REVIEW. Pathogenesis. Diagnostic criteria. C Obesity (BMI>30 kg/m 2 )* C Family history of diabetes (first degree relative with diabetes)*

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1 Gestational diabetes Katharine F Hunt Benjamin Whitelaw arol Gayle Abstract Gestational diabetes mellitus (GDM) is defined as carbohydrate intolerance resulting in hyperglycaemia of variable severity with onset or first recognition during pregnancy. It is a common condition and is associated with increased risk of perinatal complications. This review discusses diagnostic criteria, screening, complications, current management, major studies and randomised controlled trials in GDM and obstetric considerations. urrent National Institute for Health and linical Excellence (NIE) guidelines, produced by the National ollaborating entre for Women s and hildren s Health and published in 2008 by the Royal ollege of Obstetricians and Gynaecologists (ROG) press, are emphasised and controversies highlighted. Keywords blood glucose; fetal macrosomia; gestational diabetes; insulin; pregnancy; pregnancy complications; screening Introduction Gestational diabetes mellitus (GDM) is defined by WHO as carbohydrate intolerance resulting in hyperglycaemia of variable severity with onset or first recognition during pregnancy. This pragmatic definition includes diabetes mellitus which was present but undiagnosed prior to pregnancy and diabetes arising during pregnancy and which persists postpartum. However, typically GDM is used to refer to women with normal glucose tolerance prior to pregnancy (although this may not be known), who develop hyperglycaemia in the second or third trimester, and who return to normal glucose tolerance postpartum. GDM is a common condition which is usually asymptomatic in the mother. It is important because it causes excessive fetal growth and is associated with perinatal complications. Appropriate screening, diagnosis and management reduces the risk of these complications. Epidemiology The incidence of GDM varies with the ethnic origin of the population and diagnostic criteria used. It is estimated that GDM occurs in 3.5% of pregnancies in the UK. The incidence of GDM is increasing. Katharine F Hunt BA MBBS MSc MRP is a linical Lecturer in Diabetes, Diabetes Research Group, Diabetes and Nutritional Sciences Division, King s ollege London School of Medicine, Weston Education entre, Denmark Hill ampus, London, UK. onflicts of interest: none declared. Benjamin Whitelaw MA (antab) MSc MBBS MRP is a onsultant Endocrinologist at King s ollege Hospital, London, UK. onflicts of interest: none declared. arol Gayle BSc MBBS FRP is a onsultant Diabetologist at Kings ollege Hospital, London, UK. onflicts of interest: none declared. Risk factors for GDM can be considered as factors associated with pre-pregnancy metabolic dysfunction (essentially the same as risk factors for type 2 diabetes, T2DM), pregnancy factors, and previous GDM or macrosomia (which suggests previous GDM) (Box 1). Some women with GDM have no recognised risk factors. Pathogenesis Hyperglycaemia occurs when the insulin secretory capacity of pancreatic beta cells is insufficient to match insulin requirements. During normal pregnancy insulin resistance develops in the second trimester and increases to maximum late in the third trimester. The mechanism is not fully understood but is thought to be due to the production of hormones, cytokines or adipokines by the placenta. Insulin secretion increases in parallel, and normal glucose levels are maintained in the face of increased insulin resistance. Women who develop GDM have subclinical metabolic dysfunction prior to pregnancy with increased insulin resistance and reduced insulin secretory capacity. GDM occurs when insulin secretory capacity is insufficient to overcome the combined pre-pregnancy and pregnancy-associated insulin resistance. The underlying pre-pregnancy pathology also puts these women at increased risk of developing T2DM in the future. A small proportion of women with GDM have a different process with reduced insulin secretory capacity due to autoimmune destruction of beta cells. These women have an increased risk of developing type 1 diabetes (T1DM). As would be expected, women with previous GDM have an increased risk of GDM in future pregnancies (30e84%). However, this is not invariable suggesting pregnancy factors are also involved. Diagnostic criteria There is no international consensus on diagnostic criteria for GDM. It is recognised that maternal hyperglycaemia below thresholds diagnostic of diabetes mellitus outside of pregnancy is Risk factors for GDM. * indicates factors recognised by NIE for screening purposes Factors associated with increased risk of pre-pregnancy metabolic dysfunction Obesity (BMI>30 kg/m 2 )* Family history of diabetes (first degree relative with diabetes)* Family origin with high prevalence of diabetes (e.g. South Asian, black aribbean, Middle Eastern)* Increasing maternal age Polycystic ovarian syndrome Pregnancy factors Multiple pregnancy Previous GDM or suggestive of previous GDM Previous GDM* Previous macrosomic baby (4.5 kg)* Box 1 OBSTETRIS, GYNAEOLOGY AND REPRODUTIVE MEDIINE 24:8 238 Ó 2014 Elsevier Ltd. All rights reserved.

