The role of modifiable pre-pregnancy risk factors in preventing adverse fetal outcomes among women with type 1 and type 2 diabetes.

We investigated the fetal outcomes of pregnancy in women with pre-existing diabetes in relation to pre-pregnancy risk factors using a community-based cohort of women in Tayside, Scotland. There were 211 pregnancies in 132 women with insulin-requiring type 1 and 2 diabetes between January 1993 and December 2005. Adverse fetal outcome was classified as spontaneous miscarriage, termination for medical reasons, stillbirth, neonatal death, or congenital malformation and occurred in 61 (29%) pregnancies. Mothers with poor glycemic control pre-conceptually and at booking (HbA(1c)=7.5%) had almost a three-fold increase in adverse fetal outcome compared with mothers having fair control, odds ratio (OR) 2.59 (95% CI 1.11-6.03), and 2.71 (95% CI 1.39-5.28), respectively. Mothers who were still smoking at the booking visit had a two-fold increase in adverse fetal outcome (OR 2.12, 95% CI 1.09-4.10). Further improvement in the management of diabetes and pregnancy is needed through enhanced preconception services addressing the full spectrum of modifiable risk factors.

Outcomes for births booked under an independent midwife and births in NHS maternity units: matched comparison study.

OBJECTIVE: To compare clinical outcomes between women employing an independent midwife and comparable pregnant women using NHS services. DESIGN: Anonymised matched cohort analysis. Cases from the database of the Independent Midwives' Association (IMA) matched up to 1:5 with Scottish National Health Service (NHS) records for age, parity, year of birth, and socioeconomic status. Multivariable logistic regression models used to explore the relation between explanatory variables and outcomes; analyses controlled for potential confounding factors and adjusted for stratification. SETTING: UK databases 2002-5. PARTICIPANTS: Anonymised records for 8676 women (7214 NHS; 1462 IMA). MAIN OUTCOME MEASURES: Unassisted vertex delivery, live birth, perinatal death, onset of labour, gestation, use of analgesia, duration of labour, perineal trauma, Apgar scores, admission to neonatal intensive care, infant feeding. RESULTS: IMA cohort mothers were significantly more likely to achieve an unassisted vertex delivery than NHS cohort mothers (77.9% (1139) v 54.3% (3918); odds ratio 3.49, 95% confidence interval 2.99 to 4.07) but also significantly more likely to experience a stillbirth or a neonatal death (1.7% (25) v 0.6% (46); 5.91, 3.27 to 10.7). All odds ratios are adjusted for confounding factors. Exclusion of "high risk" cases from both cohorts showed a non-significant difference (0.5% (5) v 0.3% (18); 2.73, 0.87 to 8.55); the "low risk" IMA perinatal mortality rate is comparable with other studies of low risk births. Women in the IMA cohort had a higher incidence of pre-existing medical conditions (1.5% (22) v 1.0% (72) in the NHS cohort) and previous obstetric complications (21.0% (307) v 17.8% (1284)). The incidence of twin pregnancy was also higher (3.4% (50) v 3.1% (224)). In the IMA cohort, 66.0% of mothers (965/1462) had home births, compared with only 0.4% of NHS cohort mothers (27/7214). Spontaneous onset of labour was more common in the IMA group (96.6% (1405) v 74.5% (5365); 10.43, 7.74 to 14.0), and fewer mothers used pharmacological analgesia (40.2% (588) v 60.6% (4370); 0.42, 0.38 to 0.47). Mothers in the IMA cohort were much more likely to breast feed (88.0% (1286) v 64.0% (2759); 3.46, 2.84 to 4.20). Prematurity (4.3% (63) v 6.9% (498); 0.49, 0.35 to 0.69), low birth weight (4.0% (60) v 7.1%) (523); 0.93, 0.62 to 1.38), and rate of admission to neonatal intensive care (4.4% (65) v 9.3% (667); 0.43, 0.32 to 0.59) were all higher in the NHS dataset. CONCLUSIONS: Healthcare policy tries to direct patient choice towards clinically appropriate and practicable options; nevertheless, pregnant women are free to make decisions about birth preferences, including place of delivery and staff in attendance. While clinical outcomes across a range of variables were significantly better for women accessing an independent midwife, the significantly higher perinatal mortality rates for high risk cases in this group indicate an urgent need for a review of these cases. The significantly higher prematurity and admission rates to intensive care in the NHS cohort also indicate an urgent need for review.

