Increased risk of cardiovascular and renal disease, and diabetes for all women diagnosed with gestational diabetes mellitus in New Zealand-A national retrospective cohort study.

BACKGROUND: Gestational diabetes mellitus increases the risk of developing type 2 diabetes. The aim of this study is to compare cardiometabolic and renal outcomes for all women in New Zealand with gestational diabetes (2001-2010) with women without diabetes, 10-20 years following delivery. METHODS: A retrospective cohort study, utilizing a national dataset providing information for all women who gave birth between 1 January 2001 and 31 December 2010 (n = 604 398). Adolescent girls <15 years, women ≥50 years and women with prepregnancy diabetes were excluded. In total 11 459 women were diagnosed with gestational diabetes and 11 447 were matched (for age and year of delivery) with 57 235 unexposed (control) women. A national hospital dataset was used to compare primary outcomes until 31 May 2021. RESULTS: After controlling for ethnicity, women with gestational diabetes were significantly more likely than control women to develop diabetes-adjusted hazard ratio (HR) 20.06 and 95% confidence interval (CI) 18.46-21.79; a first cardiovascular event 2.19 (1.86-2.58); renal disease 6.34 (5.35-7.51) and all-cause mortality 1.55 (1.31-1.83), all p values <.0001. The HR and 95% CI remained similar after controlling for significant covariates: diabetes 18.89 (17.36-20.56), cardiovascular events 1.79 (1.52-2.12), renal disease 5.42 (4.55-6.45), and all-cause mortality 1.44 (1.21-1.70). When time-dependent diabetes was added to the model, significance remained for cardiovascular events 1.33 (1.10-1.61), p = .003 and renal disease 2.33 (1.88-2.88), p < .0001 but not all-cause mortality. CONCLUSIONS: Women diagnosed with gestational diabetes have an increased risk of adverse cardiometabolic and renal outcomes. Findings highlight the importance of follow-up screening for diabetes, cardiovascular risk factors, and renal disease.

Impact of Gestational Diabetes Detection Thresholds on Infant Growth and Body Composition: A Prospective Cohort Study Within a Randomized Trial.

OBJECTIVE: Gestational diabetes mellitus (GDM) is associated with offspring metabolic disease, including childhood obesity, but causal mediators remain to be established. We assessed the impact of lower versus higher thresholds for detection and treatment of GDM on infant risk factors for obesity, including body composition, growth, nutrition, and appetite. RESEARCH DESIGN AND METHODS: In this prospective cohort study within the Gestational Diabetes Mellitus Trial of Diagnostic Detection Thresholds (GEMS), pregnant women were randomly allocated to detection of GDM using the lower criteria of the International Association of Diabetes and Pregnancy Study Groups or higher New Zealand criteria (ACTRN12615000290594). Randomly selected control infants of women without GDM were compared with infants exposed to A) GDM by lower but not higher criteria, with usual treatment for diabetes in pregnancy; B) GDM by lower but not higher criteria, untreated; or C) GDM by higher criteria, treated. The primary outcome was whole-body fat mass at 5-6 months. RESULTS: There were 760 infants enrolled, and 432 were assessed for the primary outcome. Fat mass was not significantly different between control infants (2.05 kg) and exposure groups: A) GDM by lower but not higher criteria, treated (1.96 kg), adjusted mean difference (aMD) -0.09 (95% CI -0.29, 0.10); B) GDM by lower but not higher criteria, untreated (1.94 kg), aMD -0.15 (95% CI -0.35, 0.06); and C) GDM detected and treated using higher thresholds (1.87 kg), aMD -0.17 (95% CI -0.37, 0.03). CONCLUSIONS: GDM detected using lower but not higher criteria, was not associated with increased infant fat mass at 5-6 months, regardless of maternal treatment. GDM detected and treated using higher thresholds was also not associated with increased fat mass at 5-6 months.

Early diabetes treatment is associated with improved outcomes in pregnant women with a first antenatal HbA1c of 41-46 mmol/mol.