2 associated with adverse pregnancy outcome and therefore the glucose thresholds for diagnosis of GDM should be lower. It is generally accepted that an Oral Glucose Tolerance Test (OGTT) should be used for diagnosis with glucose measured fasting and post-challenge. However, the oral glucose load (75 g or 100 g), the post-challenge time-points (1, 2 and/or 3 hours), the diagnostic thresholds, and the number of above-threshold tests required for diagnosis vary (Table 1). In 1999, WHO recommended GDM be diagnosed using 2 hour 75 g OGTT with diagnostic thresholds of venous plasma glucose 7.0 mmol/l and/or 2 hour 7.8 mmol/l. urrent NIE guidelines, published in 2008, endorse the WHO diagnostic criteria. However, many centres using the WHO criteria would use a lower fasting plasma glucose threshold of 6.1 mmol/l (in line with WHO-defined impaired fasting glycaemia). The American ongress of Obstetricians and Gynecologists (AOG) currently support both National Diabetes Data Group (NDDG) and arpenter-oustan criteria. These criteria were essentially based on maternal risk of future T2DM, and not on risk of adverse pregnancy outcomes. In 2008 the landmark Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study was published. This was a multinational study in which 25,505 pregnant women underwent 2 hour 75 g OGTT at 24e32 weeks gestation and pregnancy outcomes were recorded. OGTT results remained blinded, providing fasting glucose 5.8 mmol/l and 2 hour glucose 11.1 mmol/l. The study confirmed that elevated maternal glucose levels, below thresholds diagnostic of diabetes outside pregnancy, were associated with adverse perinatal outcomes and made the key observation that the association was continuous and linear. There was no threshold effect to guide diagnostic criteria and no single measure (fasting, 1 hour, 2 hour) was superior in predicting adverse outcomes. The International Association of Diabetes and Pregnancy Study Group (IADPSG) reviewed the HAPO study results and proposed diagnostic criteria for GDM linked to perinatal outcome. Each time-point threshold was set at the glucose concentration at which the odds for adverse outcome were 1.75 times that for mean glucose concentration. NIE is currently reviewing whether to continue to recommend WHO criteria or move to IADPSG criteria. It has been estimated that adopting IADPSG recommendations would increase the incidence of GDM from 3.5% to over 16% of pregnancies; this has health economic implications. The Scottish Intercollegiate Guidelines Network (SIGN) guidelines have adopted IADPSG criteria. Perinatal complications (Box 2) GDM causes excessive fetal growth, leading to infants that are large for gestational age or overt macrosomia. This is associated with increased risk of birth trauma to mother and baby (including shoulder dystocia) and of induction of labour or caesarean section in order to avoid complications. GDM is associated with increased risk of neonatal hypoglycaemia, neonatal hyperbilirubinaemia, admission to neonatal intensive care unit, premature delivery, perinatal death, and maternal preeclampsia. The Pederson hypothesis describes the pathophysiological mechanisms by which maternal hyperglycaemia is thought to cause perinatal complications. High maternal blood glucose leads to increased glucose transport across the placenta, stimulating increased insulin secretion by the fetal pancreas. Fetal hyperinsulinaemia causes overgrowth of insulin-sensitive tissues such as adipose tissue especially around the shoulders, chest and abdomen. Fetal hyperinsulinaemia is associated with a hypoxaemic state in utero causing polycythaemia and hyperbilirubinaemia and may increase the risk of intrauterine fetal death. After delivery, hyperinsulinaemia may persist for a period, resulting in neonatal hypoglycaemia. Rationale for treatment Previously, while it was accepted that women with GDM with blood glucose above thresholds that would be diagnostic of diabetes outside of pregnancy should be given treatment directed at reducing blood glucose, it was controversial whether women with lesser degrees of hyperglycaemia (sometimes referred to as mild GDM) would benefit. There is now evidence from