Pregnancy in women with Type 2 diabetes: who takes metformin and what is the outcome?

AIMS: To review pregnancy outcomes in women with Type 2 diabetes (Type 2 DM), comparing women treated with those not treated with metformin. METHODS: Data were collected by case-note review for all pregnancies in women with Type 2 DM over a 6-year period (1998-2003) at the National Women's Hospital. Two hundred and fourteen pregnancies were included, metformin was taken in 93 pregnancies and continued until delivery in 32; the remaining 121 pregnancies comprised the control group. The principal outcome measures were preeclampsia, perinatal loss and neonatal morbidity. RESULTS: Baseline characteristics differed between groups: women in the metformin group had greater mean (SD) body mass index [35.5(7.6) vs. 33.5(6.6) kg/m2, P < 0.05], more chronic hypertension (19% vs. 7%, P < 0.05) and higher mean (SD) first trimester glycated haemoglobin (HbA1c) levels [8.3(1.9)% vs. 7.5(1.7)%, P < 0.005]. There was no difference between metformin and control groups, respectively, in the rate of preeclampsia (13% vs. 14%, P = 0.84), perinatal loss (3% vs. 2%, P = 0.65) or neonatal morbidity, including rate of prematurity (23% vs. 22%, P = 0.7), admission to the neonatal unit (40% vs. 48%, P = 0.27), respiratory distress (9% vs. 18%, P = 0.07) and treatment with intravenous dextrose (20% vs. 31%, P = 0.08). CONCLUSIONS: Pregnant women with Type 2 DM who were treated with metformin had more risk factors for adverse pregnancy outcomes, but no differences in outcomes were seen compared with women not taking metformin. We need randomized trials to address potential benefits of metformin treatment in this population that may be masked by current practice.     

St Vincent's Declaration 10 years on: outcomes of diabetic pregnancies.

AIMS: To monitor pregnancies in women with pregestational Type 1 diabetes for pregnancy loss, congenital malformations and fetal growth parameters, in a geographically defined area in the north west of England. METHODS: Population cohort study of 547 pregnancies in women with Type 1 diabetes from maternity clinics in 10 centres over a 5-year period (1995-1999 inclusive). Main outcome measures were numbers and rates of miscarriages, stillbirths, neonatal and post-neonatal deaths; prevalence of congenital malformations; birth weight in relation to gestational age. RESULTS: Among 547 pregnancies, there were six (1.1%) pairs of liveborn twins, 439 (80.3%) liveborn singletons; 72 (13.2%) spontaneous abortions, 14 (2.6%) stillbirths and 16 (2.9%) terminations. Four of the terminations were performed because of congenital malformations. Both the stillbirth rate (30.1/1000 total births (95% confidence interval (CI) 16.6-50.0)), and prevalence of congenital malformations (84.3/1000 live births (95% CI 60.3-113.8)) were significantly higher than the local population (P < 0.001). When corrected for gestational age, mean birth weight in the sample was 1.3 sd greater than that of infants of non-diabetic mothers (P = 0.12). Infants with congenital malformations weighed less than those without. CONCLUSION: In an unselected population, the infants of women with pregestational Type 1 diabetes mellitus have 6.4 times the reported risk of a congenital malformation and 5.1 times the reported risk of perinatal mortality than infants in the general population. Further improvements in the management of diabetes and pregnancy in these women are needed if the St Vincent's Declaration target is to be met.     

Perinatal mortality in Type 2 diabetes mellitus.

