Pregnancy in Women with Complicated Diabetes Mellitus 719 use effective contraceptive measures while waiting to attempt pregnancy until a time when the diabetes and hypertension have been optimally controlled. Prepregnancy e valuation Women with diabetes should, ideally, be evaluated for the pres- ence or absence of nephropathy before pregnancy. A 24 - hour urine collection for protein excretion and creatinine clearance (CrCl) is recommended. A renal biopsy is no longer considered to be absolutely necessary for diagnosis. Many diabetic women are currently prescribed angiotensin - converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in an effort to prevent or delay the onset of diabetic nephropathy. It has been suggested that using these com- pounds in the preconception period, until the pregnancy is diag- nosed, might decrease complications during pregnancy [26,27] . However, more recent studies show that these compounds are not safe at any time during pregnancy and should be stopped before conception [28] . Therefore, prepregnancy counseling must include the discontinuation of ACE inhibitors and ARBs before conception. Counseling should also include the discon- tinuation of statin and fi brate medications before pregnancy. Omega - 3 fatty acids may be continued or started during preg- nancy because of potential benefi ts, particularly with diabetes [29] . Further evaluation should include an ophthalmologic exam and an ECG, as well as additional cardiovascular testing including an echocardiogram and/or stress test if clinically appropriate. All women with type 1 diabetes should have an evaluation of their thyroid function [30] including a TSH level and a thyroid per- oxidase antibody titer along with the pertinent routine laboratory studies. Further dietary counseling should include the additional changes that are required when signifi cant renal impairment is present. It should be emphasized that excellent glycemic control before pregnancy may not only prevent or minimize the risk of congenital anomalies but also result in more stable renal function and lower complication rates later in the pregnancy as well [31] . Course d uring p regnancy The expected increase in CrCl during pregnancy, in the presence of diabetic nephropathy, is seen in only about a third of these women; in another third the renal function remains stable. In the remainder, a decrease occurs which may refl ect the natural pro- gression of diabetic nephropathy and/or a pregnancy effect from glomerular hyperfi ltration, heavy proteinuria, along with wors- ening hypertension and pre - eclampsia [32 – 35] . Microalbuminuria and b lood p ressure l evels The presence of microalbuminuria before or in early pregnancy is associated with a 35 – 60% risk for the development of pre - eclampsia, much higher than the 6 – 14% risk observed in diabetic 3 Active proliferative retinopathy should, ideally, be treated before pregnancy. If it develops in early gestation (fi rst trimester), and there is no response to treatment, pregnancy termination might have to be offered as an alternative. 4 Vaginal delivery may be allowed for those patients with back- ground or successfully treated proliferative retinopathy. The optimal route of delivery for those patients with active prolifera- tive retinopathy has not been determined, since in non - pregnant patients vitreous hemorrhages may occur even during periods of inactivity. Vitreous hemorrhages have been observed during both cesarean sections and vaginal deliveries, but there is concern that they may occur more readily during the active expulsion phase of vaginal birth. In patients with active proliferative retinopathy, it is recommended that the mode of delivery be determined on an individual basis and in consultation with both the obstetrician and ophthalmologist. Nephropathy Until fairly recently, women with diabetic nephropathy were strongly discouraged from attempting pregnancy, and therapeu- tic abortion was frequently recommended if pregnancy occurred. These recommendations are not supported by more recent reports, which show signifi cantly improved perinatal outcome when good metabolic and blood pressure control is achieved along with current “ state of the art ” obstetric and neonatal care. Better outcomes are consistently obtained in centers offering a multidisciplinary team approach. Perinatal complications may include congenital anomalies, fetal growth restriction, fetal death, stillbirth, and preterm deliv- ery with its associated neonatal morbidity from prematurity. Maternal complications include worsening of renal function during or after pregnancy, anemia, superimposed pre - eclampsia or eclampsia, and worsening of other diabetic complications fre- quently coexisting with nephropathy, mainly retinopathy (see previous section). These women should also be aware that they may face future signifi cant morbidity (e.g. dialysis, renal trans- plantation, etc.) and even shortened life spans due to macro- vascular disease. Diabetic nephropathy usually occurs in uncontrolled type 1 diabetes after 5 – 15 years ’ duration or longer, but it may also be seen with shorter