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Pre-existing type I and type II diabetes in pregnancy
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Pre-existing type I and type II diabetes in pregnancy
of congenital abnormalities, stillbirth and macrosomia as the hyperglycaemic state is toxic to the developing fetus. Pregnancy can also lead to the development of hypoglycaemic unawareness, progression of retinopathy and increased incidence of preeclampsia. The Confidential Enquiry into Maternal and Child Health (CEMACH) report of 2005 reviewed pre-gestational diabetic pregnancies in England, Wales and Northern Ireland and found that similar outcomes are still not being achieved in women with and without diabetes as hoped for in the St Vincent declaration of 1989. Of particular concern is that adverse outcomes in type 2 pregnancies, which previously had been considered to be less of a problem, were similar to type 1. Diabetic women should aim to achieve tight glycaemic control, as this has been shown to reduce morbidity. This message should ideally be given in the pre-conception period with advice on how to optimize glycaemic control, prescribing of high dose folic acid and review of current medication to stop any teratogenic drugs. In the last few years several large prospective multicentre trials have been published on gestational diabetes but the information gained can be applied to the management of pre-gestational diabetes. NICE has also published guidelines on the management of diabetes in pregnancy. These should provide some consistency in the approach to managing pre-gestational diabetes and hopefully improve on the pregnancy outcomes seen in the CEMACH report.
Kimberley Lambert Sarah Germain
Abstract Women with pre-gestational diabetes are high-risk pregnancies. Hyperglycaemic is toxic to the developing fetus and is associated with a higher incidence of congenital malformation, miscarriage, macrosomia and stillbirth. Complications can be reduced with tight glycaemic control, and management should ideally start pre-conceptually. During pregnancy a woman’s insulin requirements change and those managed pre-pregnancy on diet or oral medication may need to start insulin. Pre-gestational diabetics require close maternal and fetal monitoring, including screening for the progression of maternal diabetic complications such as retinopathy and nephropathy, and fetal growth scans. Their pregnancies are complex and a multidisciplinary approach should be used. In this article we will discuss the background physiology, the effect of pregnancy on diabetes, the potential fetal and maternal complications, and how these can be minimized by intensive management from pre-conception to the post-natal period, including the contribution of recent studies and guidelines.
Keywords
diabetic ketoacidosis; hypoglycaemia; nephropathy; retinopathy; type 1 and type 2 diabetes
Physiology The World Health Organisation (WHO) definition for the diagnosis of diabetes mellitus (outside of pregnancy) is detailed in Table 1. In pregnancy, the physiology of glucose metabolism alters, so even women with good control outside of pregnancy will usually need their hypoglycaemic medication doses altering. Initially there is a reduction in fasting glucose due to increased renal clearance and decreased gluconeogenesis. This puts type 1 diabetic women at risk of hypoglycaemia in the first trimester. As pregnancy progresses, the woman’s insulin requirements increase as pregnancy is a state of insulin resistance due to placental hormones which include human placental lactogen, cortisol and progesterone. Human placental lactogen causes breakdown of triglycerides for maternal energy, while sparing carbohydrate nutrition for the fetus. The insulin mediated glucose update into skeletal muscle also falls in pregnancy. Non-diabetic women increase their post-prandial insulin production by 50% to counteract this. Women with diabetes are unable to mount an adequate response to hyperglycemia due to absence (type 1) or a reduction
macrosomia;
Introduction Pre-gestational diabetes includes both type 1 and type 2 diabetes. Data from the National Institute for Clinical Excellence (NICE) suggests that in England each year there are 1800 pregnancies to mothers with type 1and 1200 pregnancies for type 2 diabetes. This compares to 20,400 pregnancies a year in women with gestational diabetes. The incidence of type 2 diabetes increases with age and obesity, and is being seen more frequently in pregnancy, reflecting changes in society with women starting their families later and an increase in body mass index of the population. Prior to the advent of insulin, women with type 1 diabetes were advised against pregnancy due to high mortality. Since then outcomes have improved but pre-gestational diabetes is still associated with increased morbidity. There is a higher incidence
WHO definition for diagnosis of diabetes mellitus Kimberley Lambert BSc MBChB MRCP is a Specialist Registrar in Diabetes and Endocrinology at Southampton General Hospital, Southampton, UK. Conflicts of interest: none declared.
WHO classification Normal Impaired glucose tolerance Impaired fasting glucose Diabetes mellitus
Sarah Germain MA MBBS DPhil MRCP is a Specialist Registrar in Obstetric Medicine/Diabetes and Endocrinology at Queen Charlotte’s Hospital and St. Thomas’ Hospital, London, UK. Conflicts of interest: none declared.
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Fasting glucose <6.1 mmol/l <7.0 mmol/l 6.1e7.0 mmol/l 7.0 mmol/l
2 h glucose <7.1 mmol/l 7.8e11.1 mmol/l <7.8 mmol/l 11.1 mmol/l
Table 1
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Renal impairment Diabetic nephropathy is usually a progressive disease divided into: Microalbuminuria (albumin to creatinine ratio (ACR) 3.5e30 mg/mmol) Macroalbuminuria (ACR >30 mg/mmol) Endstage renal failure (raised serum creatinine and uraemia) Diabetic nephropathy in pregnancy is associated with an increased incidence of pre-eclampsia, adverse fetal outcomes and the risk of progression of maternal renal disease. One study looked at 240 women with type 1 diabetes, categorizing the women into normal albumin excretion (n ¼ 203), microalbuminuria (n ¼ 26), and macroalbuminuria (n ¼ 11). The rate of preterm deliveries increased as the proteinuria increased (35, 62 and 91% respectively). The rate of pre-eclampsia also increased (6, 42 and 64%), which partly explains the high rate of preterm deliveries in the macroalbuminuria group. Prior to pregnancy, it is important that women have their renal status evaluated as part of their pre-pregnancy assessment. The CEMACH enquiry into diabetic care in pregnancy found only 58% women had renal function checked in the year before pregnancy. It found the incidence of nephropathy was the same in type 1 and 2 diabetics. Urinary protein excretion increases in all pregnant women towards the end of pregnancy, and this may become significant in women with diabetic nephropathy, with possible associated decline in renal function. It is usually reversible post-pregnancy in those with only mild renal impairment, but there is the risk of irreversible progression in those with more advanced nephropathy. Tight blood pressure and glucose control are extremely important to reduce the incidence of both progression of maternal disease and adverse pregnancy outcomes.
(type 2) of functioning beta cells. Women with type 1 diabetics will need to increase their insulin dose to counteract this physiological change, sometimes up to three times their normal dose. Type 2 diabetic women will usually require insulin during pregnancy to achieve normoglycaemia. Once the placenta is delivered, insulin resistance ceases and diabetic women can return to their pre-pregnancy treatment regime.
Effect of pregnancy on diabetes Diabetic ketoacidosis Diabetic ketoacidosis (DKA) is a medical emergency and the diagnosis should be considered in any pregnant women with type 1 diabetes who becomes unwell. Associated perinatal mortality rates are high, quoted as up to 30%. Causes in pregnancy include hyperemesis gravidarum, infections (especially urinary), corticosteroids, and beta-mimetics. Ketones are present in pregnancy, even in non-diabetic women, due to enhanced lipolysis producing an increase in free fatty acids and ketones. DKA is confirmed by a raised blood glucose in the presence of reduced bicarbonate and raised urinary ketones. DKA can present with severe dehydration and profound acidosis leading to organ impairment and cardiac arrhythmias. Ketones cross the placenta and affect the fetus at high levels. Fetal monitoring during maternal DKA has showed an absence of variability of heart rate and late decelerations. These abnormalities reverse after the woman is treated and so immediate delivery is not warranted until after maternal metabolic abnormalities have normalized. DKA in pregnancy is treated the same as for the non-pregnant state with intravenous glucose and insulin via a sliding scale algorithm. Serum potassium levels need to be closely monitored as insulin drives potassium into the cell and this should be replaced intravenously. NICE guidelines advise pregnant women with DKA to be admitted to a level 2 critical care bed where they can receive combined medical and obstetric input.
