Abstract

The prevalence of coronary artery disease in female patients is increasing due to changing lifestyle patterns including cigarette smoking, diabetes and stress. Since women are delaying childbearing until older age, acute coronary syndrome will more frequently occur during pregnancy. Although rare, acute coronary syndrome during pregnancy often has devastating consequences. It is associated with increased maternal and neonatal mortality and morbidity compared with the nonpregnant situation. Furthermore, it constitutes an important problem for the patient and the treating physician, because the selection of diagnostic and therapeutic approaches is greatly influenced not only by maternal, but also by fetal safety.

Introduction

Coronary heart disease is a major health problem. Although rare in pregnant women, during pregnancy acute coronary syndrome (ACS) is estimated to occur three- to four-times more often compared with the nonpregnant women in this age group.^[1] The incidence of ACS during pregnancy is estimated at 1 per 10,000 pregnancies ( Table 1 ).^[1,2] Actual incidence ratios may even be higher. Chest discomfort is not primarily attributed to heart problems in, otherwise healthy, pregnant women. Myocardial ischemia during pregnancy can mimic complaints typical for pregnancy. Therefore, the diagnosis of ACS is often missed during pregnancy.

The changes in the cardiac, hemodynamic, hemostatic and hormonal situation during pregnancy and in the puerperium form a broad spectrum of causes of ACS, and contribute to the increased mortality rate among pregnant women with ACS. This review will summarize the available information about pregnancy-related coronary heart disease.

Hemodynamic changes

To ensure an adequate supply of nutrients and oxygen to the developing fetus, several hemodynamic changes take place during pregnancy. Blood volume increases by 1100-1600 ml, a raise of 30-50%.^[3] At the same time red cell mass increases to a lesser extent than plasma volume, resulting in physiological anemia and decreased blood viscosity. The blood volume expands rapidly until the 34th week, after which there is only a modest rise. Cardiac output increases by 30-50%. First, preload increases owing to the rise in blood volume. Second, gestational hormones, circulating prostaglandins in combination with the low vascular resistance of the placenta and uterus, decrease the peripheral vascular resistance and blood pressure, therefore, reducing the cardiac afterload and increasing the vascular compliance.^[4] In addition, there is an increase in heart rate of 10 to 20 beats per minute (Figures 1 & 2).^[5,6

Finally, an extra effort of the cardiac function is demanded during and immediately after delivery. Uterine contractions during labor result in increased cardiac output.^[7] After delivery, cardiac preload increases as a result of decompression of the inferior caval vein and return of uterine blood into the circulation (autotransfusion). Intravascular volume is further increased by reabsorption of extracellular fluids into the circulation. After a rapid decline in the first 2 weeks, hemodynamic adaptations will slowly resolve in 3 to 6 months after delivery.^[8]

Hemostatic changes

Changes take place in all aspects of hemostasis in order to maintain placental function during pregnancy and to prevent excessive bleeding at delivery. There is an increase in the coagulation factors V, VII, VIII, IX, X and XII and von Willebrand factor increases.^[9] Resistance to activated protein C increases in the second and third trimester.^[10] Protein S decreases throughout the entire pregnancy. Plasma activator inhibitors increase during pregnancy. At the time of delivery coagulability is further enhanced through the release of tissue plasminogen-activator inhibitors from the placenta and myometrium. The plasma concentrations of the plasminogen-activator system return to normal 6 weeks after pregnancy.^[11]

Etiology of coronary heart disease in pregnancy

The prevalence of coronary artery disease is increasing as a result of changing lifestyle patterns, including cigarette smoking, diabetes and stress. As women are delaying childbearing until older age, the occurrence of an acute myocardial infarction during pregnancy is more frequently encountered. Age appears to be one of the major determinants of pregnancy-related myocardial infarction. At the age of 40 years and older, the incidence of myocardial infarction is three per 10,000 deliveries.^[1]

Increased cardiac workload and greater myocardial oxygen demand during pregnancy puts the heart in a situation where myocardial ischemia may have a more severe course. Before the current practise of percutaneous coronary intervention (PCI), the estimated mortality among pregnant women with ACS was 20%.^[12] Currently, with the application of PCI, maternal mortality rate has dropped to 5%.^[1]

Although the common cause of coronary heart disease is atherosclerosis, a spectrum of causes is found during pregnancy.^[12] Coronary atherosclerosis (with or without a thrombus) was found in 43% and a thrombus, without signs of atherosclerosis, was present in 21% of the patients who underwent coronary angiography for ACS during pregnancy. Coronary dissection was found in 16%, while normal coronary arteries were reported in 29% of patients. Coronary atherosclerosis was the primary cause of infarction in the antepartum group, while in the post-partum period dissection was the primary cause of ACS.

