Management of Cardiovascular Diseases During Pregnancy

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Management of cardiovascular diseases during pregnancy Vera Regitz-Zagrosek MD, Christa Gohlke-Baerwolf MD, Bernard Iung MD, Petronella G. Pieper MD

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S0146-2806(14)00012-7 http://dx.doi.org/10.1016/j.cpcardiol.2014.02.001 YMCD270

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Curr Probl Cardiol

Cite this article as: Vera Regitz-Zagrosek MD, Christa Gohlke-Baerwolf MD, Bernard Iung MD, Petronella G. Pieper MD, Management of cardiovascular diseases during pregnancy, Curr Probl Cardiol, http://dx.doi.org/10.1016/j.cpcardiol.2014.02.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

I.

TITLE PAGE

Management of cardiovascular diseases during pregnancy Short title: Cardiovascular diseases during pregnancy

Vera Regitz-Zagrosek1,2, MD, Christa Gohlke-Baerwolf3, MD, Bernard Iung4,5, MD, Petronella G. Pieper6, MD

1

Charite, University Medicine Berlin, Institute of Gender in Medicine (GiM)

2

Charite, University Medicine Berlin, Center for Cardiovascular Research (CCR)

3

Department of Cardiology, Heart Center Bad Krozingen. Germany

4

Cardiology Department, AP-HP, Bichat Hospital Paris

5

University Paris Diderot, Sorbonne Paris Cité, Paris, France

6

Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen,

the Netherlands

Adress for Correspondence : Dr. Christa Gohlke-Bärwolf Neue Kirchstr.22 79282 Ballrechten-Dottingen Phone: +49 7634 8171 Fax:

+49-7634 6775

E-mail: [email protected]

Disclosure statements Vera Regitz-Zagrosek No conflict of interest to declare with respect to this manuscript Christa Gohlke-Baerwolf No conflict of interest to declare with respect to this manuscript Bernard Iung has received consultant fees from Abbott, Bayer, Boehringer Ingelheim, Servier, Valtech and speaker’s fees from Edwards Lifesciences. Petronella G. Pieper No conflict of interest to declare with respect to this manuscript

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II. TABLE OF CONTENTS 1.  Abstract .......................................................................................................................... 5  2.  General considerations .................................................................................................. 6  2.1  Introduction ............................................................................................................... 6  2.2  Epidemiology ............................................................................................................ 7  2.3  Haemodynamic, haemostatic and metabolic alterations during pregnancy ............. 8  2.4  Genetic testing and counselling................................................................................ 9  2.5  Risk estimation and counselling ............................................................................... 10  2.6  Cardiovascular diagnosis in pregnancy .................................................................... 12  2.7  Interventions in the mother during pregnancy .......................................................... 15  2.8  Infective endocarditis ................................................................................................ 16  2.9  Termination of pregnancy ....................................................................................... 18   3.  Congenital heart disease and pulmonary hypertension ................................................. 17  3.1  Pulmonary hypertension and Eisenmenger syndrome ............................................. 18  3.2  Cyanotic heart disease without pulmonary hypertension ......................................... 20  3.3  Septal defects ........................................................................................................... 20  3.4  Coarctation of the aorta ............................................................................................ 21  3.5  Pulmonary valve stenosis and regurgitation ............................................................. 21  3.6  Tetralogy of Fallot ..................................................................................................... 21  3.7  Ebstein’s anomaly .................................................................................................... 22  3.8  Transposition of the great arteries ............................................................................ 22  3.9  Fontan circulation ..................................................................................................... 23  4.  Aortic diseases ............................................................................................................... 24  4.1  Marfan syndrome...................................................................................................... 25  4.2  Bicuspid aortic valve ................................................................................................. 25  4.3  Ehlers-Danlos Syndrome, Turner syndrome ............................................................ 27  4.4  Management............................................................................................................. 26  5.  Valvular heart disease .................................................................................................... 28  5.1  Epidemiology and etiology........................................................................................ 28  5.2  Stenotic valve lesions ............................................................................................... 28  5.3  Regurgitant valve lesions ......................................................................................... 31  5.4  Valvular atrial fibrillation (native valves) ................................................................... 32  5.5  Prosthetic valves, anticoagulation in mechanical valves .......................................... 33  6.  Coronary artery disease ................................................................................................. 38  6.1  Epidemiology ............................................................................................................ 38  6.2  Diagnosis, Prognosis ................................................................................................ 40  6.3  Management............................................................................................................. 40  7.  Cardiomyopathies and Heart Failure .............................................................................. 41  7.1  Peripartum Cardiomyopathy ..................................................................................... 41  7.2  Dilated cardiomyopathy ............................................................................................ 42  7.3  Hypertrophic cardiomyopathy ................................................................................... 44  8.  Arrhythmias .................................................................................................................... 46  8.1  Arrhythmias associated with structural and congenital heart disease ...................... 46  8.2  Atrioventricular re-entry tachycardia ....................................................................... 46  8.3  Focal atrial tachycardia............................................................................................. 47  8.4  Atrial flutter and atrial fibrillation ............................................................................... 47  8.5  Ventricular tachycardia ............................................................................................. 48  8.6  Interventional therapy ............................................................................................... 48  8.7  Bradyarrhythmias ..................................................................................................... 48  9.  Hypertensive disorders ................................................................................................... 50  9.1  Epidemiology, diagnosis ........................................................................................... 51   9.2  Definition and classification of hypertension and pregnancy .................................... 51  9.3  Preexisting hypertension .......................................................................................... 51  9.4  Gestational hypertension .......................................................................................... 51  9.5  Combined and antenately unclassifiable hypertension ............................................ 52  9.6  Management, prognosis ........................................................................................... 54 

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10.  Venous thromboembolism during pregnancy and puerperium ...................................... 55  10.1  Epidemiology and maternal risk ............................................................................. 55  10.2  Risk factors for venous thromboembolism and risk stratification ............................ 56  10.3  Prevention of venous thromboembolism ................................................................ 57  10.4  Management of acute venous thromboembolism ................................................... 57  11.  Drugs during pregnancy and breast feeding ................................................................. 60  12.  Acknowledgement ......................................................................................................... 64  13.  References .................................................................................................................... 64  14.  Tables ............................................................................................................................ 88  15.  Figure legends ...............................................................................................................   16.  Figures

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IV. 1. NON- STRUCTURED ABSTRACT

The prevalence of cardiovascular diseases in women of childbearing age is rising. The successes in medical and surgical treatment of congenital heart disease have led to an increasing number of women at childbearing age presenting with problems of treated congenital heart disease. Furthermore in developing countries and in immigrants from these countries rheumatic valvular heart disease still plays a significant role in young women. Increasing age of pregnant women and increasing prevalence of atherosclerotic risk factors factors lead to an increase in women with coronary artery disease at pregnancy. Successful management of pregnancy in women with cardiovascular diseases requires early diagnosis, a thorough risk stratification and appropriate management by a multidisciplinary team of obstetricians, cardiologists, anaesthesiologists and primary care physicians. The following review is based on the recent European Guidelines on the management of cardiovascular diseases during pregnancy, which aim at providing concise and simple recommendations for these challenging problems.

Keywords: pregnancy, cardiovascular disease, guidelines, risk assessment, management, congenital heart disease, valvular heart disease, hypertension, heart failure, arrhythmia

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V. TEXT

Abbreviations ACE = angiotensin-converting enzyme BMI = body mass index CVD = cardiovascular disease ECG = electrocardiogram FDA = food and drug administration HCM = hypertrophic cardiomyopathy INR = international normalized ratio LMWH = low molecular weight heparins LVEF = left ventricular ejection fraction WHO = World Health Organization

2. General considerations 2.1 Introduction Cardiovascular diseases are present in 0.2-4% of all pregnancies in western countries.1 Many women with heart disease go through uneventful pregnanies. However, a considerable

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percentage of these women experience complications during pregnancy, such as heart failure, arrhythmias, thrombo-embolic events or dissection of the aorta.2 Risk assessment and counselling before pregnancy is of major importance in women with known or suspected heart disease. They benefit from management of their pregnancies by multidisciplinary teams. For patients at high risk treatment in specialized centres is appropriate. When treating these women, the well - being of both mother and fetus should be considered. The following review is based on the recent Guidelines for the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology,3 as well as additional literature, published since their publication. The recommendations from these guidelines

3

are mainly based on expert consensus after

extensive review of the literature, since prospective studies are scarce and randomized studies are not available. 2.2 Epidemiology Hypertensive disorders occur in 6–8% of all pregnancies.4 In western countries survival of patients with congenital heart disease to adult age has improved while the prevalence of rheumatic heart disease has decreased. Congenital heart diseases are now the most frequent cardiovascular diseases present during pregnancy (75-82% of all cardiovascular diseases)2,

5,6

Moreover, the incidence of ischemic heart disease, while still low, is increasing

due to increasing age at pregnancy and higher prevalence of risk factors. Heart disease is now the most important cause of maternal death during pregnancy.7 Valvular heart disease and cardiomyopathies have a higher mortality rate than congenital heart diseases.2 In developing countries, rheumatic heart disease is still the predominating cause of cardiac disease during pregnancy (56–89%). 3 Dr. Afshan Hameed: Cardiac disease is recognized as one of the most important causes of maternal morbidity and mortality worldwide, and is surpassing other causes of maternal mortality in developed countries. Recently, it was reported as the leading cause of pregnancy related deaths in California during years 2002-2005 (Abstract # 18851, AHA scientific sessions 2013).

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2.3

Haemodynamic, haemostatic and metabolic alterations during pregnancy

Pregnancy is associated with important changes in the cardiovascular system. Increase in plasma volume induces an increase in cardiac output (30-50%) and is accommodated by a reduction in systemic vascular resistance and blood pressure, caused by vasodilatation achieved through mediators such as prostacyclin and nitric oxide. Rise in cardiac output is mainly due to increased stroke volume and, later in pregnancy, increase in heart rate. Blood pressure increases again at the end of pregnancy. During delivery there is a further increase of cardiac output, heart rate and blood pressure due to pain, anxiety and increase in plasma volume, which can be modified by anesthesia, changes in position and bleeding. After delivery cardiac output increases further due to autotransfusion from the uterus and resorption of edema. During pregnancy, diastolic ventricular dimensions and cardiac mass increase without increase in systolic diameters. There is a more marked increase in atrial diameters. Pregnancy also induces haemostatic changes. The concentration of coagulation factors and fibrinogen increases, and there is an increase of platelet adhesiveness and diminished fibrinolysis, which results in a hypercoagulative state. Additionally the enlarging uterus causes obstruction to venous return. These factors together increase the risk of thromboembolism. This is particularly pronounced in women with an increased risk of thrombo-embolism outside pregnancy e.g. women with heart failure, enlarged left atrium especially with mitral stenosis, atrial fibrillation, Fontan circulation, uncorrected cyanotic disease and pulmonary hypertension. The physiological changes of pregnancy can affect absorption, excretion, and bioavailability of drugs.8 Higher dose requirements can result from the increased intravascular blood volume. This is further complicated by the raised renal perfusion and the higher hepatic metabolism that increase drug clearance. Since pharmacokinetics of drugs change during the course of pregnancy, careful monitoring and dose adjustments are necessary. In summary, the physiologic adaptations to pregnancy influence not only hemodynamics but also hemostasis and drug metabolism and should be taken into account when evaluating and interpreting cardiac function and clinical status.

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Dr. Afshan Hameed: Hemodynamic alterations of normal pregnancy may lead to signs and symptoms that may otherwise be suggestive of cardiac disease outside of pregnancy. Additionally, these physiologic changes create challenges in diagnostic workup, interpretation of test results, and use of appropriate medications. 2.4

Genetic testing and counselling

Adolescent women with heart disease need to be informed about the importance of careful pregnancy planning. This includes information about the safety and efficacy of contraceptive methods. This information should be given already to young teenagers and should be repeated regularly throughout their fertile years. Combined contraceptives pose a risk for women with an increased risk of thrombo-embolism already outside pregnancy. 9 Women with cardiovascular disease also need to be counselled concerning the genetic aspects of their heart disease. In the general population the birth prevalence of cardiac defects is approximately 1%. The risk is significantly higher when a parent has cardiovascular disease, but differs depending on the heart condition between 3% and 50%. Generally, the risk is higher when the mother is affected compared to the father.10 For diseases with autosomal dominant inheritance, such as Marfan syndrome, hypertrophic cardiomyopathy and long QT syndrome, the inheritance risk is 50%, though the phenotype may vary depending on penetrance and pleioptropic effects. The recurrence risk is less clearly defined for other defects since they are usually inherited in a polygenic way; autosomal recessive and X-chromosomal recessive inheritance are rare. It is recommended that women with inheritable heart disease in their family as well as the family members are counselled by a geneticist, since this allows the identification of asymptomatic and diseasefree family members and enhances preventive measures and early treatment.11 Genetic testing is especially useful in cardiomyopathies, channelopathies, when other family members are affected, and when dysmorphic features or developmental abnormalities are present, or when the patient has non-cardiac congenital anomalies or syndromes. Genetic screening of the offspring of a pregnant woman can be performed with chorionic villous biopsy for an increasing number of defects. Women with congenital heart disease should be offered fetal echocardiography. Nuchal fold thickness measurement is a useful early

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screening test, with a normal measurement the risk of congenital heart disease is low (0,1%).12 Dr. Afshan Hameed: Preconception period is the ideal time to initiate care of women with cardiac issues. It provides an opportunity to thoroughly assess, counsel, and optimize underlying cardiac disease to ensure best possible outcomes for the mother and the fetus. 2.5

Risk estimation and counselling

The nature and magnitude of the risk of maternal cardiovascular complications depend on the underlying heart disease and the presence and severity of ventricular and valvular dysfunction; thus expert counselling is required, and it should be individualized. When a woman decides to pursue pregnancy, she should be informed about risks associated with pregnancy and about optimal management of the pregnancy. Drugs that are contra-indicated in pregnancy should be discontinued or when possible changed to acceptable alternatives. A follow-up plan should be constructed and discussed. Women with a high pregnancy risk should be managed by an expert multidisciplinary team in a specialist center. 3 Risk assessment should be disease-specific. Predictors of pregnancy outcome that have been defined in several large series should be taken into account. Independent prepregnancy predictors of the occurrence of maternal cardiovascular events have been identified in the CARPREG6 and ZAHARA13 studies. These predictors are a prior cardiac event, functional New York Heart Association class >II, left heart obstruction, systemic ventricular ejection fraction < 40%, mechanical valve prosthesis, more than mild systemic or pulmonary atrioventricular valve regurgitation, use of cardiac medication and repaired or unrepaired cyanotic disease. Additional factors associated with maternal outcome in other studies are smoking history, pulmonary hypertension, BNP>100 pg/ml, subpulmonary ventricular dilatation or dysfunction, or severe pulmonary regurgitation14-16 Risk scores have been developed by the CARPREG and ZAHARA investigators6,13, but these should be used with caution since such scores are highly population dependant. The ZAHARA score applies only to congenital heart diseases. Maternal risk assessment can be performed according to the modified WHO classification9, 3, since this system integrates all knowledge concerning maternal risk, taking into account both disease-specific information as well as comorbidity. Pregnancies are classified into 4 risk-

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categories, indicating the risk of cardiovascular complications and the consequences for the management during pregnancy. Women with WHO class I have a low risk of complications and their follow up during pregnancy may usually be limited to one or two visits. Women with WHO class II have a small increased risk of mortality and moderate increase in morbidity. For these women, follow up every trimester is indicated.

WHO class III indicates a

significantly increased risk of maternal mortality and a high risk of morbidity. Therefore these women need frequent (monthly or bimonthly) follow up during pregnancy, both by a cardiologist and an obstetrician. Women in WHO class IV have such high risk of mortality and morbidity that they should be advised against pregnancy. In case of pregnancy, termination should be considered, but when they choose to carry on with the pregnancy their follow up is similar as for women with WHO class III. It should be emphasized that the follow up plan should be individualized and should be adapted during pregnancy to the actual clinical situation. A practical application of the WHO classification is provided in table 1.

Table 1: Modified WHO classification of maternal cardiovascular risk: application 3 Conditions in which pregnancy risk is WHO I • Uncomplicated, small or mild - pulmonary stenosis - patent ductus arteriosus - mitral valve prolapse • Successfully repaired simple lesions (atrial or ventricular septal defect, patent ductus arteriosus, anomalous pulmonary venous drainage). • Atrial or ventricular ectopic beats, isolated Conditions in which pregnancy risk is WHO II or III WHO II if otherwise well and uncomplicated) • Unoperated atrial or ventricular septal defect • Repaired tetralogy of Fallot • Most arrhythmias WHO II-III (depending on individual) • Mild left ventricular impairment • Hypertrophic cardiomyopathy • Native or tissue valvular heart disease not considered WHO I or IV • Marfan syndrome without aortic dilatation • Aorta < 45 mm in aortic disease associated with bicuspid aortic valve • Repaired coarctation WHO III • Mechanical valve • Systemic right ventricle

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• • • • •

Fontan circulation Cyanotic heart disease (unrepaired) Other complex congenital heart disease Aortic dilatation 40-45 mm in Marfan syndrome Aortic dilatation 45-50 mm in aortic disease associated with bicuspid aortic valve

Conditions in which pregnancy risk is WHO IV (pregnancy contraindicated) • Pulmonary arterial hypertension of any cause • Severe systemic ventricular dysfunction (LVEF < 30%, NYHA III-IV) • Previous peripartum cardiomyopathy with any residual impairment of left ventricular function • Severe mitral stenosis, severe symptomatic aortic stenosis • Marfan syndrome with aorta dilated > 45 mm • Aortic dilatation > 50 mm in aortic disease associated with bicuspid aortic valve • Native severe coarctation Reproduced with permission from Regitz-Zagrosek et.al. 3

Neonatal complications, including mortally of 1-4%, preterm delivery and growth retardation, occur in 20-28% of pregnancies of women with heart disease. Neonatal complications are associated with maternal New York Heart Association class >II or cyanosis, left heart obstruction, mechanical valve prosthesis, use of oral anticoagulants, multiple gestation and smoking during pregnancy.6,13,14,17,18 Maternal cardiovascular events during pregnancy are also related to neonatal events.13 Dr. Afshan Hameed: Pregnancy is contraindicated in certain conditions listed as WHO IV risk category. Options of pregnancy termination vs. continuation should be reviewed in early pregnancy or at the time of their first prenatal visit if they present in appropriate gestational age window. Multidisciplinary meeting with direct patient participation is highly encouraged to allow for informed decision making. 2.6

Cardiovascular diagnosis in pregnancy

Pregnancy may change the interpretation of several diagnostic cardiac procedures. Additionally, choosing the most adequate diagnostic procedure requires consideration of the safety of the procedure for the mother and the fetus. History and clinical investigation Discovery of previously undiagnosed cardiac disorders starts with a careful medical history that includes complaints of dyspnoea and palpitations as well as a family history of hereditary diseases and sudden death. The interpretation of history and physical examination requires

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consideration of the physiological changes of pregnancy. Dyspnoea or a new pathological murmur is reason for further investigation. Blood pressure should be measured in upright or left lateral position to prevent compression of the caval vein. Some leg oedema is normal in pregnancy and liver enlargement is difficult to diagnose due to the enlarged uterus, therefore elevated jugular venous pressure and pulmonic rales are the most reliable signs of heart failure at physical examination. Oximetry is important in patients with cyanotic congenital heart disease or patent shunt lesions.

Electrocardiography Most pregnant women have a normal electrocardiogram. Left axis deviation and unspecific ST-T abnormalities can be present. Holter monitoring is indicated in women with previous documented relevant arrhythmias and in women with palpitations. Echocardiography Echocardiography is non-invasive and does not involve radiation. Therefore it is the preferred method to screen for structural cardiac abnormalities and to monitor ventricular and valvular function and pulmonary pressures. Transesophageal echocardiography is rarely indicated during pregnancy but has a role in, for example, the diagnosis of endocarditis and mechanical valve thrombosis. It is considered relatively safe in pregnant women. Exercise testing Exercise testing is useful for risk assessment in women with known heart disease and should preferably be performed before pregnancy. It allows assess of functional capacity as well as heart rate and blood pressure response, ischemia and arrhtyhmias. Inadequate chronotropic response is related to maternal and offspring events.19 There are few data on the safety of exercise testing during pregnancy. Exercise testing is considered safe during pregnancy when performed as a submaximal test aiming at 80% of predicted maximum heart rate.