Retinopathy The prevalence of diabetic retinopathy increases progressively with increasing duration of diabetes. Retinopathy starts to occur in type 1 after 3e5 years and most patients will have some retinopathy at 20 years. CEMACH confirmed these findings, with less women with type 2 found to have retinopathy (9% compared to 36% type 1) reflecting the shortened duration of disease. In pregnancy, there is the potential for retinopathy to progress. Studies have showed that the severity of retinopathy at conception is reflected in the risk of progression in pregnancy. This is thought to be mainly due to improvement in glycaemic control. The Diabetes Control and Complications trial found it was the magnitude rather than rapidity of improvement in glycaemic control that correlated to progression of retinopathy. Changes in hormones, growth factor and lower retinal blood flow may also contribute to exacerbation in pregnancy.
Hypoglycaemia Hypoglycaemia is diagnosed as a blood glucose value <3.9 mmol/l. In one study 45% women experienced severe hypoglycaemia throughout pregnancy with 80% occurring before 20 weeks. In early pregnancy, women can experience severe hypoglycaemia more frequently for a combination of reasons, including rapid improvement in glucose control to prevent congenital abnormalities and reduced hypoglycaemic awareness. Hypoglycaemia is the most common cause of diabetic maternal deaths, either directly or secondary via road traffic accident. If the patient has a severe hypoglyaemic event then the DVLA should be informed and the patient should be advised not to drive until a consultant confirms they have recovered their awareness. To prevent severe hypoglycaemia from occurring, insulin doses may need to be reduced. NICE guidelines advise any women treated with insulin should be given a concentrated glucose solution for emergencies. Type 1 diabetic women should also be prescribed a glucagon injection, with partner or family members instructed how to administer it. NICE advocates the use of starting insulin pump therapy if women cannot achieve adequate glycaemic control without disabling hypoglycaemia.
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Effect of diabetes on pregnancy Maternal complications Miscarriage: miscarriage rates are higher in diabetic women with higher HbA1c at the start of pregnancy. One study of 83 women with type 1 and 2 diabetes found 22 miscarriages, of which 21 occurred when HbA1c was >11.5%. Pre-eclampsia: women with diabetes have an increased risk of pre-eclampsia in pregnancy, in particular women with known
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renal disease and hypertension pre-pregnancy. A study looking at Sweden’s birth register, involving greater than 98% of all pregnancies between 1991 and 2003, included 5089 type 1 diabetic pregnancies and 1,260,207 control pregnancies. They found the rate of pre-eclampsia 14.0% in the type 1 diabetics compared to 2.8% in the non-diabetic population. Obesity is another risk factor, especially for women with type 2 diabetes.
abnormalities and women should be reassured that they can have healthy pregnancies. Pre-pregnancy Any diabetic women considering pregnancy should be offered pre-pregnancy counselling and receive advice on folic acid, glycaemic control and have their medications reviewed regarding safety in pregnancy. Screening for complications should also form part of the pre-pregnancy review and will be discussed under antenatal management.
Infection: diabetics have an increased incidence of infections, which may become an issue during pregnancy, e.g. urinary tract or post-operative wound infection. This is partly related to impaired neutrophil function. Any infection should be promptly treated with antibiotics to prevent further complications.
Folic acid: as women with diabetes have a higher incidence of neural tube defects. NICE recommends that diabetic women should be prescribed higher dose 5 mg folic acid compared to the standard 0.5 mg dose pre-conceptually until week 12 gestation. The CEMACH enquiry found that 69% of diabetic pregnancies with a poor outcome had no documentation of the women having taken folic acid.
Caesarean section: diabetic women have a higher incidence of caesarean section, quoted as 67% in the CEMACH study. This is partly iatrogenic, related to early induction of labour. Fetal complications Congenital malformations: the CEMACH enquiry confirmed that diabetes is associated with a 3e5 fold increase in the incidence of congenital abnormalities compared to the general population. Major congenital abnormalities associated with diabetes include cardiac, neural tube defects, malformations of gastrointestinal and urinary tract, and musculoskeletal. Hyperglycemia is a toxic environment for the developing embryo, and the incidence of malformation is related to glucose control. This is why optimizing glycaemic control prior to pregnancy is so important, as it may be too late to reduce the teratogenic effect of hyperglycaemia by the time of the first antenatal appointment.
Glycaemic control: HbA1c measures the percentage of glycoslated haemoglobin and reflects glucose control over the last 3 months. NICE advises women to aim for HbA1c <6.1% preconceptually if safely achievable. Many women will not be able to reach this and should be reassured that any reduction in HbA1c will reduce the incidence of congenital abnormalities. Once pregnancy is achieved HbA1c should not be used as it is no longer accurate, so insulin dose adjustments should be according to home blood glucose monitoring values. Insulin regimens may need to be altered and this is discussed in more detail in antenatal management. A study looking at 709 babies born to 488 type 1 diabetic women recorded the incidence of congenital malformation related to maternal HbA1c in the first trimester. Results showed that the higher the HbA1c the higher the incidence of congenital malformations, with HbA1c of <5.6% having a relative risk of 1.6 whereas an HbA1c > 9.4 had a relative risk of 4.8. Other studies have found a 35% incidence of congenital malformations with HbA1c over 10%.
Macrosomia and shoulder dystocia: glucose is transferred across the placenta by facilitated diffusion to the fetus. If maternal blood glucose levels are high then the fetus becomes hyperglycaemic. The fetus responds to high glucose levels by secreting more insulin. Insulin is a growth factor and high circulating fetal insulin levels stimulate fetal growth, which can lead to macrosomia (weight >4.5 kg). Characteristically, these babies have a smaller head to shoulder ratio, large shoulders, and increased body fat and skin folds. Macrosomia is associated with an increased incidence of shoulder dystocia, Erbs palsy, prolonged labour, polyhydramnios and asphyxia. A Swedish study looking at 5089 type 1 diabetic pregnancies showed 31% had large for gestational dates babies (weight >90th percentile).
Medications: diabetic women with hypertensive disease are prescribed medications with the aim to prevent or slow progression of diabetic nephropathy, usually angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers. These medications should not be used in pregnancy as they are associated with oligohydramnios, renal failure, hypotension, and skull defects in the fetus. Traditional advice was to take ACEI until a positive pregnancy test and then stop, but new evidence suggests this practice is not safe and women should not conceive on ACEI. A study looking at third trimester exposure to ACEI showed an almost three fold incidence in congenital malformations in babies exposed in the first trimester. The only exception may be women with heavy proteinuria controlled on an ACEI, and a nephrologist should review these cases. Alternative antihypertensives for use in pregnancy include methyl dopa, nifedipine or labetolol. Some diabetic women may be on treatment with a statin (HMG CoA reductase inhibitor) to reduce cholesterol levels because of the association between hyperlipidaemia and ischaemic heart disease. Women should be advised to
Stillbirth: CEMACH enquiry found that the rate of stillbirth rate was 26.8 per 1000 live and stillbirth in pre-gestational diabetics, which is higher than the national rate of 5.7 per 1000. Stillbirths most frequently occurred between 32 and 36 weeks gestation (41%).
