4.5 1 17 8.6 d i s e a s e Treatment Simvastatin 20 \200\22340 mg daily Pravastatin 40 mg daily Pravastatin 40 mg daily Pravastatin 40 mg daily Event reduction for 34% for nondiabetics 55% for diabetics 31% overall 23% for nondiabetics 25% for diabetics 23% overall 1, primary; 2, secondary; 4S, Scandinavian Simvastatin Survival Study; CARE, Cholesterol an d Recurrent Event; LIPID, Long-term Intervention with Pravastatin in Ischemic Disease; WOSC OPS, West of Scotland Coronary Prevention Study; 4 / 1 / 2 0 1 1 6 : 4 3 : 0 8 P M LIPID ABNORMALITIES FOUND IN PATIENTS WITH DIABETES 631 and ASPEN (Atorvastatin Study for the Prevention of Endpoints in Non- insulin dependent dia betes) again show signi \201 cant bene \201 t, but the Anglo- Scandinavian Cardiac Outcom es Trial lipid-lowering arm (ASCOT-LLA) was not quite so encouraging. Once lifestyle measures have been implemented, drug therapy should be considered. In the pa st, the Shef \201 eld tables, New Zealand tables, Joint British Societies Coronary Risk Pr ediction Chart, and the Framingham Risk Score calculations ( b see Tables 113.1, pp. 664 \200\223665, and 113.2, pp. 666 \200\223667) were used to determine risk in primary prevent ion, but now any person with diabetes is thought of as being at such a high risk that sec- ondary prevention targets of a total cholesterol <150 mg/dL, an LDL <80 mg/dL, and an HDL > 38 mg/dL are now advocated. A \201 t patient with diabetes has a similar risk to that of a nondiabetic of the same ag e and sex who has also had a coronary event. Other targets are advocated by many, especiall y for those patients post \200\223coronary artery bypass grafting or post-angioplasty. Trig lycerides should be brought to <140 mg/dL, as above this level atherogenic lipoprotein chan ges are said to occur. In those with mixed hyperlipidemia, a \201 brate or statin licensed for this indication s hould be considered. A \201 brate will reduce triglycerides by 30 \200\22340% and LDL cho lesterol by 20%, while a statin would reduce triglyc- erides slightly less (10 \200\22315%) and LDL cholesterol slightly more (25 \200\22335%). Fibrates also alter LDL cholesterol to its less atherogenic form. The choice of agent must be tailored to the individual patient. For hypercholesterolemia alone, a statin is \201 rst choice, as in the nondi- abetic pati ent, and in severely resistant patients combination therapy with statins, ezetimibe, \201 brates, and, less often, resins may be required. Combination statin and ezetimibe may redu ce LDL more effectively than increasing the statin dose alone. Treatment aims for lipids \200 Total cholesterol <4.0 mmol/L \200 LDL cholesterol <2.0 mmol/L \200 Aim to have triglycerides <1.5 mmol/L Box 108.1 Investigations of lipid abnormalities Take a full history and carefully examine the patient. In all patients, then check the foll owing: \200 Dip test urine for protein \200 Serum urea, electrolytes, and creatinine (a nd creatinine clearance if creatinine is raised) Fasting lipids \200 ECG (for left ventricular hypertrophy and signs of ischemia) Also con sider the following: \200 The need for a chest X-ray for signs of heart failure or cardio megaly \200 An echocardiogram \200 Cortisol + dexamethasone suppression test \200 Cat echolamines \200 Renin/aldosterone 108-Draznin-Chap108.indd 631 4/1/2011 6:43:09 PM CHAPTER 108 Macrovascular disease 632 Hypertension Epidemiology Hypertension is twice as common in the diabetic population as in the nondiabetic population, and standard ethnic differences in the prevalence of hypertensi on still hold true. Hypertension worsens the severity and increases the risk of developing both microvascular and macrovascular disease. With a cutoff of >160/90 mmHg, hypertension o ccurs in \200 10 \200\22330% of patients with type 1 diabetes \200 20 \200\22330% of mi croalbuminuric type 1 patients \200 80 \200\22390% of macroalbuminuric type 1 patients \200 30 \200\22350% of Caucasians with type 2 diabetes With suggested targets of 130/80, h ypertension is even more common. Pathogenesis Type 1 diabetes Hypertension is strongly associated with diabetic nephropathy and micro- albuminuria and occurs at an earlier stage than that seen in many other causes o f renal disease. This may in part be linked to a genetic predisposition toward i activity in red blood cell sodium \200\223lithium countertransport activity, which leads to i peripheral vascular resi stance. Insulin may also have a suppressive effect on renin release, producing hyporeninemi c hypoaldosteronism. Type 2 diabetes Hypertension is associated with insulin resistance and hyperinsulinemia; ag ain, this may be genetically mediated. Hyperinsulinemia can directly cause hypertension thr ough i sympathetic nervous system activity, i proximal tubule sodium resorption, and stimul ating vascular smooth muscle cell proliferation. Hyperglycemia also has an antinatiuretic