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Dobutamine stress and nuclear scintigraphy should be avoided. Radiation exposure No increased risk of congenital malformations exists when the radiation dose to the pregnant woman is <50mGy

20 21

(www.bt.cdc.gov/radiation/prenatalphysician.asp – accessed 31

13

October 2007). A small increased risk for childhood cancer cannot be excluded. Most medical procedures expose the fetus to a much lower dose (table 2). However, procedures that involve radiation are preferably delayed until at least 12 weeks after the last menstrual period, because organogenesis is then largely completed. Diagnostic procedures that involve radiation should only be used when other diagnostic methods fail. When used, the dose should be kept as low as reasonably achievable.22 Pregnant women should be informed about the risk and benefits of the procedure. It is useful to record the radiation dose to the mother in the medical records.23,24 Computed tomography is rarely necessary during pregnancy but may be indicated for the diagnosis of pulmonary embolism. Coronary angiography can best be performed through a radial approach. Shielding of the uterus may reduce the radiation dose to the fetus. Table 2: Estimated fetal and maternal effective doses for various diagnostic and interventional radiology procedures Procedure

Fetal exposure

Maternal exposure

Chest radiograph (PA and lateral)

< 0.01 mGy

< 0.01 mSv

0.1 mGy

0.1 mSv

CT chest

0.3 mGy

0.3 mSv

7 mGy

7 mSv

Coronary angiography*

1.5 mGy

1.5 mSv

7 mGy

7 mSv

3 mGy

3 mSv

15 mGy

15 mSv

PCI

or

radiofrequency

ablation*

catheter

*Exposure depends on the number of projections or views. CT = computed tomography; PA = postero-anterior; PCI = percutaneous coronary intervention Reproduced with permission from Regitz-Zagrosek et.al. 3

Magnetic resonance imaging Magnetic resonance imaging (MRI) is probably safe during pregnancy, particularly in the second and third trimester. It can be used when echocardiography is insufficient for complete diagnosis, for example in women with aortic pathology.25

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Gadiolinum contrast should be

avoided.27 Fetal assessment Fetal ultrasound is routinely performed in early pregnancy by obstetricians to estimate gestional age, to detect multiple pregnancy and congenital malformations (Figure 1). Optimal timing for screening for congenital heart disease is 18-22 weeks of gestation.28

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With Doppler velocimetry and additionally fetal biophysical profile testing fetal compromise can be detected.29,30 Since maternal cardiac status and cardiovascular complications are related to offspring outcome13 it is important that cardiologists are aware of these methods and refer their patients for fetal and placental assessment when cardiac problems occur or increase during pregnancy. 2.7

Interventions in the mother during pregnancy

Comparable to coronary angiography, percutaneous cardiac intervention carries some risk for the fetus, but the radiation dose is relatively low (table 2). The best time for intervention is probably after the 4th month in the second trimester, but the interest of the mother should prevail when there is an acute situation. A radial approach, brief fluoroscopy times and shielding of the gravid uterus are important. Heparin dose is 40 to 70 U/kg, with target activated clotting time of 200-300 seconds. Cardiac surgery with cardiopulmonary bypass carries the same risk for the mother as outside pregnancy. Since there is considerable fetal risk, both of neurological impairment (3-6%) and mortality (14-33%)31, surgery should only be performed when other measures have failed and the life of the mother is endangered. 3 When surgery is performed between 13 and 28 weeks the risk of abortion, fetal malformations and premature labour is relatively low.32,33 When surgery is performed at gestational age > 28 weeks, delivery before surgery should be considered after administration of corticosteroids during at least 24 hours, since the risk of damage to the baby is usually lower with early delivery than with surgery with the baby in utero. Between 26 and 28 weeks of gestation, the decision to deliver the baby before surgery depends on fetal characteristics and experience of the neonatal unit. When cardiopulmonary bypass is performed with the fetus in utero, fetal heart rate and uterine tone should be monitored. Uteroplacental blood flow can be optimized by using pulsatile pump flow >2.5 l/min/m² and normothermic perfusion with a pressure >70 mmHg. Maternal hematocrit should be maintained >28% . Cardiopulmonary bypass time should be as brief as possible.34 Dr. Afshan Hameed: A practical approach to diagnostic testing and interventions is to initially review tests and procedures that are indicated in that particular scenario in a nonpregnant woman. Once the ideal tests are identified, the risks and benefits must be weighed against gestational age of the fetus, potential benefits to the mother, and presence of

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absence of alternate tests/interventions that may be less hazardous. In general, maternal well being should always be a priority. 2.8

Infective endocarditis

Infective endocarditis has an estimated incidence of 0.5% in pregnant patients with known valvular or congenital heart disease.35 The risk is highest in women with a prosthetic valve, previous infective endocarditis, or congenital heart disease with right-to-left shunts or prosthetic material. Endocarditis prophylaxis in pregnant patients follows the same guidelines as outside pregnancy. It is now reserved for patients with a high risk to acquire endocarditis and only for dental procedures. Antibiotic prophylaxis is no longer recommended during vaginal or caesarean delivery.36

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(table 3). Diagnostic criteria and procedures for

endocarditis are similar as in non-pregnant patients. Not only maternal morbidity and mortality, but also fetal mortality is high. Pregnant women with endocarditis are treated in the same way as outside pregnancy36, but the feto-toxic effects of several antibiotics should be taken into account. Especially aminoglycosides, quinolones and tetracyclines carry a risk for the fetus.38

2.9

Delivery, termination of pregnancy

In patients with high risk delivery should be managed by a multidisciplinary team in an experienced specialized center.3,39,40,41 The team should timely construct an individual delivery plan that describes the timing of delivery (induced or spontaneous), method of induction, analgesia\regional anesthesia, level and period of monitoring during delivery and postpartum, and medication, in particular when anticoagulant therapy is needed. Caesarean delivery is recommended when labour begins while the patient is on oral anticoagulants, to avoid intracranial fetal bleeding (table 3). When pregnancy carries a major maternal or fetal risk (WHO risk class IV), termination of pregnancy should be discussed. The method must be determined on an individual basis, considering the type of heart disease, the risks of anesthesia and the hemodynamic effects of medication.42,43 General recommendations for the management of women with heart disease prior to and during pregnancy are summarized in table 3.

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Table 3: General recommendations for the management of women with heart disease prior to and during pregnancy Classa,b Pregnancy counselling and risk assessment is indicated in all women I with known or suspected congenital or acquired cardiovascular disease in childbearing age and after conception. High risk patients should be treated in specialized centres by a I multidisciplinary team. Genetic counselling should be offered to women with congenital heart I disease or congenital arrhythmia, cardiomyopathies, aortic disease or genetic malformations associated with cardiovascular diseases. Echocardiography should be performed in any pregnant patient with I unexplained or new cardiovascular signs or symptoms. Caesarean delivery is indicated when labour starts while on oral I anticoagulants MRI (without gadolinium) should be considered if echocardiography is IIa insufficient for diagnosis. Caesarean delivery should be considered for patients with dilatation of IIa the ascending aorta >45 mm, severe aortic stenosis, Eisenmenger syndrome or severe heart failure. A chest radiograph, with shielding of fetus, may be considered if other IIb methods are not successful in clarifying the cause of dyspnoea. Cardiac catheterization may be considered with very strict indications, IIb timing and shielding of fetus. CT and electrophysiological studies, with shielding of fetus, may be IIb considered in selected patients for vital indications. Coronary bypass surgery or valvular surgery may be considered when IIb conservative and medical therapy has failed, in situations that threaten the mother’s life and that are not amenable to percutaneous treatment. Bacterial endocarditis prophylaxis during delivery is not recommended. III a

Class of recommendation.b Level of evidence of all recommendations is level C

CVD = cardiovascular disease; MRI = magnetic resonance imaging Reproduced and modified with permission from Regitz-Zagrosek et.al. 3

Dr. Afshan Hameed: The value of multidisciplinary approach to management of pregnant women with significant underlying cardiac disease at a center with expertise in caring for such women cannot be overemphasized. Maternal-Fetal Medicine specialist in collaboration with cardiologist, cardiothoracic surgeon, anaesthesiologist, and neonatologist are essential to optimize maternal and fetal outcomes.

3. Congenital heart disease and pulmonary hypertension Congenital heart disease is the most prevalent maternal heart condition during pregnancy in Western countries.2 A contemporary registry show, that pregnancy in congenital heart disease is nowadays associated with fewer complications than pregnancy in women with valvular disease or cardiomyopathy, but still maternal cardiovascular complications occur in

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5-20%.18

6 14 13 2 44

The most prevalent complications are heart failure, arrhythmias and

thrombo-embolism. Maternal mortality is rare,2 reflecting present counselling practices and improvements in care. The risk of complications depends on the underlying disease, and increases with more complex disease and with higher modified WHO class.2,18 Cardiovascular complications during pregnancy may predict late cardiac events after pregnancy.45 Women with congenital heart disease do not only experience more maternal complications, but also the miscarriage rate is higher especially in more complex disease, and offspring complications (premature delivery, growth retardation and mortality) are also more prevalent than in the general population. Women with congenital heart disease need to be counselled about the risk of pregnancy. Risk assessment should be performed taking into account known predictors of outcome, the modified WHO classification (table 1), as well as additional disease-specific information, which is summarized in this chapter. To achieve adequate risk estimation, pre-pregnancy evaluation includes medical history (including functional class) and physical examination, oxygen saturation, echocardiography and exercise testing. BNP or NT-proBNP may be useful as well. Other diagnostic tests (i.e. MRI, holter monitoring) are performed on specific indications. The desire to pursue pregnancy is in itself not a reason to perform interventions, but in women who have an indication for surgery or percutaneous intervention the intervention should be performed prior to conception. 3.1

Pulmonary hypertension and Eisenmenger syndrome

Pulmonary hypertension (mean pulmonary arterial pressure ≥25 mmHg at rest) is classified as pulmonary arterial hypertension (i.e. idiopathic, heritable, associated with congenital heart disease), pulmonary hypertension related to left heart disease, pulmonary hypertension related to lung disease and/or hypoxia, chronic thromboembolic pulmonary hypertension, and pulmonary hypertension with unclear and or multifactorial mechanisms.46 The risk of maternal morbidity and mortality (17-50%) is high in all diagnostic groups, with the highest risk in Eisenmenger syndrome. In these patients decrease in systemic vascular resistance during pregnancy increases right-to-left shunt and cyanosis.47,48 Mortality occurs mainly in

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late pregnancy and after delivery, due to heart failure, pulmonary thrombosis and arrhythmias.47,48 Recent evidence showed better outcome in women with mild pulmonary hypertension (systolic pulmonary arterial pressure < 50 mm Hg), however no safe cut-off value is known.48 49-51 Offspring risk is also high. Women with pulmonary hypertension should be advised against pregnancy. Only for women with borderline elevated pulmonary pressures after closure of a shunt lesion, pregnancy risk may be acceptable with management in an expert center.3 Women with pulmonary hypertension who present with pregnancy should be offered termination, which for safety reasons must be performed in a centre with experience in management of pulmonary arterial hypertension patients. When pregnancy continues, management should take place in a centre with expertise in the management of pulmonary hypertension as well as in management of high-risk pregnancies.37 Frequent clinical review (at least monthly, later in pregnancy more frequent) should be scheduled. Bed rest and oxygen supplemental therapy may be beneficial. In women with Eisenmenger syndrome and iron deficiency resulting in microcytosis, iron supplementation should be given judiciously to avoid a rebound effect. Therapeutic anticoagulation should be continued in patients with an established indication outside pregnancy.46 In other patients, the risk of pulmonary thrombosis should be weighed against the risk of bleeding and decisions should be made on an individual basis. Women with Eisenmenger syndrome often have coagulation abnormalities with the risk of hemoptysis, on the other hand the risk of thrombosis is also high. Anticoagulation should be considered after screening for hemostatic abnormalities. Prevention of venous stasis by compression stockings is important. The choice of anticoagulation therapy is on an individual basis, but generally subcutaneous heparins are preferred, with close monitoring of the anticoagulation effect. When heart failure occurs, diuretics need to be given at the lowest effective dose to avoid volume depletion. Whereas a previous review did not reveal a beneficial effect of advanced pulmonary hypertension therapies,48 in a recent small series no mortality occurred with nebulized iloprost started early in pregnancy, upgraded to iv iloprost in some cases, and addition of sildenafil when clinically indicated.52 These medications are favoured over endothelin receptor antagonists,

19

which are teratogenic. Timely hospital admission with planned early caesarean section may improve outcome.3,52 3.2

Cyanotic heart disease without pulmonary hypertension

Pregnancy in women with uncorrected cyanotic congenital heart disease is rare. These highrisk pregnancies have a cardiovascular maternal complication rate of 30%. Pregnancy and delivery should be managed in a centre experienced in the management of complex congenital heart disease. Both maternal and offspring risk is associated with resting oxygen saturation. Pregnancy should be discouraged when oxygen saturation is below 85%, because maternal complication rate is expected to be high and the chance of a live birth is only 12%.53 Pregnant women should be followed monthly and general measures, anticoagulation, hematologic management and treatment of heart failure are comparable to Eisenmenger syndrome. 3.3

Septal defects

The risk of pregnancy in women with shunt lesions is usually low (WHO I or II), except when pulmonary hypertension exists.54-56 Significant shunts with volume overload are preferably corrected before pregnancy. Women with patent atrial septal defect or atrioventricular septal defect are at increased risk of thrombo-embolic complications including paradoxical emboli18, therefore prevention of venous stasis (compression stockings) is important. Closure of a small defect to prevent paradoxical emboli is not advised.3 Women with atrial septal defect and atrioventricular septal defect are prone for arrhythmias.55-57 In women with atrioventricular septal defects, worsening of (residual) atrioventricular valve regurgitation is described as well as deterioration of functional class.57 Heart failure is rare and occurs mainly when atrioventricular valve regurgitation is severe or when (residual) left ventricular dysfunction is present. Follow up schedule during pregnancy is dependant on the severity of underlying disease (at least once during pregnancy in corrected atrial septal defect and ventricular septal defect; at least each trimester in patent shunt defects and corrected atrioventricular septal defect). Offspring risk is limited though small for gestational age may

20

occur more frequently, and especially in atrioventricular septal defect offspring mortality can occur due to complex congenital heart disease.57 3.4

Coarctation of the aorta

Significant (re)coarctation should be repaired before pregnancy. Most women with repaired coarctation have a low to moderate risk of complications (modified WHO II), mainly for hypertensive disorders.58-60 Before pregnancy screening for re-coarctation, hypertension, bicuspid valve and aortic dilatation should be performed. During pregnancy clinical follow up with blood pressure measurement and echocardiography is recommended at least each trimester. Hypertension should be treated, taking into account the risk of placental hypoperfusion. During pregnancy percutaneous intervention for (re)-coarctation should only be performed when severe hypertension persists despite medical therapy with maternal or fetal compromise, because the risk of dissection is increased. 3.5

Pulmonary valve stenosis and regurgitation

Risk of maternal complications in women with mild or moderate pulmonary stenosis is low

61-

, however an increased risk of hypertensive disorders and offspring complications exists.62

63

Intervention before pregnancy is advised in severe PS. Severe pulmonary regurgitation with right ventricular dysfunction is associated with maternal complications.14,64 Clinical and echocardiogaphic follow up is advised each trimester in women with pulmonary stenosis or regurgitation, and more often when the lesions are severe. In women with severe pulmonary stenosis or New York Heart Association class III/IV caesarean section should be considered.3 3.6

Tetralogy of Fallot

Most women with repaired tetralogy of Fallot tolerate pregnancy well. Maternal cardiovascular complications have been described in up to 12%, mainly arrhythmias, but also heart failure and thromboembolism.65

66

Heart failure is mainly associated with the

combination of severe pulmonary regurgitation with right ventricular dysfunction.14,64,65 Persisting right ventricular dilatation and right ventricular dysfunction have been described as

21

well as accelerated right ventricular dilatation in the years after pregnancy.67 The risk of offspring complications, including mortality, is also increased.66 Follow up during pregnancy should be individualized depending on the severity of residual lesions, with a minimum follow up with echocardiography each trimester. Heart failure can be treated with diuretics and bed rest. 3.7

Ebstein’s anomaly

The risk of pregnancy in women with Ebstein’s anomaly without cyanosis and heart failure is low (WHO risk class II). Tricuspid valve repair should be considered before pregnancy in symptomatic women with severe regurgitation. Maternal complications largely depend on the severity of tricuspid regurgitation and on right ventricular size and function.68,69 Cyanosis and paradoxical emboli can occur in women with an atrial septal defect. Arrhythmias are also described. Offspring complications include premature delivery and fetal mortality. Clinical and echocardiographic follow up is advised at least each trimester. Heart failure can be managed medically. 3.8

Transposition of the great arteries

Women with a systemic right ventricle (transposition of the great arteries with atrial correction, (Mustard or Senning operation) or congenitally corrected transposition of the great arteries) have a relatively high risk of cardiovascular maternal complications (WHO risk class III).70-72 Heart failure and arrhythmias are described. Decline in right ventricular function can occur and is sometimes irreversible.73 There may be an increased rate of cardiovascular events in the years after pregnancy.74 Offspring complications occur in a high percentage, mainly miscarriage, premature delivery and high offspring mortality.70,73 Pre-eclampsia and hypertensive disorders were observed frequently in one study.70 When more than moderate systemic ventricular dysfunction, severe tricuspid regurgitation or New York Heart Association class III/IV is present, women should be advised against pregnancy. Only limited data are availble concerning pregnancies in women with arterial switch operation.75The complication rate seems lower than in women with a systemic right ventricle.

22

All pregnant women with transposition of the great arteries and congenital corrected transposition of the great arteries should be followed monthly or bimonthly with clinical evaluation

including

echocardiography

and

assessment

of

arrhythmias.

When

supraventricular arrhythymias require medical treatment, the risk of bradycardia (due to sick sinus syndrome in atrial correction of transposition of the great arteries, or atrioventricular conduction abnormalities in congenital corrected transposition of the great arteries) needs to be taken into account. Beta-blockers can only be used with close observation. 3.9

Fontan circulation

Women with a Fontan circulation are at risk for atrial arrhythmias and New York Heart Association class deterioration; heart failure has also been reported.76,77 Additionally, there is a high risk of miscarriage, premature delivery and small for gestational age babies. Women with depressed ventricular function, significant atrioventricular valve regurgitation, low oxygen saturation (< 85%), or protein loosing enteropathy should be advised against pregnancy. Women with a Fontan circulation should have monthly follow up during pregnancy in an expert center. The risk of thrombo-embolic complications is considered high, especially in atriopulmonary connections, and therapeutic anticoagulation should be considered. Recommendations for the management of women with congenital heart disease are summarized in table 4. Table 4: Recommendations for the management of congenital heart disease Classa Pre-pregnancy relief of stenosis (usually by balloon valvulotomy) should I be performed in severe pulmonary valve stenosis (peak Doppler gradient >64 mmHg). Individual follow-up schedules should be arranged; ranging from twice I during pregnancy to monthly. Symptomatic patients with Ebstein’s anomaly with cyanosis and/or heart I failure should be treated before pregnancy or advised against pregnancy. In symptomatic women with marked dilatation of the right ventricle due to I severe pulmonary regurgitation, pre-pregnancy pulmonary valve replacement (bioprosthesis) should be performed. In asymptomatic women with severely dilated right ventricle due to severe IIa pulmonary regurgitation, pre-pregnancy pulmonary valve replacement (bioprosthesis) should be considered. Anticoagulation treatment should be considered during pregnancy in IIa Fontan patients. In PAH anticoagulant treatment should be considered in patients with IIa suspicion of pulmonary embolism as cause (or partly the cause) of the

23

pulmonary hypertension. In patients who are already taking drug therapy for PAH before pregnancy, continuation should be considered after information about the teratogenic effects. Women with pulmonary hypertension, or with oxygen saturation below 85% at rest, should be advised against pregnancy. Patients with TGA and a systemic right ventricle with more than moderate impairment of RV function and/or severe TR should be advised against pregnancy. Fontan patients with depressed ventricular function and/or moderate to severe atrioventricular valvular regurgitation or with cyanosis or with protein losing enteropathy should be advised against pregnancy. a

Class of recommendation,

evidence B

37,78

b

IIa III III III

recommendation for severe pulmonary valve stenosis is level of

, all others are level C

PAH = pulmonary arterial hypertension; RV = right ventricle; TGA = transposition of the great arteries; TR = tricuspid regurgitation, Reproduced and modified with permission from Regitz-Zagrosek et.al. 3

4. Aortic diseases Several heritable disorders affect the thoracic aorta, predisposing patients to both aneurysm formation and aortic dissection. These include Marfan syndrome, bicuspid aortic valve, Ehlers-Danlos syndrome, Turner syndrome and familial forms of aortic dissection, aneurysm, or annuloaortic ectasia. Also other forms of congenital heart disease (e.g. Tetralogy of Fallot, aortic coarctation) may be accompanied by aortic dilatation or aneurysm formation. Finally non-heritable aortic pathology may occur, which is associated with hypertension and advanced maternal age. Pregnancy increases the risk of aortic dissection, because hormonal changes lead to histological changes in the aorta.79 In the UK aortic dissection is one of the leading causes of maternal death.7 The last trimester of pregnancy and early postpartum period are especially high - risk periods. Before conception women with aortic disease and women with heritable diseases that affect the aorta (i.e. Marfan syndrome) should be counselled about the risk of pregnancy (table 5). Imaging of the entire aorta is indicated prior to pregnancy. Magnetic resonance imaging or computed tomography are the preferred methods, since dilatation in the distal ascending aorta and in the thoracic descending aorta may be missed with echocardiography. Magnetic resonance imaging is preferred over computed tomography in young women, in particular when serial examinations are planned, because of the absence of radiation.

