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Management of Pregnant Patients with Diabetes with Ischemic Heart Disease
M a n a g e m e n t o f P re g n a n t P a t i e n t s with Diabetes with Ischemic Heart Disease Theodore B. Jones, MDa,*, Zeynep Alpay Savasan, MDb, Quinetta Johnson, MDa, Ray Bahado-Singh, MD, MBAb,c KEYWORDS Diabetes Ischemic heart disease Acute myocardial infarction Angina Maternal mortality KEY POINTS Multidisciplinary preconception counseling is imperative for diabetic women with ischemic heart disease (IHD) to improve outcomes for mother and infant. Untreated coronary artery disease has a high mortality and should be diagnosed before pregnancy, but 66% of diabetic women have unplanned pregnancies. Unstable angina is a contraindication to becoming pregnant. Women are more likely to have atypical clinical symptoms of IHD, which leads to delay in diagnosis and treatment. Diabetic women with IHD who have an acute myocardial infarction during pregnancy have a 62% mortality. A multidisciplinary team approach is key in the management of patients with diabetes with IHD during the pregnancy as well as postpartum.
MANAGEMENT OF PREGNANT PATIENTS WITH DIABETES WITH ISCHEMIC HEART DISEASE
As the number of diabetic women increases, the rate of complications secondary to pregestational diabetes increases. There are numerous microvascular disease processes that occur with diabetes. Proliferative diabetic retinopathy is a microvascular
a
Department of Obstetrics and Gynecology, Oakwood Hospital and Medical Center, 18101 Oakwood Boulevard, PO Box 2500, Dearborn, MI 48124, USA; b Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Oakland University William Beaumont Health System, Oakland University William Beaumont School of Medicine, 3535 West 13 Mile Road, Royal Oak, MI 48073, USA; c Obstetrics & Gynecology, Oakland University William Beaumont Health System, Royal Oak, MI, USA * Corresponding author. Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI. E-mail address: [email protected] Clin Lab Med 33 (2013) 243–256 http://dx.doi.org/10.1016/j.cll.2013.03.020 labmed.theclinics.com 0272-2712/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
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complication that is caused by the formation of new retinal blood vessels and can lead to blindness by retinal detachment and/or bleeding. Diabetic nephropathy is the most common cause of end-stage renal disease in the United States.1 Cardiovascular complications that can occur in diabetic pregnancies include chronic hypertension, pregnancy-induced hypertension, and atherosclerotic heart disease.1 This article considers one particular significant vascular complication: ischemic heart disease (IHD). The maternal mortality of women with IHD has been reported to be as high as 66% to 75%.2 It has been reported that pregnancy increases the risk of myocardial infarction (MI) by 3-fold to 4-fold.3 The incidence of myocardial ischemia in pregnancy has been reported in numerous sources as 1 case per 10,000 deliveries. There have been several factors cited as contributors to the increased incidence of myocardial ischemia in pregnancy, including diabetes mellitus, hypertension, increasing rates of obesity, increasing maternal age, and smoking.3 CLASSIFICATION OF DIABETIC COMPLICATIONS
The classification of diabetes in pregnancy by obstetricians has relied on a classification system devised by Priscilla White in 1932 that focused on the onset and duration of disease and vascular complications. However, in recent years, this classification system has become a source of debate. In this article, the complication of interest would be given a designation of class H. However, as type 2 diabetes has become more prevalent compared with type 1 diabetes (for which the White classification system was mainly based), there has been discussion as to whether or not the classification system created by the American Diabetes Association (ADA) in 1997 (modified in 2007) should replace the White classification.4 Although there may be occasional references to the White classification, this article adheres to the ADA’s diagnostic and classification system.1 In distinction to myocardial ischemia in the older population, peripartum myocardial ischemia is not usually caused by atherosclerosis. There can be several causes of myocardial ischemia during the antepartum, peripartum, and postpartum periods, including coronary artery disease, coronary dissection, coronary thrombus, and coronary spasm. Acute coronary syndrome or myocardial ischemia during pregnancy poses a challenge because symptoms of myocardial ischemia can imitate complaints typical of normal pregnancy. Therefore, the diagnosis can be overlooked and missed. Diabetes further contributes to a blunted appreciation for ischemic pain that can result in silent ischemia and silent infarcts.5 It has been well recognized that adequate diabetic control decreases maternal and fetal mortality and morbidity. It is thought to be imperative that sufficient glycemic control and preconception care be ensured before pregnancy to facilitate favorable outcomes. Preconception counseling entails a multidisciplinary team that includes a diabetologist, a physician skilled in diabetes management, an obstetrician skilled in high-risk pregnancies, and diabetic educators.6 Untreated coronary artery disease is associated with a high mortality and it is important to diagnose before pregnancy when possible. However, unplanned pregnancies occur in approximately two-thirds of women with diabetes, making preconception counseling unattainable in most cases.6 OVERVIEW OF IHD
IHD represents a unique challenge in women. It is the leading cause of death in women, with more than 421,000 IHD deaths reported in the United States in 2011.7 Although there has been a decline in IHD-related mortality in women, this lags behind
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the improvement reported in men. Higher rates of sudden death before hospitalization occur in women.8 The most likely explanations for the higher mortality are: Higher rates of comorbidities in affected women Obesity Diabetes Hypertension More frequent hospitalizations Lower rates of overall well-being beyond cardiac concerns that are reported9 CHALLENGE IN DIAGNOSIS IN WOMEN
As noted earlier, risk factors seem to be more prevalent in women than men and, when they do occur, have greater impact on IHD. Such factors include elevated triglycerides, obesity, diabetes, and metabolic syndrome.10 A significant contributory factor to worse outcomes in women seems to be an increased frequency of delay or failure to make the diagnosis. The atypical presentation of coronary artery disease in women results in delayed recognition by patients and physicians. A recent large meta-analysis of 26 studies found significant differences in symptoms in women compared with men.11 These findings are consistent with the results of numerous prior studies and meta-analyses. Chest pain is widely recognized by both the general public and medical personnel to be a sign of ischemic heart disease. Significantly lower rates of chest pain were noted in a review of women compared with men (odds ratio 0.63, 95% confidence interval [CI] 0.59, 0.68) when data were pooled from multiple studies. There were similarly higher rates of nonspecific and, therefore, confounding symptoms in women. There were higher odds of presenting with:
Fatigue: relative risk (RR) 1.19, 95% CI 1.06, 1.33 Neck pain: RR 1.54, 95% CI 1.38, 1.73 Nausea: RR 1.42, 95% CI 1.02, 1.46 Syncope: RR 1.37, 95% CI 1.11, 1.70 Right arm pain: RR 1.20, 95% CI 1.07, 1.33 Dizziness: RR 1.22, 95% CI 1.01, 1.92 Jaw pain: RR 1.39, 95% CI 1.01, 1.9211
The atypical nature of these symptoms contributes both to late recognition and presentation for care and late and missed diagnosis in women. Adjusting for age and other confounding variables, for the most part, did not have a significant impact on the effect of gender on the presenting symptoms in acute MI (AMI). DISPARITIES IN CARE FOR WOMEN WITH IHD
Compounding the challenges in women’s recognition of the significance of their symptoms and delayed and even missed diagnosis by physicians are concerns regarding gender differences in therapy for coronary artery disease between the sexes. As a consequence of the atypical presentation, there is a delay in the decision time, which represents the period between the development of symptoms and presentation for medical care. Women are said to experience reduced rates of diagnostic testing, delay in referral to specialists, and longer wait times in receiving care.12 It is also thought that the treatment women receive tends to be less aggressive, with women frequently being treated with anxiolytics and antidepressants as a result of misdiagnosis for psychological and anxiety disorders.13 Despite the equal incidence of coronary artery disease in men and women, only 30% of coronary artery bypass surgery is
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performed in women.14 Reduced use in women has been partly ascribed to the smaller caliber of female coronary arteries, smaller body size, and increased comorbidities in women. Diagnosis and treatment of IHD is therefore a major challenge in contemporary health care and demands greater attention from health care policy makers, clinicians, researchers, as well as women themselves. ACUTE MYOCARDIAL INFARCTION (AMI)