duration of diabetes as well as in patients with type 2 diabetes. In the United Kingdom Prospective Diabetes Study (UKPDS) [25] , 17% of newly diagnosed type 2 diabetics had pre - existing microalbuminuria, 3.8% had macroalbuminuria and 37% were hypertensive, most likely because many type 2 diabetics have had the disease for several years before the diagnosis. It should be widely recognized that all reproductive - age women with diabetes could become pregnant. They should be thoroughly informed about the risks of pregnancy when the diabetes is poorly controlled and the additional risks of hypertension and overt diabetic nephropathy. These women should be strongly urged to Chapter 51 720 asleep all those hours) and rest periods lasting 1 – 2 h each during the day (e.g. late moring and mid - to late afternoon) will be greatly benefi cial for those with the more advanced nephropathy. These women should be made aware that a readjustment of their lifestyle and even their work schedule would likely be recom- mended later in the pregnancy. Hypertension should be appropriately treated. There is evi- dence that blood pressure levels (e.g. ≤ 130/80 mmHg), lower than the ≤ 140/90 mmHg currently recommended, might provide additional benefi ts including a reduction in premature deliveries [57] . Antihypertensive agents that are considered safer during pregnancy, even during organogenesis, include α - methyldopa, clonidine and the β - adrenergic antagonists with low lipid solubil- ity [58 – 61] . The non - dehydropyridine calcium channel blockers (e.g. diltiazem) are reportedly benefi cial for glomerular function [62,63] . Calcium channel blockers during the fi rst trimester were associated with the possibility of limb defects in one study [64] but not found to be teratogenic in a larger prospective study [65] . Frequent visits for close monitoring and liberal hospitaliza- tions are recommended for worsening hypertension, deteriorat- ing renal function, or fetal compromise. Periodic ultrasound examinations are useful for dating (fi rst trimester), detection of congenital anomalies (later in second trimester), and assessment of fetal growth (monthly in third trimester). Intrauterine growth restriction, rather than macrosomia, is more likely in patients with vascular compromise even if the diabetes is not optimally controlled. Fetal surveillance should be instituted as soon as there is willingness to intervene for fetal distress. The mother should be carefully informed of the situation and her wishes taken into consideration. A consultation with a neonatologist is strongly recommended to make sure the mother is aware of the prematu- rity risks. Outpatient therapy is acceptable as long as the diabetes and hypertension are well controlled and the renal function is at an acceptable level (determined at least every month in stable patients and more often if unstable); otherwise hospitalization, even prolonged, is strongly advised. Delivery before term may be indicated due to maternal deterio- ration or fetal distress. For elective delivery before term, fetal lung maturation should be documented. The route of delivery should be considered on an individual basis. Many of these women (68 – 74%) will require cesarean section delivery secondary to prema- turity, malpresentation, and fetal distress. Obviously, these decisions should be made in conjunction with the obstetrician/ perinatologist and neonatal consultant. Neonatal survival has steadily improved during the last 20 – 25 years. However, perinatal mortality is still reported to be 5 – 7% mainly due to congenital anomalies or severe fetal growth restric- tion. Respiratory distress syndrome is reported in 24 – 25% of cases. The improved outcome is most likely multifactorial and includes better control of diabetes and hypertension, improved fetal surveillance, as well as improved neonatal care. Predictors of poor outcome are outlined in Table 51.2 . women without microalbuminuria before conception [36 – 39] . Blood pressure levels alone in early pregnancy have been found to have a low sensitivity and specifi city as sole predictors of hyper- tensive complications in the third trimester, while urinary micro- albumin excretion was a better predictor of pre - eclampsia ( [36] . The subset of women with both microalbuminuria and chronic hypertension is reported to have the highest rate of superimposed pre - eclampsia [40] . The highest pregnancy complication rate is seen in women with a serum creatinine level of ≥ 2.0 mg/dL or a CrCl < 50 mL/min before or in early pregnancy [31 – 32,41 – 42] . Given the high rate of maternal and fetal complications in women with this advanced degree of diabetic nephropathy some experts recommend discouraging pregnancy. Anemia Anemia due to erythropoietin defi ciency is a common complica- tion of diabetic nephropathy and may further compromise fetal oxygenation. Erythropoietin has been used during pregnancy to treat anemia in diabetic nephropathy [43 – 45] . Recently, concerns have been raised about the long - term use of this medication. However, the short - term, judicious use of erythropoietin, during pregnancy is unlikely