effect, which, along with hyper- insulinemia leadi ng to hypokalemia, results in both glucose and sodium reabsorption being increased. All of these factors increase the potential for hypertension. Management Treatment aim The current recommendation is for all patients with diabetes to ha ve a blood pressure <140/80 mmHg. The hypertension study in the UKPDS highlights the bene \201 ts for type 2 patients of this treatment level on mor- tality, diabetes-related end po ints, and microvascular end points. In this study, a 10/5 mmHg difference in BP was associa ted with a 34% risk reduc- tion in macrovascular end points, a 37% risk reduction in microv ascular end points, and a 44% risk reduction in stroke. The Hypertension Optimum Treatment (HOT) study again suggests a target of <140/80 mmHg, alt hough in those who already have signi \201 cant end-organ damage a lower target (<130/80) is advocated by some. 108-Draznin-Chap108.indd 632 4/1/2011 6:43:09 PM HYPERTENSION 633 The Anglo-Scandinavian Cardiac Outcomes Trial \200\223Blood Pressure Lowering Arm (ALLHAT \200\223BPLA) reinforced the bene \201 cial role of calcium channel blockers and ACE inhib itors in combination. Predisposing conditions Other conditions that can cause both hypertension and hyperglyc- em ia should be considered, e.g., Cushing \200\231s syndrome, acromegaly, and pheochromocytoma . End-organ damage Look for evidence of end-organ damage (eyes, heart, kidneys, and periph- e ral vascular tree in particular). Assessment of cardiac risk factors Look for associated risk factors for coronary heart dise ase. Treatment General Once this initial assessment is complete, modify other risk factors such as glycemic control, smoking, and dyslipidemia. Then look at the following: \200 Weight r eduction if obese \200 Reduced salt intake (<6 g/day) \200 Reduced alcohol intake (<21 units/week in males, <14 in females) \200 Exercise (20 \200\22340 minutes of moderate exe rtion 3 \200\2235 \227/week) Pharmacological After modifying risk factors, drug therapy should be started for the hyper- tension. Most agents currently available will drop systolic BP by no more than 20 mmHg. In the UKPDS BP study, 1/3 of those achieving the tight BP targets now aimed for required thr ee or more drugs to do so. Recently, the National Institute for Health and Clinical Excellence (NICE) guidelines for B P treatment were updated and now advocate an \200\234A/CD \200\235 approach: starting with an ACE inhibitor (or an angiotensin II receptor blocker/antagonist if the ACE inhibitor is not tolerated) and then adding in either a calcium channel blocker or a thiazide-type diur etic with an A-blocker, a B-blocker, or further diuretic therapy if this fails to reduce BP adequately. In the presence of microalbuminuria or frank proteinuria, an ACE inhibi- tor s hould always be considered \201 rst line, or an angiotensin II receptor antagonist if ACE inhibitors are not tolerated. In Afro-Caribbean diabetics, a diuretic may also be needed to improve the ef \201 cacy of ACE inhibitors, as these and B-blockers are less effective than calcium channel blockers an d diuretics in these patients. Several agents, such as high-dose thiazides and B-blockers, can worsen diabetic control, ma sk hypoglycemia, and exacerbate dyslipidemia. Thus the drugs chosen need to be tailored to each patient. A recent review of data from the Nurses Health Study (NHS I and II) and the Health Professi onals Follow-up Study (HPFS) suggested that while these agents may increase the risk of dev eloping diabetes, they may not be 108-Draznin-Chap108.indd 633 4/1/2011 6:43:09 PM CHAPTER 108 Macrovascular disease 634 Box 108.2 Management of acute myocardial infarction Patients with diabetes are more likely to have a myocardial infarction (MI) and more likely to die from it than the nondiabetic population. This may be due to a greater likelihood of myocardial pump failure. Several studies highlight this: Trial and outcome examined Nondiabetic subgroup Diabetic subgroup ISSI-2 Non-streptokinase 27% 41% 4-year mortality GUSTO In-hospital mortality 6.2% 10.6% GISSI-2 Reinfarction rates 14% 30% In those with angina, a B-blocker has added bene \201 ts. In those with peripheral vascula r disease, vasodilators such as the cal- cium channel blockers may be bene \201 cial. Up to 20 \200\22340% of patients admitted to the hospital with an MI will have hyperglycemi a, many of whom not previously diagnosed with diabetes. As in the nondiabetic population, s treptokinase, aspirin, and acute angioplasty have proven bene \201 ts. The previous contra indication for thrombolysis in those with proliferative diabetic retinopathy has been quest ioned by many investigators. Tight glycemic control (blood glucose 120 \200\223180 mg/dL) using IV glu- cose and insulin for at least 24 hours followed by SC insulin, as used in the DIGAMI study, also has bene \201 ts. In