AIMS: In many parts of the world the number of pregnancies in women with Type 2 diabetes mellitus (DM) now exceeds that in women with Type 1 DM, but there are few data published on perinatal mortality in Type 2 DM. This study reports observational data on perinatal mortality in Type 2 DM from a population with a high background rate of this disorder. METHODS: Over a 12-year period (1985-1997) at the Diabetes Clinic at National Women's Hospital, Auckland, there were 434 pregnancies in women with Type 2 DM (256 known and 178 diagnosed with gestational diabetes mellitus (GDM), but confirmed to have Type 2 DM early post-partum), 160 pregnancies in women with Type 1 DM and 932 in women with GDM. Perinatal mortality was classified as either intermediate fetal death (20-28 weeks' gestation), late fetal death (28 weeks' gestation to term) or early neonatal death (up to 1 month post-partum). RESULTS: The perinatal mortality in Type 2DM was 46.1/1,000, significantly higher than the rates for the general population (12.5), Type 1 DM (12.5) and GDM (8.9) (P < 0.0001). Congenital malformations accounted for only 10% of the perinatal mortality. There was a seven-fold increase in the rate of late fetal death and 2.5-fold increase in the rates of intermediate fetal and late neonatal death. Subjects with Type 2 DM were significantly older and more obese than subjects with Type 1 DM, and presented later to the diabetes service. CONCLUSIONS: Perinatal mortality in Type 2 DM is significantly increased, mainly owing to an excess of late fetal death. Maternal factors such as obesity may be important contributors to the high perinatal mortality. Women diagnosed with GDM who have unrecognized Type 2 DM are also at high risk, but perinatal mortality is low in women with milder degrees of glucose intolerance in pregnancy.     

Microalbuminuria in patients with Type 2 diabetes mellitus from general practice: course and predictive value.

AIMS: To assess the course of microalbuminuria in patients with Type 2 diabetes mellitus in general practice and the predictive value of urinary albumin concentration on all-cause mortality, cardiovascular mortality and cardiovascular morbidity. METHODS: Cohort study in Type 2 diabetic patients tested for microalbuminuria in 1992, and re-tested in 1998. During follow-up all cardiovascular morbidity and mortality were recorded. RESULTS: Of the original sample of 317 patients, 163 patients were re-tested. The mean change in urinary albumin concentration was +16.2 mg/l (range -122.0 to +602 mg/l). Seventy-five per cent of the patients without microalbuminuria in 1992 still had no microalbuminuria in 1998 and 40% of those with microalbuminuria in 1992 reverted to normoalbuminuria in 1998. Cox survival analysis, stratified for age, showed that microalbuminuria at baseline resulted in a risk ratio of all-cause mortality of 1.4 (95% confidence interval 0.8-2.7), of cardiovascular mortality of 1.2 (0.5-2.8) and of new cardiovascular events (including cardiovascular mortality) of 1.4 (0.8-2.3). CONCLUSIONS: In the majority of patients the change of urinary albumin excretion was small, but the range was wide. A weak non-significant relationship between microalbuminuria and all-cause mortality and cardiovascular morbidity was observed.     

Hypertensive disorders of pregnancy in women with Type 1 and Type 2 diabetes.

AIMS: Hypertensive disorders in pregnancy are common in women with Type 1 diabetes and can be associated with adverse fetal outcomes, but little is known about hypertension in pregnancy in women with Type 2 diabetes. The aim of this study was to compare the incidence and outcomes of, and risk factors for, hypertension in pregnancy in women with Type 1 and Type 2 diabetes. METHODS: One hundred consecutive singleton pregnancies in women with Type 2 and 100 in women with Type 1 diabetes were studied. Hypertension in pregnancy was classified according to Australasian Society for the Study of Hypertension in Pregnancy guidelines. Outcomes of pregnancy examined included birth weight, rates of caesarean section, premature delivery and special care unit admission, and perinatal mortality. RESULTS: The overall incidence of hypertension in pregnancy was similar in Type 2 and Type 1 diabetes (41% vs. 45%), but the distribution of subtypes differed (P = 0.028). Women with Type 2 diabetes had more chronic hypertension (diagnosed at < 20 weeks gestation), but less preeclampsia than women with Type 1 diabetes. Hypertension in pregnancy was strongly associated with a number of adverse outcomes, but the impact of hypertension was significantly less for Type 2 diabetes than it was for Type 1 (premature delivery, P < 0.005; admission to Special Care Unit, P < 0.01; caesarean section, P = 0.05). This was, in part, because the frequency of adverse outcomes was greater in women with preeclampsia. Nulliparity, poor glycaemic control at presentation, and early pregnancy blood pressure and not smoking were risk factors for hypertension of similar magnitude in both types of diabetes. Significant effects of duration of diabetes and obesity were not seen in Type 2 subjects, but were in Type 1 (P < 0.01, P < 0.05, respectively). Early pregnancy albumin excretion rate was increased more frequently in Type 2 subjects than in Type 1 (P < 0.035), but was less strongly associated with the development of preeclampsia (P < 0.035). CONCLUSIONS: The incidence of hypertension in pregnancy is similar in Type 2 and Type 1 diabetes, but the different population characteristics are reflected in a significantly different pattern of types of hypertension. Hypertension has less impact on adverse outcomes in Type 2 diabetes. Some risk factors for hypertension also differ between Type 2 and Type 1 diabetes.     