two large randomised controlled trials (RTs), the Diagnostic criteria for GDM. The table shows four of the major diagnostic criteria for GDM in use internationally. Diagnostic criteria for diabetes outside of pregnancy are shown for comparison. urrent NIE guidelines recommend WHO criteria. urrent SIGN guidelines recommend IADPSG criteria Diagnostic criteria, venous plasma glucose in mmol/l Diabetes outside of pregnancy Gestational diabetes (GDM) WHO IADPSG NDDG arpenter and oustan Fasting Glucose load 75 g 75 g 75 g 100 g 100 g 1 hour e e hour hour e e e Notes Table 1 One abnormal value required One abnormal value required One abnormal value required Two abnormal values required Two abnormal values required OBSTETRIS, GYNAEOLOGY AND REPRODUTIVE MEDIINE 24:8 239 Ó 2014 Elsevier Ltd. All rights reserved.

3 omplications and longer-term risks associated with GDM Perinatal complications Fetal macrosomia Birth trauma (to mother and baby including shoulder dystocia) Induction of labour or caesarean section Premature delivery (<37weeks) Pre-eclampsia Neonatal hypoglycaemia Neonatal hyperbilirubinaemia Perinatal death Longer term risks Mother Increased risk of T2DM GDM in future pregnancies (30e84%) hild Overweight and obesity Impaired glucose tolerance Box 2 Australian arbohydrate Intolerance Study in Pregnant Women trial (AHOIS) and the Maternal-Fetal Medicines Unit Network trial (MFMU), demonstrating improved pregnancy outcomes with intervention in such women. Both included women with mild GDM and excluded women with more severe hyperglycaemia (although the diagnostic criteria were slightly different). In both studies women were randomised either to intervention, where women were informed they had GDM, and received dietary advice, glucose monitoring and insulin therapy if required, or a control group, who were informed they did not have GDM and received usual care. In AHOIS, the primary infant outcome measure of any serious perinatal complication (composite of stillbirth or neonatal death, shoulder dystocia, bone fracture and nerve palsy) was lower in the intervention group at 1% versus 4% in the control group. In MFMU the prespecified primary outcome measure did not reach statistical significance (composite of stillbirth or neonatal death and neonatal complications, including hyperbilirubinaemia, hypoglycaemia, hyperinsulinaemia and birth trauma). However, both studies showed that intervention reduced excess fetal growth (macrosomia and proportion of large for gestational age) and reduced incidence of shoulder dystocia, with rates of caesarean delivery either no different (AHOIS) or lower (MFMU) and rates of induction of labour either increased (AHOIS) or no different (MFMU). Neither study showed impact on neonatal metabolic complications such as hypoglycaemia and hyperbilirubinaemia. Both studies showed that intervention reduced the incidence of pre-eclampsia and reduced maternal weight gain. Screening It is now widely accepted that healthcare organisations should screen for GDM, since it is an asymptomatic condition in which appropriate interventions can improve pregnancy outcomes. However, there is controversy about the method. There are three main approaches: screening by risk factors with a diagnostic test offered to higher-risk women, two-stage approach with all women have a screening biochemical test followed by diagnostic test if above threshold, and universal screening using a diagnostic test. NIE recommends screening by assessing risk factors at the booking visit and offering 2 hour 75 g OGTT to higher-risk women at specified time in pregnancy. Women with previous GDM should have an OGTT at 16e18 weeks (or alternatively one week of self-monitoring of blood glucose) and a further OGTT at 28 weeks if the first is normal. Women without previous GDM who have one or more other risk factors (Box 1) should have an OGTT at 24e28 weeks. NIE estimate that 20e50% of pregnant women in the UK will require OGTT, although proportions will vary considerably with the characteristics of local populations. This risk factor based approach has been criticised on the basis that it still requires a considerable proportion of women to undergo