Treatment with the xanthine oxidase inhibitor, allopurinol, improves nerve and vascular function in diabetic rats.

Several putative sources of reactive oxygen species could potentially contribute to diabetic neuropathy and vasculopathy. The aim was to assess the involvement of elevated xanthine oxidase activity. After 6 weeks of streptozotocin-diabetes, groups of rats were given 2 weeks of high-dose allopurinol treatment (50 and 250 mg/kg) to gauge the effect of maximal blockade of xanthine oxidase. In the final experiments, rats were subjected to sensory testing and, under butabarbital anaesthesia, measurements were made on nerve conduction velocities and neural tissue blood flow estimated by hydrogen clearance microelectrode polarography. Further groups were used to study detailed responses of the isolated mesenteric vascular bed after 4 weeks of diabetes and allopurinol (150 mg/kg) treatment. Diabetes caused 20% and 14% reduction in motor and sensory conduction velocity, which were 78% and 81% corrected by allopurinol treatment respectively, both doses giving similar results. Diabetic rats showed tactile allodynia and thermal hyperalgesia, which were completely corrected by allopurinol, whereas mechanical hyperalgesia was only 45% ameliorated. Sciatic nerve and superior cervical ganglion blood flow was halved by diabetes and allopurinol corrected this by approximately 63%. Mesenteric endothelium-dependent vascular responses to acetylcholine, which depend upon nitric oxide and endothelium derived hyperpolarizing factor, were attenuated by diabetes. Allopurinol treatment gave approximately 50% protection for both components. Thus, xanthine oxidase is an important source of reactive oxygen species that contributes to neurovascular dysfunction in experimental diabetes. Inhibition of xanthine oxidase could be a potential therapeutic approach to diabetic neuropathy and vasculopathy.

Poor glycated haemoglobin control and adverse pregnancy outcomes in type 1 and type 2 diabetes mellitus: systematic review of observational studies.

BACKGROUND: Glycaemic control in women with diabetes is critical to satisfactory pregnancy outcome. A systematic review of two randomised trials concluded that there was no clear evidence of benefit from very tight versus tight glycaemic control for pregnant women with diabetes. METHODS: A systematic review of observational studies addressing miscarriage, congenital malformations and perinatal mortality among pregnant women with type 1 and type 2 diabetes was carried out. Literature searches were performed in MEDLINE, EMBASE, CINAHL and Cochrane Library. Observational studies with data on glycated haemoglobin (HbA1c) levels categorised into poor and optimal control (as defined by the study investigators) were selected. Relative risks and odds ratios were calculated for HbA1c and pregnancy outcomes. Adjusted relative risk estimates per 1-percent decrease in HbA1c were calculated for studies which contained information on mean and standard deviations of HbA1c. RESULTS: The review identified thirteen studies which compared poor versus optimal glycaemic control in relation to maternal, fetal and neonatal outcomes. Twelve of these studies reported the outcome of congenital malformations and showed an increased risk with poor glycaemic control, pooled odds ratio 3.44 (95%CI, 2.30 to 5.15). For four of the twelve studies, it was also possible to calculate a relative risk reduction of congenital malformation for each 1-percent decrease in HbA1c, these varied from 0.39 to 0.59. The risk of miscarriage was reported in four studies and was associated with poor glycaemic control, pooled odds ratio 3.23 (95%CI, 1.64 to 6.36). Increased perinatal mortality was also associated with poor glycaemic control, pooled odds ratio 3.03 (95%CI, 1.87 to 4.92) from four studies. CONCLUSION: This analysis quantifies the increase in adverse pregnancy outcomes in women with diabetes who have poor glycaemic control. Relating percentage risk reduction in HbA1c to relative risk of adverse pregnancy events may be useful in motivating women to achieve optimal control prior to conception.

Organisational factors in relation to control of blood pressure: an observational study.