this study, patients with an admission blood glucose >200 mg/dL who were treate d with this regi- men had a 7.5% absolute risk reduction in mortality at 1 year and an 11% risk reduction at 3.5 years compared to the control group (i.e., 33% mortality with treatme nt vs. 44% in controls at 3.5 years). This equates to 1 life saved for every 9 treated with this regimen. The exact reason for this outcome is unclear. It is suggested that all patients with a blood glucose >200 mg/dL ben- e \201 t from such treatment whether previously known to have diabetes or not. Using an admission HbA1c to det ect those with undiagnosed or stress-related hyperglycemia can be useful, but should not re sult in withholding acute treatment of this hyperglycemia in such patients. It may, however , help to identify those who may be troubled by hypogly- cemia and may not therefore be sui table for SC insulin or sulfonylureas in the intermediate or long term. 108-Draznin-Chap108.indd 634 4/1/2011 6:43:09 PM HYPERTENSION 635 Box 108.2 (Contd.) Use of ACE inhibitors early after an MI gives a 0.5% absolute risk reduction in 30-day mort ality and a 4 \200\2238% risk reduction over 15 \200\22350 months in the general population . Analysis of the diabetic subgroup in the GISSI-3 study showed a 30% rel- ative risk reducti on in 6-week mortality for the diabetics (8.7% vs. 12.4%) compared to a 5% reduction for no ndiabetics. In view of the greater pro- portion of diabetics with poor left ventricular fun ction after MI than that of the nondiabetic population, this difference is very important. associated with an i risk of cardiovascular or total mortality, which may be related to BP control, although this is not certain. Further reading Hanssen L, Zanchetti A, Carruthers SG, et al. (1998). Effects of intensive blood pressure lowering and low dose aspirin in patients with hypertension: principal resul ts of the Hypertension Optimun Treatment (HOT) randomized trial. Lancet 351:1755 \200\22317 62. Malmberg K, for the DIGAMI (DM, Insulin Glucose Infusion in Acute Myocardial Infarction) st udy group (1997). Prospective randomized study of intensive insulin treatment on long-term survival after acute myocardial infarction in patients with DM. BMJ 314:1512 \200\2231515. NICE (2006). Hypertension: management of hypertension in adults in primary care. NICE clini cal guidelines 34 (partial update of NICE clinical guideline 18). http://www.nice.org.uk NICE (2008). Type 2 diabetes: the management of type 2 diabetes. Management of blood pressu re and lipids. Clinical guideline CG 66. http://www.nice.org.uk Pyorala K, Pedersen TR, Kjekshus J, et al. (1997). Cholesterol lowering with simvastatin im proves prognosis of diabetic patients with coronary heart disease. Diabetes Care 20:614 \200\223620. Taylor EN Hu FB, Curhan GC (2006). Antihypertensive medications and the risk of incident ty pe 2 diabetes. Diabetes Care 29:1065 \200\2231070. UKPDS Group (1998). Tight blood pressure control and risk of macrovascular and microvascula r complications in type 2 diabetes: UKPDS 38. BMJ 317:703 \200\223713. UKPDS Group (1998). Ef \201 cacy of atenolol and captopril in reducing the risk of acrovas cular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 317:713 \200\223720 . Zuanetti G, Latini R, Maggioni AP, et al. (1997). Effect of the ACE inhibitor lisinopril in diabetic patients with acute myocardial infarction. Data from GISSI-3 Study. Circulation 9 6:4239 \200\2234245. 108-Draznin-Chap108.indd 635 4/1/2011 6:43:09 PM CHAPTER 109 Diabetic foot 636 Diabetic foot b See Boxes 109.1 and 109.2. Box 109.1 Clinical features of diabetic feet Neuropathic feet \200 Warm \200 Dry skin \200 Palpable foot pulses \200 No discomfo rt with ulcer Callus present Ischemic feet \200 Cold/cool. \200 Atrophic/often hairless. \200 No palpable foot pul ses \200 More often tender/painful. \200 Claudication/rest pain \200 Skin blanches on elevation and reddens on dependency. Box 109.2 Wagner \200\231s classi \201 cation of diabetic foot lesions 1 \200 Grade 0 \200\224high-risk foot, no ulcer present \200 Grade 1 \200\224super \201 cial ulcer, not infected \200 Grade 2 \200\224deep ulcer with or without cellulitis but no abscess or bone involvement Grade 3 \200\224deep ulcer with bone involvement or abscess formation \200 Grade 4 \200 \224localized gangrene (toe, forefoot, heel) \200 Grade 5 \200\224gangrene of the whole f oot 1 . Reprinted with permission from Wagner FW, O \200\231Neal LW. Algorithms of diabetic foo t care. In Levin ME, O \200\231Neil LW (1983). The Diabetic Foot , 2nd ed., pp. 291 \200 \223302. Copyright 1983, Elsevier. 