1. a) F b) F c) T d) F e) T

There is no data on progression of retinopathy and pre-conception care. Although risk of preeclampsia may be related to glycaemic control in early pregnancy, data has shown no relationship between pre conception care and preeclampsia. Pre conception care is associated with a three fold reduction in risk of major malformations and risk of both major and minor malformations. There is no evidence that pre conception care has any relationship with macrosomia which appears to be related to later pregnancy glycaemic control. Several studies have suggested that pre conception care reduces the risk of spontaneous abortion.

2. a) F b) F c) T d) T e) F

Women without PCC are more likely to have type 2 diabetes but there is no evidence that women with type 1 diabetes without PCC are more likely to be obese. Research has suggested that there is no difference in risk of diabetic complications between women with and without PCC. Several studies have suggested that older women are more likely to access PCC. Research has shown women without PCC are more likely to have been discouraged from going ahead with a pregnancy. Studies have consistently shown women without PCC are more likely to be active smokers.

3. a) T b) F c) F d) T e) T

All oral hypoglycaemic agents other than metformin should be discontinued during PCC. The patient should continue effective contraception until she and her health care professional feel she has optimum glycaemic control and without significant hypoglycaemia. Only women with retinopathy should be referred to an ophthalmologist for assessment of retinopathy but all women should have a retinal assessment to determine if they have any retinopathy present. It is important to continue metformin if benefits outweigh risks but the woman must be informed there is limited data on its safety in pregnancy. Two recent UK studies recommended use of folic acid supplements (5 mg daily) to all women who attended for preconception care. Roland and colleagues, in a recent study of 535 women with type 1 and type 2 diabetes, showed folic acid supplementation was associated with a significant reduction in risk of malformations.

4. a) F b) T c) F d) F e) F

Pregnancy is contraindicated when coronary heart disease is diagnosed. Family history of ischaemic heart disease, smoking, obesity and diabetes are risk factors for cardiovascular disease only. Active gastroparesis is difficult to treat and compromises both glycaemic control and maternal nutrition. Termination has been offered in severe cases to women with gastroparesis who have become pregnant. Diabetic eye disease present prior to pregnancy may deteriorate during pregnancy. Careful monitoring during and after pregnancy is required. The development of sight threatening eye disease during pregnancy is unusual. Severe hypoglycaemia prior to pregnancy is not a contraindication to pregnancy but may indicate the need for insulin pump therapy and close monitoring during pregnancy with individualised glucose targets. Women with diabetic nephropathy with serum creatinine less than 120 μmol/l have a good pregnancy outcome.

5. a) F b) F c) F d) F e) T

The symptoms of hypoglycaemia can be confused with the symptoms associated with pregnancy. Women should be alert and test frequently. The targets for glucose control during pregnancy are very tight. As a result the frequency of hypoglycaemia is increased. Fetal mortality in Diabetic Keto Acidosis is reported as 30–90% although more recent series with more modern therapy report a fetal mortality rate of 10%. Fetal distress detected during maternal DKA is a consequence of maternal acidosis. Delivery is contraindicated until maternal metabolism is corrected. Severe hypoglycaemia is indeed the most common cause of maternal death for pregnant women with diabetes.

6. a) T b) F c) T d) F e) T

Examination of the dilated eyes by preferably digital retinal photography or by an experienced observer is mandatory at first contact. If no retinopathy is detected a further examination is required at 28 weeks gestation. ACE inhibitors are absolutely contraindicated during pregnancy. Blood pressure treatment that is safe includes drugs such as methyldopa, calcium channel blockers or labetalol. Observational research suggests that aggressive management of blood pressure during pregnancy in women with nephropathy reduces preterm labour and preeclampsia. Renal function is assessed during pregnancy by creatinine clearance. GFR increases during normal pregnancy and does not give a reliable assessment of renal function. Intrauterine growth restriction is a recognised consequence of diabetic nephropathy and tends to be correlated with the degree of nephropathy.

7. a) F b) T c) F d) F e) F

A randomised trial has shown that insulin aspart is not associated with an increased incidence of adverse pregnancy outcomes. There is no randomised trial of large longer-term study on the safety of glargine in pregnancy. The pharmacodynamic profile of both drugs does not change during pregnancy. Insulin pump therapy would be an alternative but this depends on the degree of glycaemic control, the motivation and educatability of the patient and short-acting analogue insulin would be the drug of choice in the pump. There is limited data only regarding the safety of insulin detemir currently and it should not be sued outside a clinical trial.