BACKGROUND: It is unclear whether early treatment of women with a first antenatal HbA1c of 41-46 mmol/mol improves pregnancy outcomes. Our Hospital Guideline (HG) recommends early treatment, but the New Zealand GDM Guideline (NG) recommends lifestyle advice and a 75 g OGTT at 24-28 weeks' gestation. AIMS: The aim of this study was to compare, at a single centre, pregnancy outcomes in women who were treated before 24 weeks (HG group) with women who were managed according to the NG. Our hypothesis was that earlier treatment was associated with lower rates of pre-eclampsia and preterm birth. MATERIALS AND METHODS: Women who had a first antenatal HbA1c of 41-46 mmol/mol between January 2016 and December 2019 and delivered at our institution before August 2020 were included. Baseline characteristics, management of GDM and pregnancy outcomes were collected. Univariable and multivariable analyses were performed. RESULTS: There were 141 women in the HG group and 67 women in the NG group. The NG group had fewer Indian/Chinese/Other Asian women (P = 0.004) and BMI was higher (P = 0.05). Women in the NG group, compared with the HG group, had more infants with a customised birthweight >90th centile (19.4% vs 7.8%, P = 0.014). In addition, after adjusting for ethnicity and BMI, women in the NG group had higher rates of pre-eclampsia (ORa (95th CI), 3.7 (1.1-13.3), P = 0.04) and preterm birth (2.8 (1.1-7.0), P = 0.03). CONCLUSIONS: Management according to our Hospital Guideline, compared with the National GDM Guideline, was associated with lower rates of pre-eclampsia, preterm birth and infants with a customised birthweight >90th centile.

Lower versus higher diagnostic criteria for the detection of gestational diabetes for reducing maternal and perinatal morbidity: study protocol for the GEMS randomised trial.

BACKGROUND: Gestational diabetes mellitus (GDM) has lifelong implications for the woman and her infant. Treatment reduces adverse maternal and perinatal outcomes although uncertainty remains about the optimal diagnostic criteria. The GEMS Trial aims to assess whether detection and treatment of women with GDM using the lower International Association of Diabetes in Pregnancy Study Groups diagnostic criteria compared with the higher criteria recommended in New Zealand reduces infant morbidity without increasing maternal morbidity. METHODS: GEMS is a multicentre, randomised trial. Women with a singleton pregnancy at 24 to 34 weeks' gestation are eligible who give written informed consent. Women are randomly allocated to the Lower Criteria Group or the Higher Criteria Group. Women with a normal OGTT by their allocated criteria receive routine care (Higher criteria: fasting plasma glucose < 5.5 mmol/L, AND 2 hour < 9.0 mmol/L; Lower criteria: fasting plasma glucose < 5.1 mmol/L, AND 1 hour < 10.0 mmol/L, AND 2 hour < 8.5 mmol/l). Women with GDM on OGTT by their allocated criteria receive standard care for GDM (Higher criteria: fasting plasma glucose ≥ 5.5 mmol/L, OR 2 hour ≥ 9.0 mmol/L; Lower criteria: fasting plasma glucose ≥ 5.1 mmol/L, OR 1 hour ≥ 10.0 mmol/L, OR 2 hour ≥ 8.5 mmol/L). The primary outcome is large for gestational age (birth weight > 90th centile). Secondary outcomes for the infant include a composite of serious outcomes, gestational age, anthropometry, Apgar score < 4 at 5 minutes, lung disease, use of respiratory support, hypoglycaemia, hyperbilirubinaemia, infection, and encephalopathy; and for the woman, a composite of serious outcomes, preeclampsia, induction of labour, mode of birth, weight gain, postpartum haemorrhage and infectious morbidity. A study with 4,158 women will detect an absolute difference of 2.9% in the proportion of large for gestational age infants from 10.0% using the lower criteria to 12.9% with the higher criteria. DISCUSSION: The GEMS Trial will provide high-level evidence relevant for clinical practice. If use of the lower diagnostic criteria results in significantly fewer large for gestational age infants and/or improves maternal and perinatal outcomes these criteria should be recommended for diagnosis of gestational diabetes. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry registration number ACTRN12615000290594 . Date registered: 27th March 2015.

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

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.