109-Draznin-Chap109.indd 636 3/31/2011 5:32:53 PM RISK FACTORS FOR FOOT ULCER DEVELOPMENT 637 Risk factors for foot ulcer development Several features and factors are thought to predisp ose to ulcer formation. Awareness of these may help in identifying at-risk patients for edu cation and other preventive strategies. These ulcers can occur anywhere on the foot, but the tips of claw toes and hammertoes and o ver the metatarsal heads are the most frequent sites. The risk factors and features include the following: \200 Peripheral neuropathy (seen in up to 80% of diabetic patients with f oot ulcers) reduces awareness of pain and trauma caused by footwear and foreign bodies in s hoes. Look for reduced mono \201 lament sensation (e.g., reduced to a 10 g mono \201 lame nt) and reduced vibration perception thresholds (e.g., reduced sensation to a 128 Hz tuning fork for <10 seconds or >25 V with a biosthesiometer), which suggest at-risk feet. Autonomic neuropathy leading to anhidrosis can dry out the skin and cause it to crack, thus allowing a portal of entry for infection. These feet are often warm and dry with distended veins. Motor neuropathy can result in altered foot muscle tone, wasting of small muscles, raising of the medial longitudinal arch, and clawing of the toes. This can produce more pressure on the metatarsal heads and heels, thus predisposing them to callus and ulcer formation. Elec trophysiology can help in examining this condition but is too invasive for widespread routi ne use. Peripheral vascular disease (seen in up to 10% of patients) and microvascular circulatory disease lead to local ischemia, increasing the potential for ulce r formation, and can delay wound healing when ulceration occurs. Always examine peripheral pulses and consider getting Doppler studies if they are abnormal. An ankle/brachial artery ratio of >1.1 suggests arterial disease (a ratio of the BP in the ankle and the arm measure d while at rest). Duration of diabetes relates to the presence of the above factors but is often quoted as an independent risk factor, as is i age. But type 2 diabetes may be present and have gone und iagnosed for some time. \200 The presence of other microvascular complications, such as n ephropathy and retinopathy, is also a risk factor for foot ulcer development. \200 Previous ulcerati on is another important risk factor. Anyone with previous problems deserves very careful monitoring and follow-up. \200 Lack of diabetes m onitoring and lack of previous examinations of the feet are also recognized risk factors. Mechanical, chemical, or thermal trauma or injury is often the predisposing factor. Any profession or pastime that increases the risk of any of these is a risk factor. 109-Draznin-Chap109.indd 637 3/31/2011 5:32:53 PM CHAPTER 109 Diabetic foot 638 Treatment This is a multidisciplinary problem requiring collaboration among dia- betologist s, podiatrists, orthtopedic, and vascular and plastic surgeons. Treatment is aimed at sever al distinct areas: \200 At-risk feet with no current ulceration \200 Treating existing ulcers \200 Treating infected ulcers \200 Treating osteomyelitis \200 Treating vascul ar insuf \201 ciency At-risk feet with no current ulceration When at-risk feet are identi \201 ed in any patien t with diabetes, standard advice should be given. This will need to be repeated and reinfor ced regu- larly. Such advice would usually include the following: \200 General advice on nail care, hygiene, and care with footwear \200 Reinforce the need for regular daily exam ination of the feet by the patient or caregiver. Consider regular podiatry review and self-monitoring. Also reinforce the need for more urge nt review if the patient discovers problems. \200 Consider the need for modi \201 cation of footwear or special footwear if there are abnormalities with foot posture or problems w ith pressure loading on certain parts of the foot. Padded socks can also reduce trauma. Adv ise patients to examine shoes before putting them on, wear lace-ups or shoes with lots of r oom for toes, and avoid ill- \201 tting shoes. For some people, protective toecaps can pro ve useful. Avoid walking barefoot. Currently, no other therapy is advocated in this group of patients. As discussed in Chapter 107 (Diabetic neuropathy), good diabetic control is important and other agents may be useful in the future, such as aldose reductase inhibitors, inhibitors o f nonenzymatic glycation, and various growth factors. Existing ulcers All ulcers should be considered deep and involving bone until proven oth- e rwise. The following factors are also important: \200 Optimize diabetic control. \200 R eduction of edema is important to aid healing. \200 Regular debridement of callus and dea d tissue and skin is important for both neuropathic and ischemic ulcers. Debridement is usually best done with a scalpel and forceps, although chemical agents (such as varidase, which contains streptokinase) can occa- sionally help. Because these agents c an also damage healthy tissue, they should be used under careful supervision. After debridement, dressings should be applied, and changed regularly. Be careful that tigh t dressings do not further impair a poor circulation and that thick dressings or quantities of sticky tape holding them on do not cause their own skin trauma or pressure effects. 