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Tight or less tight glycaemic targets for women with gestational diabetes mellitus for reducing maternal and perinatal morbidity? (TARGET): study protocol for a stepped wedge randomised trial.
Gestational diabetes mellitus (GDM) is strongly associated with significant adverse maternal and perinatal health outcomes that have lifelong consequences. Treatment for women with GDM aims to normalise maternal blood glucose concentrations to reduce these adverse health risks. Target recommendations for glycaemic control in women with GDM vary amongst international organisations. All their recommendations rely on consensus, as there have been no published randomised trials that compare different intensities of glucose control in women with GDM. The TARGET Trial aims to determine whether tighter targets for glycaemic control in women with GDM compared with less tight targets, reduce maternal and perinatal morbidity without adverse health consequences.
Using a stepped wedge, cluster randomised trial the 10 participating hospitals will be randomised to the timing of the change from the less tight to the tighter glycaemic target period. During the less tight target period, all health professionals at the hospital will aim to use the less tight glycaemic targets for treatment of women with GDM (fasting plasma glucose <5.5 mmol/L; 1 hour postprandial <8.0 mmol/L; 2 hour postprandial <7.0 mmol/L). During the tighter target period all health professionals at the hospital will aim to use the tighter glycaemic targets for treatment of women with GDM (fasting plasma glucose ≤5.0 mmol/L, 1 hour postprandial ≤7.4 mmol/L; 2 hour postprandial ≤6.7mmol/L). The primary study outcome is large for gestational age infant (birth weight >90th centile).
The TARGET Trial will provide high-level evidence of direct relevance for clinical practice. If tighter treatment targets for women with GDM clearly result in significantly fewer large for gestational age infants and less adverse maternal and perinatal outcomes then they should be recommended for women with GDM. This would be of great importance to these women, their children, health services and communities.
Trial registration: Australian New Zealand Clinical Trials Registry – ACTRN 12615000282583
Keywords: Gestational diabetes mellitus, Maternal glycaemic targets, Large for gestational age, Stepped wedged cluster randomised trial.
Gestational diabetes mellitus (GDM) is defined by the World Health Organization as “carbohydrate intolerance resulting in hyperglycaemia with onset or first recognition during pregnancy” . Rates for GDM are rising worldwide with significant variation in rates of between 5.2% to 25.5% depending on the population and diagnostic criteria used [2-4]. With rates rising, GDM is a significant and increasing health problem in New Zealand, now affecting one in every 11 pregnant women or over 5,500 pregnant women every year [5,6].
Health risks during pregnancy for women with GDM include pre-eclampsia, induction of labour , increased likelihood of caesarean section and perineal trauma . From a public health perspective the greatest burden is that over half of the women diagnosed with GDM will develop type 2 diabetes within 10 years .
Relationship of maternal hyperglycaemia with severity of maternal and infant health risks
There is a continuous relationship between maternal glycaemia and the risk of neonatal macrosomia and hyperinsulinaemia . Long-term effects on offspring adiposity and insulin sensitivity appear to be related to the degree of maternal glucose intolerance [11,12]. The Hyperglycaemia and Adverse Pregnancy Outcomes (HAPO) cohort study  confirmed a strong, continuous association between higher concentrations of maternal glucose and increased birth weight and high cord-blood serum C-peptide levels, a marker for fetal hyperinsulinaemia.
Treatment of GDM improves maternal and infant health
Providing women with GDM with individualised dietary and lifestyle advice, blood glucose monitoring and pharmacological treatment when required, reduces the risk of serious perinatal outcomes, the likelihood of a larger for gestational age infant and improves the woman’s health related quality of life [7,13]. Treatment for women with GDM aims to normalise maternal fasting and postprandial glucose concentrations, reducing fetal macrosomia related to fetal hyperglycaemia and fetal hyperinsulinaemia, and the associated neonatal complications.
How tight should glycaemic targets be for women with GDM?
Normal blood glucose values in the second half of pregnancy in non-obese, non-diabetic pregnant women have been determined using continuous glucose monitoring. The fasting plasma glucose was 4.2 mmol/L ± 0.7; 1 hour postprandial plasma glucose 5.8 mmol/L ± 0.7; and 2 hour postprandial plasma glucose 5.4 mmol/L ± 0.6 . These values reflect blood glucose concentrations in women with a ‘normal’ pregnancy. All are lower than current recommended glycaemic targets used for the treatment of women with GDM. A review on patterns of glycaemia in normal pregnancy has challenged the current recommendations for glycaemic targets for the treatment of women with GDM, as the maternal glucose concentrations in non-diabetic pregnant women are considerably lower than the targets in use for treating women with GDM .