to be a cause of serious long - term morbidity and may be very benefi cial for the developing fetus. Asymptomatic b acteriuria and p yelonephritis Screening for and treating asymptomatic bacteriuria seems justi- fi ed in pregnant women with diabetic nephropathy because it occurs more frequently in these women. Pyelonephritis is a par- ticularly serious, but preventable, consequence of untreated bac- teriuria [46,47] . Cigarette s moking Cigarette smoking should be strongly discouraged in all pregnant women and in diabetic women in particular. Smoking impairs fetal oxygenation and, as in the case of retinopathy, it is an independent risk factor for worsening nephropathy [48 – 50] . Worsening r enal f unction It is unusual for diabetic nephropathy to progress to end - stage renal disease during the course of pregnancy [31 – 33,41 – 43,51,52] . Nevertheless, pregnancy may have a deleterious effect and accel- erate deterioration in those with more impaired renal function (Cr ≥ 1.2 mg/dL) in early pregnancy [32 – 35,41 – 43,51,52] . Overall, parity alone does not appear to be associated with more rapid deterioration of renal function according to data from long - term follow - up of diabetic women with similar degrees of nephropathy who do not have pregnancies [4,53 – 56] . Management Strict diabetic control (HbA 1 C < 7%) should be achieved before conception and maintained at all times throughout pregnancy. Adequate rest at night (e.g. ≥ 8 hours, but it is not necessary to be Pregnancy in Women with Complicated Diabetes Mellitus 721 pressant agents. Azathioprine and cyclosporine cross the placenta but do not appear to be teratogenic or cause fetal growth restric- tion [75] . There is less experience with the newer immunosup- pressants although tacrolimus has been reported to be associated with fetal/neonatal hyperkalemia [70,76,77] . Diabetic k etoacidosis Diabetic ketoacidosis (DKA) is an acute and potentially life - threatening emergency with very serious consequences for both mother and fetus. Until recently, perinatal mortality, after an episode of maternal DKA, was reported to be as high as 90%. In the last 15 – 20 years however, it has been reduced to 10 – 35%, [78 – 82] . Maternal mortality was reported to be 4 – 15% [83] , con- siderably higher than in the non - pregnant general diabetic popu- lation [84] , but no maternal deaths have been reported in the most recent publications [78 – 82] . The frequency of DKA during pregnancy is 1.7 – 3% [78 – 82] and will likely decrease because of the widespread use of self - glucose monitoring. The occurrence of DKA has, traditionally, been considered to be solely a complication of type 1 diabetes. However, the line differentiating type 1 from type 2 diabetes is becoming increas- ingly blurred and DKA is now reported in children, adolescents and adults with the apparent phenotype of type 2 diabetes [85,86] . Consequently, an amendment to the current classifi cation of dia- betes has been recently proposed [87,88] . DKA during pregnancy has been reported in gestational diabetes as well [89 – 91] , which may represent new cases of ketosis - prone type 2 diabetes present- ing as DKA during pregnancy [92] . There are no data about the long - term outcome of fetuses surviving maternal DKA. There is, however, information about the long - term intellectual development of fetuses exposed to ketosis in utero . Ketosis alone is unlikely to have serious long - term consequences except when there is a concomitant elevation of plasma β - hydroxybutyrate and/or free fatty acids. The off- spring of those women had lower behavioral and intellectual development testing [93] . Pathophysiology DKA occurs when there is an absolute or relative lack of insulin with excessive production of counter - regulatory hormones including glucagon, catecholamines, cortisol and growth hormone. This combination leads to increased lipolysis in insu- lin - sensitive tissues including adipose tissue, skeletal muscle and liver resulting in a massive release of free fatty acids (FFAs). In the liver, FFAs undergo β - oxidation with unrestrained ketoacid ( β - hydroxybutyrate and acetoacetate) production, as well as gluconeogenesis which precipitates DKA. These conditions also favor proteolysis leading to elevated plasma aminoacids. Aminoacids serve as precursors for gluconeogenesis, which results in exacerbation of the hyperglycemia. Several glucose transporters (GLUT) are involved as well. Both GLUT 2 and GLUT 4 are reduced in insulin defi ciency. GLUT 2 transports Pregnancy in w omen on d ialysis and a fter r enal t ransplantation Dialysis The number of cases of hemodialysis and, less commonly, con- tinuous ambulatory peritoneal dialysis during pregnancy, is increasing. This information comes primarily from observational studies of women with all varieties of kidney diseases, including diabetes mellitus. Most reported cases were women on the verge of requiring dialysis when they conceived (usually unplanned pregnancies) or women who experienced a rapid decline in renal function while pregnant [66] . Although it might be tempting to recommend termination of pregnancy under