24

4.1 Marfan syndrome In women with Marfan syndrome, the risk of aortic dissection depends on the aortic diameter before pregnancy. When the aortic root diameter is not enlarged there is still a risk of 1% of severe complications and a safe diameter does not exist.80-83 Risk factors for dissection in pregnant women with Marfan syndrome are an aortic root diameter > 40mm or ≥ 27mm/m² and rapid growth of the aortic root diameter.84-86 Other studies report that the incidence of dissection is low when the aortic root diameter is <45mm

87,88

, but this may not apply to

women with small stature.86 Therefore in small women correction for body surface area is essential. Pregnancy should be discouraged when aortic diameter is >45 mm and surgery should be recommended before pregnancy (table 5).3 In women with aortic root diameters 40-45 mm other risk factors for dissection (family history, rapid aortic growth rate) must be considered.87 A recent study showed that there may be a long-term negative effect of pregnancy on the rates of dissection and elective aortic surgery.88 Women with aortic replacement remain at risk for dissection in the residual aorta. Valvular dysfunction (mitral and aortic regurgitation) should also be taken into account when estimating the risk of pregnancy complications. 4.2

Bicuspid aortic valve

Patients with bicuspid aortic valve frequently have dilatation of the ascending aorta. Since dilatation may be maximal in the distal ascending aorta, magnetic resonance imaging or computed tomography is often necessary for adequate diagnosis before pregnancy. A recent population-based study revealed no dissections in 216 pregnancies in women with bicuspid aortic valve.89 Dissection has been described, but it is probably rare and occurs especially when aortic diameter is >50mm.85 In women with aortic diameter > 50 mm replacement of the aorta should be considered before pregnancy.3,90 (table 5)

25

4.3

Ehlers-Danlos syndrome, Turner - syndrome

Pregnancy in Ehlers-Danlos syndrome type IV is associated with aortic dilatation, aortic dissection, uterus rupture, and rupture of large vessels. Therefore pregnancy is contraindicated in all women with this disease that is inherited in an autosomal dominant way.91,92 Turner syndrome is associated with cardiovascular malformations (25-50%, mainy bicuspid valve, coarctation, aortic dilatation) and hypertension. Pregancy is possible for women with Turner syndrome, sometimes spontaneously but mainly through oocyte donation. Dissection, often with fatal outcome, has been described repeatedly. It is associated with risk factors such as coarctation, hypertension and bicuspid valve.93 Aortic dilatation increases the risk but dissection can occur also when aortic diameters are normal. Since these women have a small body size, aortic diameters should be corrected for body surface area. Prophylactic surgery should be considered with an aortic diameter >27 mm/m². Pregnancy is also associated with high risk of pre-eclampsia and low birth weight.94 4.4

Management

Women with aortic pathology should be supervised by a cardiologist and obstetrician, with echocardiographic monitoring at 4-12 week intervals until 6 months postpartum. Magnetic resonance imaging without gadolinium is indicated when the maximum aortic diameter cannot be visualized echocardiographically. Chest pain occurring during pregnancy should raise the suspicion of aortic dissection. There is a possible, but not yet proven, benefical effect of β-blocking agents to reduce the rate of aortic dilatation and improve survival,95 thus the use of cardioselective β-blockers is advised.3 Since β-blockers may be associated with growth retardation, fetal growth should be monitored. In women with Ehlers Danlos syndrome celiprolol is advised because of its benefit in nonpregnant patients.92 When the aortic diameters is ≥45 mm in women with a syndrome associated with a high risk of dissection (i.e. Marfan syndrome, Ehlers Danlos) pre-pregnancy surgery is indicated. For other patients the threshold for surgery before pregnancy is an ascending aortic diameter > 50 mm or > 27 mm/m² BSA. Progressive dilatation during pregnancy is reason to consider prophylactic surgery, either with the fetus in utero or, when the fetus is viable, after

26

caesarean section. Neonatal intensive care facilities should be available. When aortic dissection occurs during pregnancy immediate caesarean section is necessary if the fetus is viable, followed directy by dissection repair.3 In women with Marfan syndrome the risk of dural ectasia must be taken into account.96 When the ascending aorta is >45 mm caesarean section is also the primary choice. Table 5: Recommendations for the management of aortic diseases Classa, b Women with Marfan syndrome or other known aortic disease should be I counselled about the risk of aortic dissection during pregnancy and the recurrence risk for the offspring. Imaging of the entire aorta (CT/MRI) should be performed before pregnancy in I patients with Marfan syndrome or other known aortic disease. Women with Marfan syndrome and an ascending aorta >45 mm should be I treated surgically pre-pregnancy. In pregnant women with known aortic dilatation, (history of) type B dissection or I genetic predisposition for dissection strict blood pressure control is recommended. Repeated echocardiographic imaging every 4-8 weeks should be performed I during pregnancy in patients with dilatation of the ascending aorta. For imaging of pregnant women with dilatation of distal ascending aorta, aortic I arch or descending aorta, magnetic resonance (without gadolinium) is recommended. In women with a bicuspid aortic valve imaging of the ascending aorta is I recommended. Women with aortic dilatation or (history of) aortic dissection should deliver in a I centre where cardiothoracic surgery is available. Surgical treatment prepregnancy should be considered in women with aortic IIa disease associated with a bicuspid aortic valve when the aortic diameter is > 50mm (or >27 mm/m2 BSA). Prophylactic surgery should be considered during pregnancy if the aortic IIa diameter is ≥ 50 mm and increasing rapidly. Patients with (or history of) type B dissection should be advised against III pregnancy. a

Class of recommendation; b all recommendations have level of evidence C.

BSA = body surface area ; CT = computed tomography; MRI = magnetic resonance imaging. Reproduced and modified with permission from Regitz-Zagrosek et.al. 3

Dr. Afshan Hameed: Women with congenital heart disease should be cared for at a center with such expertise. Frequent follow up with Maternal Fetal medicine specialist and Cardiologist is indicated. Pregnant women with connective tissue disorders, i.e. Marfans, Ehler Danlos syndrome are particularly at risk for vascular dissections in the peripartum period; these along with bicuspid aortic valve with aortopathy benefit by serial imaging during pregnancy. Hypertension should be aggressively treated in such patients. Assisted vaginal delivery without valsalva is preferred and caesarean section should be reserved in select highest risk group of patients.

27

5 5.1

Valvular heart disease Epidemiology and etiology

Valvular heart disease is present in 80% of patients with heart disease in pregnancy in developing countries, with rheumatic fever as the most common etiology97 and mitral stenosis as the most common lesion. In contrast, in developed countries valvular heart disease represents only 25 % of all heart diseases in pregnancy, second after congential heart disease.2 5.2

Stenotic valve lesions

Both acquired and congenital native valvular heart diseases are important causes of maternal and fetal morbidity and mortality. Particularly stenotic valve lesions have a higher pregnancy risk than regurgitant lesions, and left sided valve diseases are associated with a higher complication rate than right - sided valve lesions.6,13,18,98 The increase in cardiac output during pregnancy causes a rise in transvalvular gradient and in upstream pressures, leading to an increased risk of maternal and fetal complications.6,61 Mitral valve stenosis Echocardiographic confirmation of moderate or severe mitral stenosis is based on valve area (< 1.5 cm²) and mean gradient.99,100 Both are of important prognostic value, as well as pulmonary artery pressure. Prepregnancy assessment of mitral anatomy, quantitation of associated regurgitation or other valvular diseases are of importance, particularly when percutaneous mitral commissurotomy is considered. Exercise testing is useful to reveal symptoms and assess exercise tolerance before pregnancy. Prognosis The maternal and offspring risk depend on the severity of mitral stenosis, which is overall responsible for most of the morbidity and mortality of rheumatic heart disease during pregnancy.61,97,101-103 Moderate or severe mitral valve stenosis is poorly tolerated, with heart failure occurring frequently with rising heart rate or with atrial fibrillation, particularly during the second and third trimesters, even in previously asymptomatic women.61,98,101 Atrial

28

fibrillation carries the additional risk of thromboembolic events.61,101 Mortality is between 0–3% 61,98,101 and is even higher in developing countries.97,103 These deaths can be prevented by timely prepregnancy valvuloplasty. Symptoms may occur in women with mild mitral valve stenosis but they are generally not severe and are well-tolerated.61,98 Obstetric complications are mainly related to the risk of acute heart failure during or just after delivery and they depend on symptoms and pulmonary artery pressure during pregnancy.98 Offspring risk is higher in women in New York Heart Association class III/IV during pregnancy.6,98,103 Management All patients with moderate or severe mitral valve stenosis (even when asymptomatic) should be counselled against pregnancy and intervention should be performed pre-pregnancy, favouring percutaneous interventions. Regular clinical and echocardiographic follow-up is indicated, intervals depending on severity and haemodynamic tolerance. Percutaneous mitral commissurotomy during pregnancy should only be considered in women with New York Heart Association class III/IV and/or estimated systolic pulmonary artery pressure > 50 mm Hg despite optimal medical treatment, in the absence of contraindications and with suitable valve morphology.3,99,104,105 (table 6). It is preferably performed after 20 weeks of gestation with abdominal lead shielding and requires an experienced operator. It is then of low complication rate.99,104,105 If percutaneous commissurotomy is not available closed commissurotomy remains an alternative. Open-heart surgery should be reserved for patients without other options, when the mother’s life is threatened (table 6). Aortic valve stenosis Aortic valve disease was present in 23 % of pregnant patients with valve diseases, and aortic valve stenosis was the second most common stenotic valve lesion in the recent ESC registry.2 The main cause of aortic valve stenosis in childbearing age is congenital bicuspid aortic valve. Echocardiographic quantification of aortic valve stenosis severity and measurement of aortic diameter should be performed pre-pregnancy. Exercise testing is recommended in asymptomatic patients to confirm asymptomatic status and evaluate exercise tolerance, blood pressure response, arrhythmias, and/or the need for interventions.

29

Prognosis Patients usually sustain pregnancy well, even with severe AS, as long as they remain asymptomatic during exercise testing and have a normal blood pressure response during exercise.90,106 The increase in cardiac output can lead to a marked increase in gradient

98,107

and to heart failure (up to 10 %), determined by the basic severity of aortic valve stenosis and symptoms. Arrhythmias occur in up to 25 %.108 Mortality is now rare, if careful management is provided.18,45,61,98,107-110 Preterm birth, intrauterine growth retardation, and low birth weight may occur in up to 25% of the offspring. Management Symptomatic patients with severe aortic valve stenosis or asymptomatic patients with impaired left ventricular function or a pathological exercise test should be counselled against pregnancy, and valvuloplasty or surgery should be performed pre-pregnancy3,90,111 (table 6). Pregnancy should not be discouraged in asymptomatic patients, even with severe AS, when left ventricular size and function as well as the exercise test are normal and severe left ventricular hypertrophy (posterior wall >15 mm) has been excluded, as well as recent rapid progression of AS. Regular follow-up during pregnancy is required by a specialized team. Medical treatment and restricted activities are indicated for patients developing signs or symptoms of heart failure during pregnancy. Diuretics can be administered for congestive symptoms. A cardioselective β-blocker or a non-dihydropyridine calcium channel antagonist should be considered for rate control in atrial fibrillation. If both are contra-indicated, digoxin may be considered.112 Percutaneous valvuloplasty can be undertaken in non-calcified valves with minimal regurgitation113 when severe symptoms persist. Valve replacement should be reserved for life-threatening symptoms, after early delivery by caesarean section if this is an option (table 6). Caesarean section should be considered in severe, particularly symptomatic aortic stenosis .3 Dr. Afshan Hameed: Handful of cardiac conditions that benefit from caesarean delivery includes pregnant women with dilated aortic root in the presence of connective tissue disorders, pulmonary hypertension, and severe symptomatic aortic stenosis.

30

5.3

Regurgitant lesions Mitral and aortic regurgitation

Because of the decreased systemic vascular resistance during pregnancy regurgitant volume is often reduced in left-sided regurgitant lesions; therefore pregnancy is usually well tolerated and regurgitant valve lesions carry a lower pregnancy risk than stenotic valve lesions. Prepregancy evaluation should include assessment of symptoms, regurgitation severity, left ventricular dimensions and function, as well as the diameter of the ascending aorta in aortic regurgitation with a bicuspid valve. In moderate/severe regurgitation exercise testing is recommended pre-pregnancy.3 Prognosis Maternal risk is low in asymptomatic women with preserved left ventricular function, the most frequent complications are arrhythmias. However, maternal risk of heart failure98 and offspring complications are increased6 in women with severe regurgitation and symptoms and/or compromised left ventricular function.102 Management Patients with severe regurgitation and symptoms or compromised left ventricular function or left ventricular dilatation3,99 should be referred for pre-pregnancy surgery, favouring valve repair. Follow-up is required every trimester in mild/moderate regurgitation, and more often in severe regurgitation. Symptoms of fluid overload can usually be managed medically. Surgery is rarely necessary during pregnancy (table 6). Tricuspid regurgitation Maternal cardiovascular risk is usually determined by primary left-sided valve disease or pulmonary hypertension. Even severe tricuspid valve regurgitation with heart failure can usually be managed conservatively during pregnancy. When surgery is necessary for leftsided valve lesions before or during pregnancy, additional tricuspid repair is indicated in severe tricuspid valve regurgitation and should be considered in moderate tricuspid

31

regurgitation and moderate secondary tricuspid regurgitation with annular dilatation (>40mm).99 5.4

Valvular atrial fibrillation (native valves)

Valvular atrial fibrillation is associated with a high thromboembolic risk, particularly in patients with severe mitral stenosis. With the occurrence of atrial fibrillation immediate anticoagulation with intravenous unfractionated heparin is required, followed by LMWH in the first and last trimester and oral anticoagulants or LMWH for the second trimester (table 6). LMWH should be given in weight- adjusted therapeutic doses (twice daily) until 36 hours prior to delivery. If oral anticoagulants are used, the INR can be kept between 2.0 and 2.5, thus minimizing the risk for the fetus. Table 6: Recommendations for the management of valvular heart disease

a b

Mitral stenosis In patients with symptoms or pulmonary hypertension, restricted activities and β1-selective blockers are recommended. Diuretics are recommended when congestive symptoms persist despite beta-blockers. Patients with severe MS should undergo intervention before pregnancy. Therapeutic anticoagulation is recommended in case of atrial fibrillation, left atrial thrombosis, or prior embolism. Percutaneous mitral commissurotomy should be considered in pregnant patients with severe symptoms or systolic pulmonary artery pressure >50 mmHg despite medical therapy. Aortic stenosis Patients with severe AS should undergo intervention prepregnancy if: they are symptomatic or LV dysfunction ( LVEF <50%) is present Asymptomatic patients with severe AS should undergo intervention prepregnancy when they develop symptoms during exercise testing. Asymptomatic patients with severe AS should be considered for intervention prepregnancy when a fall in blood pressure below baseline during exercise testing occurs. Regurgitant lesions Patients with severe aortic or mitral regurgitation and symptoms or impaired ventricular function or ventricular dilatation should be treated surgically pre-pregnancy. Medical therapy is recommended in pregnant women with regurgitant lesions when symptoms occur. Class of recommendation. Level of evidence.

32

Classa

Levelb

I

B

I

B

I

C

I

C

IIa

C

I I

B C

I

C

IIa

C

I

C

I

C

AS = aortic stenosis; LVEF = left ventricular ejection fraction; MS = mitral stenosis Reproduced and modified with permission from Regitz-Zagrosek et.al.

5.5

3

Prosthetic valves

About 5% of valve replacements are performed in women in childbearing age.114 Bioprosthesis Bioprosthetic valves are much less thrombogenic than mechanical valves and do not require longterm anticoagulation. However, in young patients, bioprostheses are associated with a high risk of structural valve deterioration, occurring in around 50% of patients under the age of 30 years 10 years post-implantation, with the need for a reoperation, which is associated with a mortality risk of up to 5%.115-117 In patients with aortic valve disease the Ross operation (pulmonary autograft transferred to the aortic position and pulmonary valve replacement with a homograft) has been suggested as an alternative. There is no thrombogenicity and valve haemodynamics are excellent. Yet this is a two-valve operation requiring specific surgical expertise, and with a significant reoperation rate after 10 years.110 Moreover only few data are available on pregnancy in women after a Ross procedure.115,118-120 A desire for pregnancy was previously considered a Class IIb indication for a biological valve3,111, however recently it is considered a class IIa indication.99 The choice for a specific prosthesis should be made after extensive patient information and discussion, particularly regarding the risk for reoperation. Pregnancy is generally well tolerated in women with an intact bioprosthetic valve and uncompromised ventricular function.116 Mechanical valve valve prosthesis and anticoagulation Mechanical valves have an excellent haemodynamic performance and longterm durability. Women with well-functioning mechanical valves tolerate pregnancy hemodynamically well. Yet the need for anticoagulation increases maternal and fetal mortality and morbidity.

33

Maternal risk In a 30 years data collection from Denmark no valve thrombosis occurred with oral anticoagulants (Vitamin K antagonists) throughout pregnancy, and 1 maternal death due to postpartum bleeding in 79 women with 155 pregnancies after mechanical valve replacement. There were 4 thromboembolic episodes in women with mitral prosthesis on unfractionated heparin (UFH).114 A low risk of valve thrombosis with oral anticoagulants throughout pregnancy (2.4%, 7/287 pregnancies) compared to unfractionated heparin in the first trimester (10.3%, 16/156 pregnancies) was also found in a review by Abildgaard.121 Previous reviews had shown a risk of valve thrombosis of 3.9% with oral anticoagulants given throughout pregnancy, 9.2% when unfractionated heparin was used in the first trimester and oral anticoagulants in the second and third trimester, and 33% with unfractionated heparin throughout pregnancy.122 Maternal death occurred in these groups in 2%, 4%, and 15%, respectively, and was usually related to valve thrombosis.122 LMWHs are also associated with the risk of valve thrombosis.123,124 The risk is lower than with unfractionated heparin, but still present, with dose adjusting according to anti-Xa levels.121,123,125-128 Valve thrombosis occurred in 9 % of 111 pregnancies in which LMWH with dose adjustment according to anti Xa levels were used throughout pregnancy. Too low target anti-Xa levels or poor compliance probably contributed to valve thrombosis in all but one pregnancy.123 A lower frequency of valve thrombosis with LMWH in the first trimester only, was reported by Abildgaard (3.6%, 2/56 pregnancies).121 The only randomized study (HIP-CAT), comparing weight adjusted doses of LMWH (enoxaparin) with warfarin and initial unfractionated heparin in pregnant women was prematurely terminated, after the occurrence of valve thrombosis in 2 out of 7 patients on LMWH.124 No LMWH has been officially approved for pregnant women with mechanical valves in any country so far. There is a marked increase in dose requirement during pregnancy to maintain the anti- Xa levels in the therapeutic range126,129 because of increased volume of distribution and increased renal clearance. Both decrease after delivery with an increase in peak anti-Xa levels postdelivery in comparison to pre-delivery and an increased risk for bleeding.

34

Therefore regular monitoring of anti-Xa levels is necessary. Pre-dose anti-Xa levels are often subtherapeutic when peak levels are between 0.8-1.2 U/ml

125,129-131

, so that monitoring of

both predose and peak dose anti-Xa levels has been suggested.131,132 However there is no proof that this regime prevents valve thrombosis and bleeding. Therefore the use of LMWH during pregnancy in women with mechanical prostheses is still associated with several unresolved issues, concerning optimal anti-Xa levels, the importance of determination of both peak and pre-dose levels, the optimal dosing intervals and the availability and best method of anti-Xa level testing overall. Thus oral anticoagulants throughout pregnancy, under strict international normalized ratio control, is the safest regimen for the mother.114,121,122

Obstetric and offspring risk Oral anticoagulants cross the placenta and their use in the first trimester can result in embryopathy, reports ranging from 0.0–10% of cases.122,133-136 The incidence of embryopathy was found to be dose dependent in 6 studies: embryopathy was low (2.6%) in 2 small series, when warfarin dose was < 5 mg and 8% when warfarin dose was > 5 mg daily.135,136 Two cases of embryopathy (8% of all first trimester warfarin exposures in 25 patients) occurred only in patients on high warfarin dosing.114 This was also confirmed in 3 further studies 137-139, however not in other small series.131 Major central nervous system abnormalities occur in 1% of children when oral anticoagulants are used in the first trimester.140 A low risk of minor central nervous system abnormalities exists with oral anticoagulants outside the first trimester only.140 Miscarriage rate is increased with oral anticoagulants throughout, however in one large study fetal and neonatal deaths were not higher, compared to a healthy control group.114 UFH and LMWH do not cross the placenta and embryopathy does not occur. Substitution of oral anticoagulants with unfractionated heparin or LMWH in weeks 6–12 nearly eliminates the risk of embryopathy.