8. a) F b) F c) T d) F e) F

Hypoglycaemia late in the night would invariably cause elevated fasting as well as postprandial values after breakfast. The same is true for the dawn phenomenon. There is a diurnal pattern of insulin resistance and insulin requirement (both endogenous and exogenous) and the increased resistance in combination with carbohydrate intake cause the often difficult to treat elevated glucose levels after breakfast. With lunch and dinner, insulin resistance is already much lower. Late night snacks rarely cause fasting or post-breakfast high levels because the time period is long and insulin resistance (and endogenous insulin requirement) is low.

9. a) F b) F c) T d) F e) F

Insulin pump therapy has been compared with MDI in a number of small randomised trials without any beneficial effect on clinical or biochemical parameters in the pregnant woman or the foetus/neonate. The trials were however inadequately designed with small group sizes precluding any possibility to assess differences in outcome reliably. In addition, quality of life and manageability of the disease, items often mentioned by patients as important advantages of insulin pump therapy, were not assessed.

10. a) T b) T c) F d) F e) T

The ACHOIS was the first of 2 major intervention trials conducted to determine the value of standard treatment of GDM. The control group (510 women) were diagnosed by OGTT but they and their carers were blinded to the result. The intervention group (490 women) were made aware of the diagnosis. They were treated with standard therapy that included dietary advice, self-monitoring of blood glucose and, if glycaemic targets were not met, insulin therapy. In this trial, 20% of the women in the intervention group required insulin therapy. Intervention was associated with a reduced rate of serious perinatal complications. In the intervention group there were no perinatal deaths compared to 5 (1%) in the routine care group and 7 (1%) cases of shoulder dystocia compared to 16 (3%) in the routine care group. However, there was increased induction of labour in the intervention group (30% vs 29%; adjusted relative risk 1.36, 95% CI 1.15–1.62; p < 0.001) and more frequent admissions of babies to the neonatal nursery (71% vs 61%; adjusted relative risk 1.15, 95% CI 1.05–1.26; p = 0.01). Caesarean sections rates were not different between groups. Mean birth weight was reduced by 145 g by intervention associated with a highly significant reduction in the numbers of large for gestational age (LGA) and macrosomic babies. Preeclampsia rates were reduced from 18% to 12% of GDM pregnancies by intervention (adjusted treatment effect 0.70, 95% CI 0.51–0.95; p = 0.02). There was concern before conducting this trial that the diagnosis and treatment of GDM could result in psychological harm to the mothers. Analysis of quality of life during pregnancy and 3 months post-partum showed that intervention was associated with improved quality of life. Of particular note, intervention led to lower rates of depression at 3 months post-partum.

11. a) T b) F c) F d) F e) T

The study designs of the MFMUN and ACHOIS trials were very similar. The MFMUN-GDM trial randomised 495 women to the treatment group and 472 women to the control group. The intervention was very similar to that of ACHOIS. There was no significant change in the primary outcome (a composite of stillbirth or perinatal death and neonatal complications, including hyperbilirubinaemia, hypoglycaemia, hyperinsulinaemia and birth trauma). There were, however, beneficial effects of intervention on pre-determined secondary outcomes. Mean birth weight was reduced by the intervention (3302 g vs 3408 g, p < 0.001) and the rate of LGA infants was reduced from 14.5% to 7.1% (relative risk 0.49, 97% CI 0.32–0.76, p < 0.001) and macrosomia from 14.3% to 5.9% (relative risk 0.41, 97% CI 0.26–0.66, p < 0.001). Rates of small for gestational age babies were not affected by intervention. Thus, the intervention had highly comparable results to the ACHOIS study with respect to intervention effect on birth weight. Shoulder dystocia was significantly reduced by intervention (from 4% to 1.5%; RR 0.37, 97% CI 0.14–0.97; p = 0.02). This was a similar result to the ACHOIS study, although it did not quite reach statistical significance in ACHOIS. Unlike ACHOIS, induction of labour in the MFMUN trial was not altered by intervention and caesarean section rates were actually reduced by intervention (from 33.8% to 26.9%; RR 0.79, 97% CI 0.64–0.99; p = 0.02). Like ACHOIS, pre-eclampsia was significantly reduced by intervention in the MFMUN-GDM trial (2.5% vs 5.5%, RR 0.46, 97% CI 0.22–0.97; p = 0.02). Overall, the ACHOIS and MFMUN GDM intervention trials favour treatment as intervention reduces rates of LGA babies, shoulder dystocia and pre-eclampsia.