Reduced Cortical Excitability, Neuroplasticity, and Salivary Cortisol in 11-13-Year-Old Children Born to Women with Gestational Diabetes Mellitus.

BACKGROUND: Children exposed to gestational diabetes mellitus (GDM) in utero are at increased risk of neurodevelopmental difficulties, including autism and impaired motor control. However, the underlying neurophysiology is unknown. METHODS: Using transcranial magnetic stimulation, we assessed cortical excitability, long-term depression (LTD)-like neuroplasticity in 45 GDM-exposed and 12 control children aged 11-13 years. Data were analysed against salivary cortisol and maternal diabetes severity and treatment (insulin [N = 22] or metformin [N = 23]) during pregnancy. FINDINGS: GDM-exposed children had reduced cortical excitability (p = .003), LTD-like neuroplasticity (p = .005), and salivary cortisol (p < .001) when compared with control children. Higher maternal insulin resistance (IR) before and during GDM treatment was associated with a blunted neuroplastic response in children (p = .014) and this was not accounted for by maternal BMI. Additional maternal and neonatal measures, including fasting plasma glucose and inflammatory markers, predicted neurophysiological outcomes. The metformin and insulin treatment groups had similar outcomes. INTERPRETATION: These results suggest that GDM can contribute to subtle differences in child neurophysiology, and possibly cortisol secretion, persisting into early adolescence. Importantly, these effects appear to occur during second trimester, before pharmacologic treatment typically commences, and can be predicted by maternal insulin resistance. Therefore, earlier detection and treatment of GDM may be warranted. Metformin appears to be safe for these aspects of neurodevelopment.

Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition and metabolic outcomes at 7-9 years of age.

OBJECTIVE: To compare body composition and metabolic outcomes at 7-9 years in offspring of women with gestational diabetes (GDM) randomized to metformin (±insulin) or insulin treatment during pregnancy. RESEARCH DESIGN AND METHODS: Children were assessed at 7 years in Adelaide (n=109/181) and 9 years in Auckland (n=99/396) by anthropometry, bioimpedance analysis (BIA), dual-energy X-ray absorptiometry (DXA), magnetic resonance imaging (MRI) (n=92/99) and fasting bloods (n=82/99). RESULTS: In the Adelaide subgroup, mothers were similar at enrollment. Women randomized to metformin versus insulin had higher treatment glycemia (p=0.002) and more infants with birth weight >90th percentile (20.7% vs 5.9%; p=0.029). At 7 years, there were no differences in offspring measures. In Auckland, at enrollment, women randomized to metformin had a higher body mass index (BMI) (p=0.08) but gained less weight during treatment (p=0.07). Offspring birth measures were similar. At 9 years, metformin offspring were larger by measures of weight, arm and waist circumferences, waist:height (p<0.05); BMI, triceps skinfold (p=0.05); DXA fat mass and lean mass (p=0.07); MRI abdominal fat volume (p=0.051). Body fat percent was similar between treatment groups by DXA and BIA. Abdominal fat percentages (visceral adipose tissue, subcutaneous adipose tissue and liver) were similar by MRI. Fasting glucose, triglyceride, insulin, insulin resistance, glycosylated hemoglobin (HbA1c), cholesterol, liver transaminases, leptin and adiponectin were similar. CONCLUSIONS: Metformin or insulin for GDM was associated with similar offspring total and abdominal body fat percent and metabolic measures at 7-9 years. Metformin-exposed children were larger at 9 years. Metformin may interact with fetal environmental factors to influence offspring outcomes.

The use of dextrose/insulin infusions during labour and delivery in women with gestational diabetes mellitus: Is there any point?

We compared, in 733 women with gestational diabetes mellitus treated with metformin and/or insulin, rates of neonatal hypoglycaemia in those who had received a dextrose/insulin infusion during labour and prior to delivery (n = 132) with those who did not (n = 601). Women who had infusions were more likely to have been treated with insulin (87.1% vs 70.4%, P < 0.01) and have higher mean capillary glucose values (measured four times daily) in the two weeks prior to delivery (P < 0.01). They had lower mean (SD) glucose values in the 12 h prior to delivery (5.1 (1.1) mmol/L vs 5.4 (0.9) mmol/L, P < 0.01). There was no difference between the groups in rates of neonatal hypoglycaemia (glucose <2.6 mmol/L on two or more occasions), 15.9% versus 17.8%, P = 0.78, or of severe neonatal hypoglycaemia (one or more glucose <1.6 mmol/L), 8.3% versus 5.2%, P = 0.15. In the absence of randomised data comparing use of infusions with no infusions, these data are reassuring for clinicians who do not routinely use infusions.