35

All anticoagulation regimens carry an increased risk of miscarriage and of haemorrhagic complications in comparison to healthy controls, including retroplacental bleeding leading to premature birth and fetal death.114,116,122,123,125-127

Management Prepregnancy, the risks associated with the different anticoagulation regimens should be discussed thoroughly with the woman aspiring pregnancy, her partner and the interdisciplinary physicians team. Oral anticoagulation with Vitamin K antagonists is the most effective regimen to prevent valve thrombosis, therefore it is the safest regimen for the mother,

and

an

important

basic

prerequisite

for

the

child.

This

underlies

the

recommendations summarized in table 7 3, which are at variance with recommendations from other guidelines.40,141 The dose dependent risk of embryopathy and fetal haemorrhage should also be discussed as well as the necessity for meticulous, weekly control of the anticoagulant

therapy,

irrespective

of

the

regimen.

Clinical

follow-up

including

echocardiography should be performed monthly. Oral anticoagulation should be continued until pregnancy is achieved with education of the patient to signs of and testing for pregnancy. Unfractionated heparin or LMWH throughout pregnancy is not recommended because of the high risk of valve thrombosis with these regimens and the fact, that this risk for the mother also jeopardizes the child. Continuation of oral anticoagulants throughout pregnancy should be considered when warfarin dose is <5 mg daily because the risk of embryopathy is low.114,133-138 When a higher dose of oral anticoagulants is required discontinuation of oral anticoagulants between weeks 6 and 12 and replacement by adjusted-dose unfractionated heparin or LMWH should be considered. However, prior to this decision good drug compliance of the woman should be documented, because in its absence heparin is associated with a high risk. Unfractionated heparin is monitored by activated partial thromboplastin time, aiming at ≥2 times the control. Unfractionated heparin is applied in high risk patients as intravenous infusion. LMWH is given twice daily with a starting dose of 1 mg/kg bodyweight, if enoxaparin is chosen, and with dose adjustment according to increasing weight during pregnancy and to

36

anti-Xa levels, which should be maintained between 0.8–1.2 U/ml, determined 4–6 hours after application. Weekly control of peak anti-Xa levels is recommended because of the need for increasing dosages of LMWH during pregnancy (table 7).3 99,121,126,129,142,143, 144 The addition of acetylsalicylic acid to this regimen is not recommended because of lack of data proving its efficacy and safety in pregnant women. The target INR should be chosen according to the type and location of the prosthetic valve.99,142 Intense education about anticoagulation and self-monitoring of anticoagulation in suitable patients is recommended. Vaginal delivery while the mother is on oral anticoagulants is contraindicated because of the high risk of fetal intracranial bleeding. Valve thrombosis Valve thrombosis should be excluded in women with a mechanical valve when acute dyspnoea and/or an embolic event occur. Immediate transthoracic echocardiography is indicated, followed by transoesophageal echocardiography. Fluoroscopy can be performed with limited fetal risk. Management is comparable to non-pregnant patients and includes optimizing anticoagulation with intravenous heparin and resumption of oral anticoagulation in non-critically ill patients with recent sub-therapeutic anticoagulation, and surgery when anticoagulation fails and for critically ill patients with obstructive thrombosis.99 Because fetal loss is high with surgery, fibrinolysis may be considered instead in non-critically ill patients when anticoagulation fails. Fibrinolysis is associated with the risk of embolization (10%) in left sided valve thrombosis, and with the risk of subplacental bleeding. It is therapy of choice in right-sided valve thrombosis.

Table 7: Recommendations for the management of mechanical valves Mechanical valves OAC are recommended during the 2nd and 3rd trimesters until the 36th week. Change of anticoagulation regimen during pregnancy should be implemented in hospital. If delivery starts while on OAC, caesarean delivery is indicated. OAC should be discontinued and dose-adjusted UFH (a PTT ≥2× control) or adjusted-dose LMWH (target anti-Xa level 4–6 hours post-dose 0.8-1.2 U/ml) started at the 36th week of gestation. In pregnant women managed with LMWH post-dose anti-Xa level should be assessed weekly. LMWH should be replaced by intravenous UFH at least 36 hours

37

Classa,b I I I I I I

before planned delivery. UFH should be continued until 4–6 hours before planned delivery and restarted 4–6 hours after delivery if there are no bleeding complications. Immediate echocardiography is indicated in women with mechanical valves presenting with dyspnoea and/or an embolic event. Continuation of OAC should be considered during the first trimester if warfarin dose required for therapeutic anticoagulation is <5 mg/day , after patient information and consent Discontinuation of OAC between weeks 6 and 12 and replacement by adjusted-dose UFH (a PTT ≥2× control; in high risk patients applied as intravenous infusion) or LMWH twice daily (with dose adjustment according to weight and target anti-Xa level 4-6 hours post-dose 0,8-1,2 U/ml) should be considered in patients with a warfarin dose required of > 5 mg/day. LMWH should be avoided, unless anti-Xa levels are monitored. a

Class of recommendation.

b

all recommendations have the level of evidence C.

I IIa IIa

III

aPTT = activated partial thromboplastin time; LMWH = low molecular weight heparins; LVEF = left ventricular ejection fraction; OAC = oral anticoagulants; UFH = unfractionated heparin. Reproduced and modified with permission from Regitz-Zagrosek et.al.

3

Dr. Afshan Hameed: Pregnancy in women with mechanical valves requiring therapeutic anticoagulation constitutes one of the highest risk groups that need careful and frequent follow up. It is important to realize that warfarin crosses placenta anticoagulating the fetus, and therefore, caesarean delivery is indicated in a woman presenting for an imminent delivery on therapeutic anticoagulation with warfarin. This is of particular importance as fetal intracranial bleeding is a real concern. Heparin should be instituted in lieu of warfarin near term to prevent this complication. In pregnant women with prosthetic valves at high risk of thromboembolism, addition of low dose aspirin may be considered in addition to anticoagulants (Guyatt GH, akl EA, Crowther M, et. al. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:7s-47s.) 6 6.1

Coronary artery disease Epidemiology

The prevalence of atherosclerosis is low in young women, which explains that coronary artery disease is seldom encountered during pregnancy. Myocardial infarction during pregnancy is associated with common cardiovascular risk factors and, with regards to pregnancy characteristics, to twin pregnancies and pre-eclampsia.145 Coronary artery disease may also occur without underlying atherosclerosis and be the consequence of coronary thrombosis or embolism or spontaneous coronary dissection. Non-atherosclerotic coronary disease is more frequently encountered in the peri- or post-partum period.146

38

Thrombophilia, post-partum infections and severe post-partum hemorrhage may contribute to myocardial ischemia during pregnancy. Acute coronary syndrome is rare, estimated at 3-6 cases per 100,000 deliveries, but it carries a high risk in pregnant women or during the post-partum period.146,147 Recent concerns have been raised in the UK regarding an increasing mortality due to acute coronary syndrome in pregnant women, which seems partly attributable to the growing prevalence of smoking in young women and to the rise in maternal age.7,145 6.2

Diagnosis, prognosis

Angina should be considered in pregnant women with unexplained chest pain. In stable angina, exercise ECG or echocardiography can be safely performed with a target of 80% of predicted maximal heart rate.3 Radionuclide stress testing should be avoided because it involves radiation. The diagnosis of acute coronary syndrome relies on the same criteria as in non-pregnant women, i.e. chest pain, ECG changes and rise in troponin. T-wave inversion and increased troponin levels have been reported during pregnancy without coronary disease. Even though these abnormalities are less specific, in particular with regard to increased troponin levels, they should lead to consider the diagnosis of acute coronary syndrome.3 The prognosis of pregnancy is relatively good as long as coronary artery disease remains stable. Pregnancy may be considered in women with coronary artery disease if there are neither signs of residual ischemia nor left ventricular dysfunction. In these cases, preconceptional cardiac risk assessment and close follow-up during pregnancy and the early post-partum period are recommended. Maternal mortality is estimated at 5-10% in case of acute coronary syndrome and is higher during the post-partum period.146,147 Delayed diagnosis and/or management are likely to contribute to high mortality rates, which highlights the need for awareness towards the diagnosis of coronary artery disease during pregnancy. The risk for the fetus depends mainly on the severity of the maternal heart disease.

39

6.3

Management

Management principles of coronary artery disease during pregnancy are summarized in Table 8. Medical therapy is mainly based on beta-blockers and aspirin. ACE-inhibitors and angiotensin receptor blockers are contra-indicated throughout pregnancy. The use of statins should also be avoided. The use of clopidogrel should be limited to the shortest duration possible, for example after stent implantation. The use of more recent antiplatelet drugs (prasugrel, ticagrelor), bivalirudin and glycoprotein IIb/IIIa inhibitors is not recommended during pregnancy.3 Coronary angiography is not indicated in case of stable angina in pregnant women. Women with ST-segment elevation acute coronary syndrome should be referred to an interventional center with facilities for emergency coronary angiography and percutaneous coronary intervention.3 As in the general population, primary percutaneous coronary intervention is the preferred modality of reperfusion during pregnancy since it avoids potential hazards of thrombolysis and it is the only means to diagnose and treat spontaneous coronary dissection. Intravenous thrombolysis should be used only in women with ST-segment elevation acute coronary syndrome who cannot be treated with primary percutaneous intervention. Recombinant tissue plasminogen activator does not cross the placenta but carries a bleeding risk, in particular subplacental bleeding. A non-emergent invasive approach is recommended in pregnant women with non-STsegment elevation acute coronary syndrome with intermediate- or high-risk criteria in order to perform appropriate myocardial revascularization.3 Only cases of non-ST-segment elevation acute coronary syndrome without additional risk factors can be treated medically without coronary angiography.148 Coronary angiography in pregnant women should be performed in experienced centers and associated with all precautions to keep radiation as low as possible, in particular by shortening the procedure and protecting the abdomen with a lead apron. Stenting should favor the use of bare-metal stents with 3-4 weeks of dual antiplatelet therapy.3 Unfractionated heparin or low-molecular weight heparin is used during percutaneous coronary intervention and stopped after 24-48 hours.

40

Coronary artery bypass grafting is seldom needed during pregnancy and seems to be associated with a high mortality. Recent data from the UK show important variations in the management of acute coronary syndrome during pregnancy in practice and highlight the need for implementing guidelines and referring women with acute coronary syndrome during pregnancy in specialized centers.145

Table 8: Recommendations for the management of coronary artery disease. Classa,b ECG and troponin levels should be performed in case of chest pain in a I pregnant woman. Percutaneous coronary intervention is the preferred reperfusion therapy for I STEMI during pregnancy. A conservative management should be considered for non ST-elevation IIa ACS without risk criteria. An invasive management should be considered for non ST-elevation ACS IIa with risk criteria (including NSTEMI). a

Class of recommendation, b all recommendations have the level of evidence C.

ACS = acute coronary syndrome; ECG = electrocardiogram; NSTEMI = Non ST-elevation myocardial infarction; STEMI = ST-elevation myocardial infarction. Reproduced and modified with permission from Regitz-Zagrosek et.al. 3

7

Cardiomyopathies and Heart Failure

Cardiomyopathies are relatively rare causes of heart failure in pregnancy. However, they are important since they may become life threatening.149 Different forms of cardiomyopathy may occur in pregnancy: peripartum cardiomyopathy, dilated or hypertrophic cardiomyopathy or cardiomyopathies of different etiology. 7.1

Peripartum Cardiomyopathy

Peripartum cardiomyopathy (PPCM) is a disease of unknown etiology leading to heart failure during the last months of pregnancy or within five months after delivery.149,150 The incidence is highest outside European countries (Haiti, South Africa) and is lower in the US and European countries (range from 1-300:1-4000). Predisposing factors are multiparity and

41

multiple childbirths, family history, ethnicity, smoking, diabetes, hypertension, preeclampsia, malnutrition, advanced or very young age of mothers and prolonged use of β-agonists.149,150 The pathophysiology is largely unknown, but increased oxidative stress, activation of the protease cathepsin-D that cleaves prolactin into a pro-hypertrophic and anti-angiogenic fragments may be involved.151,152 Alternative disease mechanisms, inflammation, virus infection, auto-immune mechanisms or genetic mechanisms may also contribute and in some cases unmasking familial dilated cardiomyopathy has been identified as the underlying cause and circulating microparticles have been used as indicators of the disease.153-155

The diagnosis of peripartum cardiomyopathy should be made if symptoms and signs of heart failure occur and left ventricular systolic function decreases in the last months of pregnancy or within five months after delivery without other recognizable cause. Left-ventricular dilatation is usually present, but is not mandatory for the diagnosis. The manifestation can be very acute. Cases with life threatening arrhythmia or sudden deaths have also been reported. However, 50 - 75 % of patients recover spontaneously. Recovery appears to be more frequent in caucasian than in afro-american women.156,157 Patients with peripartum cardiomyopathy are at increased risk in a subsequent pregnancy, in particular, if left ventricular systolic function does not completely normalize. It is estimated that a second pregnancy is associated with a recurrence risk of 30-40% in peripartum cardiomyopathy. Based on this, a subsequent pregnancy is discouraged, if the ejection fraction has not been normalized. Dr. Afshan Hameed: The definition of peripartum cardiomyopathy has evolved since the initial description (Demakis JG, Rahimtoola SH, Sutton GC, et. al. Natural Course of Peripartum Cardiomyopathy. Circulation 1971;44:1053-61), however, it remains an important cause of maternal morbidity and mortality. It is an important entity to recognize as it may present with exaggerated symptoms considered normal for pregnancy and may go unrecognized for a period of time impacting eventual treatment and potential of recovery. 7.2

Dilated cardiomyopathy

Dilated cardiomyopathy is characterized by the same features as in the non-pregnant cases: left-ventricular dilatation and systolic dysfunction with unknown cause leading to symptoms of heart failure. The time of manifestation is frequently in the first or second trimester due to

42

increasing

hemodynamic

load

in

this

period,

distinguishing

it

from

peripartum

cardiomyopathy. Heart failure in the family or symptoms before pregnancy argue also in favor of dilated cardiomyopathy. Dilated cardiomyopathy frequently deteriorates during pregnancy and women with preexisting dilated cardiomyopathy should be informed that their risk of deterioration during pregnancy is high. Termination of the pregnancy should be advised if the left-ventricular systolic function is very low and an ejection fraction below 20% indicates high maternal mortality. Also mothers with dilated cardiomyopathy carry a major risk for a significant decrease in systolic function in a subsequent pregnancy. Management of dilated and peripartum cardiomyopathy Interdisciplinary cardiologic and obstetric management and careful supervision of the fetus are important. In cases of hemodynamic instability urgent delivery should be considered. During pregnancy, ACE inhibitors, angiotensin receptor blockers and renin inhibitors are contra-indicated because of potential fetal toxicity. ACE inhibitors are transferred into the breast milk, but in low concentrations. New data suggest that benazepril, captopril and enalapril are safe during breastfeeding. Antenatally, long-acting nitrates and hydralazine can be used for afterload reduction. Positive inotropic support can be provided by dopamine and levosimendan. Beta-blockers can be used, but beta-1 selective drugs should be preferred because of potential anti-tocolytic actions of beta-2 selective drugs. Atenolol has been associated more frequently with small-for-gestational age babies than other substances and should be avoided. The newborns should be controlled for hypoglycemia, bradycardia or depressed respiration. Diuretics may be used if indicated by pulmonary congestion, but caution is warranted since they can decrease placental blood flow. There are no solid data on aldosterone receptor antagonists. Anti-androgenic effects in third trimester have been discussed and so far there are no safety data for eplerenone. Anticoagulation should be considered if left ventricular systolic function is severely impaired. Anticoagulation therapy is recommended in all patients with an intra-cardiac thrombus and patients with atrial fibrillation. LMWH or vitamin K antagonists can be used depending on the stage of pregnancy. When

43

LMWH are used monitoring of anti-factor Xa-levels should be considered. Pregnancy is a pro-coagulatory state by itself and patients with peripartal cardiomyopathy even exhibit increased pro-coagulant activity.158 Severely ill patients should be treated in hospitals where intra-aortic balloon pumps, leftventricular assist devices, mechanical circulatory support or heart transplantation is available. These strategies have been used successfully. The decisions to use of cardiac resynchronization therapy or mechanical support during pregnancy are very difficult and are not sufficiently supported by databases. This also applies to cardiac transplantation. Discussion with experienced centers is necessary and in the future registries should be established to provide data on these issues. In patients with peripartum cardiomyopathy who did not recover at six months following presentation and still present in heart failure cardiac resynchronization therapy may be considered, if specific criteria are fulfilled. Recently the drug bromocriptine has been suggested for a novel indication in peripartal cardiomyopathy. Since thrombo-embolic events have been reported, combination with anticoagulation therapy seems important. A recent prospective randomized pilot study supports the hypothesis that the addition of bromocriptine to standard heart failure therapy has beneficial effects on ventricular ejection fraction and clinical outcome in women with acute severe peripartum cardiomyopathy and larger clinical studies are ongoing.159 7.3

Hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy is the most common genetic cardiac disease and it is frequently diagnosed for the first time in pregnancy by echocardiography. The most common substrate for complications is diastolic dysfunction due to the hypertrophied non-compliant myocardium, severe left ventricular outflow tract obstruction and arrhythmias. The symptoms are typical for heart failure with pulmonary congestion due to the increased end-diastolic pressure or syncope during physical activity as a response to outflow tract obstruction. Echocardiography is the diagnostic tool of choice. Supraventricular and ventricular arrhythmias are common.

44

Women with hypertrophic cardiomyopathy usually tolerate pregnancy well. Risk is increased in women who are symptomatic before pregnancy and in those with a high outflow tract gradient. Patients with a high- risk clinical profile before pregnancy are at higher risk and need specialized obstetrical care. β-blockers can be used for rate control in atrial fibrillation and to suppress ventricular arrhythmias (table 9). Verapamil can be used as a second choice when β-blockers are not tolerated (be aware of causing atrioventricular block in the fetus). Cardioversion

should

be

considered

for

persistent

atrial

fibrillation.

Therapeutic

anticoagulation with LMWH or Vitamin K antagonists according to stage of pregnancy is recommended for those with paroxysmal or persistent atrial fibrillation. Patients with a past history or family history of sudden death need close surveillance with prompt investigation if symptoms of palpitations or presyncope are reported

Table 9: Recommendations for the management of cardiomyopathies and heart failure in pregnancy Classa, b 1. Anticoagulation is recommended in patients with intracardiac I thrombus detected by imaging or with evidence of systemic embolism. 2. Women with heart failure during pregnancy should receive heart I failure treatment as for non-pregnant patients, respecting contraindications for some drugs in pregnancy 3. Women with dilated cardiomyopathy should be informed about the I risk of deterioration during gestation and peripartum. 4. In patients with a past history or family history of sudden death close I surveillance with prompt investigation is recommended if symptoms of palpitations or presyncope are reported. 5. Therapeutic anticoagulation with LMWH or oral Vitamin K I antagonists according to stage of pregnancy is recommended for patients with hypertrophic cardiomyopathy with atrial fibrillation. 6. Delivery should be performed with β-blocker protection in women I with hypertrophic cardiomyopathy. 7. In hypertrophic cardiomyopathy, cardioversion should be considered IIa for persistent atrial fibrillation. 8. Due to high metabolic demands of lactation and breastfeeding, IIb preventing lactation should be considered in peripartum cardiomyopathy. 9. Subsequent pregnancy is not recommended if left ventricular III ejection fraction does not normalize in women with peripartum cardiomyopathy. a

Class of recommendation, b recommendation 1 has the level of evidence A160 and recommendation 2

the level B149, all others have the level of evidence C. Reproduced and modified with permission from Regitz-Zagrosek et.al. 3

45

8

Arrhythmias

In women with previous tachy-arrhythmias, both with and without underlying structural heart disease, the risk of exacerbation during pregnancy is 20-50%.161 The risk of recurrence of arrhythmias should be weighed against fetal risk when considering to continue or stop antiarrhythmic medication during pregnancy. Risks of medication for the fetus include teratogenicity, effects on fetal growth and risk of pro-arrhythmia. When possible, women with symptomatic tachy-arrhythmias should be treated with catheter ablation therapy before pregnancy. 8.1

Arrhythmias associated with structural and congenital heart disease

In women with congenital heart disease, the incidence of supraventricular or ventricular arrhythmias is dependant on the specific underlying disease and varies from 0-17%.18 Sustained tachycardia is often not well tolerated and in those cases direct current conversion should be performed to avoid fetal hypoperfusion. Digoxin can be used for rate control. βblocking agents, class I antiarrhythmic drugs, and sotalol require caution when ventricular function is impaired. Amiodarone should only be used when absolutely necessary because of its fetotoxicity (see chapter 11). 8.2

Atrioventricular nodal re-entry tachycardia and atrioventricular re-entry tachycardia

To terminate atrioventricular nodal re-entry tachycardia or atrioventricular re-entry tachycardia involving an accessory pathway, the first choice is a vagal manoeuvre. If that fails intravenous adenosine is recommended, when this is not successful intravenous metoprolol can be used162 (table 10). Prophylactic medication is only indicated for intolerable symptoms or tachycardia causing hemodynamic compromise. First choice is then digoxin or metoprolol, followed by sotalol, flecainide or propafenone.163 Atrioventricular nodal blocking agents are contra-indicated when pre-excitation is present. Catheter ablation is usually not indicated during pregnancy.