Obstetric and diabetic care for pregnancy in diabetic women: 10 years outcome analysis, 1985-1995.

AIM: Ten-year outcome analysis of all pregnancies in diabetic women in a population of 1.5 million people. METHODS: Ascertainment of patients through the regional obstetrical computer, and by direct contact with each obstetrical unit. Retrospective assessment of early miscarriage of pregnancy from hospital records. Data are presented for the six smallest obstetrical units, the four smaller district hospitals, two larger teaching hospitals and for the regional referral centre. RESULTS: Nine hundred and eighty-six fetal outcomes were identified, 753 in mothers treated with insulin before the pregnancy, 131 in mothers in whom insulin was started for the first time during the pregnancy and 102 in mothers treated by diet only. Overall perinatal mortality rates were 35.8 per 1000 for those mothers booked and delivered at a local maternity unit, 28.9 per 1000 for those booked and delivered at the regional centre, but 75.0 per 1000 for those who had booked locally but were transferred to the centre mid-pregnancy. Information on blood glucose control before and during pregnancy was relatively poorly documented. For the available data at the regional centre, only 160 of the 416 mothers had an identifiable preconception HbA1c measurement (mean 7.9%, range 3.3-16.8%): at booking 360 of these mothers had a mean HbA1c of 7.5% and by the third trimester mean HbA1c was 6.3% (range 3.3-13.2%). CONCLUSIONS: The outcome of pregnancy in a diabetic mother in Northern Ireland remains a higher risk than for the general population. There is evidence that results in the regional centre are better, but problems arise when transfers occur mid-pregnancy. Measurement and recording of blood glucose control at all stages before and during pregnancy is incomplete. Diabet. Med. 18, 546-553 (2001)     

Congenital anomalies in the offspring of women with type 1, type 2 and gestational diabetes.

AIM: To determine the frequency of major congenital anomalies in the offspring of women with gestational diabetes (GDM), classified according to their postpartum glucose tolerance status. METHODS: A prospective study of pregnancies in women with Type 1 diabetes (n = 221), Type 2 diabetes (n = 317) and GDM (n = 1822) between 1985 and 2000 (15 years). Congenital anomalies were detected by antenatal ultrasound or postnatal examination. RESULTS: The frequency of major congenital anomalies in the offspring was 5.9% (95% confidence interval (CI) 3.2-9.8) for women with Type 1 diabetes; 4.4% (95% CI 2.4-7.3) for women with Type 2 diabetes; and 1.4% (95% CI 0.9-2.0) for women with GDM. Two hundred and thirty-seven women with GDM (13%) had diabetes diagnosed on early (6-week) postpartum glucose tolerance testing. The frequency of major congenital anomalies in their offspring was 4.6% (95% CI 2.3-8.2), compared with 0.9% (95% CI 0.5-1.5) for the remainder of the GDM group (P < 0.0001). CONCLUSIONS: GDM is not a homogeneous group with regard to the risk of major congenital anomalies. In those with diabetes on early postpartum testing, who are likely to have had unrecognized Type 2 diabetes antedating their pregnancy, the rate of major congenital anomalies is the same as for women with established Type 1 or Type 2 diabetes. In the remainder of the GDM group, the rate does not differ from the non-diabetic background rate.     

The pregnancies of women with Type 2 diabetes: poor outcomes but opportunities for improvement.