these circum- stances, it rarely results in substantial improvement in renal func- tion [67] . Interestingly, no increase risk of maternal death has been reported although severe hypertension, preterm delivery and oligohydramnios result in a perinatal mortality of 22 – 40% [68] . The judicious management of anemia (erythropoietin and/ or transfusions) and of preterm labor may help to improve out- comes [69] . Renal t ransplantation As a result of an overall increased number of renal transplanta- tions coupled with a strong desire for motherhood, more preg- nant patients with renal transplants will be seen in the future. About one - fourth of all patients on chronic dialysis or after renal transplantation have diabetes. Current recommendations empha- size the importance of waiting a minimum of 2 years before attempting pregnancy. Stable graft function including a serum creatinine < 1.5 mg/dL, proteinuria < 500 mg/day and optimal blood pressure and glucose control are also prudent requirements [70] . Data reported from pregnancies in women with kidney transplants secondary to conditions other than diabetes reveal an improved survival when serum creatinine levels are < 1.5 mg/dL, 98% vs 75% [71] . The course during pregnancy is dependent on baseline glomerular function at the time of conception, control of hypertension and prompt diagnosis and treatment of urinary tract infections [72] . The outcome of pregnancy in women with combined pancreas/kidney transplants is similar to those with kidney transplant alone [73] . There appears to be a low rate of graft dysfunction during pregnancy; however, hypertension, pre - eclampsia and preterm delivery are frequent complications [74] . A surprising low rate of complications has been reported with the use of immunosup- Table 51.2 Diabetic nephropathy: predictors of poor outcome. Proteinuria of ≥ 3g in the fi rst trimester Serum creatinine ≥ 1.2 mg/dL Chronic hypertension, pre - eclampsia, eclampsia Anemia (hematocrit < 25%) Poor compliance Chapter 51 722 ture, however, may not exclude infection. Symptoms and signs of shock will ensue if aggressive treatment is not rapidly instituted. Laboratory d iagnosis DKA is defi ned as an arterial pH of ≤ 7.30, a serum bicarbonate of ≤ 15 mmol/L, ketosis (serum acetone present at 1 : 2 dilution), and hyperglycemia of ≥ 300 mg/dL. In pregnancy, however, DKA may occur with relatively low blood sugar levels, and it is very important not to dismiss the diagnosis because the blood sugar is “ too low ” . There are reports of profound DKA in diabetic pregnant women with blood sugars of less than 200 mg/dL. This relative “ euglycemia ” may lead to misdiagnosis and inappropriate therapy [78,83,90,96,97] (Table 51.3 ). Leukocytosis is almost always present and it does not indicate infection. A left shift in the differential is more suggestive of an active infection. Calculating the anion gap [Na − (Cl + HCO 3 ) = 8 – 12] is useful. In DKA it usually is ≥ 15 although it may also be elevated in lactic acidosis, chronic renal insuffi ciency and rhabdomyolysis, or after ingestion of acid substances such as salicylates, ethylene glycol, methanol, formaldehyde, sulfur, toluene and paraldehyde. The serum osmolality [2(Na + K) + serum glucose/18] is another useful calculation because the mental status correlates better with this than with any other metabolic derangement. A value of 320 mOsm/L or higher is signifi cant with coma occurring with values of ≥ 340 mOsm/L. It is very important to determine the corrected serum sodium (Na), which is very helpful to estimate water defi cit: measured Na plasma glucose+× − () 1 6 100 100. Hyperglycemia dilutes plasma Na by 1.6 mEq/L for every 100 mg/dL of increased glucose and therefore the measured plasma Na should be lower than normal in the presence of sig- nifi cant hyperglycemia. A plasma Na that is normal or high at presentation is indicative of massive water defi cit. In pure metabolic acidosis the arterial PCO 2 level should be approximately equal to the last 2 numbers of the arterial pH. A lower than predicted PCO 2 value is indicative of respiratory alka- losis and sepsis should be suspected; if higher, respiratory acidosis should be suspected. When hypoxemia is also present, pneumo- nia or low - pressure pulmonary edema is most often the cause. Differential d iagnosis It is the same as for the non - pregnant patient including alcohol and/or drug overdose, encephalopathy of any cause, hyperosmo- glucose in and out of liver cells and GLUT 4 regulates glucose uptake by muscle cells and adipopcytes [94] . Excess ketones cause acidosis and hyperglycemia leading to osmotic diuresis with resultant volume depletion, dehydration and electrolyte loss. Decreased cardiac output, hypotension and shock may occur. If there is inadequate tissue perfusion, lactic acid will accumulate resulting in worsening acidosis. In an effort to compensate for acidosis, hydrogen ions enter into cells causing exit of intracel- lular potassium. The serum (extracellular) potassium levels will be elevated initially but total body (intracellular) potassium depletion may be severe. With insulin therapy, the