0.38; 95% confidence interval, 0.19-0.76; number needed to benefit, 11), all hypertensive disorders (odds ratio, 0.38; 95% confidence interval, 0.27-0.53; number needed to benefit, 8), postpartum hemorrhage (odds ratio, 0.32; 95% confidence interval, 0.08-1.37; number needed to benefit, 21), and caesarean delivery rates (odds ratio, 0.50; 95% confidence interval, 0.38-0.67; number needed to benefit, 9); however, group of patients showed an increase in small-for-gestational-age infants (odds ratio, 2.16; 95% confidence interval, 1.34-3.48; number needed to harm, 21), intrauterine growth restriction (odds ratio, 2.16; 95% confidence interval, 1.34-3.48; number needed to harm, 66), and preterm deliveries (odds ratio, 1.35; 95% confidence interval, 1.02-1.79; number needed to harm, 35) when compared with control subjects who were matched for presurgery body mass index. There were no differences in rates of preeclampsia, neonatal intensive care unit admissions, stillbirths, malformations, and neonatal death. Malabsorptive surgeries resulted in a greater increase in small-for-gestational-age infants (P=.0466) and a greater decrease in large-for-gestational-age infants (P=<.0001) compared with restrictive surgeries. There were no differences in outcomes when we used administrative databases vs clinical charts.

Conclusion: Although bariatric surgery is associated with a reduction in the risk of several adverse obstetric outcomes, there is a potential for an increased risk of other important outcomes that should be considered when bariatric surgery is discussed with reproductive-age women.
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http://dx.doi.org/10.1016/j.ajog.2018.02.003DOI Listing
June 2018

Type 2 diabetes after gestational diabetes: Can the progression be prevented?

Authors:
Denice S Feig

Diabetes Metab Res Rev 2018 05 8;34(4):e2988. Epub 2018 Mar 8.

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http://dx.doi.org/10.1002/dmrr.2988DOI Listing
May 2018

Caring for pregnant women whose diabetes antedates pregnancy: is there room for improvement?

Diabetologia 2018 05 7;61(5):1022-1026. Epub 2018 Feb 7.

Department of Medicine, University of Toronto, Toronto, ON, Canada.

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http://dx.doi.org/10.1007/s00125-018-4565-7DOI Listing
May 2018