AIM: To compare the outcomes of Type 1 and Type 2 diabetic pregnancies and identify risk factors for poor outcome of Type 2 pregnancies METHODS: The data from all (389 Type 1 and 146 Type 2) pre-gestational diabetic pregnancies from 10 UK hospitals were collected prospectively. RESULTS: The Type 2 mothers were less likely to have documented pre-pregnancy counselling (28.7 vs. 40.5%; P<0.05) or be taking folic acid at conception (21.9 vs. 36.4%; P<0.001) than Type 1 mothers. The percentage of pregnancies having a serious adverse outcome was higher in Type 2 patients (16.4 vs. 6.4%; P=0.002). Congenital abnormalities (12.3% in Type 2 vs. 4.4% in Type 1; P=0.002) accounted for most of this difference. The HbA1c of the Type 2 patients was similar to that of the Type 1 with mean first trimester HbA1c of 7.22 and 7.35%, respectively (P=0.5). Treatment with oral hypoglycaemic agents [odds ratio (OR), 1.8; 95% confidence interval (CI), 1.0-3.3; P=0.04], body mass index (OR, 1.09; 95% CI, 1.01-1.18; P=0.02) and folic acid supplementation (OR, 0.3; 95% CI, 0.09-1.0; P=0.04) were all independently associated with congenital malformation. CONCLUSION: Type 2 diabetic pregnancies are characterized by poor pre-pregnancy planning, inadequate folic acid supplementation and treatment with oral hypoglycaemic agents, all of which may contribute to the serious adverse outcomes affecting one in six Type 2 diabetic pregnancies. These remediable aspects of the pre-pregnancy care of women with Type 2 diabetes provide opportunities for improving the outcome towards that of women with Type 1 diabetes.     

Determinants of a good perinatal outcome in 588 pregnancies in women with type 1 diabetes

Aim

This study assessed pregnancy outcomes in women with type 1 diabetes (T1D) over the last 15 years and identified modifiable factors associated with good perinatal outcomes.

Risk of specific congenital abnormalities in offspring of women with diabetes.

AIMS: To assess the extent to which the increased risk of congenital abnormalities seen in women with pre-gestational insulin-treated diabetes mellitus is unspecific or related to the embryology of specific organs. METHODS: Cases with congenital abnormalities were identified in the population-based Hungarian Congenital Abnormality Registry from 1980 to 1996 with two newborn children without congenital abnormality selected from the National Birth Registry as controls. We adjusted for parity, maternal age, and use of antipsychotic drugs. RESULTS: Among cases we found 63/22,843 babies with maternal diabetes compared with 50/38,151 in the control group [adjusted prevalence odds ratio (POR) 2.1; 95% CI 1.5-3.1]. The association was strongest for the following congenital abnormalities: renal agenesis (POR: 14.8; 95% CI, 3.5-62.1), obstructive congenital abnormalities of the urinary tract (POR: 4.3; 95% CI, 1.3-13.9), cardiovascular congenital abnormalities (POR: 3.4; 95% CI, 2.0-5.7), and multiple congenital abnormalities (POR: 5.0; 95% CI, 2.4-10.2). CONCLUSIONS: These data indicate that pre-gestational maternal diabetes is associated with strong teratogenic effects on the kidney, urinary tract, and heart, and strongly associated with multiple congenital abnormalities. We found no material association between diabetes and spinal congenital abnormalities and limb deficiencies.     

Prognosis following first acute myocardial infarction in Type 2 diabetes: a comparative population study.