potassium quickly re - enters the cells resulting in low serum potassium. Serum potassium levels therefore, must be monitored closely and replaced accordingly. Pregnant, diabetic women may develop DKA more rapidly than their non - pregnant counterparts due to accelerated lipolysis, ketosis and protein catabolism associated with pregnancy. In addition, buffering capacity is diminished because of higher minute alveolar ventilation (progesterone effect), which in turn results in a compensatory elevated renal bicarbonate excretion. Further potential contributing factors include the increased levels of hormones that cause insulin resistance during pregnancy, such as human placental lactogen. Persistent nausea and vomiting in early pregnancy is another potential contributing factor [81] . Precipitating f actors The common precipitating factors seen outside of pregnancy are also reported during pregnancy including infection, insulin omis- sion, insulin pump failure, non - compliance, alcohol and drug use and medications including corticosteroids and adrenergic ago- nists which are frequently used in pregnancy. Failure to recognize new - onset diabetes presenting as DKA has been reported to be the main cause of fetal demise in several recent publications [80,92,95] . Given the increasing reports of ketosis - prone type 2 diabetes, more cases of DKA during pregnancy should be expected [87,88,92] . Clinical p resentation In general, DKA develops over a period of 3 – 7 days but it may develop more precipitously when alcohol ingestion is a contribut- ing factor. The usual initial symptoms of uncontrolled diabetes are present, including polyuria, polydipsia, blurred vision, anorexia, nausea, vomiting, abdominal pain, and unintentional weight loss. The abdominal symptoms are caused by elevated ketones. With severe hypokalemia, gastroparesis and even ileus may occur or be greatly worsened if pre - existing. Without treat- ment, mental changes will develop, ranging from drowsiness to deep coma. Other signs include deep, rapid respirations (Kussmaul) with a fruity odor (caused by ketones), and signs of intravascular volume depletion (dry mucous membranes, poor skin turgor and warm dry skin). Sinus tachycardia and orthostatic hypotension are other signs of inadequate intravascular volume. The body temperature is usually normal or below normal. If fever is present, an infection should be suspected. A normal tempera- Table 51.3 Diagnosis of diabetic ketoacidosis in pregnancy. Serum pH < 7.30 Serum bicarbonate < 15 Serum ketones > 1:2 dilution Any glucose level (can be < 200 mg/dL and even < 150 mg/dL Pregnancy in Women with Complicated Diabetes Mellitus 723 DKA [98,99] . Hyperchloremia almost always develops in the course of DKA treatment and the use of lactated Ringer ’ s instead of saline has been proposed as prevention. However, in uncon- trolled diabetes, lactate infusions might not be well tolerated. When the serum glucose decreases to less than or equal to 250 mg/dL dextrose solutions should be administered (D5 0.9% saline or D5 0.45% saline). Since many pregnant women with DKA may have initial glucose levels well below 250 mg/dL, dextrose - containing solutions may be started from the outset. Insulin Insulin should be administered as soon as fl uid replacement has been started because fl uids alone will not reverse DKA. Treatment should be administered by continuous intravenous infusion using only regular insulin. Many experts initiate therapy with a primary bolus of intravenous regular insulin utilizing 0.1 units/ kg ideal body weight. The general insulin requirements are also 0.1 units per kilogram of body weight per hour but this rate must be adjusted as often as necessary to maintain a steady glucose diminution. The rate of glucose fall should be greater than 10% every 1 – 2 hours, generally 60 mg/dL per hour. There is no benefi t of a more rapid normalization of the serum glucose. If, however, desired glucose control is not achieved, the insulin infusion should be readjusted accordingly. Potassium The potassium defi cit is usually greater than or equal to 3 – 5 mmol/ kg. Potassium will start re - entering the cells quickly after the initiation of insulin and a fall in serum levels should be antici- pated. No potassium is given during the fi rst 2 – 4 hours except when the initial level is already critically low. The rate of admin- istration has to be readjusted according to the serum levels and urinary output. Extreme caution is recommended if there is oli- guria or anuria. General guidelines are: (i) 40 mEq/h when the serum K level is below 3; (ii) 30 mEq/h if between 3 and 4; (iii) 20 mEq/h if between 4 and 5 and (iv) none if the level is over 5 mEq/L. Administering potassium phosphate, instead of only potassium chloride, is advocated but not universally recommended. Bicarbonate There is almost universal agreement that bicarbonate should be administered when there is severe lactic acidosis in addition to DKA, and also in the presence of life - threatening hyperkalemia with electrocardiographic changes. Otherwise, bicarbonate administration is not recommended unless the arterial pH