Symptoms of coronary heart disease in pregnancy

ACSs or progression of previous angina may at times be difficult to differentiate from signs and symptoms typically reported during normal pregnancy. Common complaints during normal pregnancy include fatiguability, decreased exercise tolerance and chest pain at rest due to oesophageal reflux. Indicators of heart disease include severe or progressive dyspnea, syncope with exertion and chest pain related to effort or emotion ( Table 2 ).^[13]

Therapeutic modalities

Treatment of ACSs is not based on randomized trials, but on limited data taken from case reports, observational studies and clinical individual experience.

Treatment of acute myocardial infarction

In the acute phase, the treatment options for ACS are thrombolysis, PCI or coronary artery bypass grafting (CABG). During pregnancy, decision-making not only depends on best maternal results, but is also influenced by fetal safety. However, if there is no other alternative therapeutic modality, the safety of the mother prevails over the possible negative influence of the therapy on fetal outcome.

Thrombolysis

A common cause of ACS is a thromboembolic process, therefore, thrombolytic therapy is useful in the general population. However, in pregnancy a substantial part of ACS is caused by nonthromboembolic processes (e.g., dissection). It is important to perform a diagnostic catheterization before giving thombolytic therapy.

There is little experience with thrombolytic therapy for ACS during pregnancy. Streptokinase and recombinant tissue-plasminogen activator do not cross the placenta in animals, but it is unknown whether they cross the human placenta. Most experience with thrombolytic therapy during pregnancy is from patients with pulmonary embolisms, deep venous thrombosis and prosthetic valve thrombosis. The complications observed included maternal hemorrhage (2.5%), uterine hemorrhages with emergency cesarean section (2%), preterm delivery (6%), fetal loss (2%), abruptio placenta (2.5%) and spontaneous abortion (1.5%).^[12,14] No teratogenic effects were mentioned in the few available reports.

Percutaneous coronary intervention

In the general population, PCI is the first-line therapy for ACS. However, PCI in pregnancy implies exposure of the fetus to higher radiation levels compared with a diagnostic angiogram alone. High doses of radiation place the fetus at risk of spontaneous abortion, organ deformation, mental retardation and childhood cancer.

The amount of fetal exposure to radiation during chest radiography in PCI results in a mean exposure of 0.02 mSv and a maximum of 0.1 mSv in difficult PCI procedures (National Council of Radiation Protection and Measurements 1998) ( Table 3 ). Radiation that scattered from the directly irradiated area reaches the fetus; this is only a small fraction of the radiation delivered to the thorax.^[15] Shielding the abdomen and pelvis will not intercept the scattered irradiation. Catheterization through the radial artery will keep fetal-radiation exposure to a minimum.

PCI in pregnancy can be considered relatively safe, taking into account the minimal radiation exposure. However, before completion of major organogenesis (before 15 weeks after menses) radiation exposure must, whenever possible, be avoided. Doses in excess of 50–100 mSv increase the incidence of fetal malformation ( Table 4 ).

With regards to the spectrum of causes of myocardial infarction in pregnancy, catheterization appears to be the first step, and in most cases, PCI will be the therapy of choice during pregnancy. Not only can thromboembolic processes be treated, but also other causes, such as coronary artery dissection, can be detected and treated immediately. Considering the use of stenting during PCI implies the use of platelet-aggregation inhibitors in the post-PCI period. In particular, the increasing use of drug-eluting stents necessitates the use of clopidogrel in the post-PCI period. No information is available about the effects of clopidogel on the fetus, although, animal experiments do not demonstrate a teratogenic effect. There are no studies in pregnant women, therefore, clopidogrel should only be used in pregnancy if clearly needed.