Neurodevelopmental outcome at 2†years in offspring of women randomised to metformin or insulin treatment for gestational diabetes.

OBJECTIVE: Gestational diabetes mellitus (GDM) is a common complication of pregnancy and is increasingly being treated with metformin that crosses the placenta rather than insulin, which does not. This study seeks to examine the neurodevelopment of offspring of women treated with metformin or insulin for GDM. DESIGN: We performed a prospective follow-up study of children whose mothers had been randomly assigned at 20-33 weeks gestation to treatment with metformin or insulin for GDM. Of the 211 children followed up at 2 years, 128 were from Auckland, New Zealand (64 metformin vs 64 insulin), and 83 from Adelaide, Australia (39 metformin vs 49 insulin). Neurodevelopment was examined with the Bayley Scales of Infant Development V.2 mental development index (MDI) and psychomotor development index (PDI). Clinical and demographic background characteristics were obtained at enrolment, birth and follow-up. RESULTS: No significant differences were found between treatment groups in clinical or demographic characteristics. The MDI and PDI composite scores were tested with general linear models. No significant differences were found between metformin and insulin, respectively, in New Zealand (MDI, M=83.6 vs 86.9 and PDI, M=83.4 vs M=85.2) or Australia (MDI, M=102.5 vs M=98.4 and PDI, M=105.6 vs M=99.9) and no interactions observed. The differences in neurodevelopmental outcomes between the Auckland and Adelaide cohorts were explained by parental ethnicity, infant birth weight >4000 g, neonatal hypoglycaemia, maternal glycaemia and smoking in the household. CONCLUSIONS: This study provides additional data supporting the safety of metformin in the treatment of GDM. TRIAL REGISTRATION NUMBER: ACTRN 12605000311651.

Women with a nondiagnostic 75 g glucose tolerance test but elevated HbA1c in pregnancy: an additional group of women with gestational diabetes.

We examined whether pregnant women with a normal glucose tolerance test (OGTT) by New Zealand (NZ) criteria, but elevated HbA1c are a clinically important group with gestational diabetes (GDM). Eighty women with a normal OGTT and HbA1c > 40 mmol/mol, compared with others with GDM, had a significantly higher BMI and were more likely Pacific. Pharmacotherapy was prescribed in 77.5%. Post-partum OGTT and HbA1c were abnormal in 9/43(20.9%) and 27/42(64.3%), respectively. In 1090 women being screened for GDM by OGTT, most women with GDM had an HbA1c ≤ 40 mmol/mol. In the 22.1% of women with an HbA1c > 40 mmol/mol, the OGTT was normal in 61.8%. For centres using HbA1c to screen for underlying prediabetes/diabetes, these data show that a result >40 mmol/mol identifies women who are likely to require pharmacotherapy. An OGTT is still recommended to diagnose GDM, but these data raise questions about a possible role for HbA1c in high risk women with a nondiagnostic OGTT.

Maternal and neonatal circulating markers of metabolic and cardiovascular risk in the metformin in gestational diabetes (MiG) trial: responses to maternal metformin versus insulin treatment.