is below 7.10. However, if there is hypotension many experts advice bicarbonate administration when the pH is 7.20 or less in an effort to increase the left ventricular ejection fraction and vascular responsiveness. Under the above conditions the benefi ts are thought to outweigh the risks of the paradoxical lowering of intracerebral pH by CO 2 diffusion, impaired oxygen- ation from a shift in the oxygen dissociation curve, hyperosmolal- ity, hypernatremia, hypokalemia, late alkalosis and cerebral lar state, hypoglycemia, uremic coma, trauma, infection, psycho- sis, syncope and seizures. Treatment All patients with DKA must be managed in an intensive care setting and the fetus continuously monitored if at a viable gesta- tional age (Table 51.4 ). A fl ow sheet detailing all aspects of man- agement is extremely important and should include the following: dates/times, serial glucose measurements, serum ketones, electro- lytes, arterial blood gases, anion gap, insulin administration, and intake and output (I & O). Fluid and e lectrolytes Restoring the extracellular volume with adequate fl uids and elec- trolytes is the fi rst priority of therapy. One of the most common mistakes made in the treatment of DKA is not giving adequate fl uids. The average defi cit is 5 – 7 L (about 100 mL/kg of body weight) but can be more severe. At least 75% of the fl uid defi cit must be replaced during the initial 24 hours. A rate of 500 – 1000 mL/h for the initial 4 hours and 250 – 500 mL/h for the fol- lowing 4 hours is recommended. The replacement must take into account the urine output as well as insensible losses. Isotonic fl uids (0.9% normal saline) are generally regarded as the optimal initial replacement (fi rst 1 – 3 L). If the reported Na level is “ normal ” or high (here is when the corrected serum Na and osmolality are very helpful to guide treatment) the fl uid defi cit is massive and the patient very hyperosmolar. Under these severe hyperosmolar conditions using hypotonic fl uids (0.45% saline) from the outset might be considered. Concerns about the devel- opment of cerebral edema following rapid fl uid replacement in the treatment of DKA are important but it appears that cerebral edema may be more the result of reduced blood volume and elevated carbon dioxide leading to cerebral vasoconstriction, ischemia and hypoxia related to the severity and duration of the Table 51.4 Management of diabetic ketoacidosis during pregnancy. Must be in the intensive care unit! Fetal monitoring (if viable) Detailed fl ow chart (vital signs, I & O, electrolytes, glucose, insulin used and serum ketones) Fluids: NS 500 – 1000 mL/h x 3 h, ½ NS thereafter Change to D 5 when glucose ≤ 250 mg/dL Start with D 5 if initial glucose ≤ 250 mg/dL Insulin: 0.10 units/kg IV push 0.10 units/kg/h (5 – 10 units/h) IV drip Readjust if glucose not decreasing by ≥ 60 mg/h Potassium: None for the fi rst 2 – 4 h None if serum K > 5 mEq/L 20 mEq/h if serum K 4 – 5, 30 mEq/h if 3 – 4 and 40 mEq/h if < 3 Partial replacement may be given as potassium phosphate Bicarbonate: None if pH > 7.10 But if hypotensive, replace when pH ≤ 7.20 Chapter 51 724 age, had higher glucose, BUN and osmolality levels, required more insulin and had a prolonged duration of recovery. Coronary a rtery d isease There is little information regarding pregnancy and ischemic heart disease in diabetic women. Two recent papers have reported on the incidence, mortality and risk factors for pregnancy - related acute myocardial infarction in the United States. During the 10 - year period from 1991 to 2000 [103] , 151 women had an acute myocardial infarction for an incidence of 1 in 35 700 deliveries; 4% were women with diabetes mellitus but not identifi ed as ges- tational or pre - gestational diabetes. The maternal mortality rate was 7.1% but fatalities occurred only in women with an acute myocardial infarction taking place before or at the time of deliv- ery. The relative risk of the various factors identifi ed by multivari- ate analysis using logistic regression were: 1 age, particularly 40 years or older: odds ratio (OR) 4.5 and confi dence interval (CI) 2.0 – 9.8 2 diabetes mellitus: OR 4.3 (CI 2.3 – 7.9) 3 chronic hypertension: OR 24.5 (CI 14.8 – 40.3 4 severe pre - eclampsia: OR 6.9 (CI 3.7 – 13.1) and 5 eclampsia: OR 15.3 (CI 5.3 – 44.1). In this report, hypertensive disorders greatly increased the risk of acute myocardial infarction and were a stronger risk factor than diabetes mellitus. The incidence of myocardial infarction during pregnancy, reporting data from the years 2000 to 2002 [104] , was 6.2 cases per 100 000 deliveries and a mortality rate of 5.1%. Single independent variables associated with increased risk were, again, age over 40 years OR 30.2 (CI 17.2 – 43.2), hyperten- sion OR 21.7 (CI 6.8 – 69.1), thrombophilia OR 25.6 (CI 9.1 – 71.2), smoking OR 8.4 (CI 5.4 – 12.9), need for blood transfusion OR 5.1 (CI 2.0 – 12.7), and diabetes mellitus OR 3.6 (CI 1.5 – 8.3). The maternal mortality was much higher (73%), in the few cases reported before 1980 either because treatment was less effective at that time or because of a tendency toward reporting