Management of diabetes in pregnancy Introduction The aim of management is a healthy baby and mother. Pregnancy in women with diabetes is high risk, with increased incidence of fetal and maternal complications, but with tight glycaemic control this can be reduced. The CEMACH study found 86% of babies were alive after 28 days with no major congenital
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discontinue statins pre-conceptually as they are associated with central nervous system and limb deficiencies in the fetus.
are associated with less hypoglycaemic events. Aspart (Novorapid) and Lispro (Humalog) have been assessed as safe in pregnancy. Glargine has been used in over 500 pregnancies with no reports of increased neonatal or maternal complications, although more data is needed on first trimester exposure. The results of the large Determir in pregnancy trial are due to be published shortly. Women with type 2 diabetes may be controlled on a number of different types of medication including sulphonylureas (e.g. gliclazide or glibenclamide), biguanides (e.g. metformin), a-glucosidase inhibitors, thiazolidinediones, meglitinides, GLP-1 analogues and DPP-IV inhibitors. During pre-pregnancy counselling they should be advised to stop all of the above medication except metformin and glibenclamide (glyburide), the latter being the only sulphonylurea not to cross the placenta. Many of these newer medications have only recently been introduced onto the market and there is no published data regarding their use in pregnancy. There is more experience with Metformin, which has been used in the first trimester of pregnancy in women with polycystic ovary syndrome to reduce miscarriage rates and has not shown any evidence of teratogenicity, although it does cross the placenta. The recent Metformin in Pregnancy Trial has also shown promising results on the safety on metformin in pregnancy when used in gestational diabetes. NICE guidelines suggest women with type 2 diabetes can continue metformin, but many will require supplemental insulin, especially as pregnancy progresses.
Antenatal General: if women have not received pre-pregnancy counselling, then the areas discussed above should be visited in early pregnancy, including prescribing of high dose folic acid, review of medication, and screening for complications. The main challenge of diabetic pregnancies is achieving tight glycaemic control to prevent complications. These women require medical and emotional support for the duration of their pregnancy. NICE advises women to have contact with the diabetes team every 1e2 weeks. Their pregnancies should be jointly managed with obstetrician, midwife, dietician, diabetic nurse and diabetologist. NICE has set out a comprehensive timetable for antenatal appointments, to include both fetal and maternal review. Glycaemic control: the aim should be to achieve euglycmia safely in pregnancy to prevent maternal and fetal morbidity. Targets for blood glucose in the recent NICE guidance are summarized in Box 1. Women with high HbA1c levels who become pregnant need to be counselled on the importance of achieving tight glycaemic control as soon as possible. If hypoglycaemic unawareness occurs in pregnancy then individualized targets should be set to prevent serious hypoglycaemic episodes. Women with type 1 diabetes will already be on insulin. Possible regimens include: twice a day mixed insulin e combination of long and short acting insulin basal bolus regime e short acting insulin with each meal and long acting insulin at night insulin pump e short acting insulin in a pump infusing subcutaneously continuously at a low rate with boluses premeals. One study including 136 women showed improved glycaemic control and lower rate of neonatal morbidity in the basal bolus regime compared to the twice a day regime. The incidence of insulin pumps used to control type 1 diabetes is increasing, therefore more women will present in pregnancy. NICE recommends offering pumps in pregnancy if adequate glycaemic control cannot be achieved on a basal bolus regime without significant disabling hypoglycaemia. Maternal insulin does not cross the placenta. The problems with human insulin are the slow onset and long duration of action that puts the patient at risk of hypoglycaemia and production of antibodies. The newer analogues have the advantages that they mimic the body’s own insulin secretion and
Home blood glucose monitoring (HBGM): women need to be advised about the difference in monitoring of blood sugars in pregnancy compared to outside of pregnancy. NICE targets are outlined in Box 1. Many women will not be checking as frequently as NICE advises and could be concentrating on the pre- rather than post-prandial readings. To aid compliance it should be explained that the aim of gaining tight control is to prevent congenital abnormalities in the fetus in the first trimester and later to prevent macrosomia and stillbirth in the third trimester. This can be achieved by reducing the glucose surge after meals and background levels of glucose. Dietary advice and weight management: a dietician review is recommended for all women. Carbohydrate counting for type 1 diabetics aids glycaemic control, by allowing insulin dose adjustment according to the carbohydrate content of the meal rather than sticking to a rigid dose. Many type 2 diabetics are obese (BMI >30), which is associated with an increased incidence of many adverse outcomes in pregnancy. Women should be advised to lose weight prior to conception to reduce these risk factors, and dietician support offered during pregnancy on how to maintain their weight. CEMACH and the RCOG have recently published guidelines on the management of obesity in pregnancy.
NICE target for blood glucose measurement in pregnancy Pre-meal 1 h post-meal
Screening for maternal complications: women with pre-gestational diabetes have an increased incidence of complications. NICE has set out a clear timetable (see Table 2) to review women at frequent intervals so any complications can be detected early and treated promptly. Prescription of low dose aspirin should be considered in those with additional risk factors for pre-eclampsia, as it has been
3.5e5.9 mmol/l If safely achievable <7.8 mmol/l
Box 1
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women and can be performed even when the head is engaged in the pelvis, although in obese type 2 diabetes it can be difficult to get an accurate measurement of growth. After the 36-week scan the women should see an obstetrician to discuss timing and mode of delivery which will be dependent on the scan results as well as other factors.
Schedule for antenatal care for a diabetic pregnant woman First appointment 7e9 weeks 16 weeks 20 weeks 28 weeks
32 weeks 36 weeks
38 weeks
Glycaemic advice, retinal and renal screening (if not done in previous 12 months) Confirm viability and gestational age Offer retinal assessment (if abnormal in first trimester) Routine antenatal scan including views of heart Growth scan Offer retinal assessment (if normal in first trimester) Growth scan Growth scan Discuss mode, timing and management of birth Advice on glycaemic control after delivery Advice on breastfeeding Offer induction or caesarean section
Labour and delivery Diabetic women should have an agreed labour plan that has been discussed with both the obstetrician and diabetologist. Women with pre-gestational diabetes should deliver on a labour ward rather than a midwife led unit. The timing, mode and glycaemic control for their delivery need to be discussed and documented in advance. Induction: NICE recommends delivery after 38 completed weeks’ gestation through induction of labour or by elective caesarean section if indicated. This is based on review of several studies which showed a reduction in the prevalence of shoulder dystocia and large for gestational age babies in the actively managed group who delivered early compared to the expectantly managed group.