AIMS: To estimate the incidence of death and macrovascular complications after a first myocardial infarction for patients with Type 2 diabetes. RESEARCH DESIGN: In a retrospective, incidence cohort study in the Tayside Region of Scotland we studied all patients hospitalized with a diagnosis of first acute myocardial infarction from 1 April 1993 to 31 December 1994. The primary endpoint was time to death. Secondary endpoints were 2-year incidence of hospital admission for angina, myocardial infarction, stroke, heart failure, coronary angiography, coronary artery bypass graft (CABG) and percutaneous transluminal coronary angioplasty (PTCA). RESULTS: The 147 patients with Type 2 diabetes had significantly worse survival with an increase in relative hazard of 67% compared with non-diabetic patients. After adjustment for age, sex, smoking status, prior heart failure, prior angina, delay to hospitalization, site of infarction, drug therapy with aspirin, beta-blockers, streptokinase and hyperlipidaemia and treated hypertension, Type 2 diabetes was still associated with a 40% higher death rate compared with people without diabetes (P < 0.05) There was no significant difference in death rates in those aged over 70 years, but an indication of a trend in younger individuals with a four-fold increase in death rate in those with diabetes aged < 60 years, compared with a rate ratio of 2.6 in those with diabetes aged 61-70 years. CONCLUSIONS: Among hospitalized patients with first acute myocardial infarction, Type 2 diabetes mellitus is consistently associated with increased mortality and increased hospital admission for heart failure. The estimated 4-year survival rate is only 50%. Our results indicate that younger subjects with Type 2 diabetes and acute myocardial infarction are a high-risk group deserving of special study, and support the argument for aggressive targeting of coronary risk factors among patients with Type 2 diabetes.     

Pregnancy in women with diabetes—after the CEMACH report,what now?

The second of three studies being undertaken by the Confidential Enquiry into Maternal and Child Health (CEMACH) has recently reported its findings and recommendations. The standards of diabetes and maternal care and the outcomes of 3808 pregnancies in England, Wales and Northern Ireland are described. Pre-pregnancy planning and care before conception is poor. Stillbirth rate (26.8 per thousand) and perinatal mortality (41.8 per thousand) were 4-5 times higher than the background population, and congenital anomaly (41.8 per thousand) double the background rate. Type 2 diabetes now represents 27.3% of pre-gestational diabetes and more often of ethnic minority and deprived background than Type 1 diabetes. The ideals of the Diabetes National Service Framework and the target of the Saint Vincent declaration are far from being achieved. Much can be done to improve the outcomes of pregnancy within existing resources with better systems and organization of care. However, if significant progress is to be made, it is incumbent upon health-care professionals and health-care commissioners to direct resources specifically at improving pre-pregnancy and maternity services. Research is needed firstly to analyse in greater detail the wealth of data collected in the CEMACH survey and consider the implications of health-care costs. Further research to discover ways of reducing the adverse outcomes is urgently required. The need to educate, motivate and bring about improved pre-pregnancy care in women with diabetes is a priority.     

Lipid but not glycaemic parameters predict total mortality from Type 2 diabetes mellitus in Canterbury,New Zealand

A cohort of 447 subjects with Type 2 diabetes mellitus (208 male, 239 female; age range 30–82, median 62 years; and of predominantly European origin) was characterized in a clinic survey in 1989. Individual status (dead or alive) at 1 June 1995 was ascertained. Mortality rates were compared with the general New Zealand population by calculating standardized mortality ratios (SMR) and the hazard ratio (HR) of prognostic factors evaluated with Cox’s proportional hazards model. At 6 years, 289 subjects were confirmed as alive and 133 as dead; only 25 were untraceable. Six-year survival for the cohort was 70 % (95 % CI 66–74). SMR was 2.53 (95 % CI 1.99–2.68) for the female cohort and 2.03 (95 % CI 1.60–2.59) for the male cohort. Factors assessed at baseline (1989) that were independently prognostic of total mortality included age, male sex, pre-existing coronary artery disease (CAD) (HR 2.2, 95 % CI 1.5–3.3) and plasma cholesterol (HR for 1.4 mmol l⁻¹ change: 1.49, 95 % CI 1.2–1.9). HDL-cholesterol was protective in women (HR for 0.4 mmol l⁻¹ change: 0.72, 95 % CI 0.51–1.00) but not men. Glycated haemoglobin was not a significant predictor of total mortality. Predictors of CAD mortality (in those subjects free of CAD in 1989) included plasma cholesterol (HR for 1.4 mmol l⁻¹ change: 1.86 95 % CI 1.20–2.89), glycated haemoglobin (HR for 1.8 % change: 1.9 95 % CI 1.04–3.47), male sex, peripheral vascular disease, and smoking. There is therefore increased mortality in Type 2 diabetic subjects in Canterbury, New Zealand. HDL-cholesterol is protective against total mortality in females. © 1998 John Wiley & Sons, Ltd.     