Systematic review of glycaemic treatment targets for women with GDM
The evidence for glucose treatment targets in pregnant women with diabetes has been summarised in a systematic review that included 34 observational studies involving 9433 women . Twenty-six of the studies included women with GDM, but only in the third trimester of pregnancy. The review authors highlighted that there have been no published randomised controlled trials comparing any two glycaemic thresholds that report on benefits and harms for the mother and infant. The evidence able to be included within the systematic review was therefore observational.
Overall the quality of the evidence included was judged to be low, with the literature limited in quality and heterogeneity found to be high amongst the studies. The studies had moderate to high risk of bias due to inconsistent reporting of outcomes and a lack of adjustment for important variables such as maternal body mass index .
The results of this systematic review showed that a fasting glucose treatment target of <5.0 mmol/L for women with GDM was associated with a significant reduction in macrosomia (p<0.01), large for gestational age infants (p=0.01), neonatal hypoglycaemia (p=0.01) and neonatal jaundice (p=0.01). For the mother there was a significant reduction in pre-eclampsia during the third trimester of pregnancy (p=0.01) .
The systematic review authors concluded that it remains unclear whether glycaemic treatment targets above or below a fasting glucose threshold of <5.0 mmol/L offer a better balance of benefits and risks . They considered that there was insufficient evidence on postprandial measures to assess different cut-off points and health outcomes.
What treatment targets for GDM are recommended for clinical practice?
Target recommendations from international professional organisations for maternal glycaemic control on GDM vary widely, and all rely on consensus given the lack of high quality evidence [3,17-20]. Treatment target recommendations for fasting glucose concentrations range from 3.5 to 5.9 mmol/L, for 1 hour postprandial from 6.0 to <8.0 mmol/L and 2 hour postprandial from 5.6 to <7.0 mmol/L. The evidence on which these recommendations have been made is generally unclear and does not compare different blood glucose thresholds at which to initiate treatment.
In New Zealand, the recommended targets for glucose for treatment of women with GDM have been a fasting plasma glucose <5.5 mmol/L; 1 hour postprandial <8.0 mmol/L; and 2 hour postprandial <7.0 mmol/L . With increasing concerns that these recommended glycaemic targets were not tight enough to normalise fetal growth and so minimise perinatal and later complications [11,16,17,22,23], the Ministry of Health Clinical Practice Guidelines “Screening, diagnosis and management of gestational diabetes in New Zealand,” have recommended tighter targets . There have been many calls for randomised trials to be conducted comparing different intensities of treatment targets [6,15,16,20,22,23].
Aims and objectives of the TARGET Trial
The TARGET Trial will assess whether tighter targets for glycaemic control in women with GDM, as now proposed by the New Zealand Ministry of Health , compared with less tight targets , reduce maternal and perinatal morbidity without adverse health consequences.
The primary hypothesisof the trial is that tighter treatment targets for glycaemic control in women with GDM compared with less tight targets will reduce the risk of the infant being born large for gestational age.
The secondary hypothesesare that tighter treatment targets for glycaemic control in women with GDM compared with less tight targets will:
- reduce the risk of serious morbidity for the infant (composite outcome measure of death, shoulder dystocia, birth trauma);
- reduce other infant morbidity including hypoglycaemia, hyperbilirubinaemia and need for respiratory support;
- reduce morbidity for the woman including preeclampsia, need for induction of labour and caesarean section;
- increase the use of pharmacological treatment and hospital services.
Gestational diabetes is a major and increasing health problem globally. Maternal risks include preeclampsia, induction of labour, and within 10 years, over half of the women will have developed type 2 diabetes. Infants born to mothers with GDM are more likely to be large for gestational age, which is highly correlated with the degree of maternal hyperglycaemia and strongly associated with birth injuries and caesarean birth [7,13]. Large for gestational age offspring are at high risk of long-term adverse health that includes obesity, diabetes, and the metabolic syndrome . Effective interventions that normalise maternal glycaemia and optimise fetal growth and so reduce the risk of being born large for gestational age have the potential for prevention of both short and long-term health problems.
Clinical practice recommendations on the glycaemic targets to use in the treatment of women with GDM vary worldwide and are based on consensus, as there have been no randomised trials published. The optimal glycaemic treatment targets to advise women with GDM to use are therefore unclear.
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