Coronary artery-bypass grafting

Cardiac surgery can be performed during pregnancy. Maternal mortality equals mortality in nonpregnant cardiac surgery, but fetal mortality risk is still high with an incidence of 20%.^[16] Most of the experience of cardiac surgery during pregnancy is obtained from valve surgery. The best results are obtained by performing surgery in the second trimester since surgery may cause abortion and fetal malformations in the first and preterm labor in the third trimester.^[16] Cardiopulmonary bypass adversely affects placental perfusion as a result of nonpulsatile blood flow and hypotension and, therefore, disrupts organogenesis and influences fetal outcome. One study found a tendency towards increased fetal mortality with increased cardiopulmonary-bypass time. Fetal mortality was also related to a longer anoxic time.^[16]Cardiopulmonary bypass in pregnancy must be performed at high flow, high pressure, in normothermia and with the shortest possible extracorporeal circulation time.

Drug therapy

Following the acute phase of myocardial infarction, several drugs can reduce the risk of recurrence of myocardial infarction, reduce the progression of atherosclerosis and prevent anginal symptoms.

Drug therapy for coronary artery disease consists of antithrombotic drugs, antianginal drugs, drugs reducing the progression of atherosclerosis and drugs used to improve myocardial remodeling after an acute myocardial infarction (Table 5 ).

The use of low-dose aspirin (<150 mg/day) is considered safe during pregnancy.^[17-19] Higher doses are associated with premature closure of the ductus arteriosus, fetal congenital abnormalities and fetal and maternal hemorrhage. There is no information available about clopidogrel during pregnancy. Treatment with (low molecular weight) heparins is safe during pregnancy. It does not cross the placenta and it can be administered up to 12 h before delivery. Coumadins can be teratogenic when used in pregnancy. Coumadins cause teratogenic effects in 6% of babyies when given in the period between the 6th and 9th week of pregnancy.^[20] There is probably a dose–effect relation. Furthermore, coumadins increase the risk of miscarriage when used in the second and third trimester. Due to an increased risk of hemorrhage, acenocoumarol should be stopped and replaced by (low molecular weight) heparins several weeks before delivery.^[21]Fenprocoumon is more teratogenic than acenocoumarol and, therefore, should not be used.

Angina pectoris is treated by decreasing the oxygen demand, decreasing cardiac workload and improving coronary perfusion. By slowing down the heart rate, oxygen demand decreases. In general, β-blockers are relatively safe. However, severe bradycardia should be avoided in order to prevent uteroplacental hypoperfusion. The use of β-blockers is associated with a mildly lower birth weight and this can theoretically cause post-partum fetal bradycardia.

Nitrates and calcium antagonists are used to induce vasodilatation. The preload increases while afterload decreases. This results in a decreased cardiac workload. Coronary perfusion is improved through coronary vasodilatation. High-dose nitrates may cause maternal hypotension and subsequent fetal hypoperfusion. No other adverse effects of nitrates during pregnancy have been reported. The calcium antagonist, diltiazem, has teratogenic effects (skeletal abnormalities) in animals. There is no information about its use in human pregnancy, therefore, it should not be used.^[22] Nifedipine is frequently used during pregnancy for the treatment of hypertension, preeclampsia and tocolysis. It appears to be safe.^[23]

Improving the lipid-profile reduces atherosclerotic progression. Hydroxymethylglutarylco-enzyme A (HMG-CoA)-reductase inhibitors (statins) are the first-line therapy for dyslipidemias in the general population. However, statins are contraindicated in pregnancy as a result of possible teratogenic effects. Evidence of fetal abnormalities (mainly skeletal defects) has been observed in animal studies.^[24] All statins are labeled as US FDA category X. There is only limited data available regarding the efficacy of ezitimibe (even in the general population).