12. a) F b) T c) F d) F e) T

HAPO was an observational study and not a clinical trial. Perinatal outcomes of 23,316 participants (25,505 women initially recruited from 15 centres within 9 countries) who underwent a 75 g OGTT between 24 and 32 weeks of pregnancy were assessed. The women and their carers were blinded of the OGTT result. The study was conducted to determine at what level of hyperglycaemia is the risk of adverse perinatal outcome increased. This came from a lack of adequate perinatal outcome data by which evidence-based criteria for the diagnosis of GDM could be developed. Four pre-determined primary outcomes were assessed: birth-weight >90 ^th percentile, primary caesarean section, clinical neonatal hypoglycaemia and cord-blood C-peptide >90 ^th percentile. The key findings of the study were continuous relationships between increasing plasma glucose at the fasting, 1 h and 2 h time-points of the OGTT with increasing rates of all of the primary outcomes. There were no inflection points for any of these relationships, such that the determination of normal vs abnormal was not easily determined. Higher plasma glucose levels were associated with higher rates of primary caesarean section (about a 13% rate for the women with the lowest plasma glucose compared to a 24–30% rate for women with the highest plasma glucose levels). Of the pre-determined secondary outcomes studied, there were positive associations between maternal glycaemia and premature delivery (1 h and 2 h OGTT plasma glucose only), shoulder dystocia, admission to neonatal intensive care (1 h and 2 h OGTT plasma glucose only), hyperbilirubinaemia (1 h and 2 h OGTT plasma glucose only) and preeclampsia.

13. a) T b) F c) T d) F e) F

The IADPSG statement does include recommendations for the diagnosis of GDM and a new category of overt diabetes in pregnancy. The rationale for the new category is that the prevalence of previously undiagnosed type 2 diabetes in pregnancy is increasing and that this condition has much greater associated risks for adverse pregnancy outcome than milder degrees of glucose intolerance. Such women will need diabetes complications screening as well as a higher level of pregnancy surveillance. Also, it is now recommended that a screen for overt diabetes in pregnancy be performed early in pregnancy in all at risk women or in all women if local prevalence rates are known to be high. The various diagnostic criteria currently used for GDM across the world are based on either the predictive value of OGTT plasma glucose results for diabetes later in life in the mothers or criteria of abnormal glucose tolerance used diagnostically in the non-pregnant population. The IADPSG recommendations are based on the predictive value of OGTT plasma glucose results for adverse perinatal outcomes determined from the HAPO study. Because of the continuous relationships between maternal plasma glucose and adverse pregnancy outcomes, there are no clear cut-off values for plasma glucose prediction of adverse pregnancy outcomes. For this reason, the IADPSG panel based its decision on an agreed but arbitrary decision about odds ratios. Thresholds chosen for the diagnostic cut-offs for the fasting, 1 h and 2 h plasma glucose levels were based on an adjusted odds ratio of 1.75 for birth-weight >90 ^th percentile, cord C-peptide >90 ^th percentile and percent body fat >90 ^th percentile. The IADPSG criteria state that only one abnormal glucose value on the 3 point OGTT is required for diagnosis. For the HAPO study cohort this equated to 17.8% of women having a hyperglycaemic disorder of pregnancy. Overt diabetes in pregnancy can be diagnosed at any gestation if the fasting plasma glucose is ≥7.0 mmol/l or the HbA1c is ≥6.5% (DCCT/UKPDS standardised). A random plasma glucose ≥11.1 mmol/l is suggestive of overt diabetes in pregnancy, but needs to be confirmed with a fasting plasma glucose or HbA1c.

14. a) T b) T c) F d) T e) T

Given the increasing incidence of type 1 diabetes, the recent emergence of type 2 diabetes as a condition that can begin during childhood and the increasing prevalence of gestational diabetes mellitus, the number of women who have some form of diabetes during their pregnancies are increasing. There is no evidence to suggest that unintended pregnancy is a risk among women with diabetes or women at risk for GDM. The International Association for Diabetes in Pregnancy Study Groups (IADPSG) recently published recommendations for the diagnosis of GDM using a 75 gram oral glucose tolerance test with the requirement that only one of three values (fasting, 1-, or 2-hour) be met or exceeded to confer a diagnosis of GDM. The lower threshold values and the need for only one abnormal value to confer a diagnosis of GDM compared with many previous guidelines that required at least two abnormal values will result in an increase in the incidence of GDM.