109-Draznin-Chap109.indd 638 3/31/2011 5:32:53 PM TREATMENT 639 Infection control Infection may be localized, but any evidence of deeper infection or sinus formation raises the possibility of osteomyelitis. Systemic symptoms of an infection may b e minimal, as may pain and tenderness in the foot itself, so be suspicious of more severe i nfection than those usually seen. The organisms may be ordinary skin commensals that have found a port of entry. Send swabs f or culture and think of Staphylococcus aureus or streptococci as likely organisms. If a sinus is present, probe it and if down to bone, assume there is osteomyelitis. Culture anything you get out. Plain radiographs may show bone erosion or destruction with osteomye litis; radioisotope scans with technetium can show i uptake with both infection and Charcot arthropa- thy. MRI scanning can be useful to differentiate the two. If infection is present, use triple therapy with \202 ucloxacillin (500 mg 4 \227 daily), ampicillin/amoxicillin (500 mg 3 \227 daily), and metronidazole (200mg 3 \227 daily) or co nsider using amoxicillin/clavulanic acid (250/125 mg 3 \227 daily) or cipro \202 oxacin (5 00 \200\223750 mg 2 \227 daily) and clindamycin (300 \200\223450 mg 2 \227 daily) depending on the organisms grown and patient tolerability. This will need to be given IV initially i f the infection is severe. For deeper infections, several months of therapy may be needed. If osteomyelitis is present, consider using cipro \202 oxacin or sodium fusidate, both of which have better bone penetration. Use for several months. Linezolid is also useful as a second- or third-line agent, but requires extra caution used in those with hepatic and renal impairment. This caveat and the need to monitor for potenti al thrombocytopenia, anemia, or pan- cytopenia may limit its use. In some patients, this approach fails to control osteomyelitis adequately and resection or amputation is required. Regular consultation with a capa- ble surgeon is imperative. Reducing trauma and pressure relief For treatment of neuropathic ulcers, padded socks can r educe sheer stress and trauma. Suitable shoes and insoles can help relieve pressure to enab le healing, as long as unnecessary walking is minimized. If these measures are not enough, a pneumatic or Aircast boot or a total contact cast may b e needed. These allow the patient to be mobile while taking the weight away from the ulcera ted area or foot. Instead, all of the weight and pressure is directed through to the calf. The involvement of podiatrists and orthotists is essential. Revascularization Always consider coexistent vascular disease in a neuropathic foot or pre- dominantly ischemic ulcers and feet. Vascular bypass grafting and recon- struction or angi oplasty can give excellent results, with a 70 \200\22395% limb salvage rate often quoted. T he improved blood supply will also help heal- ing of existing ulcers and may negate the nee d for amputation or minimize the area requiring resection. If vascular intervention is unsuccessful or not possible, then amputation is required, pref erably as a below-knee procedure, to give a better mobi- lization potential postoperatively . 109-Draznin-Chap109.indd 639 3/31/2011 5:32:53 PM CHAPTER 109 Diabetic foot 640 Box 109.3 The Charcot foot Epidemiology This is a relatively rare complication of diabetes: an average general hos- pi tal clinic will have 3 \200\22310 patients with this problem. Pathogenesis Blood \202 ow increases from sympathetic nerve loss. This causes osteo- clas t activity and bone turnover to increase, thus making the bones of the foot more susceptibl e to damage. Even minor trauma can result in destructive changes in this susceptible bone. Clinical features The most likely site is the tarsal \200\223metatarsal region or the metat ar- sophalangeal joints. Initially, the foot is warm or hot, swollen, and often uncomfortab le, features that may be indistinguishable from cellulitis and gout. Peripheral pulses are invariably present, and peripheral neuropathy is evident clinically. Plain radiographs will be normal initially and later show fractures with osteolysis and joi nt reorganization with subluxation of the metatar- sophalangeal joints and dislocation of t he large joints of the foot. Isotope scans with technetium are abnormal from early on; differen- tiation from infective or other in \202 ammatory causes can be dif \201 cult. MRI scanning may prove more useful for this, as may 111 indium-labeled white cell studies if infection is suspected. Eventually, in the untreated patient, two classic deformities are seen: \200 A \200\234r ocker bottom \200\235 deformity due to displacement and subluxation of the tarsus downward Medial