Table 2
Mode of delivery: diabetic women have a higher incidence of caesarean section. The estimated fetal weight should be taken into consideration when advising women about the mode of delivery. Shoulder dystocia is a recognized complication of delivering a macrosomic baby vaginally, which can be reduced by caesarean section. Women with diabetes can be offered a vaginal birth after a caesarean section previously. A large retrospective study from the USA showed that there was no difference in the women with gestational diabetes who failed induced vaginal birth after previous caesarean section compared to the non-diabetic group.
shown to reduce the risk of pre-eclampsia in high-risk women. NICE is due to give advice soon regarding it’s use in all pregnant diabetic women. Usual antenatal assessment of blood pressure and urinary protein should be followed. Baseline renal function and urinary protein quantification at the beginning of pregnancy is a NICE recommendation. If serum creatinine >120 mmol/l or total protein excretion >2 g/day then consider referral to nephrologists. An increase in urinary protein during pregnancy needs further investigation to differentiate between diabetic nephropathy progression and pre-eclampsia. Every diabetic patient should have annual retinal screening with digital imaging of dilated eyes. Women with advanced retinopathy should ideally be treated before conception to reduce the risk of progression in pregnancy. On their first antenatal visit women should be referred for retinal screening, unless it has been performed in the last 6 months. This should be repeated at 28 weeks if the first examination was normal, and if any abnormality detected then closer monitoring is required. If progression does develop then it should be managed in the standard way with laser treatment or vitrectomy. Any progression should be followed up for 6 months postpartum. NICE advocates women with known proliferative retinopathy and poor control should be encouraged to achieve tight control rapidly despite the risk of progression of retinopathy to reduce adverse outcomes to the fetus. Diabetic retinopathy should not be considered a contraindication for vaginal birth.
Steroids: there is a potential risk that steroid administration required for fetal lung maturation, can lead to type 1 diabetics developing DKA as steroids increase insulin resistance. This can be avoided by increasing the subcutaneous insulin doses or admission for an intravenous insulin sliding scale regimen. An alternative approach would be to prospectively increase insulin doses for 5 days post-injection. NICE did not advocate a particular method of management but advised they should have additional insulin according to an agreed protocol. It also reassured that there was no contraindication for diabetic women being given steroids. Glycaemia control peri-delivery: strict glycaemic control during labour and delivery is vital to prevent neonatal hypoglycaemia. Studies show that if the blood glucose is kept between 4 and 7 mmol/l then the incidence of neonatal hypoglycaemia declines dramatically. Neonatal hypoglycaemia is due to maternal hyperglycaemia driving the fetal pancreas to produce increased amounts of insulin. Post-delivery, the fetus needs time to down regulate insulin production and this lag period exposes the fetus to hypoglycaemia unless it is fed straightaway. The CEMACH review found that intravenous sliding scales were badly managed in pregnancy exposing labouring women to the risk of hypoglycaemia. NICE guidelines allow the clinician to choose the method of glycaemic control, with the aim to keep the
Ultrasound scans: recommendations for the schedule of ultrasound scans for a diabetic pregnancy are detailed in Table 2. A specialist cardiac scan should only be offered if cardiac abnormalities are detected on the routine anomaly scan. NICE recommends extra scans to monitor fetal growth in diabetic women at 28, 32 and 36 weeks gestation. The fetal abdominal wall fat is a useful measurement of macrosomia in diabetic
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BMs between 4 and 7 mmol/l. Women should have the option of continuing on their insulin pump or basal bolus regime if they are capable of giving and adjusting the dose throughout labour. If the method chosen does not keep the BMs between 4 and 7 mmol/l, then women should be changed to a sliding scale.
NICE guidelines cannot stop adverse outcomes occurring but they do provide an evidence-based, structured approach to the management of pre-gestational diabetic pregnancies. Hopefully over the next few years, diabetic pregnancy outcomes will improve from those found in the CEMACH survey, and we will get closer to achieving the St Vincent declaration of similar outcomes to those of non-diabetic pregnant women. A
Post-natal Women with diabetes need to stay in hospital for at least 24 h post-delivery to assess that the baby is maintaining normoglycaemia and feeding is established. CEMACH reported that a third of babies were admitted to NICU and 40% of these admissions were avoidable. They recommend that all units have a written policy that babies will stay with the mothers in the absence of complications. Post-delivery, insulin resistance falls due to the absence of placental hormones, and therefore women should convert back to pre-pregnancy regimes, usually lower doses. Women are advised to monitor blood glucose levels closely post-delivery, as pre-pregnancy doses may need adjusting. Diabetic women should be encouraged to breast feed and informed about the advantages to the baby. Type 1 diabetics should be warned about the potential for hypoglycaemia when breastfeeding, and advised to eat prior to feeding and have a snack available. Type 2 diabetics can continue taking metformin, which is considered safe in breastfeeding as <0.3% passes into the breast milk. Glipizide and glibenclamide are not detected in breast milk and therefore are safe in breastfeeding. All other oral hypoglycaemic agents should be avoided until after breastfeeding is discontinued. CEMACH found that less than half the women were given contraceptive advice before discharge from hospital and less than 20% had a documented plan for post-natal diabetes management. NICE recommends that women should be referred back to their routine caregiver before discharge and given advice about contraception and pre-conception care for future pregnancies.
FURTHER READING CEMACH. Confidential enquiry into maternal and child health: pregnancy in women with type 1 and type 2 diabetes in 2002e03, England, Wales and Northern Ireland. London: CEMACH, 2005. Cooper WO, Hernandez-Diaz S, Arbogast PG, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 2006; 354: 2443e51. Ekbom P, Damm P, Feldt-Rasmussen B, Feldt-Rasmussen U, Mølvig J, Mathiesen ER. Pregnancy outcome in type 1 diabetic women with microalbuminuria. Diabetes Care 2001; 24: 1739e44. NICE. Diabetes in pregnancy management of diabetes and its complications from preconception to the postnatal period. National Collaborating Centre for Women’s and Children’s Health, 2008. Nielsen LR, Pedersen-Bjergaard U, Thorsteinsson B, Johansen M, Damm P, Mathiesen ER. Hypoglycemia in pregnant women with type 1 diabetes: predictor and role of metabolic control. Diabetes Care 2008; 31: 9e14. Persson M, Norman M, Hanson U. Obstetric and perinatal outcomes in type 1 diabetic pregnancies: a large, population-based study. Diabetes Care 2009; 32: 2005e9. Smith MC, Moran P, Ward MK, Davison JM. Assessment of glomerular filtration rate during pregnancy using the MDRD formula. BJOG 2008; 115: 109e12. Suhonen L, Hiilesmaa V, Teramo K. Glycaemic control during early pregnancy and fetal malformations in women with type I diabetes mellitus. Diabetologia 2000; 43: 79e82.
Discussion Education is important for women with pre-gestational diabetes and pregnancy should be discussed in their annual diabetic review. Women need to be given information about the benefits of good glycaemic control rather than just focussing on potential complications. Ideally, they should attend pre-pregnancy clinics and receive the information to plan their pregnancy with the support of the diabetic team. Realistically, many pregnancies are unplanned and women should be aware they need to contact the team early so they can get advice on optimizing glycaemic control and receive high dose folic acid. The diabetic woman’s pregnancy journey will be more medicalized than she might wish, including frequent clinic appointments for review by the multidisciplinary team. Women can get disheartened that they are not achieving their glycaemic targets. Input from all members of the team including the dietician, midwife, doctor and diabetic nurse should be given to support women. Recent large trials have demonstrated that there is still much to learn about the management of diabetic pregnancies. The
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Diabetic women have a higher risk of both maternal and fetal pregnancy complications, and this is similar for type 1 and type 2 diabetes. The most important measure to improve pregnancy outcomes is tight glycaemic control. Diabetic women should ideally be given pre-pregnancy counselling to optimize glycaemic control, stop any teratogenic drugs, and review diabetic complications. Multidisciplinary care involving both the diabetic and obstetric teams is important. Metformin can be continued in type 2 diabetes. Delivery should be offered after 38 completed weeks gestation.