OBJECTIVE: This study was designed to compare glucose, lipids, and C-reactive protein (CRP) in women with gestational diabetes mellitus treated with metformin or insulin and in cord plasma of their offspring and to examine how these markers relate to infant size at birth. RESEARCH DESIGN AND METHODS: Women with gestational diabetes mellitus were randomly assigned to metformin or insulin in the Metformin in Gestational Diabetes trial. Fasting maternal plasma glucose, lipids, and CRP were measured at randomization, 36 weeks' gestation, and 6-8 weeks postpartum as well as in cord plasma. Women with available cord blood samples (metformin n = 236, insulin n = 242) were included. RESULTS: Maternal plasma triglycerides increased more from randomization to 36 weeks' gestation in women treated with metformin (21.93%) versus insulin (9.69%, P < 0.001). Maternal and cord plasma lipids, CRP, and neonatal anthropometry did not differ between treatments. In logistic regression analyses adjusted for confounders, the strongest associations with birth weight >90th centile were maternal triglycerides and measures of glucose control at 36 weeks. CONCLUSIONS: There were few differences in circulating maternal and neonatal markers of metabolic status and no differences in measures of anthropometry between the offspring of women treated with metformin and the offspring of women treated with insulin. There may be subtle effects of metformin on maternal lipid function, but the findings suggest that treating gestational diabetes mellitus with metformin does not adversely affect lipids or CRP in cord plasma or neonatal anthropometric measures.

Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition at 2 years of age.

OBJECTIVE: In women with gestational diabetes mellitus, who were randomized to metformin or insulin treatment, pregnancy outcomes were similar (Metformin in Gestational diabetes [MiG] trial). Metformin crosses the placenta, so it is important to assess potential effects on growth of the children. RESEARCH DESIGN AND METHODS: In Auckland, New Zealand, and Adelaide, Australia, women who had participated in the MiG trial were reviewed when their children were 2 years old. Body composition was measured in 154 and 164 children whose mothers had been randomized to metformin and insulin, respectively. Children were assessed with anthropometry, bioimpedance, and dual energy X-ray absorptiometry (DEXA), using standard methods. RESULTS: The children were similar for baseline maternal characteristics and pregnancy outcomes. In the metformin group, compared with the insulin group, children had larger mid-upper arm circumferences (17.2 ± 1.5 vs. 16.7 ± 1.5 cm; P = 0.002) and subscapular (6.3 ± 1.9 vs. 6.0 ± 1.7 mm; P = 0.02) and biceps skinfolds (6.03 ± 1.9 vs. 5.6 ± 1.7 mm; P = 0.04). Total fat mass and percentage body fat assessed by bioimpedance (n = 221) and DEXA (n = 114) were not different. CONCLUSIONS: Children exposed to metformin had larger measures of subcutaneous fat, but overall body fat was the same as in children whose mothers were treated with insulin alone. Further follow-up is required to examine whether these findings persist into later life and whether children exposed to metformin will develop less visceral fat and be more insulin sensitive. If so, this would have significant implications for the current pandemic of diabetes.

Glycemia and its relationship to outcomes in the metformin in gestational diabetes trial.

OBJECTIVE: To determine how glucose control in women with GDM treated with metformin and/or insulin influenced pregnancy outcomes. RESEARCH DESIGN AND METHODS: Women randomly assigned to metformin or insulin treatment in the Metformin in Gestational Diabetes (MiG) trial had baseline glucose tolerance test (OGTT) results and A1C documented, together with all capillary glucose measurements during treatment. In the 724 women who had glucose data for analysis, tertiles of baseline glucose values and A1C and of mean capillary glucose values during treatment were calculated. The relationships between maternal factors, glucose values, and outcomes (including a composite of neonatal complications, preeclampsia, and large-for-gestational-age [LGA] and small-for-gestational-age infants) were examined with bivariable and multivariate models. RESULTS: Baseline OGTT did not predict outcomes, but A1C predicted LGA infants (P = 0.003). During treatment, fasting capillary glucose predicted neonatal complications (P < 0.001) and postprandial glucose predicted preeclampsia (P = 0.016) and LGA infants (P = 0.001). Obesity did not influence outcomes, and there was no interaction between glycemic control, randomized treatment, or maternal BMI in predicting outcomes. The lowest risk of complications was seen when fasting capillary glucose was <4.9 mmol/l (mean +/- SD 4.6 +/- 0.3 mmol/l) compared with 4.9-5.3 mmol/l or higher and when 2-h postprandial glucose was 5.9-6.4 mmol/l (6.2 +/- 0.2 mmol/l) or lower. CONCLUSIONS: Glucose control in women with gestational diabetes mellitus treated with metformin and/or insulin is strongly related to outcomes. Obesity is not related to outcomes in this group. Targets for fasting and postprandial capillary glucose may need to be lower than currently recommended.