Renal damage in patients with Type 2 diabetes: a strong predictor of mortality.

AIMS: (i) To compare mortality rates in a cohort of Type 2 diabetic patients with those of the general population; (ii) to assess the prognostic role of pre-existing chronic conditions; (iii) to evaluate the impact of different severity of renal damage on mortality. METHODS: All 3892 patients with Type 2 diabetes attending our Diabetic Clinic during 1995 and alive on 1 January 1996 were identified and followed for 4.5 years. Information on vital status (100% complete) and causes of death (98.5% complete) for 599 deceased subjects was derived from death certificates. RESULTS: In comparison with the general population, standardized mortality ratios (x 100) were: 125 (95% confidence interval 104-148) in patients aged < 75 and 85 (75-95) in patients > or = 75 years. Cardiovascular diseases and diabetes were responsible for most of the excess deaths. In a Cox-proportional hazard model, renal damage was a powerful predictor of death (hazard ratio = 2.39; 95% confidence intervals = 2.00-2.85). The severity of renal damage was associated with increasing hazard ratios for death from all-cause mortality and from specific causes (especially coronary artery disease, other cardiovascular causes and diabetes) after multiple adjustments. Other significant predictors of death were: greater age, glycated haemoglobin, smoking, lower body mass index, pre-existing coronary and peripheral artery disease and known co-morbidity (cirrhosis and cancer). CONCLUSIONS: Renal damage of any severity is significantly associated with subsequent mortality from all causes and from cardiovascular diseases. These associations are not confounded by pre-existing co-morbidity or coronary diseases.     

Metformin in management of pregnant insulin-independent diabetics

Summary Sixty pregnant maturity-onset (insulin-independent), established and gestational, diabetics were treated with Metformin in the second and third trimester after dietary treatment had failed. The incidence of Metformin failure was 53.8% in the established diabetics and 28.6% in the gestational diabetics. The 27 Metformin failures were transferred to other therapy, leaving for further analysis 33 patients who received Metformin up till delivery. Two neonatal deaths occurred in this group (1 congenital abnormality and 1 preterm infant) giving a perinatal mortality of 61/1000. This compares with a perinatal mortality of 103/1000 in the Metformin failure group and 105/1000 in a group of insulin-dependent diabetics treated during the same period. Apart from a high incidence of neonatal jaundice requiring phototherapy the infant morbidity in the Metformin group was low. The mothers of 3 infants with congenital abnormalities had received Metformin only during the last trimester of their pregnancy.     

Pregnancy outcome in Type 1 diabetes mellitus treated with insulin lispro (Humalog).

AIMS: The use of insulin lispro in pregnancy has not been systematically investigated despite its increasing use. Pooled data from seven centres with experience in the use of insulin lispro were accumulated to evaluate pregnancy outcome in women with Type 1 diabetes. METHODS: Seven units with specialist obstetric diabetes services were recruited to describe their total experience with insulin lispro in pregnancy. Outcomes with respect to the rate of miscarriage, congenital abnormality, perinatal mortality and maternal parameters were recorded in a standardized format. RESULTS: Outcomes on 71 babies from 76 pregnancies were documented. There were six (7.8%) early miscarriages. All 71 babies were liveborn with a mean gestational age of 37.2 weeks, and median birthweight of 3230 g. Seven babies weighed > 4 kg. There were four congenital abnormalities (5.6%). There was a 72% increase in the mean insulin dose (0.75-1.29 IU/kg per day). Maternal glycaemic control improved throughout pregnancy. No women developed retinopathy de novo during pregnancy and six with established retinopathy required laser therapy during pregnancy. CONCLUSIONS: The use of insulin lispro in Type 1 diabetes during pregnancy results in outcomes comparable to other large studies of diabetic pregnancy.