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Pre-existing type I and type II diabetes in pregnancy
of congenital abnormalities, stillbirth and macrosomia as the hyperglycaemic state is toxic to the developing fetus. Pregnancy can also lead to the development of hypoglycaemic unawareness, progression of retinopathy and increased incidence of preeclampsia. The Confidential Enquiry into Maternal and Child Health (CEMACH) report of 2005 reviewed pre-gestational diabetic pregnancies in England, Wales and Northern Ireland and found that similar outcomes are still not being achieved in women with and without diabetes as hoped for in the St Vincent declaration of 1989. Of particular concern is that adverse outcomes in type 2 pregnancies, which previously had been considered to be less of a problem, were similar to type 1. Diabetic women should aim to achieve tight glycaemic control, as this has been shown to reduce morbidity. This message should ideally be given in the pre-conception period with advice on how to optimize glycaemic control, prescribing of high dose folic acid and review of current medication to stop any teratogenic drugs. In the last few years several large prospective multicentre trials have been published on gestational diabetes but the information gained can be applied to the management of pre-gestational diabetes. NICE has also published guidelines on the management of diabetes in pregnancy. These should provide some consistency in the approach to managing pre-gestational diabetes and hopefully improve on the pregnancy outcomes seen in the CEMACH report.
Kimberley Lambert Sarah Germain
Abstract Women with pre-gestational diabetes are high-risk pregnancies. Hyperglycaemic is toxic to the developing fetus and is associated with a higher incidence of congenital malformation, miscarriage, macrosomia and stillbirth. Complications can be reduced with tight glycaemic control, and management should ideally start pre-conceptually. During pregnancy a woman’s insulin requirements change and those managed pre-pregnancy on diet or oral medication may need to start insulin. Pre-gestational diabetics require close maternal and fetal monitoring, including screening for the progression of maternal diabetic complications such as retinopathy and nephropathy, and fetal growth scans. Their pregnancies are complex and a multidisciplinary approach should be used. In this article we will discuss the background physiology, the effect of pregnancy on diabetes, the potential fetal and maternal complications, and how these can be minimized by intensive management from pre-conception to the post-natal period, including the contribution of recent studies and guidelines.
Keywords
diabetic ketoacidosis; hypoglycaemia; nephropathy; retinopathy; type 1 and type 2 diabetes
Physiology The World Health Organisation (WHO) definition for the diagnosis of diabetes mellitus (outside of pregnancy) is detailed in Table 1. In pregnancy, the physiology of glucose metabolism alters, so even women with good control outside of pregnancy will usually need their hypoglycaemic medication doses altering. Initially there is a reduction in fasting glucose due to increased renal clearance and decreased gluconeogenesis. This puts type 1 diabetic women at risk of hypoglycaemia in the first trimester. As pregnancy progresses, the woman’s insulin requirements increase as pregnancy is a state of insulin resistance due to placental hormones which include human placental lactogen, cortisol and progesterone. Human placental lactogen causes breakdown of triglycerides for maternal energy, while sparing carbohydrate nutrition for the fetus. The insulin mediated glucose update into skeletal muscle also falls in pregnancy. Non-diabetic women increase their post-prandial insulin production by 50% to counteract this. Women with diabetes are unable to mount an adequate response to hyperglycemia due to absence (type 1) or a reduction
macrosomia;
Introduction Pre-gestational diabetes includes both type 1 and type 2 diabetes. Data from the National Institute for Clinical Excellence (NICE) suggests that in England each year there are 1800 pregnancies to mothers with type 1and 1200 pregnancies for type 2 diabetes. This compares to 20,400 pregnancies a year in women with gestational diabetes. The incidence of type 2 diabetes increases with age and obesity, and is being seen more frequently in pregnancy, reflecting changes in society with women starting their families later and an increase in body mass index of the population. Prior to the advent of insulin, women with type 1 diabetes were advised against pregnancy due to high mortality. Since then outcomes have improved but pre-gestational diabetes is still associated with increased morbidity. There is a higher incidence
WHO definition for diagnosis of diabetes mellitus Kimberley Lambert BSc MBChB MRCP is a Specialist Registrar in Diabetes and Endocrinology at Southampton General Hospital, Southampton, UK. Conflicts of interest: none declared.
WHO classification Normal Impaired glucose tolerance Impaired fasting glucose Diabetes mellitus
Sarah Germain MA MBBS DPhil MRCP is a Specialist Registrar in Obstetric Medicine/Diabetes and Endocrinology at Queen Charlotte’s Hospital and St. Thomas’ Hospital, London, UK. Conflicts of interest: none declared.
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Fasting glucose <6.1 mmol/l <7.0 mmol/l 6.1e7.0 mmol/l 7.0 mmol/l
2 h glucose <7.1 mmol/l 7.8e11.1 mmol/l <7.8 mmol/l 11.1 mmol/l
Table 1
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Renal impairment Diabetic nephropathy is usually a progressive disease divided into: Microalbuminuria (albumin to creatinine ratio (ACR) 3.5e30 mg/mmol) Macroalbuminuria (ACR >30 mg/mmol) Endstage renal failure (raised serum creatinine and uraemia) Diabetic nephropathy in pregnancy is associated with an increased incidence of pre-eclampsia, adverse fetal outcomes and the risk of progression of maternal renal disease. One study looked at 240 women with type 1 diabetes, categorizing the women into normal albumin excretion (n ¼ 203), microalbuminuria (n ¼ 26), and macroalbuminuria (n ¼ 11). The rate of preterm deliveries increased as the proteinuria increased (35, 62 and 91% respectively). The rate of pre-eclampsia also increased (6, 42 and 64%), which partly explains the high rate of preterm deliveries in the macroalbuminuria group. Prior to pregnancy, it is important that women have their renal status evaluated as part of their pre-pregnancy assessment. The CEMACH enquiry into diabetic care in pregnancy found only 58% women had renal function checked in the year before pregnancy. It found the incidence of nephropathy was the same in type 1 and 2 diabetics. Urinary protein excretion increases in all pregnant women towards the end of pregnancy, and this may become significant in women with diabetic nephropathy, with possible associated decline in renal function. It is usually reversible post-pregnancy in those with only mild renal impairment, but there is the risk of irreversible progression in those with more advanced nephropathy. Tight blood pressure and glucose control are extremely important to reduce the incidence of both progression of maternal disease and adverse pregnancy outcomes.
(type 2) of functioning beta cells. Women with type 1 diabetics will need to increase their insulin dose to counteract this physiological change, sometimes up to three times their normal dose. Type 2 diabetic women will usually require insulin during pregnancy to achieve normoglycaemia. Once the placenta is delivered, insulin resistance ceases and diabetic women can return to their pre-pregnancy treatment regime.
Effect of pregnancy on diabetes Diabetic ketoacidosis Diabetic ketoacidosis (DKA) is a medical emergency and the diagnosis should be considered in any pregnant women with type 1 diabetes who becomes unwell. Associated perinatal mortality rates are high, quoted as up to 30%. Causes in pregnancy include hyperemesis gravidarum, infections (especially urinary), corticosteroids, and beta-mimetics. Ketones are present in pregnancy, even in non-diabetic women, due to enhanced lipolysis producing an increase in free fatty acids and ketones. DKA is confirmed by a raised blood glucose in the presence of reduced bicarbonate and raised urinary ketones. DKA can present with severe dehydration and profound acidosis leading to organ impairment and cardiac arrhythmias. Ketones cross the placenta and affect the fetus at high levels. Fetal monitoring during maternal DKA has showed an absence of variability of heart rate and late decelerations. These abnormalities reverse after the woman is treated and so immediate delivery is not warranted until after maternal metabolic abnormalities have normalized. DKA in pregnancy is treated the same as for the non-pregnant state with intravenous glucose and insulin via a sliding scale algorithm. Serum potassium levels need to be closely monitored as insulin drives potassium into the cell and this should be replaced intravenously. NICE guidelines advise pregnant women with DKA to be admitted to a level 2 critical care bed where they can receive combined medical and obstetric input.