Coronary artery disease, particularly MI, is a rare but consequential event in pregnancy. A nationwide study based on the Nationwide Inpatient Sample (NIS) database for the years 2000 to 2002 reported a US prevalence of AMI of 6.2 (95% CI 3.0–9.4) per 100,000 deliveries.15 There was a case fatality rate of as high as 37%. With the overall maternal mortality at 12 per 100,000, myocardial infraction accounts for a significant percentage of maternal mortality. Risk factors significantly associated with AMI in pregnancy include increasing maternal age, with women older than 30 years of age showing significantly increased rates of AMI than those younger than that age threshold.15 Preexisting medical disorders frequently increase the AMI risk: factors include chronic hypertension, thrombophilia, diabetes mellitus, as well as cigarette smoking. In thrombophilia and hypertension, the increase in risk based on the previously referenced NIS study was greater than 20-fold.15 Complication risks were also greater when an AMI occurred. The need for transfusion and the development of postpartum infection had a significantly increased association with AMI in pregnancy. In this large study group, traditionally quoted risk factors such as maternal race, preeclampsia, postpartum hemorrhage, and anemia did not persist as independent risk factors for AMI in pregnancy.15 Other significant risk factors reported in pregnancy-related AMI include hyperlipidemia, family history of MI, and diabetes. The overall rate of AMI is increased in pregnancy by 3-fold to 4-fold.16 Apart from the known and suspected contributions to the increased risk discussed earlier, it seems that the physiologic changes of pregnancy might also enhance the risk of AMI. Coronary artery dissection is a rare cause of AMI in the nonpregnant population but occurred in between 16% and 27% of AMI in 2 case series reviewed by Roth and colleagues.16 It has been suggested that the increased rate of dissection may be the result of the effect of progesterone on the vessel wall leading to loss and fragmentation of fibers in vessel walls17 and decreased acid mucopolysaccharide. The profound hemodynamic changes in pregnancy increase the oxygen demand of the heart and could predispose to cardiac ischemic changes. During labor, the pain associated with uterine contractions could increase the work of the heart, further increasing the risk of AMI. In addition, during the postpartum period, increased venous return from reduced vena caval compression and expulsion of blood from the uterine circulation further exacerbates cardiac work and risk of ischemia. RISK FOR IHD IN DIABETES
The frequency of diabetes based on surveys of individuals in the United States has increased to 9%.18 The frequency of this disorder is known to be equal in men and women. In general, diabetes is known to be a significant risk factor for IHD. The pathogenesis of coronary artery disease in diabetes is multifactorial, with contributory factors being increased plaque formation with the risk of ulceration or thrombus formation. Hyperglycemia seems to promote endothelial dysfunction, hypercoagulability, and platelet dysfunction. In addition, hyperglycemia increases oxidative stress, which
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inhibits nitric oxide production. Nitric oxide is a potent vasolidator and regulates platelet activation factor.19 Among women, the cooccurrence of both IHD and diabetes (ie, class H diabetes) in pregnancy is rare, with only a limited number of cases reported in the English literature. In a prior report, all 11 of 24 class H patients with diabetes with myocardial ischemia before pregnancy survived.20 Of 13 with AMI in pregnancy, 5 (38.5%) survived. Although this finding seems to confirm a high risk of mortality when AMI occurs in pregnant patients with diabetes, advances in critical care may have reduced the mortality in contemporary practice. In 2 separate series, Roth and Elkayam16 reported that, among cases of AMI during pregnancy, 4% and 10.7% of such cases were diabetic. The frequency of diabetes reportedly varies with the timing of the AMI in pregnancy, with significantly higher rates in the antepartum versus postpartum ischemic event (19% vs 1.6%, P<.001). The national study by James and colleagues15 confirmed that diabetes significantly increased the risk IHD in pregnancy by 3.6-fold. Most studies have not distinguished gestational and preexisting diabetes in terms of the increased AMI risk. However, the study by Ladner and colleagues21 found that preexisting rather than gestational diabetes was the significant associated factor with IHD in pregnancy. PRECONCEPTION COUNSELING OF WOMEN WITH IHD AND DIABETES
Counseling in the preconception period has become an important intervention for perinatal providers working with patients and their families considering beginning a pregnancy. In many cases, their understanding of the risks associated with pregnancy is informed primarily by their understanding of diabetes in general as well as a rationalized opinion that their current state of health is likely to be superior to tomorrow’s. Although this conventional wisdom may be true in many cases, there may be justifiable concern about the current state of health and the advisability of pregnancy. Moreover, even if physician approval of a pregnancy is a possible recommendation, there is often a need for careful evaluation and health improvement before giving support for the conception. Any discussion in this area must consider the limited information concerning the subject. Despite nearly 4 decades of recognition of increased risk for poor maternal and fetal outcomes for women with diabetes and vascular complications, information useful to the clinician remains difficult to assemble and evaluate. Much of the earlier information came from articles focused on case reports coupled with literature reviews. The complexity of these cases generally involved the management of other affected end organs as well, rendering definitive management inferences problematic. It is important that the consultant have access to as much of the patient’s medical documentation as is available to aid in understanding the magnitude of the patient’s cardiac disease. Because multiple consultants are commonly a part of the patient’s care, reconciling her records before final recommendations is required. An updated assessment of the patient’s diabetic status and the state of her IHD is important. The New York Heart Association (NYHA) classification system is helpful in evaluating a patient’s functional status. However, it has little specificity to the underlying cardiac abnormality. When a patient has an NYHA class I or II at the time of counseling, a reasonable assumption is that the rate of complications related to the cardiac disease is less than that of individuals with class III or IV disease.22 Additional useful information for counseling includes the maternal risk for complications, including death, associated with pregnancy. This risk ranges from minimal (<1%) to moderate (5%–15%) to major (>25%). IHD should be considered as a moderate risk for complications, consistent with the classification placing previous MI in
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this category. It is important to remember that the class of risk may change during a pregnancy, thereby leading to greater risk than was appreciated at the preconception counseling.23 Outcome information shared by investigators in the past must be sorted through carefully to maximize applicability to the patient. Much of the information related to IHD and diabetes mellitus in pregnancy is a result of reports in the literature about women with diabetes with either an MI during pregnancy or the management of a patient with an unplanned pregnancy with history of IHD. However, the counseling of such patients should exercise caution, because it seems that diabetic women with IHD in pregnancy face more risks than just the risks associated with their cardiac disease in isolation. There may be a precarious balance between the possibility of a successful pregnancy and the significant potential for fetal and maternal complications. Combined with the likelihood of a shorter life even without pregnancy, this finding creates many issues that must be discussed deliberately and with candor. Counseling should use the following information: Evaluation of the patient should include diabetic control currently and in the recent past (review of glucose logs, hemoglobin A1C) Review of past history of evaluation, treatment, and care related to the patient’s IHD If there has been no recent evaluation of cardiac function, consideration should be given to updating patient’s assessment (electrocardiogram, echocardiogram, nuclear medicine cardiac imaging, cardiac catheterization) Assessment of diabetes-related noncardiac end organs for evidence of compromise With this information, the counseling may proceed as follows: Recap findings from history review and any recent laboratory assessment. This information provides a starting point for the recommendations that follow. Any need for additional evaluation before final recommendation should be discussed as well. Emphasize that all women with diabetes and IHD considering pregnancy must acknowledge that there is a quantifiable risk for poor outcome associated with a pregnancy even in the best of circumstances. A review of complications associated with diabetes in pregnancy should include information about risk for potential worsening of function in their cardiac function as well as other target organs. Although such deterioration is usually transient, there are instances of permanent loss of function. Risk to the prospective mother who has experienced a recent MI or has unstable angina at the time of counseling is substantial. This risk is frequently thought to be an absolute contraindication to pregnancy until greater stability and elapse of time has occurred.24 The physiologic changes associated with pregnancy may increase the risk for a repeat MI. Women who are currently on treatment of IHD are usually asked to discontinue medications that pose risk to the fetus. Discontinuation of these medications, such as angiotensin-converting enzyme inhibitors and statins, may lead to loss of stability of cardiac disease that had improved previously with interventions (eg, medications, stents). It is important to be as balanced as possible about the chance of success when contrasted with the risk for poor outcome. It is common for patients and families to find encouragement in the seemingly minor aspects of the counseling. Although an
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argument can be made that it is unlikely that the patient’s health will not improve substantially with additional time, there is often quantifiable risk at the start of the pregnancy that would make pregnancy unwise and, in some cases, a risk for premature death. If a patient with a significantly guarded prognosis decides to proceed with a pregnancy against medical advice, clear documentation of the discussion should be followed by an outlined plan of care coordinated with other key specialists. MANAGEMENT First Trimester