46

8.3

Focal atrial tachycardia

Focal atrial tachycardia is often associated with structural heart disease and difficult to treat during pregnancy. Recurrence rate is high which means that electrical cardioversion is often not appropriate. Rate control can be achieved with β-blocking agents and/or digitalis. Prophylactic drug therapy can be indicated for symptomatic patients (flecainide, propafenone or sotalol). Amiodarone should only be used when other therapy fails. In poorly tolerated and drug-resistant cases catheter ablation should be considered. 8.4

Atrial flutter and atrial fibrillation

Atrial flutter and atrial fibrillation mainly occur in pregnant women with underlying structural heart disease or hyperthyroidism. Therefore diagnosis and treatment of the underlying condition are primarily important. Electrical cardioversion is indicated when haemodynamic instability exists. In stable patients with structurally normal hearts pharmacological cardioversion may be considered with intravenous ibutilide or flecainide.164 When all attempts for cardioversion fail propafenone or vernakalant may be considered. Amiodarone is not recommended unless absolutely necessary. When duration of AF is < 48 hours, pericardioversion anticoagulation with LMWH or intravenous heparin may be considerd. When duration of AF is > 48 hours or unknown, therapeutic anticoagulation for 3 weeks prior to and at least 4 weeks after cardioversion is indicated, alternatively transesophageal echo to exclude thrombus is an option.165 An indication for anticoagulation irrespective of the maintenance of sinus rhythm exists in patients with elevated risk according to the CHA2DS2VASC score 112 (2 or more risk points). Anticoagulation is chosen according to the stage of pregnancy with LMWH (with anti-Xa factor monitoring) in the first trimester and last months, while vitamin K antagonists are recommended during the remaining period of pregnancy. The newer anticoagulants (dabigatran, rivaroxaban) are not recommended during pregnancy or breastfeeding. Rate control should be considered with β-blocking agents, digoxin, or (as second choice) verapamil. In symptomatic patients despite rate control, prophylactic antiarrhythmic drugs may be considered (sotalol, or flecainide or

47

propafenone with atrioventricular nodal blocking agents combined). Dronedarone is not advised.3 8.5

Ventricular tachycardia

Life-threatening ventricular tachycardia is rare during pregnancy. Underlying structural cardiac disorders (including peripartum cardiomyopathy) and inherited arrhythmic disorders (such as Long QT-syndrome) should be searched for. Idiopathic right ventricular outflow tract tachycardia should be treated when severely symptomatic with verapamil or a β-blocker, or as last resort with catheter ablation.166, 167 In long QT-syndrome the risk of sudden death is especially increased the months postpartum and β-blockers are advised during and after pregnancy.168 Restoration of sinus rhythm is always desirable in patients with ventricular tachycardia, either with electrical cardioversion, or pharmacologically (intravenous sotalol or procainamide, or even amiodarone when necessary) (see table 10). Prophylactic therapy with metoprolol can be effective, and in the absence of structural heart disease sotalol or class IC antiarrhythmic drugs may be used. Amiodarone as prophylactic therapy is fetotoxic but may be considered when necessary. 8.6

Interventional therapy

Catheter ablation may be indicated for drug-refractory and poorly tolerated tachycardias, preferably after the first trimester and with minimal radiation as well as shielding of the uterus. Presence of an implantable cardioverter-defibrillator is compatible with pregnancy and implantation should be considered during pregnancy when necessary (table 10).166, 167 8.7

Bradyarrhythmias

Bradyarrhythmias and conduction disturbances are rare during pregnancy and when they occur usually have a favourable outcome in patients without underlying heart disease. Sinus bradycardia may occur during delivery or due to uterine compression of the inferior vena cava. In the latter case the mother should be placed in a left lateral decubitus position. Congenital atrioventricular block may present for the first time during pregnancy but has a good outcome especially when the escape rhythm has a narrow QRS complex. In

48

symptomatic women with atrioventricular block temporary pacing during delivery may be indicated. When permanent pacing during pregnancy becomes necessary implantation can be carried out with low risk, but radiation should be minimized.

Table 10: Recommendations for the management of arrhythmias in pregnancy Management of Supraventricular tachycardia (SVT) For acute conversion of paroxysmal SVT vagal manoeuvre followed by i.v. adenosine is recommended. Immediate electrical cardioversion is recommended for acute treatment of any tachycardia with haemodynamic instability. For long-term management of SVT oral digoxinc or metoprolol/propranololcd is recommended. For acute conversion of paroxysmal SVT i.v. metoprolol cd or propranolold should be considered. For long-term management of SVT oral sotalole or flecainidef should be considered if digoxin or a beta-blocking agent fail. For acute conversion of paroxysmal SVT i.v. verapamil may be considered. For long-term management of SVT oral propafenonef, or procainamide may be considered as last option if other suggested agents fail and before amiodarone e is used. For long-term management of SVT oral verapamil may be considered for rate regulation if the other AV nodal blocking agents fail. Atenolol d should not be used for any arrhythmia.

Classa,b I I I IIa IIa IIb IIb IIb III

Management of Ventricular tachycardia (VT) The implantation of an ICD, if clinically indicated, is recommended prior to pregnancy but is also recommended whenever indicated, during pregnancy. For long-term management of the congenital long QT syndrome, βblocking agents are recommended during pregnancy and also postpartum when they have a major benefit. For long-term management of idiopathic sustained VT oral metoprolol cd, propranolol cd or verapamil cf is recommended. Immediate electrical cardioversion of VT is recommended for sustained, unstable and stable VT. For acute conversion of VT that is sustained, haemodynamically stable, and monomorphic, i.v. sotalol e or procainamide should be considered. Implantation of permanent pacemakers or ICDs (preferably one chamber) should be considered with echocardiographical guidance, especially if the fetus is beyond 8 weeks gestation. For acute conversion of VT that is sustained, monomorphic, haemodynamically unstable, refractory to electrical cardioversion or not responding to other drugs, i.v. amiodarone e should be considered. For long-term management of idiopathic sustained VT oral sotalole , flecainidef , propafenone f should be considered if other drugs fail. Catheter ablation may be considered in the case of drug-refractory and poorly tolerated tachycardias.

49

I I I I IIa IIa IIa

IIa IIb

For drug dosing information please refer to three published guidelines on the management of patients 112 163 167 with atrial fibrillation, supraventricular arrhythmias, and ventricular arrhythmias . a Class of recommendation b all recommendations have the level of evidence C c, d,e AV nodal blocking agents should not be used in patients with pre-excitation on resting ECG. d β-blocking agents should be used with caution in the first trimester f Class III drugs should not be used in cases with prolonged QTc e AV nodal blocking agents should not be used in patients with pre-excitation on resting ECG. f Consider AV nodal blocking agents in conjunction with flecainide and propafenone for certain atrial tachycardias. AV = atrioventricular; ECG, electrocardiogram; ICD = implantable cardioverter-defibrillator; i.v. = intravenous; SVT = supraventricular tachycardia; VT = ventricular tachycardia Reproduced and modified with permission from Regitz-Zagrosek et.al.

9 9.1

3

Hypertensive disorders Epidemiology and diagnosis

Hypertensive disorders complicate 10 - 15% of pregnancies and cause about a quarter of hospital admissions during pregnancies.169 They put the fetus at risk for growth retardation or prematurity and may cause intrauterine death. A recent large israelian survey suggests that hypertension during pregnancy remains an independent and significant risk factor for adverse perinatal outcomes such as intrauterine growth restriction, small for gestational age, and preterm delivery even with medical therapy.170 Hypertensive disorders put the mothers at risk for abruptio placentae and cerebrovascular accidents, by causing eclampsia, preeclampsia or disseminated intravascular coagulation.171 Major risk factors for the development of hypertensive disorders in pregnancy are high maternal age, dyslipidemia, obesity as well as positive family history. The diagnosis of hypertension in pregnancy requires some specific precautions. Blood pressure should be measured at least twice, preferentially by mercury sphygmomanometry, in the sitting position or in left-lateral recumbency.172 Validated ambulatory blood pressure monitoring devices are useful, since they are more precise in predicting outcomes than single office measurements.173-175 Hypertensive pregnant patients should be monitored by regular laboratory investigations including hematocrit, blood cell count, liver enzymes, serum creatinine, serum urid acid. Proteinuria should be determined in 24-hour urine collections. Pheochromocytoma should be excluded by urine measurements of catecholamine

50

derivatives.176 Utero-placental hypo-perfusion can be detected by ultrasound of uterine arteries.177 Recent data suggest a future promising role for microparticles in diagnosis.178 9.2

Definition and classification of hypertension in pregnancy

In pregnancy, absolute values and specific limits are used for the definition of hypertension.179,180 Systolic blood pressures above 140 and below 160 mm Hg or diastolic blood pressures above 90 and below 110 mm Hg indicate mild hypertension, whereas values above 160/110 mm Hg indicate severe hypertension and values above 170 mm Hg are considered an emergency.3 Different forms of hypertension in pregnancy are distinguished. 9.3

Preexisting hypertension

Chronic preexisting hypertension is diagnosed, if hypertension is known before pregnancy or manifests before week 20 and persists more than 6 weeks post-partum. Chronic preexisting hypertension manifests in 1 - 5% of pregnancies. 95% of pregnancies with chronic hypertension show no significant complications.181,182 A fall in blood pressure in the first trimesters may mask chronic hypertension in pregnancy. 9.4

Gestational hypertension

Gestational hypertension manifests in 5-10 % of pregnancies. Gestational hypertension usual manifests after week 20 and disappears within 6 weeks after partum. It may be associated with proteinuria and the risk of poor organ perfusion. If it appears together with clinically significant proteinuria (≥ 0.3 g/d in 24h or ≥ 30 mg/mmol urinary creatinine in a random sample), it is designated as preeclampsia. Preeclampsia complicates about 5-7% of pregnancies, but the prevalence may be higher in women with preexisting hypertension. It is one of the most frequent causes of prematurity and is the reason for 25% of very low birthweight cases (<1500 g). Preeclampsia is the pregnancies’ specific syndrome that can only be cured by delivery of the placenta. It occurs more frequently during a first pregnancy, in multisibling pregnancies associated with hydatiform mole or diabetes. It is often associated with placental insufficiency.

51

Clinical manifestations of preeclampsia Symptoms and signs of severe preeclampsia include -

right upper quadrant epigastric pain,

-

headache and visual disturbance,

-

occipital lobe blindness,

-

hyper-reflexia and clonus,

-

convulsions,

-

HELLP syndrome: hemolysis, elevated liver enzymes, low platelet counts.

Since proteinuria may be a late manifestation, preeclampsia should be suspected, if new onset hypertension is accompanied by headache, visual disturbances, abdominal pain or abnormal laboratory tests. Such patients should be treated as having preeclampsia. 9.5

Combined and antenately unclassifiable hypertension

Combined hypertension occurs when preexisting hypertension is super-imposed with gestational hypertension with or without proteinuria. If hypertension is only diagnosed after 20 weeks of gestation and no previous measurements are available, it is not classifiable. Follow-up after 6 weeks is necessary to differentiate between chronic preexisting hypertension and gestational hypertension. 9.6 Management 9.6.1

Indications for treatment

No internationally recognized limits for blood pressure exist as an indication for treatment. Women with mild hypertension with normal renal function, without preeclampsia have a good prognosis and do not need pharmacological therapy. So far, no benefit for mother or child was documented, if pharmacological therapy was started at blood pressure values below 160/110 mm mercury, if no additional risk factors such as end-organ damage, high age of mother (>40 years old), TIA, stroke, microvascular diseases, previous miscarriages or secondary causes of hypertension are present. However, even though the benefit of treating women with mild hypertension is not documented, the thresholds for treatment set by the

52

European Society of Hypertension and the European Society of Cardiology are 150/95 mm Hg and the recent European Society of Cardiology guideline task force followed these recommendations.3 Women with severe hypertension (> 160/110 mm Hg) should be treated as well as women with mild hypertension and additional risk factors like gestational hypertension or hypertension with subclinical organ damage. Treatment goals are mean blood pressure values of 125 mm mercury (systolic 130-150 and diastolic 80-95 mm Hg).182 Blood pressure values of more than 170/110 represent an emergency and hospitalization is recommended.3 9.6.2

Prevention of hypertension and preeclampsia

Nonpharmacological management may be considered in women with mild hypertension, after secure exclusion of preeclampsia (table 11). If this is done, a normal diet without salt restriction is recommended. Calcium supplements, (1 g/day) reduced the risk of preeclampsia in some but not all women.183 Low dose acetylsalecylid acid (75-100 mg/d) has been suggested to prevent preeclampsia mainly in high- risk women, based on metaanalyses, but was not effective in a randomized study.184,185 Weight reduction in obese women is not recommended. However, pregnant women should not have an excessive weight gain. Recommended weight gain is 11.2-15.9 kg in normal weight women, 6.8-11.2 kg in overweight pregnant women and less than 6.8 kg in obese women. 9.6.3

Pharmacological treatment of hypertension in pregnancy

Few systematic studies are available. One of the landmark studies on the treatment of hypertension in pregnancy with long-term infant follow-up (7.5 years) proved the beneficial effect of alpha methyldopa.186,187 Therefore, alpha methyldopa is still considered drug of choice for long-term treatment (table 11). In addition, beta-blockers are used in increasing frequency. Significant experiences exist with metoprolol and the alpha/beta-blocker labetolol.188,189 Atenolol should be avoided, because small-for-date babies have been reported with this drug. Calcium channel blockers may be used as drugs of second choice.190

53

ACE inhibitors, angiotensin receptor blockers and direct renin inhibitors are strictly contraindicated. Diuretics should be avoided, since they cause placental hypoperfusion. In hypertensive emergency or hypertension caused by preeclampsia intravenous treatment may be requested. Urapidil or magnesium sulfate are the drugs of choice. Selection of drug should be made depending on the expected time of delivery. Pharmacological treatment should be started with intravenous labetolol or oral methyldopa or nifedipine. In hypertensive crisis, intravenous sodium nitroprusside should be chosen (table 11). Prolonged treatment should be avoided, since it may lead to fetal cyanide poisoning. Intravenous hydralazine is associated with more perinatal adverse effects than other drugs and should therefore be avoided. In preeclampsia with pulmonary edema, intravenous nitroglycerine (glyceryl trinitrate) is recommended (5 µg/min, increase every 3–5 minutes up to 100 µg/min). 9.7

Prognosis

Blood pressure increases after delivery occur frequently. Women should not be treated with methyldopa in this period, since this may lead to post-natal depression. Women with hypertension in pregnancy have an increased risk of recurrence of hypertension in a subsequent pregnancy.191 The earlier the onset of hypertension in the first pregnancy, the greater the risk of recurrence.192 Women with hypertensive disorders in pregnancy have an increased risk of developing atherosclerosis, hypertension and stroke or ischemic heart disease later in lifetime.193 The highest risk is observed in women with early onset preeclampsia and fetal complications. Hypertensive disorders in pregnancy are now suspected as a significant risk factor for the development of atherosclerosis and other cardiovascular diseases in later life and more studies have been set up to quantitate this risk.169,194 Systematic prevention by life style modifications and regular controls are recommended. Table 11: Recommendations for the management of hypertension in pregnancy Classa,b Non-pharmacological management for pregnant women with SBP of 140-150 mmHg or DBP of 90-99 mmHg is I recommended. In women with gestational hypertension or pre-existing I hypertension superimposed by gestational hypertension or with

54

a b

hypertension and subclinical organ damage or symptoms at any time during pregnancy, initiation of drug treatment is recommended at BP of 140/90 mmHg. In any other circumstances, initiation of drug treatment is recommended if SBP ≥ 150 mmHg or DBP ≥ 95 mmHg. SBP ≥ 170 mmHg or DBP ≥ 110 mmHg in a pregnant woman is an emergency, and hospitalization is recommended. Induction of delivery is recommended in gestational hypertension with proteinuria with adverse conditions such as visual disturbances, coagulation abnormalities, or fetal distress. In pre-eclampsia associated with pulmonary oedema, nitroglycerine given as an intravenous infusion, is recommended. In severe hypertension, drug treatment with intravenous labetalol or oral methyldopa or nifedipine is recommended. Women with pre-existing hypertension should be considered to continue their current medication except for ACE inhibitors, angiotensin II antagonists and direct renin inhibitors under close BP-control.

I I I I IIa

Class of recommendation all recommendations have the level of evidence C

BP = blood pressure; DBP = diastolic blood pressure; SBP = systolic blood pressure Reproduced and modified with permission from Regitz-Zagrosek et.al.

3

Dr. Afshan Hameed: Acute onset severe hypertension > 160/110 for a period of 15 minutes is considered hypertensive emergency requiring immediate use of antihypertensives. It is important to keep that cut-off in mind when caring for pregnant women, as immediate/aggressive treatment may not be indicated with similar blood pressures if noted in a woman remote from pregnancy (American College of Obstetrics and Gynecology Committee Opinion # 514. December 2011, Executive Summary: Hypertension in Pregnancy. Obstet Gynecol 2013:122:1122-31.)

10 Venous thromboembolism during pregnancy and the puerperium 10.1 Epidemiology and maternal risk Venous thromboembolism, encompassing pulmonary embolism and deep vein thrombosis, occurs in about 0.05 - 0.20 % of all pregnancies.195-199 Pulmonary embolism was the most common cause of direct maternal death in the UK up to 2005.200 Between 2006 and 2008 a significant decline in death due to pulmonary embolism occurred (to 0.70 / 100 000 maternities), representing now the third most common cause of direct maternal mortality.7 The case fatality rate of antenatal pulmonary embolism in the UKOSS study was 3.5 %.201

55

10.2 Risk factors for pregnancy - related venous thromboembolism and risk stratification The presence of risk factors contributes to the increased risk of venous thromboembolism during pregnancy and the puerperium. Seventy nine percent of women dying from an antenatal pulmonary embolism had identifiable risk factors200,201, with the most significant risk factors being a prior history of unprovoked deep vein thrombosis or pulmonary embolism and thrombophilias. Risk factors were also present in 88% of women dying of pulmonary embolism in the most recent CEMACE report7, but overweight and obesity were the most important risk factors. Therefore identification of risk factors in the individual patient is important for risk assessment and choice of preventive strategies. Thus all women should undergo a documented assessment of risk factors for venous thromboembolism before or in early pregnancy 3. (table 12) Based on type and number of risk factors present in the individual patient, three risk groups can be identified (high, intermediate and low risk group) and preventive measures applied accordingly.202,203 Patients at high risk are those with previous recurrent venous thromboembolism (> 1) or previous unprovoked or oestrogen related venous thromboembolism or single previous venous thromboembolism plus thrombophilia or family history. Patients with intermediate risk are those with 3 or more risk factors other than listed as high risk. These risk factors include: medical comorbidities, age > 35 years, obesity (BMI> 30 kg/m2), hyperemesis and dehydration, smoking, gross varicous veins, and obstetric factors like pre-ecclampsia, ovarian hyperstimulation syndrom, multiple pregnancy, emergency and elective caesarean section, prolonged labour (> 24 hours) and peripartum hemorrhage (> 1 litre or transfusion). Transient risk factors are current systemic infection, immobility, surgical procedure in pregnancy or < 6 weeks post-partum. Patients at low risk are those with less than 3 risk factors, except for overweight and obesity, which were shown to be important as single risk factors.