Retinopathy The prevalence of diabetic retinopathy increases progressively with increasing duration of diabetes. Retinopathy starts to occur in type 1 after 3e5 years and most patients will have some retinopathy at 20 years. CEMACH confirmed these findings, with less women with type 2 found to have retinopathy (9% compared to 36% type 1) reflecting the shortened duration of disease. In pregnancy, there is the potential for retinopathy to progress. Studies have showed that the severity of retinopathy at conception is reflected in the risk of progression in pregnancy. This is thought to be mainly due to improvement in glycaemic control. The Diabetes Control and Complications trial found it was the magnitude rather than rapidity of improvement in glycaemic control that correlated to progression of retinopathy. Changes in hormones, growth factor and lower retinal blood flow may also contribute to exacerbation in pregnancy.
Hypoglycaemia Hypoglycaemia is diagnosed as a blood glucose value <3.9 mmol/l. In one study 45% women experienced severe hypoglycaemia throughout pregnancy with 80% occurring before 20 weeks. In early pregnancy, women can experience severe hypoglycaemia more frequently for a combination of reasons, including rapid improvement in glucose control to prevent congenital abnormalities and reduced hypoglycaemic awareness. Hypoglycaemia is the most common cause of diabetic maternal deaths, either directly or secondary via road traffic accident. If the patient has a severe hypoglyaemic event then the DVLA should be informed and the patient should be advised not to drive until a consultant confirms they have recovered their awareness. To prevent severe hypoglycaemia from occurring, insulin doses may need to be reduced. NICE guidelines advise any women treated with insulin should be given a concentrated glucose solution for emergencies. Type 1 diabetic women should also be prescribed a glucagon injection, with partner or family members instructed how to administer it. NICE advocates the use of starting insulin pump therapy if women cannot achieve adequate glycaemic control without disabling hypoglycaemia.
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Effect of diabetes on pregnancy Maternal complications Miscarriage: miscarriage rates are higher in diabetic women with higher HbA1c at the start of pregnancy. One study of 83 women with type 1 and 2 diabetes found 22 miscarriages, of which 21 occurred when HbA1c was >11.5%. Pre-eclampsia: women with diabetes have an increased risk of pre-eclampsia in pregnancy, in particular women with known
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renal disease and hypertension pre-pregnancy. A study looking at Sweden’s birth register, involving greater than 98% of all pregnancies between 1991 and 2003, included 5089 type 1 diabetic pregnancies and 1,260,207 control pregnancies. They found the rate of pre-eclampsia 14.0% in the type 1 diabetics compared to 2.8% in the non-diabetic population. Obesity is another risk factor, especially for women with type 2 diabetes.
abnormalities and women should be reassured that they can have healthy pregnancies. Pre-pregnancy Any diabetic women considering pregnancy should be offered pre-pregnancy counselling and receive advice on folic acid, glycaemic control and have their medications reviewed regarding safety in pregnancy. Screening for complications should also form part of the pre-pregnancy review and will be discussed under antenatal management.
Infection: diabetics have an increased incidence of infections, which may become an issue during pregnancy, e.g. urinary tract or post-operative wound infection. This is partly related to impaired neutrophil function. Any infection should be promptly treated with antibiotics to prevent further complications.
Folic acid: as women with diabetes have a higher incidence of neural tube defects. NICE recommends that diabetic women should be prescribed higher dose 5 mg folic acid compared to the standard 0.5 mg dose pre-conceptually until week 12 gestation. The CEMACH enquiry found that 69% of diabetic pregnancies with a poor outcome had no documentation of the women having taken folic acid.
Caesarean section: diabetic women have a higher incidence of caesarean section, quoted as 67% in the CEMACH study. This is partly iatrogenic, related to early induction of labour. Fetal complications Congenital malformations: the CEMACH enquiry confirmed that diabetes is associated with a 3e5 fold increase in the incidence of congenital abnormalities compared to the general population. Major congenital abnormalities associated with diabetes include cardiac, neural tube defects, malformations of gastrointestinal and urinary tract, and musculoskeletal. Hyperglycemia is a toxic environment for the developing embryo, and the incidence of malformation is related to glucose control. This is why optimizing glycaemic control prior to pregnancy is so important, as it may be too late to reduce the teratogenic effect of hyperglycaemia by the time of the first antenatal appointment.
Glycaemic control: HbA1c measures the percentage of glycoslated haemoglobin and reflects glucose control over the last 3 months. NICE advises women to aim for HbA1c <6.1% preconceptually if safely achievable. Many women will not be able to reach this and should be reassured that any reduction in HbA1c will reduce the incidence of congenital abnormalities. Once pregnancy is achieved HbA1c should not be used as it is no longer accurate, so insulin dose adjustments should be according to home blood glucose monitoring values. Insulin regimens may need to be altered and this is discussed in more detail in antenatal management. A study looking at 709 babies born to 488 type 1 diabetic women recorded the incidence of congenital malformation related to maternal HbA1c in the first trimester. Results showed that the higher the HbA1c the higher the incidence of congenital malformations, with HbA1c of <5.6% having a relative risk of 1.6 whereas an HbA1c > 9.4 had a relative risk of 4.8. Other studies have found a 35% incidence of congenital malformations with HbA1c over 10%.
Macrosomia and shoulder dystocia: glucose is transferred across the placenta by facilitated diffusion to the fetus. If maternal blood glucose levels are high then the fetus becomes hyperglycaemic. The fetus responds to high glucose levels by secreting more insulin. Insulin is a growth factor and high circulating fetal insulin levels stimulate fetal growth, which can lead to macrosomia (weight >4.5 kg). Characteristically, these babies have a smaller head to shoulder ratio, large shoulders, and increased body fat and skin folds. Macrosomia is associated with an increased incidence of shoulder dystocia, Erbs palsy, prolonged labour, polyhydramnios and asphyxia. A Swedish study looking at 5089 type 1 diabetic pregnancies showed 31% had large for gestational dates babies (weight >90th percentile).
Medications: diabetic women with hypertensive disease are prescribed medications with the aim to prevent or slow progression of diabetic nephropathy, usually angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers. These medications should not be used in pregnancy as they are associated with oligohydramnios, renal failure, hypotension, and skull defects in the fetus. Traditional advice was to take ACEI until a positive pregnancy test and then stop, but new evidence suggests this practice is not safe and women should not conceive on ACEI. A study looking at third trimester exposure to ACEI showed an almost three fold incidence in congenital malformations in babies exposed in the first trimester. The only exception may be women with heavy proteinuria controlled on an ACEI, and a nephrologist should review these cases. Alternative antihypertensives for use in pregnancy include methyl dopa, nifedipine or labetolol. Some diabetic women may be on treatment with a statin (HMG CoA reductase inhibitor) to reduce cholesterol levels because of the association between hyperlipidaemia and ischaemic heart disease. Women should be advised to
Stillbirth: CEMACH enquiry found that the rate of stillbirth rate was 26.8 per 1000 live and stillbirth in pre-gestational diabetics, which is higher than the national rate of 5.7 per 1000. Stillbirths most frequently occurred between 32 and 36 weeks gestation (41%).