Patients with pregestational diabetes with IHD should have preconceptional counseling and have their baseline evaluations before pregnancy. Detailed history and physical examination, electrocardiogram, echocardiogram, stress test, and, if indicated, coronary angiogram and nuclear studies should be performed before pregnancy in any woman if coronary artery disease is suspected. Every effort should be made to treat coronary insufficiency before conception (Box 1). Pregnancy is usually discouraged in patients with coronary insufficiency because of a significantly increased risk of maternal mortality. However, a large proportion of these patients start obstetric care after they confirm their pregnancies. A detailed history and physical examination with baseline evaluations should be evaluated at the first prenatal visit (Box 2). Electrocardiogram evaluation for IHD does not vary significantly in pregnancy.24 Echocardiogram is valuable in defining cardiac wall motion abnormalities. Noninvasive stress testing with radiologic or electrocardiographic imaging techniques may be used in special circumstances. Angiographic evaluation can be used to better define the coronary disease and potentially correct the lesion. Abdominal shielding is used to limit fetal exposure. In women with angina, b-blockers, are the drug of choice because of their relative safety for the fetus. Low-dose aspirin can be used. Nitrates have also been used without adverse fetal effects. Patients who have stable angina pectoris only experience chest pain at high levels of exertion. The treatment option for these patients is beta-adrenergic blocking agents. In this setting, the likelihood of major complications during pregnancy, labor, or delivery is low. Unstable angina is diagnosed when there is confirmed angina at rest or with mild exertion. These unstable anginas typically, but not necessarily, follow a series of stable anginas and they are usually the warning signs for a major ischemic event such as AMI or fatal ventricular arrhythmia. Pregnancy under these circumstances is not advisable. Aggressive therapy including coronary angioplasty and percutaneous coronary
Box 1 Preconception care Before conception: Detailed history and physical examination Electrocardiogram and echocardiogram Stress test and, if indicated, coronary angiogram and nuclear studies Pregnancy is usually discouraged, especially if AMI was recent or current condition is not stable
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Box 2 Early antenatal care First trimester: A detailed history and physical examination with baseline evaluations Electrocardiogram Echocardiogram Complete blood count with platelet count Prothrombin time and International Normalization Ratio, activated partial thrombin time Electrolytes, magnesium, blood urea nitrogen, creatinine Blood glucose, hemoglobin A1c 24-hour urine protein, creatinine clearance Ophthalmology examination Noninvasive stress testing in special circumstances Angiographic evaluation with abdominal shielding Diabetes should be controlled but not tight (to decrease the incidence of hypoglycemia)
intervention or coronary artery bypass is recommended. If the outcome is satisfactory and condition is stable, pregnancy can be considered. If unstable angina develops during pregnancy, aggressive treatment should be initiated in an intensive care unit. Percutaneous coronary intervention with stenting or bypass surgery may be necessary (Box 3). A coronary bypass operation should be performed without cardiopulmonary bypass to decrease risk to the fetus.1 The treatment of an AMI during pregnancy includes starting IV morphine sulfate to control pain, oxygen by nasal cannula or mask, sublingual nitroglycerine, and chewable aspirin. The goal is to complete this treatment in less than 10 minutes to avoid permanent or extensive damage. A 12-lead electrocardiogram should be performed Box 3 Acute MI care Unstable angina: Coronary angioplasty and percutaneous coronary intervention or coronary artery bypass AMI treatment: Intravenous (IV) morphine sulfate to control pain Oxygen by nasal cannula or mask Sublingual nitroglycerine Chewable aspirin IV heparin b-Blockers (unless acute heart failure is present) IV nitroglycerine Antiplatelet therapy (clopidogrel) Systemic thrombolytic therapy (tissue plasminogen activator) is controversial Percutaneous coronary intervention with extensive lead shielding
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and repeated after 5 to 10 minutes if there is suspected MI despite an initial electrocardiogram reading of no abnormalities. If there is any sign of ST elevation or new left bundle branch block, treatment of an AMI should be started and cardiologists should be consulted. The recommended treatment is outlined in Box 3. The use of systemic thrombolytic therapy (tissue plasminogen activator) in pregnancy is controversial. There are some reports with successful outcomes.25 However, there is a potential increased risk for both maternal and fetal hemorrhage with the use of thrombolytic agents. Therefore, percutaneous coronary intervention is the preferred procedure by many care givers.26 Although there is radiation exposure risk to the fetus, extensive lead shielding can be used. The radial artery approach has been described and used successfully in pregnancy.27 This technique has a theoretical advantage in minimizing radiation to the fetus and prolonging maternal/fetal platelet inhibition. An important consideration is that AMI is associated with excess catecholamine production, making optimal glycemic control more difficult to achieve in diabetic patients. Moreover, excess catecholamine production may create a burden on the myocardial function and oxygenation. After an AMI in a pregnancy, several important decisions have to be addressed. If the gestational age is less than 14 to 16 weeks, pregnancy termination should be considered, because there is a risk for potential reinfarction. Although Husaini and colleagues28 claimed that an early gestational age for termination is safer for these patients, they reported no maternal deaths in 8 patients with first-trimester AMI who continued pregnancy without reinfarction. In these patients, the overall rate of reinfarction was 6%. However, Silfen and colleagues29 think that even an early abortion presents serious risk and recommend continuing the pregnancy. In the study by Hankins and colleagues,30 no maternal deaths occurred in women who delivered more than 2 weeks after infarction. Unstable angina, heart failure, dysrhythmia, and reinfarction are some of the complications that may develop after an AMI. In these patients, pregnancy termination is usually advised because of the increased cardiac demand of pregnancy.28 If pregnancy is continued after the complications, medical therapy and limitation of maternal exertion with adequate bed rest should be encouraged to decrease the myocardial oxygen demand.30 These patients have prolonged hospitalization and stay in cardiac rehabilitation units. Repeat echocardiogram to assess the recovery of cardiac function is helpful in determining maternal outcome.31 Diabetes should be controlled but hypoglycemia should be avoided to prevent catecholamine release and tachycardia, which increase myocardial demands.30 Tight glucose control in patients with diabetes during pregnancy is the general practice. However, this type of management may lead to more frequent episodes of hypoglycemia. Therefore, some investigators recommend accepting higher glucose values to avoid hypoglycemia.32 Early ultrasound for the confirmation of pregnancy and correct dates is essential, particularly for the correct diagnosis of fetal growth restriction or small for gestational age as the pregnancy advances. First-trimester genetic screening should be offered to the patient, because early pregnancy associated placental protein A and human chorionic gonadotropin measurements with nuchal translucency have been used to predict the poor outcome in high-risk population. Second and Third Trimester
Detailed fetal anatomy and echocardiogram should be done to screen for fetal congenital defects (Box 4). Uterine artery Doppler measurements may be helpful in
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Box 4 Late antenatal care Second and third trimesters: Detailed fetal anatomy and fetal echocardiogram Uterine artery Doppler measurements Monitor closely for the signs and symptoms of coronary insufficiency Always remember the atypical presentation of MI in patients with autonomic neuropathy Start serial fetal growth evaluations and antenatal testing earlier
predicting preeclampsia or placenta-related maternal and fetal complications in this high-risk population. These patients should be monitored closely for the signs and symptoms of coronary insufficiency. If there are any new symptoms the work-up and evaluation should be repeated. MI should be always in the differential even with vague symptoms. Particularly in diabetic patients, the autonomic neuropathy may predispose to infarction and result in atypical presenting symptoms, making diagnosis difficult and delaying treatment. The diagnostic approach and management for angina and AMI is the same as for nonpregnant patients. The potential concomitant uteroplacental vascular abnormalities increase the risk of fetal growth restriction and fetal demise, therefore serial fetal growth evaluations and antenatal testing should start earlier in these patients.30 LABOR AND DELIVERY, AND POSTPARTUM
Delivery within 2 weeks of MI is associated with increased mortality so, if possible, attempts should be made to allow adequate convalescence before delivery (Boxes 5 and 6). If the cervix is favorable, under controlled circumstances cautious induction after a period of hemodynamic stabilization is optimal. Labor in the lateral recumbent position, with oxygen administration and adequate pain relief, and preferably with epidural anesthesia and, in selected cases, hemodynamic monitoring with a pulmonary artery catheter, are important management considerations. The route of delivery should be individualized and a maternal fetal medicine specialist should be consulted for the best management plan. In the past, recommendations for route of delivery have focused on an operative vaginal delivery (forceps, vacuum) to shorten the second stage of labor to decrease the Valsalva maneuver and cesarean section used for obstetric indications.31 Continuous cardiac monitoring is routinely advised and the use of central line catheters should be individualized. Continuous epidural anesthesia is recommended to avoid pain-related stress and tachycardia along with the accompanying increased myocardial oxygen demand and increased risk of acute cardiac events. The greatest risk is the delivery and postpartum period for these patients. Issues to be clarified with the maternal fetal medicine specialist include, but are not limited to, the following: Timing of delivery Use of central monitoring Type of anesthesia