OGTT, identifying women who require OGTT adds complexity, and some women will be missed because they do not have recognised risk factors. NIE do not regard age as a risk factor for screening purposes because of the large number of women who would have an OGTT on the basis of age alone. Although both polycystic ovarian syndrome (POS) and multiple pregnancy are associated with increased risk of GDM, current NIE guidelines do not consider these in relation to screening. ROG recommends women with POS (such as those requiring ovulation induction for conception) should be screened for GDM before 20 weeks (and presumably again at 24e28 weeks). In the USA it is common practice to screen universally at 24e28 weeks using a two-step approach: women first have a 50 g oral glucose challenge with blood glucose tested at 1 hour and those over a screening threshold undergo a diagnostic 3 hour OGTT. AOG support this approach. IADPSG recommends screening all women with 2 hour 75 g OGTT at 24e28 weeks. Other tests of glycaemia have been proposed for screening. NIE state that fasting plasma glucose, random blood glucose, glucose challenge test or urinalysis for glucose should not be used to screen for GDM. HbA1c reflects blood glucose over the preceding 2e3 months and therefore should not be used to screen for GDM because hyperglycaemia can develop over a much shorter timeframe. In order for women to make an informed decision about whether they wish to undergo screening, they should be advised that GDM is associated with increased risk of pregnancy complications, risks can be reduced with treatment (usually diet and exercise but medication may be needed), and that extra monitoring and care may be required in pregnancy and labour. Screening for probable pre-pregnancy diabetes The incidence of T2DM in younger age groups is increasing. Poor glycaemic control in early pregnancy is associated with increased risk of miscarriage and congenital abnormalities. These risks can be reduced by improved glycaemic control. OBSTETRIS, GYNAEOLOGY AND REPRODUTIVE MEDIINE 24:8 240 Ó 2014 Elsevier Ltd. All rights reserved.

4 There is also risk of maternal diabetes complications requiring treatment during pregnancy. IADPSG recommends that either all or only high risk women are screened for diabetes at their first antenatal visit and that if identified pregnancy should be managed as for women with known pre-existing diabetes. Such women should be reassessed postpartum for persistent diabetes. urrent NIE guidelines do not consider screening for diabetes in early pregnancy. Some UK centres offer screening for diabetes at the booking visit in women with previous GDM. Management Women with GDM should be under the care of an experienced multi-disciplinary diabetes and obstetric team. Referral should be done urgently and an appointment offered within a few days. Women with GDM should be given information about the associated risks, and that risks can be reduced with good blood glucose control. The primary goal of interventions is to improve pregnancy outcomes by maintaining near-normal blood glucose. Key components of management are dietary and lifestyle changes and self-monitoring of blood glucose with pharmacological treatment added if blood glucose targets are not achieved and maintained. The duration of trial of diet and lifestyle alone depends on degree of dysglycaemia and gestational age, but should certainly be no more than 1e2 weeks. Women with more severe dysglycaemia should be started on insulin at diagnosis. NIE guidelines also recommend that hypoglycaemic therapy be considered if ultrasound suggests incipient fetal macrosomia (abdominal circumference above 70th percentile) at diagnosis. The two large RTs suggest that the majority of women with mild GDM achieve blood glucose targets on diet alone (20% required insulin in AHOIS, 7.6% in MFMU). However, in clinical practice requirements for pharmacological therapy may be higher due to the presence of women with more severe hyperglycaemia and the differences of a non-trial cohort. Insulin is the established first-line pharmacological treatment in GDM. Selected oral hypoglycaemic agents (OHAs) may have a role in some cases. Diet & lifestyle Women with GDM should receive ethnically appropriate nutritional advice, preferably from a trained dietician. Women who are obese should be advised on moderate calorie restriction as this improves glycaemic control and limits maternal weight gain. Woman with GDM should be advised to restrict total carbohydrate intake and distribute carbohydrate intake through the day (e.g. three meals containing 30e50 g carbohydrate per meal and two or three snacks of 10e20 g carbohydrate) and eat complex carbohydrates with low glycaemic index, such as wholegrain breads and cereals, instead of simple sugars, because this improves overall glucose control and limits post-prandial glucose excursions. Eating vegetables and foods high in fibre is encouraged. Increasing activity levels and exercise helps to reduce blood glucose. Thirty minutes per day of physical activity, such as walking, swimming or yoga, is suggested. Self-monitoring of blood glucose Women with GDM should be provided with a glucose meter and taught how to use it. They are normally advised to monitor at least four times per day: on waking in the morning (fasting) and then 1 hour after the first bite of each meal. It should be noted that this is different from glucose monitoring advice for people with diabetes who are not pregnant, who are advised to test premeals and pre-bed. In GDM, there is evidence that adjusting treatment based on 1 hour post-meal testing, rather than premeal testing, improves glycaemic control and pregnancy outcomes. One hour post-meal monitoring is thought to give tighter glucose control and better outcomes compared with 2 hour postmeal monitoring but the evidence for this is not conclusive. There is general agreement that blood glucose should be controlled tightly but organisations vary in the recommended glucose targets. NIE recommends targets of fasting blood glucose 3.5e5.9 mmol/l and 1 hour post-meal <7.8 mmol/l. AOG recommends fasting target of <5.3 mmol/l and 1 hour post-meal <7.2 mmol/l. Some experts recommend even tighter glucose targets. Pharmacological treatment Insulin: insulin is the established first-line pharmacological treatment in GDM. Insulin does not cross the placenta. It is common to recommend a basal-bolus (or multiple daily injection, MDI) insulin regimen. This involves an injection of fastacting insulin before each meal (the bolus, usually three injections per day) to control post-meal blood glucose and a single injection of long-acting insulin (the basal ) at bedtime to control blood glucose overnight (indicated by blood glucose on waking). Individual doses are adjusted to achieve blood glucose targets. The fast-acting bolus insulin should either be standard soluble insulin (Actrapid or Humulin S) or an established rapid-acting insulin analogue (Novorapid, Humalog). There is some evidence that rapid-acting insulin analogues are preferable as they reduce the risk of late post-meal hypoglycaemia. The basal insulin of choice is intermediate-acting NPH insulin (Insulatard or Humulin I) which lasts about 12 hours with a peak of action at about 4e6 hours. Long-acting insulin analogues (Lantus, Levemir) are not currently recommended, because evidence of safety in pregnancy is limited. Twice daily biphasic (mixed) insulin is an alternative to the basal-bolus regimen. It involves fewer injections but is less flexible in terms of meal timing. An RT comparing the two regimens in pregnancy found that basal-bolus gave better blood glucose control with no increase in severe hypoglycaemia and a lower rate of neonatal complications (17% versus 29%). Women who are treated with insulin require education about insulin administration and recognition and treatment of hypoglycaemia. Insulin doses need to be adjusted to achieve and maintain blood glucose targets. Oral hypoglycaemic agents (OHAs): the role of OHAs in GDM is controversial. None of the OHAs are licenced for use in pregnancy in the UK or have USA Food and Drug Administration (FDA) approval for use in pregnancy. urrent NIE guidelines, and AOG, say that either metformin or glibenclamide can be OBSTETRIS, GYNAEOLOGY AND REPRODUTIVE MEDIINE 24:8 241 Ó 2014 Elsevier Ltd. All rights reserved.