Management of diabetes in pregnancy Introduction The aim of management is a healthy baby and mother. Pregnancy in women with diabetes is high risk, with increased incidence of fetal and maternal complications, but with tight glycaemic control this can be reduced. The CEMACH study found 86% of babies were alive after 28 days with no major congenital
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discontinue statins pre-conceptually as they are associated with central nervous system and limb deficiencies in the fetus.
are associated with less hypoglycaemic events. Aspart (Novorapid) and Lispro (Humalog) have been assessed as safe in pregnancy. Glargine has been used in over 500 pregnancies with no reports of increased neonatal or maternal complications, although more data is needed on first trimester exposure. The results of the large Determir in pregnancy trial are due to be published shortly. Women with type 2 diabetes may be controlled on a number of different types of medication including sulphonylureas (e.g. gliclazide or glibenclamide), biguanides (e.g. metformin), a-glucosidase inhibitors, thiazolidinediones, meglitinides, GLP-1 analogues and DPP-IV inhibitors. During pre-pregnancy counselling they should be advised to stop all of the above medication except metformin and glibenclamide (glyburide), the latter being the only sulphonylurea not to cross the placenta. Many of these newer medications have only recently been introduced onto the market and there is no published data regarding their use in pregnancy. There is more experience with Metformin, which has been used in the first trimester of pregnancy in women with polycystic ovary syndrome to reduce miscarriage rates and has not shown any evidence of teratogenicity, although it does cross the placenta. The recent Metformin in Pregnancy Trial has also shown promising results on the safety on metformin in pregnancy when used in gestational diabetes. NICE guidelines suggest women with type 2 diabetes can continue metformin, but many will require supplemental insulin, especially as pregnancy progresses.
Antenatal General: if women have not received pre-pregnancy counselling, then the areas discussed above should be visited in early pregnancy, including prescribing of high dose folic acid, review of medication, and screening for complications. The main challenge of diabetic pregnancies is achieving tight glycaemic control to prevent complications. These women require medical and emotional support for the duration of their pregnancy. NICE advises women to have contact with the diabetes team every 1e2 weeks. Their pregnancies should be jointly managed with obstetrician, midwife, dietician, diabetic nurse and diabetologist. NICE has set out a comprehensive timetable for antenatal appointments, to include both fetal and maternal review. Glycaemic control: the aim should be to achieve euglycmia safely in pregnancy to prevent maternal and fetal morbidity. Targets for blood glucose in the recent NICE guidance are summarized in Box 1. Women with high HbA1c levels who become pregnant need to be counselled on the importance of achieving tight glycaemic control as soon as possible. If hypoglycaemic unawareness occurs in pregnancy then individualized targets should be set to prevent serious hypoglycaemic episodes. Women with type 1 diabetes will already be on insulin. Possible regimens include: twice a day mixed insulin e combination of long and short acting insulin basal bolus regime e short acting insulin with each meal and long acting insulin at night insulin pump e short acting insulin in a pump infusing subcutaneously continuously at a low rate with boluses premeals. One study including 136 women showed improved glycaemic control and lower rate of neonatal morbidity in the basal bolus regime compared to the twice a day regime. The incidence of insulin pumps used to control type 1 diabetes is increasing, therefore more women will present in pregnancy. NICE recommends offering pumps in pregnancy if adequate glycaemic control cannot be achieved on a basal bolus regime without significant disabling hypoglycaemia. Maternal insulin does not cross the placenta. The problems with human insulin are the slow onset and long duration of action that puts the patient at risk of hypoglycaemia and production of antibodies. The newer analogues have the advantages that they mimic the body’s own insulin secretion and
Home blood glucose monitoring (HBGM): women need to be advised about the difference in monitoring of blood sugars in pregnancy compared to outside of pregnancy. NICE targets are outlined in Box 1. Many women will not be checking as frequently as NICE advises and could be concentrating on the pre- rather than post-prandial readings. To aid compliance it should be explained that the aim of gaining tight control is to prevent congenital abnormalities in the fetus in the first trimester and later to prevent macrosomia and stillbirth in the third trimester. This can be achieved by reducing the glucose surge after meals and background levels of glucose. Dietary advice and weight management: a dietician review is recommended for all women. Carbohydrate counting for type 1 diabetics aids glycaemic control, by allowing insulin dose adjustment according to the carbohydrate content of the meal rather than sticking to a rigid dose. Many type 2 diabetics are obese (BMI >30), which is associated with an increased incidence of many adverse outcomes in pregnancy. Women should be advised to lose weight prior to conception to reduce these risk factors, and dietician support offered during pregnancy on how to maintain their weight. CEMACH and the RCOG have recently published guidelines on the management of obesity in pregnancy.
NICE target for blood glucose measurement in pregnancy Pre-meal 1 h post-meal
Screening for maternal complications: women with pre-gestational diabetes have an increased incidence of complications. NICE has set out a clear timetable (see Table 2) to review women at frequent intervals so any complications can be detected early and treated promptly. Prescription of low dose aspirin should be considered in those with additional risk factors for pre-eclampsia, as it has been
3.5e5.9 mmol/l If safely achievable <7.8 mmol/l
Box 1
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women and can be performed even when the head is engaged in the pelvis, although in obese type 2 diabetes it can be difficult to get an accurate measurement of growth. After the 36-week scan the women should see an obstetrician to discuss timing and mode of delivery which will be dependent on the scan results as well as other factors.
Schedule for antenatal care for a diabetic pregnant woman First appointment 7e9 weeks 16 weeks 20 weeks 28 weeks
32 weeks 36 weeks
38 weeks
Glycaemic advice, retinal and renal screening (if not done in previous 12 months) Confirm viability and gestational age Offer retinal assessment (if abnormal in first trimester) Routine antenatal scan including views of heart Growth scan Offer retinal assessment (if normal in first trimester) Growth scan Growth scan Discuss mode, timing and management of birth Advice on glycaemic control after delivery Advice on breastfeeding Offer induction or caesarean section
Labour and delivery Diabetic women should have an agreed labour plan that has been discussed with both the obstetrician and diabetologist. Women with pre-gestational diabetes should deliver on a labour ward rather than a midwife led unit. The timing, mode and glycaemic control for their delivery need to be discussed and documented in advance. Induction: NICE recommends delivery after 38 completed weeks’ gestation through induction of labour or by elective caesarean section if indicated. This is based on review of several studies which showed a reduction in the prevalence of shoulder dystocia and large for gestational age babies in the actively managed group who delivered early compared to the expectantly managed group.