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Box 5 Labor and delivery care Labor and delivery: After a recent MI, try to delay delivery until after 2 weeks of the event of MI If cervix is favorable, time induction for when the mother is hemodynamically stable Continuous cardiac monitoring Selected cases require hemodynamic monitoring with a pulmonary artery catheter Adequate pain relief, preferably with epidural anesthesia Cesarean section for obstetric indications Shortening of second stage of labor
Route of delivery Type of anesthesia and the continuation of monitoring postpartum for complication detection Time of infarction, maternal cardiac function and hemodynamic status, concomitant pregnancy-related maternal complications, fetal condition, and gestational age are important factors to be considered when timing the delivery. If both maternal and fetal conditions are stable, induction can be considered after confirmation of fetal lung maturity and that the cervix is favorable. The facility should be familiar with the central monitoring. Although not every patient needs central line and monitoring, patients with recent infarction (1–2 months), unstable angina, impaired cardiac function, or pulmonary edema should have central monitoring.33 In patients who have not had an MI in the 3 weeks before delivery, with or without evidence of ischemia, heart failure, or severe left ventricular dysfunction, simple electrocardiographic monitoring is sufficient during labor. If a large myocardial ischemia has occurred during pregnancy, arterial blood pressure, central venous pressure, and pulmonary arterial and pulmonary wedge pressure with cardiac output should be monitored invasively. Monitoring should continue until after delivery because the preload abruptly increases with the delivery. The delivery route should be decided by obstetric indications. Cesarean section has not been shown to have benefit in the morbidity.30 In contrast, one study noted that the incidence of maternal mortality was higher with cesarean delivery than with vaginal delivery, although there were multiple confounding factors.30 Elective cesarean without labor can increase the cardiac output suddenly up to 50% of predelivery values compared with an appropriately managed labor.33 In addition, cesarean delivery
Box 6 Postpartum care Postpartum: Continuation of monitoring during postpartum Central catheters and epidural should stay for at least 24 hours after delivery Extended period of close postpartum follow-up evaluation Contraception options should be discussed
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increases the blood loss and postpartum complications.30 However, cesarean delivery with controlled analgesia may result in a less pronounced fluid shift. Timing the delivery, avoidance of long or unpredictable labor, and a possibility of rapid resolution of pulmonary edema are the proposed advantages of cesarean delivery.33 Epidural analgesia is effective in controlling pain in labor and is associated with decreased catecholamine excess and tachycardia and decreased cardiac stress. It may also decrease the afterload and preload and help to diminish the myocardial load.33 During labor, oxygen supplementation, lateral recumbent position, and avoidance of tachycardia and hypertension are important. Cases with parenteral nitrate therapy during labor to decrease myocardial demand have been reported.33 Some investigators recommend shortening of the second stage of labor to avoid the adverse effects of maternal pushing on cardiac function. However, there are limited data to support this approach.1,31 Ergot alkoloids and prostaglandins should be avoided because they may cause coronary vasoconstriction. After delivery, a series of important physiologic changes occur. There is a significant and immediate fluid shift and increase in the cardiac output by release of venocaval obstruction, autotransfusion of uteroplacental blood, and rapid mobilization of extravascular fluid. For these reasons, these patients must be closely monitored. Both central catheters and epidural analgesia should stay for at least 24 hours after delivery to help manage fluid shifts. An extended period of close postpartum follow-up evaluation is required because the cardiovascular hemodynamics do not return to the prepregnancy state even by 12 weeks postpartum.33 SUMMARY OF MANAGEMENT
It is essential to inform the patient with diabetes and IHD about the serious maternal risk of pregnancy. Preconception counseling with a maternal-fetal medicine (MFM) specialist should be strongly recommended by the patient’s cardiologist, endocrinologist, or primary caregiver if the patient wishes to get pregnant. Risk and prognosis should be brought up by the MFM specialist and permanent sterilization should be considered, especially in severely affected patients. If the patient is determined to become pregnant and is aware of the risks and accepts them, every effort should be made by the obstetrician, maternal-fetal medicine specialist, the endocrinologist, and the cardiologist to create a perinatal care plan that is collaborative and that fosters good communication. A thorough antenatal cardiac evaluation should be obtained and optimal glycemic control should be obtained while being mindful of the need to avoid hypoglycemia. Continuous surveillance of maternal and fetal status throughout the pregnancy and meticulous management of the delivery and postpartum period creates the best chance for success for the patient and her caregivers. REFERENCES
1. Creasy RK, Resnik R, Iams JD, et al. Diabetes in pregnancy. Creasy & Resnik’s maternal-fetal medicine. 6th edition. Pennsylvania: Saunders Elsevier; 2009. p. 953–93. 2. Davies GA, Herberet WN. Ischemic heart disease and cardiomyopathy in pregnancy. J Obstet Gynaecol Can 2007;29(7):575–9. 3. El-Deeb M, El-Menyar A, Gehani A, et al. Acute coronary syndrome in pregnant women. Expert Rev Cardiovasc Ther 2011;9(4):505–15. 4. Cormier CM, Martinez CA, Refuerzo JS, et al. White’s classification of diabetes in pregnancy in the 21st century: is it still valid? Am J Perinatol 2010;27:349–52.
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5. Boras J, Pavlic-Renar I, Car N, et al. Diabetes and coronary heart disease. Diabetol Croat 2002;31(4):199–208. 6. American Diabetes Association: preconception care of women with diabetes (position statement). Diabetes Care 2003;26:591. 7. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics – 2011 update: a report from the American Heart Association. Circulation 2011; 123:e18–209. 8. Ni H, Coady S, Rosanond W, et al. Trends from 1987 to 2004 in sudden death due to coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study. Am Heart J 2009;157:46–52. 9. Olson MB, Kelsey SF, Matthews K, et al. Symptoms, myocardial ischemia and quality of life in women: results from the NHLBI-sponsored WISE Study. Eur Heart J 2003;24:1506–14. 10. Guleltz M, Show LJ, Merz CN. Myocardial ischemia in women: lesson from the NHLBI WISE Study. Clin Cardiol 2012;35:14–8. 11. Coventry LL, Finn J, Bremner AP. Sex differences in symptom presentation in acute myocardial infarction: a systematic review and meta-analysis. Heart Lung 2011;40:477–91. 12. Rosenfeld A, Lindauer A, Darney B. Understanding treatment-seeking delay in women with acute myocardial infraction: descriptions of decision making patterns. Am J Crit Care 2005;14:285–93. 13. Cantus DS, Ruiz M. Ischemic heart disease in women. Rev Lat Am Enfermagem 2011;19:1464–9. 14. Lawton JS. Sex and gender differences in coronary artery disease. Semin Thorac Cardiovasc Surg 2011;23:126–30. 15. James AH, Jamison MG, Biswas MS, et al. Acute myocardial infarction in pregnancy: a United States population-based study. Circulation 2006;113:1564–71. 16. Roth A, Elkayam V. Acute myocardial infraction associated with pregnancy. J Am Coll Cardiol 2008;52:171–80. 17. Bonnet J, Aumailley M, Thomas D, et al. Spontaneous coronary artery dissection: case report and evidence for a defect in collagen metabolism. Eur Heart J 1986; 7:904–9. 18. Schiller JS, Lucas JW, Ward BW, et al. Summary health statistics for US adults National Health Interview Survey, 2010. Vital Health Stat 10 2012;(252):1–207. 19. D’Souza A, Hussain E, Howarth E, et al. Pathogenesis and pathophysiology of accelerated atherosclerosis in the diabetic heart. Molec Cell Biol Chem 2009; 331:89–116. 20. Bagg W, Henley PG, MacPherson P, et al. Pregnancy in women with diabetes and ischemic heart disease. Aust N Z J Obstet Gynaecol 1999;1:99–102. 21. Ladner HE, Danielsen B, Gilbert WM, et al. Acute myocardial infarction in pregnancy and the puerperium: a population-based study. Obstet Gynecol 2005;105:480–4. 22. Clark SL. Structural cardiac disease in pregnancy. In: Clark SL, Cotton DB, Phelan JP, editors. Critical care obstetrics. Madden (MA): Blackwell Science; 1997. p. 290–304. 23. Gast MJ, Rigg LA. Class H diabetes and pregnancy. Obstet Gynecol 1985;66:5S. 24. Veille JC, Kitzman DW, Bacevice AE. Effects of pregnancy on the electrocardiogram in healthy subjects during strenuous exercise. Am J Obstet Gynecol 1996; 175(5):1360–4. 25. Schumacher B, Belfort MA, Card RJ. Successful treatment of acute myocardial infarction during pregnancy with tissue plasminogen activator. Am J Obstet Gynecol 1997;176(3):716–9.
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26. Sebastian C, Scherlag M, Kugelmass A, et al. Primary stent implantation for acute myocardial infarction during pregnancy: use of abciximab, ticlopidine, and aspirin. Cathet Cardiovasc Diagn 1998;45(3):275–9. 27. Sharma GL, Loubeyre C, Morice MC. Safety and feasibility of the radial approach for primary angioplasty in acute myocardial infarction during pregnancy. J Invasive Cardiol 2002;14(6):359–62. 28. Husaini MH. Myocardial infarction during pregnancy: report of two cases with a review of the literature. Postgrad Med J 1971;47(552):660–5. 29. Silfen SL, Wapner RJ, Gabbe SG. Maternal outcome in class H diabetes mellitus. Obstet Gynecol 1980;55(6):749–51. 30. Hankins GD, Wendel GD Jr, Leveno KJ, et al. Myocardial infarction during pregnancy: a review. Obstet Gynecol 1985;65(1):139–46. 31. Sheikh AU, Harper MA. Myocardial infarction during pregnancy: management and outcome of two pregnancies. Am J Obstet Gynecol 1993;169(2 Pt 1): 279–83 [discussion: 283–4]. 32. Pombar X, Strassner HT, Fenner PC. Pregnancy in a woman with class H diabetes mellitus and previous coronary artery bypass graft: a case report and review of the literature. Obstet Gynecol 1995;85(5 Pt 2):825–9. 33. Gordon MC, Landon MB, Boyle J, et al. Coronary artery disease in insulindependent diabetes mellitus of pregnancy (class H): a review of the literature. Obstet Gynecol Surv 1996;51(7):437–44.