5 used, off-licence, in GDM. However, the American Diabetes Association recommends OHAs should only be used in pregnancy in the context of clinical trials. There are insufficient data on the use of other OHAs in pregnancy and their use is not recommended. Metforminemetformin increases insulin sensitivity and does not cause weight gain or hypoglycaemia. Metformin crosses the placenta and could affect fetal physiology directly, but evidence suggests it is safe in all trimesters. The Metformin in Gestational Diabetes (MiG) trial randomised 751 women with GDM, who met criteria to be started on insulin, to metformin with insulin supplementation if required, or insulin. There was no difference in composite perinatal morbidity between the two groups (32% in metformin group and 32.2% in insulin group). Within this composite there was a lower rate of severe neonatal hypoglycaemia in the metformin group (3.3% versus 8.1%) but increased preterm delivery (<37 weeks gestation, 12.1% versus 7.6%), although no difference in rates of delivery at <32 weeks. In the metformin group, 46% of women required addition of insulin. There was less maternal weight gain in the metformin group. This and other studies suggest metformin is an effective and safe alternative to insulin in GDM with equivalent neonatal outcomes, and reductions in maternal hypoglycaemia and weight gain. However, a considerable number of women will need the addition of insulin to achieve glycaemic control. It is important that exposure to hyperglycaemia is minimised and doses should be escalated rapidly, if tolerated, to the maximum dose and insulin start should not be delayed if required. In women who are unlikely to reach glycaemic targets on metformin alone (e.g. those with more marked hyperglycaemia), insulin should be first line therapy. There is minimal evidence regarding long-term effects of metformin on offspring exposed in utero. Glibenclamide (Glyburide) e glibenclamide (glyburide in the USA) is a sulphonylurea. Sulphonylureas act by increasing insulin secretion by pancreatic beta cells and therefore can cause hypoglycaemia and weight gain. Older sulphonylureas have been shown to cross the placenta and stimulate fetal insulin secretion, which is of obvious concern given that neonatal complications of GDM are due to fetal hyperinsulinaemia. Early laboratory studies suggested glibenclamide did not cross the human placenta; this led Langer and colleagues to conduct a trial (published 2000) in which 404 women with GDM were randomised to either glibenclamide, with insulin supplementation if required, or insulin. The primary outcome measure was maternal glycaemic control and there was no difference between the two groups. Only 4% of women in the glibenclamide arm required addition of insulin. There were no significant differences in pregnancy outcomes between the groups, although the trial was underpowered to demonstrate differences in neonatal complications and there was a non-significant increase in macrosomia and neonatal hypoglycaemia in the glibenclamide group. In this study glibenclamide was not detected in cord blood, however, a more recent study has shown fetal plasma concentrations of glibenclamide of about 70% maternal levels. Of four further small RTs published between 2005 and 2009, three showed increased fetal growth and/or neonatal hypoglycaemia with glibenclamide. Although current NIE guidelines support the use of glibenclamide in GDM, there remain concerns and it is not widely used in the UK. Acceptability of treatment urrent GDM management guidelines make scarce reference to effects on maternal quality of life. It seems likely that screening, diagnosis, dietary interventions, monitoring, hospital visits and insulin would constitute a significant burden to pregnant women. However, the AHOIS trial showed improved healthrelated quality of life during and after pregnancy, and lower incidence of postpartum depression, in the intervention group, although this may reflect the psychological approach of women who have agreed to participate in an intervention trial and may not reflect the antenatal population as a whole. The MiG trial found that 77% of women in the metformin group and only 27% of the insulin group would choose to receive their assigned treatment again. These studies suggest that intervention may be acceptable, but there is a preference for less invasive treatments. Obstetric considerations A key obstetric issue is decision about timing and mode of delivery. Factors taken into consideration include estimated fetal weight and growth velocity and maternal glycaemic control. Ultrasound monitoring of fetal growth and amniotic fluid volume should be performed every 4 weeks between 28 and 36 weeks. Induction of labour, or elective caesarean section if indicated, is often considered from 38 weeks gestation, especially if there is concern about poor metabolic control or excessive fetal growth. Even in the absence of these concerns, induction, or caesarean section if indicated, would normally be recommended if the pregnancy continued beyond 40 weeks. GDM is not a contraindication to the use of antenatal steroids if required for fetal lung maturation. However, steroid treatment will cause maternal hyperglycaemia and normally this will require inpatient monitoring and treatment with supplemental intravenous insulin. Maternal blood glucose must be controlled during labour and delivery, to reduce the risk of neonatal hypoglycaemia. NIE recommends maternal blood glucose be monitored hourly during labour and delivery and maintained between 4 and 7 mmol/l. If blood glucose is outside this range a variable rate intravenous (IV) insulin infusion with IV glucose ( sliding scale ) should be started. In women with GDM treated with insulin or oral hypoglycaemic agents, these should be stopped once in active labour (or nil by mouth for caesarean section) and blood glucose monitored hourly as above. Women with GDM who require long-acting insulin will usually require insulin infusion and a clear plan should be made in advance, which may include starting it as soon as in active labour. The insulin infusion, if required, should be stopped on delivery. Note this is different from management of women with preexisting diabetes in which insulin infusion must be continued at a lower rate post-delivery until reviewed by a healthcare professional with expertise in management of diabetes in this situation. OBSTETRIS, GYNAEOLOGY AND REPRODUTIVE MEDIINE 24:8 242 Ó 2014 Elsevier Ltd. All rights reserved.