convexity due to displacement of the talonavicular joint or tarsometatarsal dislocation Management If diagnosed early, immobilization may help prevent joint destruction. While the best means of doing this is not agreed on, use of a non- walking plaster cast or an Aircas t type of boot is needed for at least 2 \200\2233 months while bone repair or remodeling is taking place. Some clinicians advocate immobilization for up to a year. The recent use of bisphosphates t o speed up the repair process by reducing osteo- clast activity is interesting and under fu rther evaluation. Further reading Boulton AJM (2003). Foot problems in patients with DM. In Williams G, Picku p JC (Eds.), Textbook of Diabetes , 3rd ed. Oxford, UK: Blackwell Science. NICE (2004). NICE clinical guideline. Type 2 diabetes \200\224foot care. http://www.nice.or g.uk Scottish Intercollegiate Network (SIGN) (1997). National Clinical Guideline (recommended fo r use in Scotland). Management of diabetic foot disease. Available from SIGN Secretariat, 9 Queen Street, Edinburgh, EH2 1JQ. http://www.sign.ac.uk/guidelines/ Wagner FW (1983). Algorithms of diabetic foot care. In Levin ME, O \200\231Neil LW (Eds), T he Diabetic Foot , 2nd ed. St. Louis: Mosby Yearbook, pp. 291 \200\223302. 109-Draznin-Chap109.indd 640 3/31/2011 5:32:53 PM RISKS 641 Diabetes and pregnancy Background Of women who become pregnant, 0.27% have previously diagnosed dia- betes and acc ount for 0.10% of live births, and 2 \200\2233% of pregnant women have a diagnosis of gesta tional diabetes made during their pregnancy. In both cases, there are risks to both the mot her and the fetus. These fetuses have a historical fetal abnormality rate of up to 30%, or 12 x that of the background population. Given the increasing proportion of women with type 2 diabetes, these pregnancies should also be looked for. Risks Fetal With greater emphasis on improving glycemic control, a 2.5- to 3-fold i in congenital malformation rate in mothers with previously known diabetes and a 1.8-fold increase in tho se without it being known, compared to rates in the nondiabetic population, is more realist ic now. Cardiac, renal, and neural tube defects occur, particularly sacral agenesis. Hyperglycemia in the \201 rst 8 weeks of fetal life, during organogenesis, is thought to be the underlying cause. This explains the lower rate in those with gestational diabetes, w hich classically occurs later, but not com- pletely. Alterations in oxygen free radicals, m yosinositol, and arachidonic acid metabolism and alterations in zinc metabolism are also im plicated. The most common problem seen in the infant is macrosomia (in 8 \200\22350%), which can resu lt in birth trauma and an i intervention rate. As well as causing obesity, fetal hyperinsul inemia also accelerates skeletal maturation, delays pulmonary maturation, and causes i grow th of insulin- sensitive tissues producing hypertrophy of the liver and heart. These infants also have an i risk of hypoglycemia, seen transiently in up to 50%, and jaund ice, with rates of 6 \200\22350% quoted. Up to 50% of these infants require phototherapy. P olycythemia is also seen. Maternal Maternal problems include an i risk of infection and of pre-eclampsia, which is 2 \200\2233 times as likely to occur as in a nondiabetic mother. Women with type 1 diabetes h ave a 3-fold i prevalence of thyroid dysfunction dur- ing the pregnancy and postpartum, so this needs to be screened for. 110-Draznin-Chap110.indd 641 3/31/2011 5:33:18 PM CHAPTER 110 Diabetes and pregnancy 642 Inheritance of diabetes If the background rate of diabetes is 0.15%, the infant of a diabet ic mother has a 2% risk and the infant of a diabetic father a 6% risk of developing diabete s. The risk of type 2 diabetes in a child of a type 2 mother is much higher, at 15 \200\223 30%, and rises to 50 \200\22360% if both parents have type 2 diabetes. Known diabetes and pregnancy Most women with diabetes have normal deliveries and normal bab ies. In most instances, these are women with type 1 diabetes, although in some ethnic group s type 2 patients may make up a sizable group. In both groups it is of utmost importance to have pre-conception glycemic control opti- mized, e.g., preferably an HbAlc level in the n ondiabetic range or <7.0% if that is not possible. The congenital malformation and spontaneous abortion rates are sig- ni \201 cantly higher when the HbA1c is elevated. Once the HbA1c is 4 \200\2236 standard deviations above the nor mal nondiabetic range, there is a 4-fold increase in the malformation rate; at over 6 stand ard deviations above normal, this rises to a 12-fold risk. In type 2 patients, converting from oral agents to insulin is important. If this is not pos sible prior to conception, it should be done as soon as a woman is found to be pregnant. Pre-conception management Pre-conception and post-conception advice to diabetic