Angiotensin converting enzyme (ACE)-inhibitors improve myocardial remodeling after an acute myocardial infarction. ACE-inhibitors are teratogenic in pregnancy, even during the first trimester and, therefore, should not be given.^[25] Reported complications include neonatal lung hypoplasia, intra-uterine growth restriction, persisting ductus arteriosus and skull hypoplasia. Few data are available regarding angiotensin (AT)-II-receptor antagonists in pregnancy, but their actions, similar to that of ACE-inhibitors, also makes them contraindicated.^[26]

Previous myocardial infarction

Besides patients with an ACS presenting during pregnancy, patients with previous coronary disease may also wish to have children. Impairment of left ventricular function is one of the main determinants of poor maternal and fetal outcome. Pregnancy should be discouraged if the left ventricular ejection fraction is below 40%.^[27]

It is important to provide general advice to patients with heart disease and to their close relatives before conception. Before taking any medication during pregnancy and during lactation, the safety and tolerability for the fetus and infant, the physiological maternal changes and the risk:benefit ratio must all be considered. In patients who are already taking cardiovascular medications, the discontinuation or the switch to a ‘safer' drug should be discussed and tried before conception. ACE-inhibitors and/or AT-II should be stopped and echocardiographic and exercise evaluation can be performed 3 months later to assess changes in the cardiac condition before deciding on pregnancy advice.

Heart failure

One of the complications of myocardial infarction is deterioration of left ventricular function with subsequent heart failure. Treatment of heart failure consists primarily of diuretics. Furosemide has been proven safe during pregnancy, however, it should be used with caution to prevent hypovolemia and subsequent reduction in uteroplacental flow. ACE-inhibitors and/or AT-II antagonists are contraindicated. Hydralazine is safe and can be useful in the treatment of heart failure in pregnancy. β-blockers are indicated to optimize diastolic filling once the patient is in a stable situation.

Advice during pregnancy should include salt and fluid restriction and limitation of physical activity up to complete bed rest in the case of manifest heart failure. Self-weighing should be encouraged, and in the case of sudden unexpected weight gain (although pregnant), contacting the physician is recommended.

Arrythmias

Acute and previous myocardial infarctions might cause potential life-threatening arrythmias. Particular attention should be given to the recognition of ventricular arrythmias during pregnancy and during, and after, delivery. Pregnancy might increase the incidence of arrythmias due to increased mechanical stretch of the myocardium. Conservative therapy is recommended for benign, well-tolerated arrhythmias, but, if the systolic function of the heart becomes impaired or life-threatening arrhythmias occur, treatment is important and should not be withdrawn. Most of the antiarrythmic drugs can be prescribed safely in pregnancy. All antiarrhythmic drugs cross the placental barrier and their potentially toxic effect on the fetus should be taken in consideration, particularly during the initial weeks of pregnancy.

Delivery

During delivery, cardiac workload increases to maximum. In the case of recent infarction this can theoretically lead to myocardial rupture. Therefore, in order to allow adequate healing, delivery should be postponed, if possible, for at least 2–3 weeks after myocardial infarction. The mode of delivery should be determined by obstetric reasons and the clinical status of the mother. No convincing data proclaiming either vaginal delivery or cesearean section have been reported. However, cesearean section leads to more blood loss at delivery, therefore, vaginal delivery is preferable in patients with heart disease. Cardiac effort during delivery can further be reduced by administering epidural anesthesia for pain relief and shortening the second stage of labour.

Puerperium

In the puerperium patients with coronary heart disease are still at risk for new events. Delivery causes a volume overload due to autotransfusion. Patients at risk have a higher chance of developing heart failure or arrythmias and, therefore, clinical observation for at least 3 days after delivery is recommended.

Conclusion

ACS is rare in pregnancy, however, because of older maternal age and changing lifestyle patterns (e.g., smoking and diabetes) it will be encountered more frequently. Acute myocardial infarction in pregnancy is estimated to occur in one per 10,000 pregnancies and is associated with high maternal and neonatal mortality and morbidity. Atherosclerosis is one of the causes of myocardial infarction during pregnancy, but other causes, such as dissection and thrombus, are found relatively frequent. A possible explanation could be found in the combined changes of the hemodynamic, hemostatic and hormonal system during pregnancy. Thrombolytic therapy can be given, but not without a definite diagnosis of the etiology. Serious side effects of thrombolytic therapy have been reported. Radiation exposure of the fetus during cardiac catherization is acceptable, especially after the 15th week of pregnancy. The widespread use of PCI has led to a drastic reduction in maternal death.^[1,12] Therefore, PCI is the first-choice treatment during pregnancy when indicated. Cardiac surgery during pregnancy is associated with high fetal mortality. We recommend that pregnant women with ACS should be treated in tertiary centers with interventional possibilities.

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