Table 2
Mode of delivery: diabetic women have a higher incidence of caesarean section. The estimated fetal weight should be taken into consideration when advising women about the mode of delivery. Shoulder dystocia is a recognized complication of delivering a macrosomic baby vaginally, which can be reduced by caesarean section. Women with diabetes can be offered a vaginal birth after a caesarean section previously. A large retrospective study from the USA showed that there was no difference in the women with gestational diabetes who failed induced vaginal birth after previous caesarean section compared to the non-diabetic group.
shown to reduce the risk of pre-eclampsia in high-risk women. NICE is due to give advice soon regarding it’s use in all pregnant diabetic women. Usual antenatal assessment of blood pressure and urinary protein should be followed. Baseline renal function and urinary protein quantification at the beginning of pregnancy is a NICE recommendation. If serum creatinine >120 mmol/l or total protein excretion >2 g/day then consider referral to nephrologists. An increase in urinary protein during pregnancy needs further investigation to differentiate between diabetic nephropathy progression and pre-eclampsia. Every diabetic patient should have annual retinal screening with digital imaging of dilated eyes. Women with advanced retinopathy should ideally be treated before conception to reduce the risk of progression in pregnancy. On their first antenatal visit women should be referred for retinal screening, unless it has been performed in the last 6 months. This should be repeated at 28 weeks if the first examination was normal, and if any abnormality detected then closer monitoring is required. If progression does develop then it should be managed in the standard way with laser treatment or vitrectomy. Any progression should be followed up for 6 months postpartum. NICE advocates women with known proliferative retinopathy and poor control should be encouraged to achieve tight control rapidly despite the risk of progression of retinopathy to reduce adverse outcomes to the fetus. Diabetic retinopathy should not be considered a contraindication for vaginal birth.
Steroids: there is a potential risk that steroid administration required for fetal lung maturation, can lead to type 1 diabetics developing DKA as steroids increase insulin resistance. This can be avoided by increasing the subcutaneous insulin doses or admission for an intravenous insulin sliding scale regimen. An alternative approach would be to prospectively increase insulin doses for 5 days post-injection. NICE did not advocate a particular method of management but advised they should have additional insulin according to an agreed protocol. It also reassured that there was no contraindication for diabetic women being given steroids. Glycaemia control peri-delivery: strict glycaemic control during labour and delivery is vital to prevent neonatal hypoglycaemia. Studies show that if the blood glucose is kept between 4 and 7 mmol/l then the incidence of neonatal hypoglycaemia declines dramatically. Neonatal hypoglycaemia is due to maternal hyperglycaemia driving the fetal pancreas to produce increased amounts of insulin. Post-delivery, the fetus needs time to down regulate insulin production and this lag period exposes the fetus to hypoglycaemia unless it is fed straightaway. The CEMACH review found that intravenous sliding scales were badly managed in pregnancy exposing labouring women to the risk of hypoglycaemia. NICE guidelines allow the clinician to choose the method of glycaemic control, with the aim to keep the
Ultrasound scans: recommendations for the schedule of ultrasound scans for a diabetic pregnancy are detailed in Table 2. A specialist cardiac scan should only be offered if cardiac abnormalities are detected on the routine anomaly scan. NICE recommends extra scans to monitor fetal growth in diabetic women at 28, 32 and 36 weeks gestation. The fetal abdominal wall fat is a useful measurement of macrosomia in diabetic
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BMs between 4 and 7 mmol/l. Women should have the option of continuing on their insulin pump or basal bolus regime if they are capable of giving and adjusting the dose throughout labour. If the method chosen does not keep the BMs between 4 and 7 mmol/l, then women should be changed to a sliding scale.
NICE guidelines cannot stop adverse outcomes occurring but they do provide an evidence-based, structured approach to the management of pre-gestational diabetic pregnancies. Hopefully over the next few years, diabetic pregnancy outcomes will improve from those found in the CEMACH survey, and we will get closer to achieving the St Vincent declaration of similar outcomes to those of non-diabetic pregnant women. A
Post-natal Women with diabetes need to stay in hospital for at least 24 h post-delivery to assess that the baby is maintaining normoglycaemia and feeding is established. CEMACH reported that a third of babies were admitted to NICU and 40% of these admissions were avoidable. They recommend that all units have a written policy that babies will stay with the mothers in the absence of complications. Post-delivery, insulin resistance falls due to the absence of placental hormones, and therefore women should convert back to pre-pregnancy regimes, usually lower doses. Women are advised to monitor blood glucose levels closely post-delivery, as pre-pregnancy doses may need adjusting. Diabetic women should be encouraged to breast feed and informed about the advantages to the baby. Type 1 diabetics should be warned about the potential for hypoglycaemia when breastfeeding, and advised to eat prior to feeding and have a snack available. Type 2 diabetics can continue taking metformin, which is considered safe in breastfeeding as <0.3% passes into the breast milk. Glipizide and glibenclamide are not detected in breast milk and therefore are safe in breastfeeding. All other oral hypoglycaemic agents should be avoided until after breastfeeding is discontinued. CEMACH found that less than half the women were given contraceptive advice before discharge from hospital and less than 20% had a documented plan for post-natal diabetes management. NICE recommends that women should be referred back to their routine caregiver before discharge and given advice about contraception and pre-conception care for future pregnancies.
FURTHER READING CEMACH. Confidential enquiry into maternal and child health: pregnancy in women with type 1 and type 2 diabetes in 2002e03, England, Wales and Northern Ireland. London: CEMACH, 2005. Cooper WO, Hernandez-Diaz S, Arbogast PG, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 2006; 354: 2443e51. Ekbom P, Damm P, Feldt-Rasmussen B, Feldt-Rasmussen U, Mølvig J, Mathiesen ER. Pregnancy outcome in type 1 diabetic women with microalbuminuria. Diabetes Care 2001; 24: 1739e44. NICE. Diabetes in pregnancy management of diabetes and its complications from preconception to the postnatal period. National Collaborating Centre for Women’s and Children’s Health, 2008. Nielsen LR, Pedersen-Bjergaard U, Thorsteinsson B, Johansen M, Damm P, Mathiesen ER. Hypoglycemia in pregnant women with type 1 diabetes: predictor and role of metabolic control. Diabetes Care 2008; 31: 9e14. Persson M, Norman M, Hanson U. Obstetric and perinatal outcomes in type 1 diabetic pregnancies: a large, population-based study. Diabetes Care 2009; 32: 2005e9. Smith MC, Moran P, Ward MK, Davison JM. Assessment of glomerular filtration rate during pregnancy using the MDRD formula. BJOG 2008; 115: 109e12. Suhonen L, Hiilesmaa V, Teramo K. Glycaemic control during early pregnancy and fetal malformations in women with type I diabetes mellitus. Diabetologia 2000; 43: 79e82.
Discussion Education is important for women with pre-gestational diabetes and pregnancy should be discussed in their annual diabetic review. Women need to be given information about the benefits of good glycaemic control rather than just focussing on potential complications. Ideally, they should attend pre-pregnancy clinics and receive the information to plan their pregnancy with the support of the diabetic team. Realistically, many pregnancies are unplanned and women should be aware they need to contact the team early so they can get advice on optimizing glycaemic control and receive high dose folic acid. The diabetic woman’s pregnancy journey will be more medicalized than she might wish, including frequent clinic appointments for review by the multidisciplinary team. Women can get disheartened that they are not achieving their glycaemic targets. Input from all members of the team including the dietician, midwife, doctor and diabetic nurse should be given to support women. Recent large trials have demonstrated that there is still much to learn about the management of diabetic pregnancies. The
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Practice points C
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Diabetic women have a higher risk of both maternal and fetal pregnancy complications, and this is similar for type 1 and type 2 diabetes. The most important measure to improve pregnancy outcomes is tight glycaemic control. Diabetic women should ideally be given pre-pregnancy counselling to optimize glycaemic control, stop any teratogenic drugs, and review diabetic complications. Multidisciplinary care involving both the diabetic and obstetric teams is important. Metformin can be continued in type 2 diabetes. Delivery should be offered after 38 completed weeks gestation.
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