women is si milar to that given to nondiabetic women: stop smoking, reduce alcohol intake, avoid unpast eurized dairy products, and add oral folate supplements (5 mg/day). Any potentially teratog enic drugs they may be taking (e.g., antihypertensive agents) also need to be reviewed. Ideally, all patients who have diabetes and are pregnant should be man- aged in a combined clinic by an obstetrician and a diabetologist. Reviews are initially every 2 \200\2234 week s then every 1 \200\2232 weeks in the last 1/3 of preg- nancy. Screening and monitoring for conditions such as associated thyroid disease at these reviews is also advisable. Maintaining good glycemic control This is important not just because of the risk of ketoaci dosis, which occurs in <1 % of diabetic pregnancies and is associated with fetal loss in 20 % of episodes, but also because of macrosomia in the fetus and the i fetal mortality (up to 2.2% of births in diabetic mothers) and i intervention rate at delivery. The aim is to keep the glucose and HbAlc levels in the nondiabetic range, to reduce the mor bidity and mortality associated with pregnancy and diabetes (Box 110.1). Even with perfect control, however, there is a small but signi \201 cant excess of major congenital malforma tions in these children and an unexplained risk of late stillbirths. 110-Draznin-Chap110.indd 642 3/31/2011 5:33:18 PM KNOWN DIABETES AND PREGNANCY 643 Box 110.1 Monitoring during pregnancy \200 Capillary blood glucose monitoring is performe d at least 4 \227 per day. \200 Monitor thyroid function. Target glycemic control \200 Fasting glucoses of <90 mg/dL \200 Postprandial glucoses of <126 mg/dL \200 Keep the Hb A1c level in the nondiabetic range. Treatment regimen A basal bolus regimen gives the greatest \202 exibility and is commonly used to achieve this target. In type 1 patients, insulin requirements often fall in the \201 rst trimester, increase slightly in the second, then continue to rise until about 36 w eeks, falling back to pre-pregnancy levels after delivery. In type 1 women, early pregnancy is a cause of falling insulin require- ments and recurrent hypoglycemia. It has been suggested that up to 40% of women with type 1 diabetes will expe rience signi \201 cant hypoglycemic episodes when pregnant and hypoglycemic awareness may alter. Advice regarding care with driving and other potentially hazardous pursuits is there fore needed early in pregnancy, if not before conception. Type 2 women requiring insulin usually need 0.9 units/kg/day initially and 1.6 units/kg/day later in the pregnancy. Monitoring of diabetic complications during pregnancy Certain diabetic complications are kn own to worsen during pregnancy. Screening for nephropathy and retinopathy in particular is advised at least each trimester. Fetal monitoring Scanning of the fetus is performed at 10 \200\22312 weeks to look for cong enital abnormalities and to con \201 rm dates. Repeat scanning is used to check for excessive growth or macrosomia at 18 \200\22320 weeks, 28 weeks, 32 weeks, and 36 weeks, although the exact timing and frequency can vary between centers. Management of delivery At delivery, most units have set protocols (see Box 110.2 ). In gene ral, induc- tion soon after 38 weeks \200\231 gestation (or not later than the expected del ivery date) and use of a continuous insulin infusion with a separate dextrose and potassium infusion to maintain stable blood glucose levels are advisable. This infusion is important, as maternal hyperglycemia during delivery can be associated wit h neonatal hypoglycemia and an adverse neurological outcome in the infant. The infant respo nds to a hyperglycemic environ- ment in utero by increasing its own insulin production. After delivery Monitoring of the infant \200\231s capillary blood glucose levels post-deliv ery is also often performed. The i potential for hypoglycemia in the mother 110-Draznin-Chap110.indd 643 3/31/2011 5:33:18 PM CHAPTER 110 Diabetes and pregnancy 644 Box 110.2 Treatment regimen for labor and delivery \200 If labor is induced, omit the pre vious evening \200\231s long-acting insulin. \200 Infuse 10% glucose at 75 \200\223125 mL /h (with 20 mmol potassium per 500 mL bag). Infuse via syringe driver 2 \200\2234 units/h o f soluble insulin initially (usually made as 50 mL soluble insulin in 50 mL of 0.9% saline in a 50 mL syringe). Monitor capillary blood glucose levels hourly and adjust infusion rate of the insulin to keep blood glucose levels in the 110 \200\223150 mg/dL range. Monitor \202 uid balance carefully (especially if oxytocin is also being given). oxytocin) Check serum sodium if labor lasts over 24 hours (or 8 hours with and the baby if breast-feeding also needs to be watched for. Extra car- bohydrate snacks fo r the mother are often needed, along with a 20 \200\22325% reduction in pre-conception insu lin requirements. One day \200\231s worth