15. a) T b) F c) F d) T e) T

Several studies reported maternal anxiety around the time of diabetes but did not find any differences in the desire to be screened in future pregnancies based on the test results that the women received. Almost all of the women wished to be tested for GDM in future pregnancies regardless of the results of their oral glucose challenge test or oral glucose tolerance test during pregnancy. Studies reported differences in beliefs and perceptions related to the cultural backgrounds of the women. They also reported that women expressed disbelief about the GDM diagnosis due to its asymptomatic nature, particularly women who had not previously been pregnant or women who had not previously experienced symptomatic pregnancy complications.

16. a) T b) T c) T d) T e) F

Responses a, b, c, and d are drawn from qualitative studies of women with diabetes. While they cannot be generalized to all women with diabetes, they provide information about the experiences of women with diabetes that may be used to reduce the anxiety women have about pre-conception counselling as well as to address different expectations of women with diabetes during their pregnancies. A program developed and evaluated by Charron-Prochownik and colleagues at the University of Pittsburgh encourages education about preconception health issues for teenagers with diabetes in an effort to provide knowledge about the importance of planning for pregnancy.

17. a) F b) T c) F d) F e) F

The concept of “eating for 2” is a myth that may have been important when women were underweight (Pre-pregnancy BMI <18.5 kg/m ² ), but is now associated with greater gestational weight gain and an increased risk of obstetric and neonatal complications. The Institute of Medicine has recently reviewed the evidence for the safety of different degrees of weight gain during pregnancy and recommended that women with a BMI of 30 kg/m ² or more increase their weight by 5–9 kg over the whole pregnancy. This is an average weight gain of 0.22 kg/week. Weight gain of 11.5–16 kg over the whole pregnancy remains the recommended weight gain for women of normal pre-pregnancy weight (18.5-24.9 kg/m2) not obese women. This is 0.42 kg/week. Regular physical activity is recommended during pregnancy especially among obese women to reduce the chance of gestational diabetes (although evidence for this remains rudimentary), gestational weight gain and its downstream consequences (e.g. Caesarean section) and may have direct benefits on blood pressure during pregnancy. Weight loss is not recommended during pregnancy and there are suggestions of association with adverse pregnancy outcomes. Ketogenesis may be associated with reduced intellectual capacity in the offspring, but the data for these complications remain very limited.

18. a) T b) F c) F d) F e) T

There are now 2 major randomized controlled trials that show reduction in macrosomia, pre-eclampsia, shoulder dystocia and other adverse pregnancy outcomes. High dose folic acid supplementation is now recommended to reduce congenital neural tube defects because prospective studies show some benefit. However there are no randomized trials for it to be conclusive. High glycaemic index foods are associated with peaks in glycaemia and hence would potentially increase the risk of macrosomia. There is a randomized controlled trial of using the glycaemic index in women with GDM resulting in a reduction in large for dates babies. There have been no randomized controlled trials of Vitamin C in pregnancy. Vitamin D levels are low in the majority of obese women and 10 micrograms Vitamin D daily supplementation has now been recommended by the Confidential Enquiry into Maternal and Child Health in the UK.

19. a) F b) F c) T d) T e) T

Both type 1 and type 2 diabetes appear to have similar perinatal outcome and need to be carefully managed. PNM in diabetic mothers have reduced but is much higher than the PNM in the normal population. Strangely the diabetic population in most developed countries appear to have high PNM compared with their normal population and is consistent in the countries in Europe. Intrapartum causes contribute to intrapartum and immediate neonatal deaths. Congenital anomaly is still a leading case of perinatal deaths in the diabetic population.

20. a) F b) F c) F d) F e) F

Unless indicated there is no need for routine neonatal attendance. There is no need for routine admission of a baby of a diabetic mother. Blood sugar at 3–4 h is adequate. Early estimation at 2 h may necessitate unnecessary interventions. Early and regular breast feeding is encouraged. Unless there are symptoms suggestive of cardio-respiratory difficulty there is no need for routine echocardiography.

21. a) F b) F c) T d) F e) F

The genesis of congenital malformation is in the first trimester and insulin does not cross the placenta up to ten weeks. Genetic factors may contribute but does not appear to be a main cause. Children born to fathers with diabetes do not carry the same risk of congenital malformation although genetic material is transferred. Mothers with poorly controlled diabetes and hyperglycaemia have a higher incidence of congenital malformation. No direct link has been established between hyperketonaemia and congenital anomalies. There has been no direct link between congenital anomalies and fetal insulin as fetal insulin secretion to any significant level is seen after the first trimester.