56

10.3 Prevention of venous thromboembolism LMWH has become the drug of choice for the prophylaxis of venous thromboembolism in pregnant patients.204 It causes less bone loss than unfractionated heparin and the osteoporotic fracture rate is lower (0.04% of pregnant women treated with LMWH).204 The dose of LMWH for thromboprophylaxis is based on bodyweight. However, previously recommended doses are mostly based on studies in nonpregnant patients and there are no data on appropriate doses of LMWH for pregnant women who are obese or puerperal.141,195 Although the incidence of venous thromboembolism decreased recently, particularly in obese patients a significant residual risk of venous thromboembolism remains7,193, in spite of prophylactic doses of LMWH considered appropriate at the time. It is therefore suggested, that women of high risk should receive a prophylactic dose of LMWH that is half of the therapeutic dose, weight adjusted, applied twice daily (eg. enoxaparin 0.5 mg/kg body weight twice daily or dalteparin 50 units/kg 12 hourly) 3, and studies should be conducted on the optimal dose ranges in pregnancy. 10.4 Management of acute venous thromboembolism 10.4.1 Pulmonary embolism A high index of suspicion, particularly in women with any chest discomfort or new dyspnoe, is important for the timely diagnosis of pulmonary embolism. D-Dimer levels show a physiological increase in each trimester, thus an elevated D-Dimer level, based on cut-off values in nonpregnant patients is not diagnostic for pulmonary embolism. However levels are usually not in the range of pulmonary embolism. Although prospective studies in pregnant women are lacking, and new cut-off values need to be determined in pregnancy, D-dimer concentration should be measured in patients with suspected pulmonary embolism, followed by bilateral compression ultrasonography.

3

When this is normal in the presence of negative

D-dimer levels then pulmonary embolism is unlikely and anticoagulation with LMWH is not warranted. With positive D-dimer levels and positive compression ultrasonography, anticoagulation treatment is indicated. If D-dimer levels are markedly elevated and

57

compression ultrasonography is negative, further testing is required. Computed tomography pulmonary angiography should then be considered with appropriate abdominal shielding. LMWH has also become the drug of choice for the treatment of pulmonary embolism in pregnancy and puerperium.141,204 In a recent meta-analysis including 822 patients receiving LMWH the estimated mean incidences of recurrent venous thromboembolism during pregnancy was 1.97 %, of major antenatal bleeding 1.41 %, and of major bleeding during the first 24 hours after delivery 1.90 % respectively. With marked heterogeneity in the treatment regimens in the reported studies information on optimal dosing regimens could not be determined.205 The therapeutic dose is calculated on bodyweight according to the manufacturers suggestions (eg. dalteparin 100 IU/kg body weight twice daily, or enoxaparin 1 mg/kg body weight twice daily), aiming at 4 to 6 hours peak anti Xa levels of 0.6 to 1.2 IU/ml, which should be regularly determined. 3 Unfractioned heparin is favoured in patients with renal failure and when urgent reversal of anticoagulation by protamine is needed as well as in the acute treatment of massive pulmonary emboli. The effect should be controlled by the activated partial thromboplastin time, determined 4- 6 hours after the loading dose, 6 hours after any dose change and then daily. The therapeutic target activated partial thromboplastin time ratio is usually 2.0-2.5 times the average laboratory control value. A therapeutic activated partial thromboplastin time is defined as the activated partial thromboplastin time that corresponds to an anti-Xa level of 0.3 to 0.7 IU/mL. LMWH should be switched to intravenous unfractionated heparin at least 36 hours before the induction of labour or caesarean delivery. Unfractionated heparin should be discontinued 4–6 hours before anticipated delivery. In the absence of bleeding, heparin treatment may be restarted 6 hours after a vaginal birth and 12 hours after a caesarean delivery with careful dose adjustment. Vitamin K antagonists may be started after the second day after delivery and continued for at least 3 months or for 6 months if pulmonary embolism occurred late in pregnancy. The INR should be between 2 and 3 and needs regular monitoring, ideally once every 1 to 2 weeks after initial stabilisation.

58

Vitamin K antagonists do not enter the breast milk in active forms and are safe for nursing mothers. Neither unfractionated heparin nor LWMH are found in breast milk in any significant amount and do not represent a contraindication to breastfeeding. Oral direct thrombin (eg. dabigatran) and anti-Xa inhibitors (eg. rivaroxaban, apixaban) have not been evaluated during pregnancy or breastfeeding in humans. Since they cross the placental barrier and appear in animal breast milk they are neither recommended during pregnancy nor during breastfeeding. 10.4.2 Management of acute deep vein thrombosis Although leg swelling is a frequent finding in pregnancy, it should raise the suspicion of deep vein thrombosis (DVT), particularly when it is left sided. Due to compression of the left iliac vein by the right iliac artery and the gravid uterus deep vein thrombosis occurs in over 85% of cases in the left leg. A clinical decision rule, considering 3 variables: left leg presentation, > 2 cm calf circumference difference and first trimester allows a negative predictive value of 100 %(95 % CI 95.8-100 %) if none of the three variables are present and ultrasound of the legs are negative.206 Determination of D-Dimer levels and compression ultrasound leg vein imaging are the diagnostic procedures of choice for suspected deep vein thrombosis in pregnancy. Compression ultrasound leg vein imaging has a high sensitivity and specificity for proximal deep vein thrombosis. Serial compression ultrasonography with Doppler imaging of the iliac vein performed over a 7-day period excludes deep-vein thrombosis in symptomatic pregnant women.207,208 When an acute deep vein thrombosis is detected, treatment with therapeutic doses of LMWH should be applied, weight adjusted, twice daily.

Table

12:

Recommendations

for

the

prevention

and

management

thromboembolism in pregnancy and puerperium Classa,b In all women who are pregnant or consider pregnancy assessment I of risk factors for VTE is recommended. Mothers should be informed about the signs and symptoms of VTE I in pregnancy and the necessity to contact the physicians if they occur.

59

of

venous

High- risk patients should receive antenatal prophylaxis with LMWH as well as postpartum for the duration of 6 weeks. In intermediate risk patients postpartum prophylaxis with LMWH should be given for at least 7 days or longer, if > 3 risk factors persist. In low risk patients early mobilisation and avoidance of dehydration is recommended. Graduated compression stockings are recommended antepartum and postpartum in all women at high risk. D-Dimer measurement and compression ultrasonography is recommended in patients with suspected VTE during pregnancy. For treatment of acute VTE during pregnancy UFH is recommended in high-risk and LMWH in non-high risk patients. Graduated compression stockings should be considered in women with intermediate risk during pregnancy and postpartum. In intermediate risk patients antenatal prophylaxis with LMWH should be considered. a

Class of recommendation

b

all recommendations have the level of evidence C.

I I

I I I I IIa IIa

LMWH = low molecular weight heparin, VTE = venous thromboembolism. Reproduced and modified with permission from Regitz-Zagrosek et.al.

3

11 Drugs during pregnancy and breast feeding At present, there are insufficient human safety data for most cardiovascular drugs in pregnancy. As a consequence physicians are reluctant to prescribe drugs to pregnant women, even if there is a clear need. To reduce this problem databases and registries have been

established

(www.embryotox.de, www.safefetus.com).

Data

on

risk

exposed

pregnancies are collected and the pregnancies are followed through as to birth outcome and beyond. These follow-up data allow the detection of signals and the quantification of safety or risks for the unborn. Both a detailed risk characterisation and/or quantification of safety after inadvertent drug exposure are essential to risk management or when looking for a drug of choice. Regularly updated information is also available via the open access. There are no uniform recommendations for the treatment of pregnant women yet or for the timing of treatment initiation and selection of medications. As drug treatment in pregnancy concerns the mother and the fetus optimum treatment of both must be targeted. Whether drug treatment is necessary is dependent on the urgency of the indication. In case of emergency, drugs that are not recommended by the pharmaceutical industry during

60

pregnancy and breast feeding, should not be withheld to the mother. The potential risk of a drug and the possible benefit of the therapy must be weighed against each other. Different sources of evidence can be used for risk classification of drugs applied during pregnancy. The U.S. Food and Drug Administration classification has been published by the U.S Department of Health and Human Services.209 Five categories from A (safest) to X – (contraindicated) are used for drugs during pregnancy and breast feeding. Category A means that there are well-controlled studies in humans that do not reveal harm to the fetus. Category B drugs either did not demonstrate risk in animal reproduction studies but there are no controlled studies in humans; or human controlled studies did not show risk for the fetus while animal studies did show an adverse effect. Many drugs are classified as category C, meaning that studies in animals and women are not available, or animal studies did show adverse effects but controlled studies in women are not available. Category D drugs did demonstrate human fetal risk, but the benefits to the mother may warrant the use of these drugs despite the risk to the fetus. Category X means that fetal harm is demonstrated and the risk to the fetus clearly outweighs any possible benefit for the mother, therefore these drugs are contra-indicated. The manufacturers’ instructions are mainly based on the fact that drugs are not tested sufficiently during pregnancy and breastfeeding. For this and for legal reasons, drugs are frequently considered prohibited during pregnancy and breastfeeding. 11.1 Cardiovascular drug groups Angiotension receptor blockers and ACE inhibitors: These drugs are placenta-permeable and are associated with renal, lung and skull abnormalities. They should not be used throughout pregnancy. FDA-category: D in second and third trimester, C in first trimester. Most of these drugs appear in low doses in breast milk and breast-feeding is not advised. In analogy, other inhibitors of the RAS, renin inhibitors, are not recommended. Aldosterone antogonists: Spironolactone is placenta-permeable and is associated with antiandrogenic effects and endocrine dysfunction in animals. FDA-category: D. Since tumorogenic metabolites may appear in breast-milk, breast-feeding is not advised.

61

Eplenerone is classified as FDA-category B based on animal studies. It appears in breast milk in animals and breastfeeding is not advised. Anticoagulants: Vitamin K antagonists cross the placenta and are fetotoxic in the first trimester (dose-dependant). In women with mechanical valves, benefit may outweigh the risk also in the first trimester. They are discussed in detail in previous sections. The dose in breast milk is very low and breast feeding is possible. Unfractionated and low molecular weight heparin are not placenta-permeable and are discussed in more detail in the previous sections. They are FDA-category B. They can be used during breast-feeding. For the new antiplatelet and anticoagulants, not enough safety data are yet available and these drugs are therefore mostly classified as FDA-category C, but their use is not advised during pregnancy. However Clopidogrel has recently been upgraded from C to B in its FDA classification based on animal studies, but human data are not available, therefore it should be used with caution and for the shortest possible period. Data on transfer to breastmilk are not available for most of these drugs and breast-feeding is not advised. Antiarrhythmic drugs: Adenosin is classified as FDA category C. It is probably not harmful to the fetus. There are no data regarding breast feeding. Amiodarone is placenta permeable, it is FDA category D. It should only be used for otherwise refractory severe arrhythmias. Fetal toxicity comprises hypothyroidism, hyperthyroidism, growth retardation, psychomotor retardation, bradycardia, and structural cardiac abnormalities. To avoid fetal exposure it is necessary to stop the drug several months before pregnancy occurs. Since amiodarone concentrates in breast milk, it should not be used during breastfeeding. Procainamide crosses the placenta. Its FDA category is C. Teratogenic effects have not been demonstrated, but data are limited, therefore caution is advised. It concentrates in breastmilk but expected serum levels in the neonate are low. Flecainide is placenta permeable. It is classified as FDA category C. Since animal toxicity has been described and data in humans are limited, it should only be used on strict indication. Concentrations in breast milk are low and its use is compatible with breastfeeding. Sotalol is placenta permeable and is classified by the FDA in category B. Animal studies did not reveal fetotoxic effects. Data in humans are limited. It may cause fetal bradycardia and

62

hypoglycaemia. It concentrates in breast milk, therefore monitoring of fetal glucose levels, heart rate and QT-time is advised when it is used during breastfeeding. ß-blockers: All beta-blockers cross the placenta and have been associated with intrauterine growth retardation as well as fetal bradycardia and fetal hypoglycaemia, but teratogenicity is not demonstrated. Great differences exist according to receptor affinity of different substances. Tocolytic effects have been discussed for ß1 selective and non-selective drugs. Most experience exist with Metoprolol (and Labetolol) and both appear relatively safe (FDA class C). Atenolol should be avoided (class D). Metoprolol has a low dose in breastmilk and can be used during breastfeeding. Atenolol concentrates in breastmilk and should not be used. Calcium antagonists are an inhomogenous group. Diltiazem, Nifedipine and Verapamil substances are classified as C. Potentially teratogenic effects have been discussed concerning diltiazem, and it appears in breast milk. It is not advised during pregnancy or breastfeeding. Nifedipine is teratogenic in animals but data in humans are reassuring. It is tocolytic. It can cause placental hypoperfusion and maternal hypotension. It should be used with caution. The dose in breast milk is low. Verapamil may also cause placental hypoperfusion and hypotension, and additionally it may cause fetal atrioventricular block. The dose in breast milk is unlikely to cause harm to the newborn. Ca-antagonists may be needed to treat arrhythmia and are drugs of second choice for hypertension management. Diuretics may cause placental hypoperfusion and oligohydramnion. More data are available with furosemide compared to bumetanide. Both drugs cross the placenta. Furosemide is unlikely to have fetotoxic effects. It is classified in FDA category C. It is not advised for hypertension but may be used for heart failure. It may reduce the milk production and should be used with caution during breastfeeding. Hydrocholorthiazide is placenta-permeable and is classified as FDA category B. Data in humans are however limited. It has a low dose in breast milk. Inotropes: Dopamin, Levosimendan, and Digitalis can be used with caution. Digoxin is placenta permeable and is FDA category C.

63

Statins cross the placenta, they cause congenital anomalies in animals and are probably harmful in humans. FDA category is X and they are contraindicated during pregnancy. Since data on transfer to breastmilk are lacking, breastfeeding is not advised.

12 Acknowledgement We thank Prof. Dr. med. W. Henrich, Director of the Departments of obstetrics, Charité, Campus Virchow Klinikum, Campus Mitte, Berlin, Augustenburger Platz 1, 13353 Berlin, for providing Figure 1.

Dr. Afshan Hameed: The authors have done an outstanding job in summarizing this very important topic. Cardiovascular disease is a major cause of maternal morbidity and mortality worldwide. Early recognition of signs and symptoms suggestive of cardiac disease, and prompt referrals and diagnostic testing play a key role in preventing complications. Persistent symptoms of shortness of breath, cough, dizziness, or palpitations in pregnancy should prompt further work up and must not be ignored. Women with pre-existing cardiac disease should receive contraception advice, family planning counselling, referral to a geneticist in cases of congenital heart disease, and preconception counselling by Maternal Fetal Medicine specialist and a cardiologist. Ideally, their underlying condition should be maximally optimized to achieve best possible outcomes for the mother and the fetus. Care of women with cardiac issues extends beyond pregnancy and postpartum period. High risk women should be referred to tertiary care centers with expertise in managing such women in a multidisciplinary manner. Fortunately, most women with cardiac disease tend to have safe and successful pregnancies with meticulous followup.

13 References 1.

Weiss BM, von Segesser LK, Alon E, Seifert B, Turina MI. Outcome of cardiovascular surgery and pregnancy: a systematic review of the period 1984-1996. American journal of obstetrics and gynecology 1998;179:1643-53.

2.

Roos-Hesselink JW, Ruys TP, Stein JI, Thilen U, Webb GD, Niwa K et al. Outcome of pregnancy in patients with structural or ischaemic heart disease: results of a registry of the European Society of Cardiology. European heart journal 2013;34:657-65.

64

3.

Regitz-Zagrosek V, Blomstrom Lundqvist C, Borghi C, Cifkova R, Ferreira R, Foidart JM et al. ESC Guidelines on the management of cardiovascular diseases during pregnancy: The Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC). European heart journal 2011;32:3147-97.

4.

Peters RM, Flack JM. Hypertensive disorders of pregnancy. J Obstet Gynecol Neonatal Nurs 2004;33:209-20.

5.

Stangl V, Schad J, Gossing G, Borges A, Baumann G, Stangl K. Maternal heart disease and pregnancy outcome: a single-centre experience. European journal of heart failure 2008;10:855-60.

6.

Siu SC, Sermer M, Colman JM, Alvarez AN, Mercier LA, Morton BC et al. Prospective multicenter study of pregnancy outcomes in women with heart disease. Circulation 2001;104:515-21.

7.

Cantwell R, Clutton-Brock T, Cooper G, Dawson A, Drife J, Garrod D et al. Saving Mothers' Lives: Reviewing maternal deaths to make motherhood safer: 2006-2008. The Eighth Report of the Confidential Enquiries into Maternal Deaths in the United Kingdom. BJOG : an international journal of obstetrics and gynaecology 2011;118 Suppl 1:1-203.

8.

Anderson GD. Pregnancy-induced changes in pharmacokinetics: a mechanisticbased approach. Clin Pharmacokinet 2005;44:989-1008.

9.

Thorne S, MacGregor A, Nelson-Piercy C. Risks of contraception and pregnancy in heart disease. Heart 2006;92:1520-5.

10.

Burn J, Brennan P, Little J, Holloway S, Coffey R, Somerville J et al. Recurrence risks in offspring of adults with major heart defects: results from first cohort of British collaborative study. Lancet 1998;351:311-6.

11.

Pierpont ME, Basson CT, Benson DW, Jr., Gelb BD, Giglia TM, Goldmuntz E et al. Genetic basis for congenital heart defects: current knowledge: a scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council

65

on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 2007;115:3015-38. 12.

Hyett J, Perdu M, Sharland G, Snijders R, Nicolaides KH. Using fetal nuchal translucency to screen for major congenital cardiac defects at 10-14 weeks of gestation: population based cohort study. BMJ 1999;318:81-5.

13.

Drenthen W, Boersma E, Balci A, Moons P, Roos-Hesselink JW, Mulder BJ et al. Predictors of pregnancy complications in women with congenital heart disease. European heart journal 2010;31:2124-32.

14.

Khairy P, Ouyang DW, Fernandes SM, Lee-Parritz A, Economy KE, Landzberg MJ. Pregnancy outcomes in women with congenital heart disease. Circulation 2006;113:517-24.

15.

Song YB, Park SW, Kim JH, Shin DH, Cho SW, Choi JO et al. Outcomes of pregnancy in women with congenital heart disease: a single center experience in Korea. J Korean Med Sci 2008;23:808-13.

16.

Tanous D, Siu SC, Mason J, Greutmann M, Wald RM, Parker JD et al. B-type natriuretic peptide in pregnant women with heart disease. Journal of the American College of Cardiology 2010;56:1247-53.

17.

Siu SC, Colman JM, Sorensen S, Smallhorn JF, Farine D, Amankwah KS et al. Adverse neonatal and cardiac outcomes are more common in pregnant women with cardiac disease. Circulation 2002;105:2179-84.

18.

Drenthen W, Pieper PG, Roos-Hesselink JW, van Lottum WA, Voors AA, Mulder BJ et al. Outcome of pregnancy in women with congenital heart disease: a literature review. Journal of the American College of Cardiology 2007;49:2303-11.

19.

Lui GK, Silversides CK, Khairy P, Fernandes SM, Valente AM, Nickolaus MJ et al. Heart Rate Response During Exercise and Pregnancy Outcome in Women With Congenital Heart Disease. Circulation 2011;123:242-248.

20.

Brent RL. The effect of embryonic and fetal exposure to x-ray, microwaves, and ultrasound: counseling the pregnant and nonpregnant patient about these risks. Semin Oncol 1989;16:347-68.

66

21.

ACOG Committee Opinion. Number 299, September 2004 (replaces No. 158, September 1995). Guidelines for diagnostic imaging during pregnancy. Obstetrics and gynecology 2004;104:647-51.

22.

Bourguignon MH. Implications of ICRP 60 and the patient directive 97/43 Euratom for nuclear medicine. Q J Nucl Med 2000;44:301-9.

23.

Osei EK, Faulkner K. Fetal doses from radiological examinations. Br J Radiol 1999;72:773-80.

24.

Patel SJ, Reede DL, Katz DS, Subramaniam R, Amorosa JK. Imaging the pregnant patient for nonobstetric conditions: algorithms and radiation dose considerations. Radiographics 2007;27:1705-22.

25.

Shellock FG, Crues JV. MR procedures: biologic effects, safety, and patient care. Radiology 2004;232:635-52.

26.

De Wilde JP, Rivers AW, Price DL. A review of the current use of magnetic resonance imaging in pregnancy and safety implications for the fetus. Prog Biophys Mol Biol 2005;87:335-53.

27.

Kanal E, Barkovich AJ, Bell C, Borgstede JP, Bradley WG, Jr., Froelich JW et al. ACR guidance document for safe MR practices: 2007. AJR Am J Roentgenol 2007;188:1447-74.

28.

Thaman R, Varnava A, Hamid MS, Firoozi S, Sachdev B, Condon M et al. Pregnancy related

complications

in

women

with

hypertrophic

cardiomyopathy.

Heart

2003;89:752-6. 29.

Neilson JP, Alfirevic Z. Doppler ultrasound for fetal assessment in high risk pregnancies. Cochrane Database Syst Rev 2000:CD000073.

30.

Manning FA. Fetal biophysical profile. Obstet Gynecol Clin North Am 1999;26:557-77, v.

31.

Chambers CE, Clark SL. Cardiac surgery during pregnancy. Clin Obstet Gynecol 1994;37:316-23.