fatal cases. The prognosis is better if the myocardial infarction occurs before pregnancy or early in the fi rst trimester than when it takes place later in the pregnancy or during labor. The few cases reported after angioplasty or coronary artery revascularization before conception tolerated pregnancy better and had less neo- natal morbidity from prematurity [105,106] . Women with coronary artery disease tend to be older and have longstanding diabetes. A detailed history, physical examination, ECG, echocardiogram, a stress test and, if indicated, a coronary angiogram should be performed before conception in any woman contemplating pregnancy if coronary artery disease is suspected. Every effort should be made to treat coronary insuffi ciency before pregnancy. Because of the possibility of maternal mortality, preg- nancy is usually discouraged in this group of patients. However, if pregnancy occurs before treatment and termination is not an option, the treatment should be the same as in non - pregnant dysfunction [98,99] . Nevertheless, if bicarbonate replacement is deemed necessary the use of dilute therapy (i.e. putting the bicar- bonate in a liter of fl uid) is preferable to direct concentrated administration. Other DKA c omplications If hypotension persists after adequate volume replacement, sepsis should be suspected. Another possibility could be a silent myo- cardial infarction, which would be unusual in a childbearing - age woman but possible in long - standing diabetes with nephropathy and hypertension. Pulmonary edema has been reported in preg- nant women receiving large amounts of fl uids, ß - adrenergic ago- nists for premature labor and steroids for lung maturation. These agents have been reported to cause DKA even in gestational dia- betes [100] . Cerebral edema has been reported more frequently in children and young adults but may be seen at any age. This condition should be suspected when neurologic defi cits reappear after initial improvement or if there is no improvement despite adequate biochemical normalization [98,99] . Other reported complications include pancreatitis, hyperlipidemia, hypocalce- mia, renal failure and vascular thrombosis. It is extremely important that the process of switching from intravenous to subcutaneous insulin, once DKA resolves and the patient is ready to resume oral intake, be done properly because worsening of or even a relapse back into DKA may occur. Intravenous insulin disappears from the plasma in a few minutes. This must be anticipated and subcutaneous insulin injected 1 – 2 hours before stopping intravenous insulin so that the patient is not left without adequate insulin coverage. In addition, gastroin- testinal dysfunction is common while the CO 2 level is 20 mEq/L or less, even in the absence of other gastrointestinal conditions such as gastroparesis or gastritis. Therefore, feeding the patient prematurely may lead to nausea and vomiting. Other c onsiderations The reports of the autopsies performed after fetal demise have not shown an obvious pathology and therefore a metabolic derangement is thought to be the most probable cause of fetal death. Contributing factors include: 1 reduced uterine blood fl ow (from maternal hypovolemia and excess catecholamines) and indeed transient abnormal blood fl ow has been reported by Doppler ultrasonography [101] 2 decreased myocardial contractility from hyperglycemia (shown in experimental animals) and 3 acidosis since ketoacids cross the placenta freely. Examples of fetal stress that subsided after the maternal DKA was successfully treated have been published [80,102] . These reports form the basis for recommending rapid and aggressive treatment of maternal DKA, in an effort to correct the maternal condition, before emergently intervening for non - reassuring fetal heart rate tracing. A review of published papers suggests that the women with DKA who had a fetal demise were at a more advanced gestational Pregnancy in Women with Complicated Diabetes Mellitus 725 pregnancy in a variety of ways: (i) prevent adjustment to the hemodynamic demands of pregnancy; (ii) make it diffi cult, or impossible, to achieve the tight diabetes control usually recom- mended during pregnancy due to hypoglycemia unawareness and slow gastric emptying; (iii) maternal and fetal malnutrition; and (iv) increased fetal loss, intrauterine growth restriction and preterm labor [110,111] . The therapeutic possibilities are limited for this condition in general, and particularly during pregnancy. Antiemetics are seldom of value. Metoclopramide may provide symptomatic relief in some patients. Intravenous erythromycin (not as effec- tive when given orally) has a motilin - like effect and has been reported to be useful in non - pregnant patients [112] . Erythromycin is safe for the fetus. We have used this form of therapy in several pregnant women after all other measures failed, with temporary improvement for days to weeks. Parenteral nutrition may become necessary despite its potential risks when used long term. It should be initiated before the mother becomes severely malnour- ished and when it becomes obvious that all other available mea- sures have proven ineffective. References 1 Axer - Siegel R , Hod M , Fink - Cohen S , et al. Diabetic retinopathy during pregnancy . Ophthalmology 1996 ; 103 ( 11 ): 1815 – 1819 . 