MANAGEMENT OF PREGNANT PATIENTS WITH DIABETES WITH ISCHEMIC HEART DISEASE
As the number of diabetic women increases, the rate of complications secondary to pregestational diabetes increases. There are numerous microvascular disease processes that occur with diabetes. Proliferative diabetic retinopathy is a microvascular
a
Department of Obstetrics and Gynecology, Oakwood Hospital and Medical Center, 18101 Oakwood Boulevard, PO Box 2500, Dearborn, MI 48124, USA; b Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Oakland University William Beaumont Health System, Oakland University William Beaumont School of Medicine, 3535 West 13 Mile Road, Royal Oak, MI 48073, USA; c Obstetrics & Gynecology, Oakland University William Beaumont Health System, Royal Oak, MI, USA * Corresponding author. Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI. E-mail address: [email protected] Clin Lab Med 33 (2013) 243–256 http://dx.doi.org/10.1016/j.cll.2013.03.020 labmed.theclinics.com 0272-2712/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
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complication that is caused by the formation of new retinal blood vessels and can lead to blindness by retinal detachment and/or bleeding. Diabetic nephropathy is the most common cause of end-stage renal disease in the United States.1 Cardiovascular complications that can occur in diabetic pregnancies include chronic hypertension, pregnancy-induced hypertension, and atherosclerotic heart disease.1 This article considers one particular significant vascular complication: ischemic heart disease (IHD). The maternal mortality of women with IHD has been reported to be as high as 66% to 75%.2 It has been reported that pregnancy increases the risk of myocardial infarction (MI) by 3-fold to 4-fold.3 The incidence of myocardial ischemia in pregnancy has been reported in numerous sources as 1 case per 10,000 deliveries. There have been several factors cited as contributors to the increased incidence of myocardial ischemia in pregnancy, including diabetes mellitus, hypertension, increasing rates of obesity, increasing maternal age, and smoking.3 CLASSIFICATION OF DIABETIC COMPLICATIONS
The classification of diabetes in pregnancy by obstetricians has relied on a classification system devised by Priscilla White in 1932 that focused on the onset and duration of disease and vascular complications. However, in recent years, this classification system has become a source of debate. In this article, the complication of interest would be given a designation of class H. However, as type 2 diabetes has become more prevalent compared with type 1 diabetes (for which the White classification system was mainly based), there has been discussion as to whether or not the classification system created by the American Diabetes Association (ADA) in 1997 (modified in 2007) should replace the White classification.4 Although there may be occasional references to the White classification, this article adheres to the ADA’s diagnostic and classification system.1 In distinction to myocardial ischemia in the older population, peripartum myocardial ischemia is not usually caused by atherosclerosis. There can be several causes of myocardial ischemia during the antepartum, peripartum, and postpartum periods, including coronary artery disease, coronary dissection, coronary thrombus, and coronary spasm. Acute coronary syndrome or myocardial ischemia during pregnancy poses a challenge because symptoms of myocardial ischemia can imitate complaints typical of normal pregnancy. Therefore, the diagnosis can be overlooked and missed. Diabetes further contributes to a blunted appreciation for ischemic pain that can result in silent ischemia and silent infarcts.5 It has been well recognized that adequate diabetic control decreases maternal and fetal mortality and morbidity. It is thought to be imperative that sufficient glycemic control and preconception care be ensured before pregnancy to facilitate favorable outcomes. Preconception counseling entails a multidisciplinary team that includes a diabetologist, a physician skilled in diabetes management, an obstetrician skilled in high-risk pregnancies, and diabetic educators.6 Untreated coronary artery disease is associated with a high mortality and it is important to diagnose before pregnancy when possible. However, unplanned pregnancies occur in approximately two-thirds of women with diabetes, making preconception counseling unattainable in most cases.6 OVERVIEW OF IHD
IHD represents a unique challenge in women. It is the leading cause of death in women, with more than 421,000 IHD deaths reported in the United States in 2011.7 Although there has been a decline in IHD-related mortality in women, this lags behind
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the improvement reported in men. Higher rates of sudden death before hospitalization occur in women.8 The most likely explanations for the higher mortality are: Higher rates of comorbidities in affected women Obesity Diabetes Hypertension More frequent hospitalizations Lower rates of overall well-being beyond cardiac concerns that are reported9 CHALLENGE IN DIAGNOSIS IN WOMEN
As noted earlier, risk factors seem to be more prevalent in women than men and, when they do occur, have greater impact on IHD. Such factors include elevated triglycerides, obesity, diabetes, and metabolic syndrome.10 A significant contributory factor to worse outcomes in women seems to be an increased frequency of delay or failure to make the diagnosis. The atypical presentation of coronary artery disease in women results in delayed recognition by patients and physicians. A recent large meta-analysis of 26 studies found significant differences in symptoms in women compared with men.11 These findings are consistent with the results of numerous prior studies and meta-analyses. Chest pain is widely recognized by both the general public and medical personnel to be a sign of ischemic heart disease. Significantly lower rates of chest pain were noted in a review of women compared with men (odds ratio 0.63, 95% confidence interval [CI] 0.59, 0.68) when data were pooled from multiple studies. There were similarly higher rates of nonspecific and, therefore, confounding symptoms in women. There were higher odds of presenting with:
Fatigue: relative risk (RR) 1.19, 95% CI 1.06, 1.33 Neck pain: RR 1.54, 95% CI 1.38, 1.73 Nausea: RR 1.42, 95% CI 1.02, 1.46 Syncope: RR 1.37, 95% CI 1.11, 1.70 Right arm pain: RR 1.20, 95% CI 1.07, 1.33 Dizziness: RR 1.22, 95% CI 1.01, 1.92 Jaw pain: RR 1.39, 95% CI 1.01, 1.9211
The atypical nature of these symptoms contributes both to late recognition and presentation for care and late and missed diagnosis in women. Adjusting for age and other confounding variables, for the most part, did not have a significant impact on the effect of gender on the presenting symptoms in acute MI (AMI). DISPARITIES IN CARE FOR WOMEN WITH IHD
Compounding the challenges in women’s recognition of the significance of their symptoms and delayed and even missed diagnosis by physicians are concerns regarding gender differences in therapy for coronary artery disease between the sexes. As a consequence of the atypical presentation, there is a delay in the decision time, which represents the period between the development of symptoms and presentation for medical care. Women are said to experience reduced rates of diagnostic testing, delay in referral to specialists, and longer wait times in receiving care.12 It is also thought that the treatment women receive tends to be less aggressive, with women frequently being treated with anxiolytics and antidepressants as a result of misdiagnosis for psychological and anxiety disorders.13 Despite the equal incidence of coronary artery disease in men and women, only 30% of coronary artery bypass surgery is
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performed in women.14 Reduced use in women has been partly ascribed to the smaller caliber of female coronary arteries, smaller body size, and increased comorbidities in women. Diagnosis and treatment of IHD is therefore a major challenge in contemporary health care and demands greater attention from health care policy makers, clinicians, researchers, as well as women themselves. ACUTE MYOCARDIAL INFARCTION (AMI)
Coronary artery disease, particularly MI, is a rare but consequential event in pregnancy. A nationwide study based on the Nationwide Inpatient Sample (NIS) database for the years 2000 to 2002 reported a US prevalence of AMI of 6.2 (95% CI 3.0–9.4) per 100,000 deliveries.15 There was a case fatality rate of as high as 37%. With the overall maternal mortality at 12 per 100,000, myocardial infraction accounts for a significant percentage of maternal mortality. Risk factors significantly associated with AMI in pregnancy include increasing maternal age, with women older than 30 years of age showing significantly increased rates of AMI than those younger than that age threshold.15 Preexisting medical disorders frequently increase the AMI risk: factors include chronic hypertension, thrombophilia, diabetes mellitus, as well as cigarette smoking. In thrombophilia and hypertension, the increase in risk based on the previously referenced NIS study was greater than 20-fold.15 Complication risks were also greater when an AMI occurred. The need for transfusion and the development of postpartum infection had a significantly increased association with AMI in pregnancy. In this large study group, traditionally quoted risk factors such as maternal race, preeclampsia, postpartum hemorrhage, and anemia did not persist as independent risk factors for AMI in pregnancy.15 Other significant risk factors reported in pregnancy-related AMI include hyperlipidemia, family history of MI, and diabetes. The overall rate of AMI is increased in pregnancy by 3-fold to 4-fold.16 Apart from the known and suspected contributions to the increased risk discussed earlier, it seems that the physiologic changes of pregnancy might also enhance the risk of AMI. Coronary artery dissection is a rare cause of AMI in the nonpregnant population but occurred in between 16% and 27% of AMI in 2 case series reviewed by Roth and colleagues.16 It has been suggested that the increased rate of dissection may be the result of the effect of progesterone on the vessel wall leading to loss and fragmentation of fibers in vessel walls17 and decreased acid mucopolysaccharide. The profound hemodynamic changes in pregnancy increase the oxygen demand of the heart and could predispose to cardiac ischemic changes. During labor, the pain associated with uterine contractions could increase the work of the heart, further increasing the risk of AMI. In addition, during the postpartum period, increased venous return from reduced vena caval compression and expulsion of blood from the uterine circulation further exacerbates cardiac work and risk of ischemia. RISK FOR IHD IN DIABETES