BACKGROUND: Studies show that 60-75% of treated patients with hypertension in general practice, still do not reach the recommended blood pressure targets of <150/90 mmHg. AIM: To investigate aspects of hypertension management in relation to sociodemographic variables, antihypertensive drug treatment, and organisational factors in primary care. DESIGN OF STUDY: Observational study over 3 years. SETTING: Eight general practices in Tayside, UK. METHOD: Participants were 560 randomly selected patients aged 40-79 years receiving treatment for hypertension. The outcome measurement was blood pressure control, expressed in binary form based on the British Hypertension Society audit standard of <150/90 mmHg. RESULTS: Of 536 eligible patients, 261 (49%) were defined as having inadequate blood pressure control at the end of the study period. No significant associations were discovered with sex, age, deprivation score and comorbidity. In those patients with inadequate control, 30% had no modifications to their drug treatment during the study period. Blood pressure control at the end of the study period was not associated with number of antihypertensive drugs taken or number of antihypertensive drug modifications. The mean number of clinician contacts was 11 (standard deviation = 8), and mean continuity in primary care was high, although this was not associated with improved blood pressure control. A higher proportion of hypertension-related consultations were associated with increased odds of having inadequate blood pressure control. CONCLUSION: Achieving adequate blood pressure control continues to represent a substantial health problem in a significant proportion of the hypertensive population. Patient, physician and organisational elements play a role in ensuring effective delivery of hypertension care in the community.

Looking to the future: diabetic neuropathy and effects of rosuvastatin on neurovascular function in diabetes models.

Vascular defects contribute substantially to neuropathic changes associated with metabolic abnormalities in diabetes. Statins appear to exert beneficial effects on vascular function independent of cholesterol lowering. In studies of the streptozotocin-induced diabetes rat model, rosuvastatin treatment was shown to correct sciatic motor and saphenous sensory nerve conduction velocity deficits (large fiber defects), thermal hyperalgesia (small fiber defects) and deficits in sciatic nerve and superior cervical ganglion blood flow. Rosuvastatin reversed deficits in nitrergic nerve-mediated vasodilation in the corpus cavernosum and corrected deficits in endothelium-derived hyperpolarising factor-mediated vasodilation in mesenteric vessels. Rosuvastatin did not alter plasma cholesterol in diabetic animals (a characteristic effect in this model), but significantly lowered triglycerides at high doses. Treatment with mevalonate reversed the beneficial effects of rosuvastatin on nerve function and blood flow, suggesting that the effects are mediated by inhibition of the cholesterol biosynthesis pathway in the absence of cholesterol reduction. Thus, rosuvastatin has wide-ranging neurovascular actions in diabetic rats that may be independent of lipid-lowering activity.

Effects of trientine, a metal chelator, on defective endothelium-dependent relaxation in the mesenteric vasculature of diabetic rats.

Diabetes mellitus compromises endothelium-dependent relaxation of blood vessels. This has been linked to the generation of reactive oxygen species (ROS), which neutralise nitric oxide (NO) and interfere with vasodilator function. Experiments using chelators have emphasised the importance of ROS produced by transition metal catalysed reactions. However, particularly for the small arteries and arterioles that control microcirculatory blood flow, NO is not the only endothelium-derived mediator; endothelium-derived hyperpolarizing factor (EDHF) has a major role. EDHF-mediated vasodilation is severely curtailed by diabetes; however, little information exists on the underlying pathophysiology. Deficits in the EDHF system, alone or in combination with the NO system, are crucial for the development of diabetic microvascular complications. To further elucidate the mechanisms involved, the aim was to examine the effects of diabetes and preventive and intervention chelator therapy with trientine on a preparation that has well-defined NO and EDHF-mediated responses, the rat mesenteric vascular bed. In phenylephrine-preconstricted preparations, maximum vasodilation to acetylcholine was reduced by 35 and 44% after 4 and 8 weeks of streptozotocin-induced diabetes, respectively. Trientine treatment over the first 4 weeks gave 72% protection; intervention therapy over the final 4 weeks prevented deterioration and corrected the initial deficit by 68%. These responses depend on both NO and EDHF. When the latter mechanism was isolated by NO synthase inhibition, diabetic deficits of 53.4 (4 weeks) and 65.4% (8 weeks) were revealed, that were 65% prevented and 50% corrected by trientine treatment. Neither diabetes nor trientine altered vascular smooth muscle responses to the NO donor, sodium nitroprusside (SNP). Thus, the data suggest that metal catalysed ROS production makes a substantial contribution to defects in both the EDHF and NO endothelial mechanisms in diabetes, which has therapeutic implications for microvascular complications.