2 Temple RC , Aldridge VA , Sampson MJ , et al. Impact of pregnancy on the progression of diabetic retinopathy in Type 1 diabetes . Diabet Med 2001 ; 18 ( 7 ): 573 – 577 . 3 Lovestam - Adrian M , Agardh CD , Aberg A , Agardh E . Pre - eclampsia is a potent risk factor for deterioration of retinopathy during preg- nancy in Type 1 diabetic patients . Diabet Med 1997 ; 14 ( 12 ): 1059 – 1065 . 4 Diabetes Control and Complications Trial Research Group . Effect of pregnancy on microvascular complications in the Diabetes Control and Complications Trial . Diabet Care 2000 ; 23 : 1084 – 1091 . 5 Nathan DM , Davis M , Cleary P , Lachin J . Letter: Response to “ Do all women require intensive retinal surveillance during pregnancy? ” Diabet Care 2001 ; 24 ( 4 ): 795 – 796 . 6 Moloney JB , Drury MI . The effect of pregnancy on the natural course of diabetic retinopathy . Am J Ophthalmol 1986 ; 93 : 745 – 756 . 7 Serup L . The infl uence of pregnancy on diabetic retinopathy . Acta Endocrinol 1986 ; 277 (Suppl): 122 – 124 . 8 Phelps RL , Sakol P , Metzger BE , et al. Changes in diabetic retinopa- thy during pregnancy: correlation with regulation of hyperglycemia . Arch Ophthalmol 1986 ; 104 : 1806 – 1810 . 9 Klein BEK , Moss SE , Klein R . Effect of pregnancy on progression of diabetic retinopathy . Diabet Care 1990 ; 13 : 34 – 40 . 10 Lauszus F , Klebe JB , Bek T . Diabetic retinopathy in pregnancy during tight metabolic control . Acta Obstet Gynecol Scand 2000 ; 79 ( 5 ): 367 – 370 . 11 Larsen M , Colmorn LB , Bonnelycke M , et al. Retinal artery and vein diameters during pregnancy in diabetic women . Invest Ophthalmol Vis Sci 2005 ; 42 ( 2 ): 709 – 713 . patients with coronary insuffi ciency. Diabetes should be con- trolled but with care to avoid hypoglycemia in order to prevent catecholamine release and tachycardia, which will increase myo- cardial demands [105] . The route of delivery should be individu- alized and in consultation with the obstetrician/perinatologist. Shortening the duration of the second stage of labor, to decrease the Valsalva maneuver, has been suggested [107] . The route of delivery in the reported cases has been 60% cesarean section and 40% vaginal deliveries. Continuous cardiac monitoring is rou- tinely advised but the placement of central line catheters is not universally endorsed and should be individualized. Continuous epidural anesthesia is recommended for patients in labor to avoid pain - related stress and tachycardia, which also increases myocar- dial demands and the risk of an acute cardiac event. Diabetic n europathy The distal peripheral neuropathy commonly seen in many dia- betic patients is seldom of any consequence during pregnancy. Several studies have concluded that pregnancy does not adversely affect neuropathy [108 – 110] , and even improvement of nerve conduction has been observed towards the third trimester. This phenomenon was attributed to tight glucose control achieved during pregnancy [110] . It has been concluded that pregnancy is not a signifi cant risk factor for neuropathy and improved glyce- mic control may actually ameliorate abnormalities with nerve conduction. Diabetic autonomic neuropathy, however, may pose serious diffi culties for pregnant women. It may be asymptomatic in the early stages and found only by specifi c examination. Diagnosing autonomic neuropathy for the fi rst time during pregnancy may not be easy [111] because pregnancy affects the heart rate response during respiration, as well as the role of the autonomic nervous system in the cardiovascular adaptation to pregnancy. Symptoms may include loss of sweating in the feet, urinary bladder dysfunc- tion (and higher risk of urinary tract infections), abnormal car- diovascular refl exes (e.g. loss of beat to beat variability, postural hypotension etc.), and in the more advanced states, sweat distur- bances of the upper body, gastroparesis, diarrhea, and bladder atony. Pregnancy may exacerbate gastroparesis and postural hypoten- sion. Vomiting usually starts early in gestation and may not subside until after delivery. The women with asymptomatic auto- nomic neuropathy before pregnancy have a better prognosis for postpartum resolution of symptoms and a more benign course during pregnancy. Vomiting interferes with diabetic control and impairs the nutritional status of the mother (weight loss, ketone production, etc.) and the fetus (growth restriction). Autonomic neuropathy may block the early “ alarm ” symptoms of the cate- cholamine phase of hypoglycemia, thus making these women vulnerable to neuroglycopenia; this is particularly true when tight control of the diabetes is attempted, such as is commonly the case during pregnancy. Therefore, autonomic neuropathy may affect Chapter 51 726 30 Surks MI , Ortiz E , Daniels GH , et al. Subclinical thyroid diseases: scientifi c review and guidelines for diagnosis and management . 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