The frequency of diabetes based on surveys of individuals in the United States has increased to 9%.18 The frequency of this disorder is known to be equal in men and women. In general, diabetes is known to be a significant risk factor for IHD. The pathogenesis of coronary artery disease in diabetes is multifactorial, with contributory factors being increased plaque formation with the risk of ulceration or thrombus formation. Hyperglycemia seems to promote endothelial dysfunction, hypercoagulability, and platelet dysfunction. In addition, hyperglycemia increases oxidative stress, which
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inhibits nitric oxide production. Nitric oxide is a potent vasolidator and regulates platelet activation factor.19 Among women, the cooccurrence of both IHD and diabetes (ie, class H diabetes) in pregnancy is rare, with only a limited number of cases reported in the English literature. In a prior report, all 11 of 24 class H patients with diabetes with myocardial ischemia before pregnancy survived.20 Of 13 with AMI in pregnancy, 5 (38.5%) survived. Although this finding seems to confirm a high risk of mortality when AMI occurs in pregnant patients with diabetes, advances in critical care may have reduced the mortality in contemporary practice. In 2 separate series, Roth and Elkayam16 reported that, among cases of AMI during pregnancy, 4% and 10.7% of such cases were diabetic. The frequency of diabetes reportedly varies with the timing of the AMI in pregnancy, with significantly higher rates in the antepartum versus postpartum ischemic event (19% vs 1.6%, P<.001). The national study by James and colleagues15 confirmed that diabetes significantly increased the risk IHD in pregnancy by 3.6-fold. Most studies have not distinguished gestational and preexisting diabetes in terms of the increased AMI risk. However, the study by Ladner and colleagues21 found that preexisting rather than gestational diabetes was the significant associated factor with IHD in pregnancy. PRECONCEPTION COUNSELING OF WOMEN WITH IHD AND DIABETES
Counseling in the preconception period has become an important intervention for perinatal providers working with patients and their families considering beginning a pregnancy. In many cases, their understanding of the risks associated with pregnancy is informed primarily by their understanding of diabetes in general as well as a rationalized opinion that their current state of health is likely to be superior to tomorrow’s. Although this conventional wisdom may be true in many cases, there may be justifiable concern about the current state of health and the advisability of pregnancy. Moreover, even if physician approval of a pregnancy is a possible recommendation, there is often a need for careful evaluation and health improvement before giving support for the conception. Any discussion in this area must consider the limited information concerning the subject. Despite nearly 4 decades of recognition of increased risk for poor maternal and fetal outcomes for women with diabetes and vascular complications, information useful to the clinician remains difficult to assemble and evaluate. Much of the earlier information came from articles focused on case reports coupled with literature reviews. The complexity of these cases generally involved the management of other affected end organs as well, rendering definitive management inferences problematic. It is important that the consultant have access to as much of the patient’s medical documentation as is available to aid in understanding the magnitude of the patient’s cardiac disease. Because multiple consultants are commonly a part of the patient’s care, reconciling her records before final recommendations is required. An updated assessment of the patient’s diabetic status and the state of her IHD is important. The New York Heart Association (NYHA) classification system is helpful in evaluating a patient’s functional status. However, it has little specificity to the underlying cardiac abnormality. When a patient has an NYHA class I or II at the time of counseling, a reasonable assumption is that the rate of complications related to the cardiac disease is less than that of individuals with class III or IV disease.22 Additional useful information for counseling includes the maternal risk for complications, including death, associated with pregnancy. This risk ranges from minimal (<1%) to moderate (5%–15%) to major (>25%). IHD should be considered as a moderate risk for complications, consistent with the classification placing previous MI in
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this category. It is important to remember that the class of risk may change during a pregnancy, thereby leading to greater risk than was appreciated at the preconception counseling.23 Outcome information shared by investigators in the past must be sorted through carefully to maximize applicability to the patient. Much of the information related to IHD and diabetes mellitus in pregnancy is a result of reports in the literature about women with diabetes with either an MI during pregnancy or the management of a patient with an unplanned pregnancy with history of IHD. However, the counseling of such patients should exercise caution, because it seems that diabetic women with IHD in pregnancy face more risks than just the risks associated with their cardiac disease in isolation. There may be a precarious balance between the possibility of a successful pregnancy and the significant potential for fetal and maternal complications. Combined with the likelihood of a shorter life even without pregnancy, this finding creates many issues that must be discussed deliberately and with candor. Counseling should use the following information: Evaluation of the patient should include diabetic control currently and in the recent past (review of glucose logs, hemoglobin A1C) Review of past history of evaluation, treatment, and care related to the patient’s IHD If there has been no recent evaluation of cardiac function, consideration should be given to updating patient’s assessment (electrocardiogram, echocardiogram, nuclear medicine cardiac imaging, cardiac catheterization) Assessment of diabetes-related noncardiac end organs for evidence of compromise With this information, the counseling may proceed as follows: Recap findings from history review and any recent laboratory assessment. This information provides a starting point for the recommendations that follow. Any need for additional evaluation before final recommendation should be discussed as well. Emphasize that all women with diabetes and IHD considering pregnancy must acknowledge that there is a quantifiable risk for poor outcome associated with a pregnancy even in the best of circumstances. A review of complications associated with diabetes in pregnancy should include information about risk for potential worsening of function in their cardiac function as well as other target organs. Although such deterioration is usually transient, there are instances of permanent loss of function. Risk to the prospective mother who has experienced a recent MI or has unstable angina at the time of counseling is substantial. This risk is frequently thought to be an absolute contraindication to pregnancy until greater stability and elapse of time has occurred.24 The physiologic changes associated with pregnancy may increase the risk for a repeat MI. Women who are currently on treatment of IHD are usually asked to discontinue medications that pose risk to the fetus. Discontinuation of these medications, such as angiotensin-converting enzyme inhibitors and statins, may lead to loss of stability of cardiac disease that had improved previously with interventions (eg, medications, stents). It is important to be as balanced as possible about the chance of success when contrasted with the risk for poor outcome. It is common for patients and families to find encouragement in the seemingly minor aspects of the counseling. Although an
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argument can be made that it is unlikely that the patient’s health will not improve substantially with additional time, there is often quantifiable risk at the start of the pregnancy that would make pregnancy unwise and, in some cases, a risk for premature death. If a patient with a significantly guarded prognosis decides to proceed with a pregnancy against medical advice, clear documentation of the discussion should be followed by an outlined plan of care coordinated with other key specialists. MANAGEMENT First Trimester
Patients with pregestational diabetes with IHD should have preconceptional counseling and have their baseline evaluations before pregnancy. Detailed history and physical examination, electrocardiogram, echocardiogram, stress test, and, if indicated, coronary angiogram and nuclear studies should be performed before pregnancy in any woman if coronary artery disease is suspected. Every effort should be made to treat coronary insufficiency before conception (Box 1). Pregnancy is usually discouraged in patients with coronary insufficiency because of a significantly increased risk of maternal mortality. However, a large proportion of these patients start obstetric care after they confirm their pregnancies. A detailed history and physical examination with baseline evaluations should be evaluated at the first prenatal visit (Box 2). Electrocardiogram evaluation for IHD does not vary significantly in pregnancy.24 Echocardiogram is valuable in defining cardiac wall motion abnormalities. Noninvasive stress testing with radiologic or electrocardiographic imaging techniques may be used in special circumstances. Angiographic evaluation can be used to better define the coronary disease and potentially correct the lesion. Abdominal shielding is used to limit fetal exposure. In women with angina, b-blockers, are the drug of choice because of their relative safety for the fetus. Low-dose aspirin can be used. Nitrates have also been used without adverse fetal effects. Patients who have stable angina pectoris only experience chest pain at high levels of exertion. The treatment option for these patients is beta-adrenergic blocking agents. In this setting, the likelihood of major complications during pregnancy, labor, or delivery is low. Unstable angina is diagnosed when there is confirmed angina at rest or with mild exertion. These unstable anginas typically, but not necessarily, follow a series of stable anginas and they are usually the warning signs for a major ischemic event such as AMI or fatal ventricular arrhythmia. Pregnancy under these circumstances is not advisable. Aggressive therapy including coronary angioplasty and percutaneous coronary