32.

Salazar E, Zajarias A, Gutierrez N, Iturbe I. The problem of cardiac valve prostheses, anticoagulants, and pregnancy. Circulation 1984;70:I169-77.

67

33.

Becker RM. Intracardiac surgery in pregnant women. The Annals of thoracic surgery 1983;36:453-8.

34.

Chandrasekhar S, Cook CR, Collard CD. Cardiac surgery in the parturient. Anesthesia and analgesia 2009;108:777-85.

35.

Avila WS, Rossi EG, Ramires JA, Grinberg M, Bortolotto MR, Zugaib M et al. Pregnancy in patients with heart disease: experience with 1,000 cases. Clin Cardiol 2003;26:135-42.

36.

Habib G, Hoen B, Tornos P, Thuny F, Prendergast B, Vilacosta I et al. Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009): the Task Force on the Prevention, Diagnosis, and Treatment of Infective Endocarditis of the European Society of Cardiology (ESC). European heart journal 2009;30:2369413.

37.

Warnes CA, Williams RG, Bashore TM, Child JS, Connolly HM, Dearani JA et al. ACC/AHA 2008 guidelines for the management of adults with congenital heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Develop Guidelines on the Management of Adults With Congenital Heart Disease). Developed in Collaboration With the American Society of Echocardiography, Heart Rhythm Society, International Society for Adult Congenital Heart Disease, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Journal of the American College of Cardiology 2008;52:e1-121.

38.

Schaefer C, Spielmann, H., Vetter, K. Arzneiverordnung in der Schwangerschaft und Stillzeit. München: Urban & Fischer, 2006.

39.

Warnes CA, Williams RG, Bashore TM, Child JS, Connolly HM, Dearani JA et al. ACC/AHA 2008 Guidelines for the Management of Adults with Congenital Heart Disease:

Executive

Summary:

a

report

of

the

American

College

of

Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to develop guidelines for the management of adults with congenital heart disease). Circulation 2008;118:2395-451.

68

40.

Bonow RO, Carabello BA, Chatterjee K, de Leon AC, Jr., Faxon DP, Freed MD et al. 2008 Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular

Heart

Disease):

endorsed

by

the

Society

of

Cardiovascular

Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2008;118:e523-661. 41.

Goldszmidt E, Macarthur A, Silversides C, Colman J, Sermer M, Siu S. Anesthetic management of a consecutive cohort of women with heart disease for labor and delivery. International journal of obstetric anesthesia 2010;19:266-72.

42.

Jain JK, Mishell DR, Jr. A comparison of intravaginal misoprostol with prostaglandin E2 for termination of second-trimester pregnancy. N Engl J Med 1994;331:290-3.

43.

Secher NJ, Thayssen P, Arnsbo P, Olsen J. Effect of prostaglandin E2 and F2alpha on the systemic and pulmonary circulation in pregnant anesthetized women. Acta Obstet Gynecol Scand 1982;61:213-8.

44.

Fesslova VM, Villa L, Chessa M, Butera G, Salmona S, Acaia B. Prospective evaluation from single centre of pregnancy in women with congenital heart disease. International journal of cardiology 2009;131:257-64.

45.

Balint OH, Siu SC, Mason J, Grewal J, Wald R, Oechslin EN et al. Cardiac outcomes after pregnancy in women with congenital heart disease. Heart 2010;96:1656-61.

46.

Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). European heart journal 2009;30:2493-537.

69

47.

Weiss BM, Zemp L, Seifert B, Hess OM. Outcome of pulmonary vascular disease in pregnancy: a systematic overview from 1978 through 1996. Journal of the American College of Cardiology 1998;31:1650-7.

48.

Bedard E, Dimopoulos K, Gatzoulis MA. Has there been any progress made on pregnancy outcomes among women with pulmonary arterial hypertension? European heart journal 2009;30:256-65.

49.

Katsuragi S, Yamanaka K, Neki R, Kamiya C, Sasaki Y, Osato K et al. Maternal outcome in pregnancy complicated with pulmonary arterial hypertension. Circulation journal : official journal of the Japanese Circulation Society 2012;76:2249-54.

50.

Subbaiah M, Sharma V, Kumar S, Rajeshwari S, Kothari SS, Roy KK et al. Heart disease in pregnancy: cardiac and obstetric outcomes. Archives of gynecology and obstetrics 2013.

51.

Jais X, Olsson KM, Barbera JA, Blanco I, Torbicki A, Peacock A et al. Pregnancy outcomes in pulmonary arterial hypertension in the modern management era. The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology 2012;40:881-5.

52.

Kiely DG, Condliffe R, Webster V, Mills GH, Wrench I, Gandhi SV et al. Improved survival in pregnancy and pulmonary hypertension using a multiprofessional approach. BJOG : an international journal of obstetrics and gynaecology 2010;117:565-74.

53.

Presbitero P, Somerville J, Stone S, Aruta E, Spiegelhalter D, Rabajoli F. Pregnancy in cyanotic congenital heart disease. Outcome of mother and fetus. Circulation 1994;89:2673-6.

54.

Yap SC, Drenthen W, Pieper PG, Moons P, Mulder BJ, Vliegen HW et al. Pregnancy outcome in women with repaired versus unrepaired isolated ventricular septal defect. BJOG : an international journal of obstetrics and gynaecology 2010;117:683-9.

55.

Webb G, Gatzoulis MA. Atrial septal defects in the adult: recent progress and overview. Circulation 2006;114:1645-53.

70

56.

Yap SC, Drenthen W, Meijboom FJ, Moons P, Mulder BJ, Vliegen HW et al. Comparison of pregnancy outcomes in women with repaired versus unrepaired atrial septal defect. BJOG : an international journal of obstetrics and gynaecology 2009;116:1593-601.

57.

Drenthen W, Pieper PG, van der Tuuk K, Roos-Hesselink JW, Voors AA, Mostert B et al. Cardiac complications relating to pregnancy and recurrence of disease in the offspring of women with atrioventricular septal defects. European heart journal 2005;26:2581-7.

58.

Vriend JW, Drenthen W, Pieper PG, Roos-Hesselink JW, Zwinderman AH, van Veldhuisen DJ et al. Outcome of pregnancy in patients after repair of aortic coarctation. European heart journal 2005;26:2173-8.

59.

Beauchesne LM, Connolly HM, Ammash NM, Warnes CA. Coarctation of the aorta: outcome of pregnancy. Journal of the American College of Cardiology 2001;38:172833.

60.

Krieger EV, Landzberg MJ, Economy KE, Webb GD, Opotowsky AR. Comparison of risk of hypertensive complications of pregnancy among women with versus without coarctation of the aorta. The American journal of cardiology 2011;107:1529-34.

61.

Hameed A, Karaalp IS, Tummala PP, Wani OR, Canetti M, Akhter MW et al. The effect of valvular heart disease on maternal and fetal outcome of pregnancy. Journal of the American College of Cardiology 2001;37:893-9.

62.

Drenthen W, Pieper PG, Roos-Hesselink JW, Schmidt AC, Mulder BJ, van Dijk AP et al. Non-cardiac complications during pregnancy in women with isolated congenital pulmonary valvar stenosis. Heart 2006;92:1838-43.

63.

Hameed AB, Goodwin TM, Elkayam U. Effect of pulmonary stenosis on pregnancy outcomes--a case-control study. American heart journal 2007;154:852-4.

64.

Greutmann M, Von Klemperer K, Brooks R, Peebles D, O'Brien P, Walker F. Pregnancy outcome in women with congenital heart disease and residual haemodynamic lesions of the right ventricular outflow tract. European heart journal 2010;31:1764-70.

71

65.

Veldtman GR, Connolly HM, Grogan M, Ammash NM, Warnes CA. Outcomes of pregnancy in women with tetralogy of Fallot. Journal of the American College of Cardiology 2004;44:174-80.

66.

Balci A, Drenthen W, Mulder BJ, Roos-Hesselink JW, Voors AA, Vliegen HW et al. Pregnancy in women with corrected tetralogy of Fallot: occurrence and predictors of adverse events. American heart journal 2011;161:307-13.

67.

Egidy Assenza G, Cassater D, Landzberg M, Geva T, Schreier J, Graham D et al. The effects of pregnancy on right ventricular remodeling in women with repaired tetralogy of Fallot. International journal of cardiology 2013.

68.

Donnelly JE, Brown JM, Radford DJ. Pregnancy outcome and Ebstein's anomaly. Br Heart J 1991;66:368-71.

69.

Connolly HM, Warnes CA. Ebstein's anomaly: outcome of pregnancy. Journal of the American College of Cardiology 1994;23:1194-8.

70.

Drenthen W, Pieper PG, Ploeg M, Voors AA, Roos-Hesselink JW, Mulder BJ et al. Risk of complications during pregnancy after Senning or Mustard (atrial) repair of complete transposition of the great arteries. European heart journal 2005;26:2588-95.

71.

Therrien J, Barnes I, Somerville J. Outcome of pregnancy in patients with congenitally corrected transposition of the great arteries. The American journal of cardiology 1999;84:820-4.

72.

Hornung TS, Bernard EJ, Celermajer DS, Jaeggi E, Howman-Giles RB, Chard RB et al. Right ventricular dysfunction in congenitally corrected transposition of the great arteries. The American journal of cardiology 1999;84:1116-9, A10.

73.

Guedes A, Mercier LA, Leduc L, Berube L, Marcotte F, Dore A. Impact of pregnancy on the systemic right ventricle after a Mustard operation for transposition of the great arteries. Journal of the American College of Cardiology 2004;44:433-7.

74.

Zentner D, Wheeler M, Grigg L. Does pregnancy contribute to systemic right ventricular dysfunction in adults with an atrial switch operation? Heart, lung & circulation 2012;21:433-8.

72

75.

Tobler D, Fernandes SM, Wald RM, Landzberg M, Salehian O, Siu SC et al. Pregnancy outcomes in women with transposition of the great arteries and arterial switch operation. The American journal of cardiology 2010;106:417-20.

76.

Drenthen W, Pieper PG, Roos-Hesselink JW, van Lottum WA, Voors AA, Mulder BJ et al. Pregnancy and delivery in women after Fontan palliation. Heart 2006;92:1290-4.

77.

Canobbio MM, Mair DD, van der Velde M, Koos BJ. Pregnancy outcomes after the Fontan repair. Journal of the American College of Cardiology 1996;28:763-7.

78.

Hayes CJ, Gersony WM, Driscoll DJ, Keane JF, Kidd L, O'Fallon WM et al. Second natural history study of congenital heart defects. Results of treatment of patients with pulmonary valvar stenosis. Circulation 1993;87:I28-37.

79.

Manalo-Estrella P, Barker AE. Histopathologic findings in human aortic media associated with pregnancy. Arch Pathol 1967;83:336-41.

80.

Januzzi JL, Isselbacher EM, Fattori R, Cooper JV, Smith DE, Fang J et al. Characterizing the young patient with aortic dissection: results from the International Registry of Aortic Dissection (IRAD). Journal of the American College of Cardiology 2004;43:665-9.

81.

Katz NM, Collea JV, Moront MG, MacKenzie RD, Wallace RB. Aortic dissection during pregnancy: treatment by emergency cesarean section immediately followed by operative repair of the aortic dissection. The American journal of cardiology 1984;54:699-701.

82.

Pyeritz RE. Maternal and fetal complications of pregnancy in the Marfan syndrome. Am J Med 1981;71:784-90.

83.

Therrien J, Gatzoulis M, Graham T, Bink-Boelkens M, Connelly M, Niwa K et al. Canadian

Cardiovascular

Society

Consensus

Conference

2001

update:

Recommendations for the Management of Adults with Congenital Heart Disease-Part II. Can J Cardiol 2001;17:1029-50. 84.

Deanfield J, Thaulow E, Warnes C, Webb G, Kolbel F, Hoffman A et al. Management of grown up congenital heart disease. European heart journal 2003;24:1035-84.

73

85.

Immer FF, Bansi AG, Immer-Bansi AS, McDougall J, Zehr KJ, Schaff HV et al. Aortic dissection in pregnancy: analysis of risk factors and outcome. The Annals of thoracic surgery 2003;76:309-14.

86.

Katsuragi S, Ueda K, Yamanaka K, Neki R, Kamiya C, Sasaki Y et al. Pregnancyassociated aortic dilatation or dissection in Japanese women with Marfan syndrome. Circulation journal : official journal of the Japanese Circulation Society 2011;75:254551.

87.

Meijboom LJ, Vos FE, Timmermans J, Boers GH, Zwinderman AH, Mulder BJ. Pregnancy and aortic root growth in the Marfan syndrome: a prospective study. European heart journal 2005;26:914-20.

88.

Donnelly RT, Pinto NM, Kocolas I, Yetman AT. The immediate and long-term impact of pregnancy on aortic growth rate and mortality in women with Marfan syndrome. Journal of the American College of Cardiology 2012;60:224-9.

89.

McKellar SH, MacDonald RJ, Michelena HI, Connolly HM, Sundt TM, 3rd. Frequency of cardiovascular events in women with a congenitally bicuspid aortic valve in a single community and effect of pregnancy on events. The American journal of cardiology 2011;107:96-9.

90.

Baumgartner H, Bonhoeffer P, De Groot NM, de Haan F, Deanfield JE, Galie N et al. ESC Guidelines for the management of grown-up congenital heart disease (new version 2010). European heart journal 2010;31:2915-57.

91.

Pepin M, Schwarze U, Superti-Furga A, Byers PH. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med 2000;342:673-80.

92.

Ong KT, Perdu J, De Backer J, Bozec E, Collignon P, Emmerich J et al. Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial. Lancet 2010;376:1476-84.

93.

Matura LA, Ho VB, Rosing DR, Bondy CA. Aortic dilatation and dissection in Turner syndrome. Circulation 2007;116:1663-70.

74

94.

Alvaro Mercadal B, Imbert R, Demeestere I, Englert Y, Delbaere A. Pregnancy outcome after oocyte donation in patients with Turner's syndrome and partial X monosomy. Human reproduction 2011;26:2061-8.

95.

Gersony DR, McClaughlin MA, Jin Z, Gersony WM. The effect of beta-blocker therapy on clinical outcome in patients with Marfan's syndrome: a meta-analysis. International journal of cardiology 2007;114:303-8.

96.

Gordon CF, 3rd, Johnson MD. Anesthetic management of the pregnant patient with Marfan syndrome. J Clin Anesth 1993;5:248-51.

97.

Watkins DA, Sebitloane M, Engel ME, Mayosi BM. The burden of antenatal heart disease in South Africa: a systematic review. BMC cardiovascular disorders 2012;12:23.

98.

Lesniak-Sobelga A, Tracz W, KostKiewicz M, Podolec P, Pasowicz M. Clinical and echocardiographic assessment of pregnant women with valvular heart diseases-maternal and fetal outcome. International journal of cardiology 2004;94:15-23.

99.

Joint Task Force on the Management of Valvular Heart Disease of the European Society of C, European Association for Cardio-Thoracic S, Vahanian A, Alfieri O, Andreotti F, Antunes MJ et al. Guidelines on the management of valvular heart disease (version 2012). European heart journal 2012;33:2451-96.

100.

Baumgartner H, Hung J, Bermejo J, Chambers JB, Evangelista A, Griffin BP et al. Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice. Eur J Echocardiogr 2009;10:1-25.

101.

Silversides CK, Colman JM, Sermer M, Siu SC. Cardiac risk in pregnant women with rheumatic mitral stenosis. The American journal of cardiology 2003;91:1382-5.

102.

Gumrukcuoglu HA, Guler A, Odabasi D, Simsek H, Sahin M, Akdag S et al. Clinical and echocardiographic follow-up in pregnant patients with valvular heart disease. Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidir 2013;41:31-7.

75

103.

Diao M, Kane A, Ndiaye MB, Mbaye A, Bodian M, Dia MM et al. Pregnancy in women with heart disease in sub-Saharan Africa. Archives of cardiovascular diseases 2011;104:370-4.

104.

Elkayam U, Bitar F. Valvular heart disease and pregnancy part I: native valves. Journal of the American College of Cardiology 2005;46:223-30.

105.

Hameed AB, Mehra A, Rahimtoola SH. The role of catheter balloon commissurotomy for severe mitral stenosis in pregnancy. Obstetrics and gynecology 2009;114:133640.

106.

Elkayam U. Cardiac problems in pregnancy. In: Elkayam U, editor Cardiac problems in pregnancy, 3rd ed. New York: Wiley-Liss, 1998.

107.

Silversides CK, Colman JM, Sermer M, Farine D, Siu SC. Early and intermediateterm outcomes of pregnancy with congenital aortic stenosis. The American journal of cardiology 2003;91:1386-9.

108.

Yap SC, Drenthen W, Pieper PG, Moons P, Mulder BJ, Mostert B et al. Risk of complications during pregnancy in women with congenital aortic stenosis. International journal of cardiology 2008;126:240-6.

109.

Khairy P, Ionescu-Ittu R, Mackie AS, Abrahamowicz M, Pilote L, Marelli AJ. Changing mortality in congenital heart disease. Journal of the American College of Cardiology 2010;56:1149-57.

110.

Mokhles MM, Rizopoulos D, Andrinopoulou ER, Bekkers JA, Roos-Hesselink JW, Lesaffre E et al. Autograft and pulmonary allograft performance in the second postoperative decade after the Ross procedure: insights from the Rotterdam Prospective Cohort Study. European heart journal 2012;33:2213-24.

111.

Vahanian A, Baumgartner H, Bax J, Butchart E, Dion R, Filippatos G et al. Guidelines on the management of valvular heart disease: The Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology. European heart journal 2007;28:230-68.

112.

Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial

76

Fibrillation of the European Society of Cardiology (ESC). European heart journal 2010;31:2369-429. 113.

Bhargava B, Agarwal R, Yadav R, Bahl VK, Manchanda SC. Percutaneous balloon aortic valvuloplasty during pregnancy: use of the Inoue balloon and the physiologic antegrade approach. Cathet Cardiovasc Diagn 1998;45:422-5.

114.

Sillesen M, Hjortdal V, Vejlstrup N, Sorensen K. Pregnancy with prosthetic heart valves - 30 years' nationwide experience in Denmark. European journal of cardiothoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 2011.

115.

Hung L, Rahimtoola SH. Prosthetic heart valves and pregnancy. Circulation 2003;107:1240-6.

116.

Elkayam U, Bitar F. Valvular heart disease and pregnancy: part II: prosthetic valves. Journal of the American College of Cardiology 2005;46:403-10.

117.

Rahimtoola SH. Choice of prosthetic heart valve in adults an update. Journal of the American College of Cardiology 2010;55:2413-26.

118.

Yap SC, Drenthen W, Pieper PG, Moons P, Mulder BJ, Klieverik LM et al. Outcome of pregnancy in women after pulmonary autograft valve replacement for congenital aortic valve disease. The Journal of heart valve disease 2007;16:398-403.

119.

Arabkhani B, Heuvelman HJ, Bogers AJ, Mokhles MM, Roos-Hesselink JW, Takkenberg JJ. Does pregnancy influence the durability of human aortic valve substitutes? Journal of the American College of Cardiology 2012;60:1991-2.

120.

Heuvelman HJ, Arabkhani B, Cornette JM, Pieper PG, Bogers AJ, Takkenberg JJ et al. Pregnancy outcomes in women with aortic valve substitutes. The American journal of cardiology 2013;111:382-7.

121.

Abildgaard U, Sandset PM, Hammerstrom J, Gjestvang FT, Tveit A. Management of pregnant women with mechanical heart valve prosthesis: thromboprophylaxis with low molecular weight heparin. Thrombosis research 2009;124:262-7.

77

122.

Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature. Arch Intern Med 2000;160:191-6.

123.

Oran B, Lee-Parritz A, Ansell J. Low molecular weight heparin for the prophylaxis of thromboembolism in women with prosthetic mechanical heart valves during pregnancy. Thromb Haemost 2004;92:747-51.

124.

Elkayam U, Singh H, Irani A, Akhter MW. Anticoagulation in pregnant women with prosthetic heart valves. Journal of cardiovascular pharmacology and therapeutics 2004;9:107-15.

125.

McLintock C, McCowan LM, North RA. Maternal complications and pregnancy outcome in women with mechanical prosthetic heart valves treated with enoxaparin. BJOG : an international journal of obstetrics and gynaecology 2009;116:1585-92.

126.

Quinn J, Von Klemperer K, Brooks R, Peebles D, Walker F, Cohen H. Use of high intensity adjusted dose low molecular weight heparin in women with mechanical heart valves during pregnancy: a single-center experience. Haematologica 2009;94:160812.

127.

Yinon Y, Siu SC, Warshafsky C, Maxwell C, McLeod A, Colman JM et al. Use of low molecular weight heparin in pregnant women with mechanical heart valves. The American journal of cardiology 2009;104:1259-63.