Customised birthweight centiles are useful for identifying small-for-gestational-age babies in women with type 2 diabetes.

BACKGROUND: Customised birthweight centiles identify small-for-gestational-age (SGA) babies at increased risk of morbidity more accurately than population centiles, but they have not been validated in obese populations. AIMS: To compare the rates of SGA by population and customised birthweight centiles in babies of women with type 2 diabetes and examine perinatal outcomes in customised SGA infants. METHODS: Data were from a previous retrospective cohort study detailing pregnancy outcomes in 212 women with type 2 diabetes. Customised and population birthweight centiles were calculated; pregnancy details and neonatal outcomes were compared between groups that delivered infants who were SGA (birthweight < 10th customised centile) and appropriate weight for gestational age (AGA) (birthweight 10-90th customised centile). RESULTS: Fifteen (7%) babies were SGA by population centiles and 32 (15%) by customised centiles. Two babies of Indian women were reclassified from SGA to AGA by customised centiles. Nineteen babies were reclassified from AGA to SGA by customised centiles; of these, 15 (79%) were born to Polynesian women, five (26%) were born less than 32 weeks and two (11%) were stillborn. Customised SGA infants, compared with AGA infants, were more likely to be born preterm (19 (59%) vs 20 (16%), P < 0.001) and more likely to be stillborn (4 (13%) vs 0 P = 0.001). After excluding still births, admission to the neonatal unit was also more common (19 of 28 (68%) vs 43 of 127 (34%), P < 0.001). CONCLUSIONS: In our population more babies were classified as SGA by customised compared with population centiles. These customised SGA babies have high rates of morbidity.

Metformin versus insulin for the treatment of gestational diabetes.

BACKGROUND: Metformin is a logical treatment for women with gestational diabetes mellitus, but randomized trials to assess the efficacy and safety of its use for this condition are lacking. METHODS: We randomly assigned 751 women with gestational diabetes mellitus at 20 to 33 weeks of gestation to open treatment with metformin (with supplemental insulin if required) or insulin. The primary outcome was a composite of neonatal hypoglycemia, respiratory distress, need for phototherapy, birth trauma, 5-minute Apgar score less than 7, or prematurity. The trial was designed to rule out a 33% increase (from 30% to 40%) in this composite outcome in infants of women treated with metformin as compared with those treated with insulin. Secondary outcomes included neonatal anthropometric measurements, maternal glycemic control, maternal hypertensive complications, postpartum glucose tolerance, and acceptability of treatment. RESULTS: Of the 363 women assigned to metformin, 92.6% continued to receive metformin until delivery and 46.3% received supplemental insulin. The rate of the primary composite outcome was 32.0% in the group assigned to metformin and 32.2% in the insulin group (relative risk, 0.99 [corrected]; 95% confidence interval, 0.80 [corrected] to 1.23 [corrected]). More women in the metformin group than in the insulin group stated that they would choose to receive their assigned treatment again (76.6% vs. 27.2%, P<0.001). The rates of other secondary outcomes did not differ significantly between the groups. There were no serious adverse events associated with the use of metformin. CONCLUSIONS: In women with gestational diabetes mellitus, metformin (alone or with supplemental insulin) is not associated with increased perinatal complications as compared with insulin. The women preferred metformin to insulin treatment. (Australian New Zealand Clinical Trials Registry number, 12605000311651.).

Metformin therapy and diabetes in pregnancy.

No adverse pregnancy outcomes with metformin use have been reported, except in one unmatched study. Otherwise, the studies are small and non-randomised, with the exception of one prospective, randomised controlled trial, currently under way, comparing metformin with insulin in women with gestational diabetes mellitus (the MiG trial). No long-term follow-up data for offspring of mothers receiving metformin have been published. Any woman with diabetes should be as close to euglycaemia as possible before pregnancy. In some circumstances (eg, severe insulin resistance), metformin therapy during pregnancy may be warranted. When metformin treatment is being considered, the individual risks and benefits need to be discussed with the patient so that an appropriate decision can be reached.