Box 1 Preconception care Before conception: Detailed history and physical examination Electrocardiogram and echocardiogram Stress test and, if indicated, coronary angiogram and nuclear studies Pregnancy is usually discouraged, especially if AMI was recent or current condition is not stable
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Box 2 Early antenatal care First trimester: A detailed history and physical examination with baseline evaluations Electrocardiogram Echocardiogram Complete blood count with platelet count Prothrombin time and International Normalization Ratio, activated partial thrombin time Electrolytes, magnesium, blood urea nitrogen, creatinine Blood glucose, hemoglobin A1c 24-hour urine protein, creatinine clearance Ophthalmology examination Noninvasive stress testing in special circumstances Angiographic evaluation with abdominal shielding Diabetes should be controlled but not tight (to decrease the incidence of hypoglycemia)
intervention or coronary artery bypass is recommended. If the outcome is satisfactory and condition is stable, pregnancy can be considered. If unstable angina develops during pregnancy, aggressive treatment should be initiated in an intensive care unit. Percutaneous coronary intervention with stenting or bypass surgery may be necessary (Box 3). A coronary bypass operation should be performed without cardiopulmonary bypass to decrease risk to the fetus.1 The treatment of an AMI during pregnancy includes starting IV morphine sulfate to control pain, oxygen by nasal cannula or mask, sublingual nitroglycerine, and chewable aspirin. The goal is to complete this treatment in less than 10 minutes to avoid permanent or extensive damage. A 12-lead electrocardiogram should be performed Box 3 Acute MI care Unstable angina: Coronary angioplasty and percutaneous coronary intervention or coronary artery bypass AMI treatment: Intravenous (IV) morphine sulfate to control pain Oxygen by nasal cannula or mask Sublingual nitroglycerine Chewable aspirin IV heparin b-Blockers (unless acute heart failure is present) IV nitroglycerine Antiplatelet therapy (clopidogrel) Systemic thrombolytic therapy (tissue plasminogen activator) is controversial Percutaneous coronary intervention with extensive lead shielding
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and repeated after 5 to 10 minutes if there is suspected MI despite an initial electrocardiogram reading of no abnormalities. If there is any sign of ST elevation or new left bundle branch block, treatment of an AMI should be started and cardiologists should be consulted. The recommended treatment is outlined in Box 3. The use of systemic thrombolytic therapy (tissue plasminogen activator) in pregnancy is controversial. There are some reports with successful outcomes.25 However, there is a potential increased risk for both maternal and fetal hemorrhage with the use of thrombolytic agents. Therefore, percutaneous coronary intervention is the preferred procedure by many care givers.26 Although there is radiation exposure risk to the fetus, extensive lead shielding can be used. The radial artery approach has been described and used successfully in pregnancy.27 This technique has a theoretical advantage in minimizing radiation to the fetus and prolonging maternal/fetal platelet inhibition. An important consideration is that AMI is associated with excess catecholamine production, making optimal glycemic control more difficult to achieve in diabetic patients. Moreover, excess catecholamine production may create a burden on the myocardial function and oxygenation. After an AMI in a pregnancy, several important decisions have to be addressed. If the gestational age is less than 14 to 16 weeks, pregnancy termination should be considered, because there is a risk for potential reinfarction. Although Husaini and colleagues28 claimed that an early gestational age for termination is safer for these patients, they reported no maternal deaths in 8 patients with first-trimester AMI who continued pregnancy without reinfarction. In these patients, the overall rate of reinfarction was 6%. However, Silfen and colleagues29 think that even an early abortion presents serious risk and recommend continuing the pregnancy. In the study by Hankins and colleagues,30 no maternal deaths occurred in women who delivered more than 2 weeks after infarction. Unstable angina, heart failure, dysrhythmia, and reinfarction are some of the complications that may develop after an AMI. In these patients, pregnancy termination is usually advised because of the increased cardiac demand of pregnancy.28 If pregnancy is continued after the complications, medical therapy and limitation of maternal exertion with adequate bed rest should be encouraged to decrease the myocardial oxygen demand.30 These patients have prolonged hospitalization and stay in cardiac rehabilitation units. Repeat echocardiogram to assess the recovery of cardiac function is helpful in determining maternal outcome.31 Diabetes should be controlled but hypoglycemia should be avoided to prevent catecholamine release and tachycardia, which increase myocardial demands.30 Tight glucose control in patients with diabetes during pregnancy is the general practice. However, this type of management may lead to more frequent episodes of hypoglycemia. Therefore, some investigators recommend accepting higher glucose values to avoid hypoglycemia.32 Early ultrasound for the confirmation of pregnancy and correct dates is essential, particularly for the correct diagnosis of fetal growth restriction or small for gestational age as the pregnancy advances. First-trimester genetic screening should be offered to the patient, because early pregnancy associated placental protein A and human chorionic gonadotropin measurements with nuchal translucency have been used to predict the poor outcome in high-risk population. Second and Third Trimester
Detailed fetal anatomy and echocardiogram should be done to screen for fetal congenital defects (Box 4). Uterine artery Doppler measurements may be helpful in
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Box 4 Late antenatal care Second and third trimesters: Detailed fetal anatomy and fetal echocardiogram Uterine artery Doppler measurements Monitor closely for the signs and symptoms of coronary insufficiency Always remember the atypical presentation of MI in patients with autonomic neuropathy Start serial fetal growth evaluations and antenatal testing earlier
predicting preeclampsia or placenta-related maternal and fetal complications in this high-risk population. These patients should be monitored closely for the signs and symptoms of coronary insufficiency. If there are any new symptoms the work-up and evaluation should be repeated. MI should be always in the differential even with vague symptoms. Particularly in diabetic patients, the autonomic neuropathy may predispose to infarction and result in atypical presenting symptoms, making diagnosis difficult and delaying treatment. The diagnostic approach and management for angina and AMI is the same as for nonpregnant patients. The potential concomitant uteroplacental vascular abnormalities increase the risk of fetal growth restriction and fetal demise, therefore serial fetal growth evaluations and antenatal testing should start earlier in these patients.30 LABOR AND DELIVERY, AND POSTPARTUM
Delivery within 2 weeks of MI is associated with increased mortality so, if possible, attempts should be made to allow adequate convalescence before delivery (Boxes 5 and 6). If the cervix is favorable, under controlled circumstances cautious induction after a period of hemodynamic stabilization is optimal. Labor in the lateral recumbent position, with oxygen administration and adequate pain relief, and preferably with epidural anesthesia and, in selected cases, hemodynamic monitoring with a pulmonary artery catheter, are important management considerations. The route of delivery should be individualized and a maternal fetal medicine specialist should be consulted for the best management plan. In the past, recommendations for route of delivery have focused on an operative vaginal delivery (forceps, vacuum) to shorten the second stage of labor to decrease the Valsalva maneuver and cesarean section used for obstetric indications.31 Continuous cardiac monitoring is routinely advised and the use of central line catheters should be individualized. Continuous epidural anesthesia is recommended to avoid pain-related stress and tachycardia along with the accompanying increased myocardial oxygen demand and increased risk of acute cardiac events. The greatest risk is the delivery and postpartum period for these patients. Issues to be clarified with the maternal fetal medicine specialist include, but are not limited to, the following: Timing of delivery Use of central monitoring Type of anesthesia
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Box 5 Labor and delivery care Labor and delivery: After a recent MI, try to delay delivery until after 2 weeks of the event of MI If cervix is favorable, time induction for when the mother is hemodynamically stable Continuous cardiac monitoring Selected cases require hemodynamic monitoring with a pulmonary artery catheter Adequate pain relief, preferably with epidural anesthesia Cesarean section for obstetric indications Shortening of second stage of labor