6 In women with GDM, blood glucose will usually normalise within hours to days after delivery. Dietary restrictions are relaxed and no insulin or oral hypoglycaemic agents taken. Women should continue to monitor for 24e48 hours postdelivery to detect the small number of women in whom hyperglycaemia persists immediately post-delivery; such women should be reviewed by the diabetes team. Some women with GDM will have impaired glucose regulation or frank diabetes mellitus which persists after pregnancy. This includes women who had undiagnosed diabetes or dysglycaemia prior to pregnancy. Women with GDM should be reassessed at 6e12 weeks postpartum. OGTT is the most comprehensive assessment. For pragmatic reasons, NIE suggests performing fasting plasma glucose at the 6-week postnatal appointment. Earlier testing is not recommended as blood glucose may remain artificially low for some weeks postpartum. However, women should be advised on the symptoms of hyperglycaemia (polyuria, thirst, polydipsia) and advised to seek medical review if symptoms develop. Neonatal care Babies of women who have GDM are at increased risk of hypoglycaemia. Mothers should be advised to feed their babies as soon as possible (within 30 minutes of delivery) and then frequently (every 2e3 hours) until pre-feed blood glucose levels are maintained 2 mmol/l. The baby should stay with the mother unless extra neonatal care is required. NIE recommends that babies of mothers with diabetes should not be transferred into community care until they are at least 24 hours old, maintaining their blood glucose levels and feeding well. Long-term risks for women Women who have had GDM have a 7-fold increased risk of developing diabetes, usually T2DM, in the future. The absolute risk depends on the prevalence of diabetes in the population: estimates range from 19 to 42% at 9e11 years. There is evidence that lifestyle, dietary modification and pharmacological treatment can prevent or delay onset of T2DM. Women with GDM should be advised of this increased risk and advised on weight control, diet and exercise. T2DM may remain asymptomatic for many years, while still causing diabetes complications, and therefore women with previous GDM should be screened for diabetes every one to three years. Women with previous GDM should be screened for diabetes when planning future pregnancy, because diabetes is associated with increased risk of miscarriage and congenital malformation which can be substantially reduced if diabetes is diagnosed and appropriately managed. GDM is likely to recur in future pregnancies (recurrence rate 30e84%, 75% if required insulin treatment) and often develops earlier in pregnancy. They should be screened for GDM at 16e18 weeks and again at 28 weeks if the first test is normal. Long-term risks for baby Offspring of mothers with GDM have an increased risk of developing childhood obesity and impaired glucose tolerance. It is not known whether treatment of GDM impacts on these risks. A follow up study of 199 offspring of mothers in the AHOIS study showed no difference in BMI at 4e5 years old, although it has been suggested that this may be too early. Follow up data on 318 offspring of mothers in the MiG study showed no difference in total fat mass at 2 years old, but children from the metformin group had more subcutaneous fat. It remains to be seen whether this potentially metabolically favourable pattern of fat distribution persists and impacts on long-term diabetes risk. onclusions There is clear evidence that management of GDM reduces the risks of excessive fetal growth and perinatal complications. There remain controversies around screening approaches and diagnostic criteria. Dietary and lifestyle interventions and insulin therapy if required remain the key management interventions, with increasing use of metformin. In the future, strategies for management of the large numbers of women with GDM, prevention of GDM, prevention of future T2DM, and detection of diabetes prior to future pregnancy are likely to be of increasing importance. Follow-up of offspring of women who participated in the large RTs in order to determine if intervention reduces risk of obesity and T2DM in the next generation is important. A FURTHER READING Bellamy L, asas J, Hingorani AD, Williams D. Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis. Lancet 2009; 373: 1773e9. atalano PM. Trying to understand gestational diabetes. Diabet Med 2014; 31: 273e81. rowther A, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS, Australian arbohydrate Intolerance Study in Pregnant Women (AHOIS) Trial Group. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med 2005; 352: 2477e86. Holt RIG, Lambert KD. The use of oral hypoglycaemic agents in pregnancy. Diabet Med 2014; 31: 282e90. International Association of Diabetes and Pregnancy Study Groups (IADPSG) onsensus Panel. Recommendations on the Diagnosis and lassification of Hyperglycemia in Pregnancy. Diabetes are 2010; 33: 676e82. Landon MB, Spong Y, Thom E, et al. Eunice Kennedy Shriver National Institute of hild Health and Human Development Maternal-Fetal Medicine Units Network. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med 2009; 361: 1339e48. Lindsay RS, atalano PM, Nelson SM. Diagnosis and treatment of Gestational Diabetes. Scientific Impact Paper No 23. Royal oll Obstet Gynaecol 2011, diagnosis-and-treatment-gestational-diabetes-sac-opinion-paper-23. Metzger BE, Lowe LP, Dyer AR, et al. HAPO Study ooperative Research Group. Hyperglycemia and Adverse Pregnancy Outcomes. N Engl J Med 2008; 358: 1991e2002. National ollaborating entre for Women s and hildren s Health. Diabetes in pregnancy: management of diabetes and its complications from pre-conception to the postnatal period. NIE clinical guideline 63. July London: ROG Press, Rowan JA, Hague WM, Gao W, Battin MR, Moore MP, MiG Trial Investigators. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008; 358: 2003e15. OBSTETRIS, GYNAEOLOGY AND REPRODUTIVE MEDIINE 24:8 243 Ó 2014 Elsevier Ltd. All rights reserved.

7 Practice points GDM is associated with an increased risk of serious perinatal complications. There is evidence that intervention reduces risk of fetal overgrowth, shoulder dystocia, maternal pre-eclampsia, and maternal weight gain. It is less clear whether treatment impacts on the neonatal metabolic complications such as hypoglycaemia and hyperbilirubinaemia. Screening for GDM is recommended. NIE recommends risk factor based screening. Diagnostic criteria for GDM are controversial. NIE recommends 2 hour 75 g OGTT and WHO criteria. GDM is managed with dietary modification, exercise and selfmonitoring of blood glucose with pharmacological treatment added if blood glucose targets are not achieved. Blood glucose targets are fasting 3.5e5.9 mmol/l and 1 hour post-meal <7.8 mmol/l, or even tighter. Insulin therapy is first-line pharmacological treatment in GDM if required. Oral hypoglycaemic agents are not licenced in pregnancy and their role in GDM remains controversial. urrent NIE guidelines support the use of either metformin or glibenclamide. The use of metformin is increasing in the UK. There remain concerns about glibenclamide and it is not widely used in the UK. Induction of labour, or elective caesarean section if indicated, is often considered after 38 weeks gestation, especially if there is concern about poor maternal metabolic control or excessive fetal growth. Maternal blood glucose should be controlled (4e7 mmol/l) during labour and delivery using intravenous insulin infusion if required. GDM is a recurrent condition. Women with previous GDM should be made aware of the need for early referral and screening in subsequent pregnancies. Women who have had GDM have a 7-fold increased risk of developing T2DM, and should be given appropriate advice and follow-up to manage this increased risk. OBSTETRIS, GYNAEOLOGY AND REPRODUTIVE MEDIINE 24:8 244 Ó 2014 Elsevier Ltd. All rights reserved.