of breast milk contains about 50 g of carbohydrate. Also consider m onitoring thyroid function at 3 and 6 months post- delivery. After delivery \200 Halve the IV insulin infusion rate. \200 Continue to monitor capill ary blood glucose hourly for at least 4 hours then every 2 \200\2234 hours until the mother is eating normally. Return to the pre-pregnancy regimen when the mother is eating normally, but be careful, as insulin requirements can be low for the \201 rst 24 hours. Gestational diabetes Epidemiology Pregnancy induces a state of insulin resistance with increases in the levels o f growth hormone, placental growth hormone, progesterone, placental lactogen, and cortisol. This can result in altered glucose handling. Impaired glucose tolerance during pregnancy occurs in up to 2 \200\2233% of pregnant women and may be associated with an i risk of subsequent type 2 diabetes in 20 \200\22350% of pat ients. Worsening maternal insulin resistance and associated hyperglycemia usually becomes e vident from the second trimester on if it is going to occur. As with women previously known to have diabetes, there is an associa- tion with worsening c arbohydrate intolerance and a worse maternal and fetal outcome. Untreated gestational diabetes has a perinatal mortality of 4.4 \200\2236.4% com- pared to 0.5 \200\2231.5% in a similar ethnic normoglycemic population. Intensive insulin treatment has been shown to reduce such complications. This is the rationale for careful multidiscipl inary care of these patients. 110-Draznin-Chap110.indd 644 3/31/2011 5:33:18 PM GESTATIONAL DIABETES 645 Treatment Initial treatment is with dietary advice; in 10 \200\22330%, insulin is also requ ired. Insulin therapy should be considered if fasting blood glucoses are >110 mg/dL or post prandial levels are >150 mg/dL. Obesity is not uncommon in these patients. The importance of post- delivery dietary modi \201 cation and weight reduction, to reduce the risk of future type 2 diabetes, should also be reinforced. The varying insulin requirements during pregnancy occur as in those with previously known d iabetes, and most (but not all) patients will not need insulin treatment following delivery . Monitoring is with home capil- lary blood glucose measurements, daily if on diet alone an d more fre- quently if on insulin therapy. The frequency needed depends on the results obtained, with the aim of keeping all readings <126 mg/dL. If diet alone fails, a basal bolus insulin regimen as used in the known diabeti c is usually required. The total ini- tial daily dose is determined on the basis of the deg ree of hyperglycemia present; 4 \200\2236 units per bolus is usual. As with the previously known diabetic mother, the aim is to have a nor- mal delivery, more often at 38 weeks to term, depending on fetal growth. An oral glucose tolerance test (OGTT) should be performed 6 weeks after delivery in all patients not requiring insulin post-deli very, to con \201 rm a return to normal glucose metabolism. A further reinforcement of die t and weight advice at this time is also usual practice. Whether these patients should be followed up because of their i risk of diabetes is unclear , although annual fasting blood glucose levels in asymptomatic women with a normal 6-week p ostpartum OGTT is often advised. More careful review is suggested for those with abnormal O GTTs. High-risk groups Most women with gestational diabetes are found on routine screening at abo ut 30 weeks, but certain high-risk groups should be screened earlier (see Box 110.3 for scr eening methods). These risk factors include the following: Previous gestational diabetes \200 A large baby in their last pregnancy, e.g., >4.0 kg at term \200 A previous unexplained stillbirth or perinatal death \200 Maternal obesity \200 Family history of diabetes ( \201 rst-degree relatives) \200 Polyhydramnios Contraception and diabetes Oral contraceptives The early combined oral contraceptive pills (OCP) impaired glucose tole r- ance and so were not advised in patients with diabetes. The use of third- generation low -dose estrogen-containing combined OCPs (e.g., 20 mcg ethinylestradiol) is safe in women <3 5 years of age. Third-generation OCPs are advised, as they have a better risk pro \201 le for arterial disease and only occasionally increase insulin requirements. 110-Draznin-Chap110.indd 645 3/31/2011 5:33:18 PM CHAPTER 110 Diabetes and pregnancy 646 Box 110.3 Methods of screening \200 Urine dip testing for glucose should be performed on every pregnant woman at every antenatal visit. If glycosuria is found, a fasting glucose test is performed, and if >110 mg/dL, a 75 g OGTT is needed (see Table 110.1). Routine screening at 28 \200\22332 weeks is also often done, either with random blood gluco se tests or a fasting blood glucose level. If a fasting level is >110 mg/dL or a postprandi al level is >126 mg/dL, an OGTT is required.