Route of delivery Type of anesthesia and the continuation of monitoring postpartum for complication detection Time of infarction, maternal cardiac function and hemodynamic status, concomitant pregnancy-related maternal complications, fetal condition, and gestational age are important factors to be considered when timing the delivery. If both maternal and fetal conditions are stable, induction can be considered after confirmation of fetal lung maturity and that the cervix is favorable. The facility should be familiar with the central monitoring. Although not every patient needs central line and monitoring, patients with recent infarction (1–2 months), unstable angina, impaired cardiac function, or pulmonary edema should have central monitoring.33 In patients who have not had an MI in the 3 weeks before delivery, with or without evidence of ischemia, heart failure, or severe left ventricular dysfunction, simple electrocardiographic monitoring is sufficient during labor. If a large myocardial ischemia has occurred during pregnancy, arterial blood pressure, central venous pressure, and pulmonary arterial and pulmonary wedge pressure with cardiac output should be monitored invasively. Monitoring should continue until after delivery because the preload abruptly increases with the delivery. The delivery route should be decided by obstetric indications. Cesarean section has not been shown to have benefit in the morbidity.30 In contrast, one study noted that the incidence of maternal mortality was higher with cesarean delivery than with vaginal delivery, although there were multiple confounding factors.30 Elective cesarean without labor can increase the cardiac output suddenly up to 50% of predelivery values compared with an appropriately managed labor.33 In addition, cesarean delivery
Box 6 Postpartum care Postpartum: Continuation of monitoring during postpartum Central catheters and epidural should stay for at least 24 hours after delivery Extended period of close postpartum follow-up evaluation Contraception options should be discussed
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increases the blood loss and postpartum complications.30 However, cesarean delivery with controlled analgesia may result in a less pronounced fluid shift. Timing the delivery, avoidance of long or unpredictable labor, and a possibility of rapid resolution of pulmonary edema are the proposed advantages of cesarean delivery.33 Epidural analgesia is effective in controlling pain in labor and is associated with decreased catecholamine excess and tachycardia and decreased cardiac stress. It may also decrease the afterload and preload and help to diminish the myocardial load.33 During labor, oxygen supplementation, lateral recumbent position, and avoidance of tachycardia and hypertension are important. Cases with parenteral nitrate therapy during labor to decrease myocardial demand have been reported.33 Some investigators recommend shortening of the second stage of labor to avoid the adverse effects of maternal pushing on cardiac function. However, there are limited data to support this approach.1,31 Ergot alkoloids and prostaglandins should be avoided because they may cause coronary vasoconstriction. After delivery, a series of important physiologic changes occur. There is a significant and immediate fluid shift and increase in the cardiac output by release of venocaval obstruction, autotransfusion of uteroplacental blood, and rapid mobilization of extravascular fluid. For these reasons, these patients must be closely monitored. Both central catheters and epidural analgesia should stay for at least 24 hours after delivery to help manage fluid shifts. An extended period of close postpartum follow-up evaluation is required because the cardiovascular hemodynamics do not return to the prepregnancy state even by 12 weeks postpartum.33 SUMMARY OF MANAGEMENT
It is essential to inform the patient with diabetes and IHD about the serious maternal risk of pregnancy. Preconception counseling with a maternal-fetal medicine (MFM) specialist should be strongly recommended by the patient’s cardiologist, endocrinologist, or primary caregiver if the patient wishes to get pregnant. Risk and prognosis should be brought up by the MFM specialist and permanent sterilization should be considered, especially in severely affected patients. If the patient is determined to become pregnant and is aware of the risks and accepts them, every effort should be made by the obstetrician, maternal-fetal medicine specialist, the endocrinologist, and the cardiologist to create a perinatal care plan that is collaborative and that fosters good communication. A thorough antenatal cardiac evaluation should be obtained and optimal glycemic control should be obtained while being mindful of the need to avoid hypoglycemia. Continuous surveillance of maternal and fetal status throughout the pregnancy and meticulous management of the delivery and postpartum period creates the best chance for success for the patient and her caregivers. REFERENCES
1. Creasy RK, Resnik R, Iams JD, et al. Diabetes in pregnancy. Creasy & Resnik’s maternal-fetal medicine. 6th edition. Pennsylvania: Saunders Elsevier; 2009. p. 953–93. 2. Davies GA, Herberet WN. Ischemic heart disease and cardiomyopathy in pregnancy. J Obstet Gynaecol Can 2007;29(7):575–9. 3. El-Deeb M, El-Menyar A, Gehani A, et al. Acute coronary syndrome in pregnant women. Expert Rev Cardiovasc Ther 2011;9(4):505–15. 4. Cormier CM, Martinez CA, Refuerzo JS, et al. White’s classification of diabetes in pregnancy in the 21st century: is it still valid? Am J Perinatol 2010;27:349–52.
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5. Boras J, Pavlic-Renar I, Car N, et al. Diabetes and coronary heart disease. Diabetol Croat 2002;31(4):199–208. 6. American Diabetes Association: preconception care of women with diabetes (position statement). Diabetes Care 2003;26:591. 7. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics – 2011 update: a report from the American Heart Association. Circulation 2011; 123:e18–209. 8. Ni H, Coady S, Rosanond W, et al. Trends from 1987 to 2004 in sudden death due to coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study. Am Heart J 2009;157:46–52. 9. Olson MB, Kelsey SF, Matthews K, et al. Symptoms, myocardial ischemia and quality of life in women: results from the NHLBI-sponsored WISE Study. Eur Heart J 2003;24:1506–14. 10. Guleltz M, Show LJ, Merz CN. Myocardial ischemia in women: lesson from the NHLBI WISE Study. Clin Cardiol 2012;35:14–8. 11. Coventry LL, Finn J, Bremner AP. Sex differences in symptom presentation in acute myocardial infarction: a systematic review and meta-analysis. Heart Lung 2011;40:477–91. 12. Rosenfeld A, Lindauer A, Darney B. Understanding treatment-seeking delay in women with acute myocardial infraction: descriptions of decision making patterns. Am J Crit Care 2005;14:285–93. 13. Cantus DS, Ruiz M. Ischemic heart disease in women. Rev Lat Am Enfermagem 2011;19:1464–9. 14. Lawton JS. Sex and gender differences in coronary artery disease. Semin Thorac Cardiovasc Surg 2011;23:126–30. 15. James AH, Jamison MG, Biswas MS, et al. Acute myocardial infarction in pregnancy: a United States population-based study. Circulation 2006;113:1564–71. 16. Roth A, Elkayam V. Acute myocardial infraction associated with pregnancy. J Am Coll Cardiol 2008;52:171–80. 17. Bonnet J, Aumailley M, Thomas D, et al. Spontaneous coronary artery dissection: case report and evidence for a defect in collagen metabolism. Eur Heart J 1986; 7:904–9. 18. Schiller JS, Lucas JW, Ward BW, et al. Summary health statistics for US adults National Health Interview Survey, 2010. Vital Health Stat 10 2012;(252):1–207. 19. D’Souza A, Hussain E, Howarth E, et al. Pathogenesis and pathophysiology of accelerated atherosclerosis in the diabetic heart. Molec Cell Biol Chem 2009; 331:89–116. 20. Bagg W, Henley PG, MacPherson P, et al. Pregnancy in women with diabetes and ischemic heart disease. Aust N Z J Obstet Gynaecol 1999;1:99–102. 21. Ladner HE, Danielsen B, Gilbert WM, et al. Acute myocardial infarction in pregnancy and the puerperium: a population-based study. Obstet Gynecol 2005;105:480–4. 22. Clark SL. Structural cardiac disease in pregnancy. In: Clark SL, Cotton DB, Phelan JP, editors. Critical care obstetrics. Madden (MA): Blackwell Science; 1997. p. 290–304. 23. Gast MJ, Rigg LA. Class H diabetes and pregnancy. Obstet Gynecol 1985;66:5S. 24. Veille JC, Kitzman DW, Bacevice AE. Effects of pregnancy on the electrocardiogram in healthy subjects during strenuous exercise. Am J Obstet Gynecol 1996; 175(5):1360–4. 25. Schumacher B, Belfort MA, Card RJ. Successful treatment of acute myocardial infarction during pregnancy with tissue plasminogen activator. Am J Obstet Gynecol 1997;176(3):716–9.
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Jones et al
26. Sebastian C, Scherlag M, Kugelmass A, et al. Primary stent implantation for acute myocardial infarction during pregnancy: use of abciximab, ticlopidine, and aspirin. Cathet Cardiovasc Diagn 1998;45(3):275–9. 27. Sharma GL, Loubeyre C, Morice MC. Safety and feasibility of the radial approach for primary angioplasty in acute myocardial infarction during pregnancy. J Invasive Cardiol 2002;14(6):359–62. 28. Husaini MH. Myocardial infarction during pregnancy: report of two cases with a review of the literature. Postgrad Med J 1971;47(552):660–5. 29. Silfen SL, Wapner RJ, Gabbe SG. Maternal outcome in class H diabetes mellitus. Obstet Gynecol 1980;55(6):749–51. 30. Hankins GD, Wendel GD Jr, Leveno KJ, et al. Myocardial infarction during pregnancy: a review. Obstet Gynecol 1985;65(1):139–46. 31. Sheikh AU, Harper MA. Myocardial infarction during pregnancy: management and outcome of two pregnancies. Am J Obstet Gynecol 1993;169(2 Pt 1): 279–83 [discussion: 283–4]. 32. Pombar X, Strassner HT, Fenner PC. Pregnancy in a woman with class H diabetes mellitus and previous coronary artery bypass graft: a case report and review of the literature. Obstet Gynecol 1995;85(5 Pt 2):825–9. 33. Gordon MC, Landon MB, Boyle J, et al. Coronary artery disease in insulindependent diabetes mellitus of pregnancy (class H): a review of the literature. Obstet Gynecol Surv 1996;51(7):437–44.