22. a) T b) F c) F d) T e) T

Polycythaemia appears to be related to fetal hypoxia. Macrosomia is not a consequence of hypoxia-ischaemia. It appears to be related more to poor control of the diabetes. Hypocalcaemia is not related to hypoxia-ischaemia. Diabetic pregnancies are at high risk of hypoxia in labour and this may be due to intrauterine growth restriction in some, or because of the high metabolic rate, or iatrogenic due to overuse of oxytocin for induction of labour or as a delay in delivery following shoulder dystocia. If the hypoxia-ischaemia was severe due to any of the above they may present with encephalopathy. Stillbirth is thought to be either due to poor diabetic control in the antenatal period and it can occur in labour due to hypoxia or as a consequence of severe shoulder dystocia.

23. a) F b) T c) T d) T e) T

Antihypertensive therapy in women with microalbuminuria or diabetic nephropathy reduces the risk of preeclampsia and preterm delivery and thereby probably also the risk of stillbirth. However, antihypertensive drugs blocking the renin-angiotensin-system (i.e. ACE inhibitors and angiotensin II receptor blockers) should be stopped before and during pregnancy. The single most important factor to reduce the risk of stillbirth is to obtain and maintain good glycaemic control during pregnancy to avoid fetal hypoxia. Pregnant women with pre-gestational diabetes are examined frequently with ultrasound. In the first half of pregnancy the purpose is particularly to identify congenital malformations. Later observation of fetal growth is important to diagnose intrauterine growth restriction most often seen in women with diabetic nephropathy, chronic hypertension or preeclampsia and to diagnose excess growth since these fetuses also are at increased risk of stillbirth. Fetal hyperinsulinaemia leads to fetal pancreatic beta cell overstimulation. This in turn causes accelerated fetal growth, excess subcutaneous fat and increased hepatic glycogen storage. The increased fetal metabolism associated with hyperglycaemia may lead to relative fetal hypoxia. As congenital malformation is linked to stillbirth and perinatal loss, the only way to reduce this is to provide pre-pregnancy counselling.

24. a) F b) F c) T d) F e) T

Glyburide, a second-generation sulfonylurea and metformin, a biguanide, are two commonly used oral diabetes medications. First-generation sulfonylureas (e.g. Tolbutamide, Chlopropamide) are not recommended in pregnancy since these drugs cross the placenta and can adversely affect fetal metabolism. Use of thiazolidinediones (e.g. Roglitizone) and glitinides (Repaglinide) during pregnancy is considered experimental at this time.

25. a) F b) T c) F d) F e) F

Metformin inhibits gluconeogenesis in the liver and stimulates glucose uptake in peripheral tissues by enhancing insulin sensitivity in peripheral tissues.

26. a) T b) T c) T d) F e) F

The starting oral dose of glyburide is 2.5 mg twice daily and can be increased to 10 mg daily (5 mg twice daily). Glyburide binds to pancreatic beta cell ATP-calcium channel receptors, to increase insulin secretion and insulin sensitivity of peripheral tissues. There are conflicting studies about transfer of glyburide across the placenta. In vitro studies show minimal transfer of glyburide, but the fetal response to various dosages of the drug is not completely understood. Glyburide is a second-generation sulfonylurea.

27. a) T b) T c) T d) F e) F

One large randomized clinical trial and two smaller trials reported no substantial differences in fasting or 2 h postprandial glucose levels with glyburide or insulin treatment.

28. a) T b) F c) T d) T e) T

A meta-analysis of one large trial and two smaller trials shows a higher (93 gms), but not clinically relevant infant birth weight in infants born to women treated with glyburide compared to insulin.

29. a) T b) T c) T d) T e) F

There were few cases of congenital anomalies reported and no substantial differences in one large trial of glyburide versus insulin and one large trial of metformin compared to insulin.

30. a) T b) T c) T d) T e) T

There are substantial gaps in our current knowledge of maternal and neonatal outcomes in pregnancies managed with oral diabetes medications compared to insulin. Future trials should be adequately powered to detect small differences in important outcomes, such as congenital anomalies, and establish consistent definitions for outcomes, including maternal and neonatal hypoglycemia.