128.

Nelson-Piercy C, Greer IA. Anticoagulation with Tinzaparin for women with mechanical valves in pregnancy: a retrospective case series. Thrombosis research 2013;131:185-6.

129.

Barbour LA, Oja JL, Schultz LK. A prospective trial that demonstrates that dalteparin requirements increase in pregnancy to maintain therapeutic levels of anticoagulation. American journal of obstetrics and gynecology 2004;191:1024-9.

130.

Friedrich E, Hameed AB. Fluctuations in anti-factor Xa levels with therapeutic enoxaparin anticoagulation in pregnancy. Journal of perinatology : official journal of the California Perinatal Association 2010;30:253-7.

78

131.

McLintock C. Anticoagulant choices in pregnant women with mechanical heart valves: balancing maternal and fetal risks--the difference the dose makes. Thrombosis research 2013;131 Suppl 1:S8-10.

132.

Elkayam U, Goland S. The search for a safe and effective anticoagulation regimen in pregnant women with mechanical prosthetic heart valves. Journal of the American College of Cardiology 2012;59:1116-8.

133.

Schaefer C, Hannemann D, Meister R, Elefant E, Paulus W, Vial T et al. Vitamin K antagonists and pregnancy outcome. A multi-centre prospective study. Thromb Haemost 2006;95:949-57.

134.

Meschengieser SS, Fondevila CG, Santarelli MT, Lazzari MA. Anticoagulation in pregnant women with mechanical heart valve prostheses. Heart 1999;82:23-6.

135.

Vitale N, De Feo M, De Santo LS, Pollice A, Tedesco N, Cotrufo M. Dose-dependent fetal complications of warfarin in pregnant women with mechanical heart valves. Journal of the American College of Cardiology 1999;33:1637-41.

136.

Cotrufo M, De Feo M, De Santo LS, Romano G, Della Corte A, Renzulli A et al. Risk of warfarin during pregnancy with mechanical valve prostheses. Obstetrics and gynecology 2002;99:35-40.

137.

Khamooshi AJ, Kashfi F, Hoseini S, Tabatabaei MB, Javadpour H, Noohi F. Anticoagulation for prosthetic heart valves in pregnancy. Is there an answer? Asian cardiovascular & thoracic annals 2007;15:493-6.

138.

Geelani MA, Singh S, Verma A, Nagesh A, Betigeri V, Nigam M. Anticoagulation in patients with mechanical valves during pregnancy. Asian cardiovascular & thoracic annals 2005;13:30-3.

139.

Mazibuko B, Ramnarain H, Moodley J. An audit of pregnant women with prosthetic heart valves at a tertiary hospital in South Africa: a five-year experience. Cardiovascular journal of Africa 2012;23:216-21.

140.

van Driel D, Wesseling J, Sauer PJ, Touwen BC, van der Veer E, Heymans HS. Teratogen update: fetal effects after in utero exposure to coumarins overview of cases, follow-up findings, and pathogenesis. Teratology 2002;66:127-40.

79

141.

Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e691S-736S.

142.

Butchart EG, Gohlke-Barwolf C, Antunes MJ, Tornos P, De Caterina R, Cormier B et al. Recommendations for the management of patients after heart valve surgery. European heart journal 2005;26:2463-71.

143.

Bonow RO, Carabello BA, Chatterjee K, de Leon AC, Jr., Faxon DP, Freed MD et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing Committee to Revise the 1998 guidelines for the management of patients with valvular heart disease) developed in collaboration with the Society of Cardiovascular Anesthesiologists endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. Journal of the American College of Cardiology 2006;48:e1-148.

144.

Lebaudy C, Hulot JS, Amoura Z, Costedoat-Chalumeau N, Serreau R, Ankri A et al. Changes in enoxaparin pharmacokinetics during pregnancy and implications for antithrombotic therapeutic strategy. Clin Pharmacol Ther 2008;84:370-7.

145.

Bush N, Nelson-Piercy C, Spark P, Kurinczuk JJ, Brocklehurst P, Knight M et al. Myocardial infarction in pregnancy and postpartum in the UK. European journal of preventive cardiology 2013;20:12-20.

146.

Roth A, Elkayam U. Acute myocardial infarction associated with pregnancy. Journal of the American College of Cardiology 2008;52:171-80.

147.

James AH, Jamison MG, Biswas MS, Brancazio LR, Swamy GK, Myers ER. Acute myocardial infarction in pregnancy: a United States population-based study. Circulation 2006;113:1564-71.

148.

O'Donoghue M, Boden WE, Braunwald E, Cannon CP, Clayton TC, de Winter RJ et al. Early invasive vs conservative treatment strategies in women and men with

80

unstable angina and non-ST-segment elevation myocardial infarction: a metaanalysis. JAMA : the journal of the American Medical Association 2008;300:71-80. 149.

Sliwa K, Hilfiker-Kleiner D, Petrie MC, Mebazaa A, Pieske B, Buchmann E et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of peripartum cardiomyopathy: a position statement from the Heart Failure Association of the European Society of Cardiology Working Group on peripartum cardiomyopathy. European journal of heart failure 2010;12:767-78.

150.

Sliwa K, Fett J, Elkayam U. Peripartum cardiomyopathy. Lancet 2006;368:687-93.

151.

Hilfiker-Kleiner D, Kaminski K, Podewski E, Bonda T, Schaefer A, Sliwa K et al. A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell 2007;128:589-600.

152.

Patten IS, Rana S, Shahul S, Rowe GC, Jang C, Liu L et al. Cardiac angiogenic imbalance leads to peripartum cardiomyopathy. Nature 2012;485:333-8.

153.

Morales A, Painter T, Li R, Siegfried JD, Li D, Norton N et al. Rare variant mutations in pregnancy-associated or peripartum cardiomyopathy. Circulation 2010;121:217682.

154.

van Spaendonck-Zwarts KY, van Tintelen JP, van Veldhuisen DJ, van der Werf R, Jongbloed JD, Paulus WJ et al. Peripartum cardiomyopathy as a part of familial dilated cardiomyopathy. Circulation 2010;121:2169-75.

155.

Walenta K, Schwarz V, Schirmer SH, Kindermann I, Friedrich EB, Solomayer EF et al. Circulating microparticles as indicators of peripartum cardiomyopathy. European heart journal 2012;33:1469-79.

156.

Habli M, O'Brien T, Nowack E, Khoury S, Barton JR, Sibai B. Peripartum cardiomyopathy: prognostic factors for long-term maternal outcome. American journal of obstetrics and gynecology 2008;199:415 e1-5.

157.

Elkayam U. Clinical characteristics of peripartum cardiomyopathy in the United States: diagnosis, prognosis, and management. Journal of the American College of Cardiology 2011;58:659-70.

81

158.

Brenner B. Haemostatic changes in pregnancy. Thrombosis research 2004;114:40914.

159.

Sliwa K, Blauwet L, Tibazarwa K, Libhaber E, Smedema JP, Becker A et al. Evaluation

of bromocriptine

in

the treatment of acute severe peripartum

cardiomyopathy: a proof-of-concept pilot study. Circulation 2010;121:1465-73. 160.

McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. European journal of heart failure 2012;14:803-69.

161.

Silversides CK, Harris L, Haberer K, Sermer M, Colman JM, Siu SC. Recurrence rates of arrhythmias during pregnancy in women with previous tachyarrhythmia and impact on fetal and neonatal outcomes. The American journal of cardiology 2006;97:1206-12.

162.

Elkayam U, Goodwin TM. Adenosine therapy for supraventricular tachycardia during pregnancy. The American journal of cardiology 1995;75:521-3.

163.

Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. European heart journal 2012;33:2719-47.

164.

Kockova R, Kocka V, Kiernan T, Fahy GJ. Ibutilide-induced cardioversion of atrial fibrillation during pregnancy. J Cardiovasc Electrophysiol 2007;18:545-7.

165.

Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillationexecutive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001

82

Guidelines for the Management of Patients with Atrial Fibrillation). European heart journal 2006;27:1979-2030. 166.

Natale A, Davidson T, Geiger MJ, Newby K. Implantable cardioverter-defibrillators and pregnancy: a safe combination? Circulation 1997;96:2808-12.

167.

Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death--executive summary: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. European heart journal 2006;27:2099-140.

168.

Rashba EJ, Zareba W, Moss AJ, Hall WJ, Robinson J, Locati EH et al. Influence of pregnancy on the risk for cardiac events in patients with hereditary long QT syndrome. LQTS Investigators. Circulation 1998;97:451-6.

169.

Drost J, van der Schouw Y, Maas A, Verschuren W. Longitudinal analysis of cardiovascular risk parameters in women with a history of hypertensive pregnancy disorders: the Doetinchem Cohort Study. BJOG : an international journal of obstetrics and gynaecology 2013.

170.

Orbach H, Matok I, Gorodischer R, Sheiner E, Daniel S, Wiznitzer A et al. Hypertension and antihypertensive drugs in pregnancy and perinatal outcomes. American journal of obstetrics and gynecology 2013;208:301 e1-6.

171.

James PR, Nelson-Piercy C. Management of hypertension before, during, and after pregnancy. Heart 2004;90:1499-504.

172.

National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy. American journal of obstetrics and gynecology 1990;163:1691-712.

83

173.

Peek M, Shennan A, Halligan A, Lambert PC, Taylor DJ, De Swiet M. Hypertension in pregnancy: which method of blood pressure measurement is most predictive of outcome? Obstetrics and gynecology 1996;88:1030-3.

174.

Brown MA, Mangos G, Davis G, Homer C. The natural history of white coat hypertension during pregnancy. BJOG : an international journal of obstetrics and gynaecology 2005;112:601-6.

175.

Brown M. Is there a role for ambulatory blood pressure monitoring in pregnancy? Clinical and experimental pharmacology & physiology 2013.

176.

Rossi GP, Seccia TM, Pessina AC. Clinical use of laboratory tests for the identification of secondary forms of arterial hypertension. Crit Rev Clin Lab Sci 2007;44:1-85.

177.

Cnossen JS, Morris RK, ter Riet G, Mol BW, van der Post JA, Coomarasamy A et al. Use of uterine artery Doppler ultrasonography to predict pre-eclampsia and intrauterine growth restriction: a systematic review and bivariable meta-analysis. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 2008;178:701-11.

178.

Marques FK, Campos FM, Sousa LP, Teixeira-Carvalho A, Dusse LM, Gomes KB. Association of microparticles and preeclampsia. Molecular biology reports 2013.

179.

Levine RJ, Ewell MG, Hauth JC, Curet LB, Catalano PM, Morris CD et al. Should the definition of preeclampsia include a rise in diastolic blood pressure of >/=15 mm Hg to a level <90 mm Hg in association with proteinuria? American journal of obstetrics and gynecology 2000;183:787-92.

180.

Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G et al. 2007 ESH-ESC Practice Guidelines for the Management of Arterial Hypertension: ESHESC Task Force on the Management of Arterial Hypertension. J Hypertens 2007;25:1751-62.

181.

Brown MA, Lindheimer MD, de Swiet M, Van Assche A, Moutquin JM. The classification and diagnosis of the hypertensive disorders of pregnancy: statement

84

from the International Society for the Study of Hypertension in Pregnancy (ISSHP). Hypertens Pregnancy 2001;20:IX-XIV. 182.

Regitz-Zagrosek V, Seeland U, Geibel-Zehender A, Gohlke-Barwolf C, Kruck I, Schaefer

C.

Cardiovascular

diseases

in

pregnancy.

Deutsches

Arzteblatt

international 2011;108:267-73. 183.

Hofmeyr GJ, Atallah AN, Duley L. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database Syst Rev 2006;3:CD001059.

184.

Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev 2007:CD004659.

185.

Villa PM, Kajantie E, Raikkonen K, Pesonen AK, Hamalainen E, Vainio M et al. Aspirin in the prevention of pre-eclampsia in high-risk women: a randomised placebocontrolled PREDO Trial and a meta-analysis of randomised trials. BJOG : an international journal of obstetrics and gynaecology 2013;120:64-74.

186.

Cockburn J, Moar VA, Ounsted M, Redman CW. Final report of study on hypertension during pregnancy: the effects of specific treatment on the growth and development of the children. Lancet 1982;1:647-9.

187.

Redman CW. Fetal outcome in trial of antihypertensive treatment in pregnancy. Lancet 1976;2:753-6.

188.

Hogstedt S, Lindeberg S, Axelsson O, Lindmark G, Rane A, Sandstrom B et al. A prospective controlled trial of metoprolol-hydralazine treatment in hypertension during pregnancy. Acta Obstet Gynecol Scand 1985;64:505-10.

189.

Markfeld-Erol F, Farthmann J, Prompeler H, Kunze M. [Fetal renal failure after intrauterine exposure to inhibitors of the renin-angiotensin system]. Deutsche medizinische Wochenschrift 2012;137:1297-300.

190.

Magee LA, Cham C, Waterman EJ, Ohlsson A, von Dadelszen P. Hydralazine for treatment of severe hypertension in pregnancy: meta-analysis. Bmj 2003;327:955-60.

191.

Hargood JL, Brown MA. Pregnancy-induced hypertension: recurrence rate in second pregnancies. Med J Aust 1991;154:376-7.

85

192.

Zhang J, Troendle JF, Levine RJ. Risks of hypertensive disorders in the second pregnancy. Paediatr Perinat Epidemiol 2001;15:226-31.

193.

Wilson BJ, Watson MS, Prescott GJ, Sunderland S, Campbell DM, Hannaford P et al. Hypertensive diseases of pregnancy and risk of hypertension and stroke in later life: results from cohort study. Bmj 2003;326:845.

194.

Mosca L, Benjamin EJ, Berra K, Bezanson JL, Dolor RJ, Lloyd-Jones DM et al. Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease in Women--2011 Update: A Guideline From the American Heart Association. Circulation 2011.

195.

Liu S, Rouleau J, Joseph KS, Sauve R, Liston RM, Young D et al. Epidemiology of pregnancy-associated venous thromboembolism: a population-based study in Canada. J Obstet Gynaecol Can 2009;31:611-20.

196.

Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton LJ, 3rd. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30year population-based study. Ann Intern Med 2005;143:697-706.

197.

O'Connor DJ, Scher LA, Gargiulo NJ, 3rd, Jang J, Suggs WD, Lipsitz EC. Incidence and Characteristics of Venous Thromboembolic Disease During Pregnancy and the Postnatal Period: A Contemporary Series. Ann Vasc Surg 2010.

198.

Rutherford SE, Phelan JP. Deep venous thrombosis and pulmonary embolism in pregnancy. Obstet Gynecol Clin North Am 1991;18:345-70.

199.

Sullivan EA, Ford JB, Chambers G, Slaytor EK. Maternal mortality in Australia, 19731996. Aust N Z J Obstet Gynaecol 2004;44:452-7; discussion 377.

200.

CEMACH. CEMACH Saving mothers' lives: reviewing maternal deaths to make motherhood safer — 2003–2005: the seventh report on confidential enquiries into maternal deaths in the United Kingdom. In: Health) CCEiMaC, editor. London: Centre for Maternal and Child Enquiries, 2008.

201.

Knight M. Antenatal pulmonary embolism: risk factors, management and outcomes. BJOG : an international journal of obstetrics and gynaecology 2008;115:453-61.

86

202.

Royal College of Obstetricians and Gynecologists; Reducing the Risk of Thrombosis And Embolism During Pregnancy and the Puerperium. Green-top Guideline No37a, Nov 2009.

203.

Marik PE, Plante LA. Venous thromboembolic disease and pregnancy. N Engl J Med 2008;359:2025-33.

204.

Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood 2005;106:401-7.

205.

Romualdi E, Dentali F, Rancan E, Squizzato A, Steidl L, Middeldorp S et al. Anticoagulant therapy for venous thromboembolism during pregnancy: a systematic review and a meta-analysis of the literature. Journal of thrombosis and haemostasis : JTH 2013;11:270-81.

206.

Chan WS, Lee A, Spencer FA, Crowther M, Rodger M, Ramsay T et al. Predicting deep venous thrombosis in pregnancy: out in "LEFt" field? Ann Intern Med 2009;151:85-92.

207.

Dargaud Y, Rugeri L, Vergnes MC, Arnuti B, Miranda P, Negrier C et al. A risk score for the management of pregnant women with increased risk of venous thromboembolism: a multicentre prospective study. British journal of haematology 2009;145:825-35.

208.

Chan WS, Spencer FA, Lee AY, Chunilal S, Douketis JD, Rodger M et al. Safety of withholding anticoagulation in pregnant women with suspected deep vein thrombosis following negative serial compression ultrasound and iliac vein imaging. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 2013;185:E194-200.

209.

USP DI: Drug Information for the Healthcare Professional. 23rd ed: Thomson Micromedex, 2003.

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14 Tables Table 1: Modified WHO classification of maternal cardiovascular risk: application Conditions in which pregnancy risk is WHO I • Uncomplicated, small or mild - pulmonary stenosis - patent ductus arteriosus - mitral valve prolapse • Successfully repaired simple lesions (atrial or ventricular septal defect, patent ductus arteriosus, anomalous pulmonary venous drainage). • Atrial or ventricular ectopic beats, isolated Conditions in which pregnancy risk is WHO II or III WHO II if otherwise well and uncomplicated) • Unoperated atrial or ventricular septal defect • Repaired tetralogy of Fallot • Most arrhythmias WHO II-III (depending on individual) • Mild left ventricular impairment • Hypertrophic cardiomyopathy • Native or tissue valvular heart disease not considered WHO I or IV • Marfan syndrome without aortic dilatation • Aorta < 45 mm in aortic disease associated with bicuspid aortic valve • Repaired coarctation WHO III • Mechanical valve • Systemic right ventricle • Fontan circulation • Cyanotic heart disease (unrepaired) • Other complex congenital heart disease • Aortic dilatation 40-45 mm in Marfan syndrome • Aortic dilatation 45-50 mm in aortic disease associated with bicuspid aortic valve Conditions in which pregnancy risk is WHO IV (pregnancy contraindicated) • Pulmonary arterial hypertension of any cause • Severe systemic ventricular dysfunction (LVEF < 30%, NYHA III-IV) • Previous peripartum cardiomyopathy with any residual impairment of left ventricular function • Severe mitral stenosis, severe symptomatic aortic stenosis • Marfan syndrome with aorta dilated > 45 mm • Aortic dilatation > 50 mm in aortic disease associated with bicuspid aortic valve • Native severe coarctation Adapted from Thorne et.al.9

LVEF = left ventricular ejection fraction; NYHA = New York Heart Association, WHO = World Health Organization Reproduced with permission from Regitz-Zagrosek et.al. 3

88

Table 2: Estimated fetal and maternal effective doses for various diagnostic and interventional radiology procedures Procedure

Fetal exposure

Maternal exposure

Chest radiograph (PA and lateral)

< 0.01 mGy

< 0.01 mSv

0.1 mGy

0.1 mSv

CT chest

0.3 mGy

0.3 mSv

7 mGy

7 mSv

Coronary angiography*

1.5 mGy

1.5 mSv

7 mGy

7 mSv

3 mGy

3 mSv

15 mGy

15 mSv

PCI

or

radiofrequency

ablation*

catheter

*Exposure depends on the number of projections or views. CT = computed tomography; PA = postero-anterior; PCI = percutaneous coronary intervention Reproduced with permission from Regitz-Zagrosek et.al. 3

Table 3: General recommendations for the management of women with heart disease prior to and during pregnancy Classa,b Pregnancy counselling and risk assessment is indicated in all women I with known or suspected congenital or acquired cardiovascular disease in childbearing age and after conception. High risk patients should be treated in specialized centres by a I multidisciplinary team. Genetic counselling should be offered to women with congenital heart I disease or congenital arrhythmia, cardiomyopathies, aortic disease or genetic malformations associated with cardiovascular diseases. Echocardiography should be performed in any pregnant patient with I unexplained or new cardiovascular signs or symptoms. Caesarean delivery is indicated when labour starts while on oral I anticoagulants MRI (without gadolinium) should be considered if echocardiography is IIa insufficient for diagnosis. Caesarean delivery should be considered for patients with dilatation of IIa the ascending aorta >45 mm, severe aortic stenosis, Eisenmenger syndrome or severe heart failure. A chest radiograph, with shielding of fetus, may be considered if other IIb methods are not successful in clarifying the cause of dyspnoea. Cardiac catheterization may be considered with very strict indications, IIb timing and shielding of fetus. CT and electrophysiological studies, with shielding of fetus, may be IIb considered in selected patients for vital indications. Coronary bypass surgery or valvular surgery may be considered when IIb conservative and medical therapy has failed, in situations that threaten the mother’s life and that are not amenable to percutaneous treatment. Bacterial endocarditis prophylaxis during delivery is not recommended. III a

b

Class of recommendation. Level of evidence of all recommendations is level C

CVD = cardiovascular disease; MRI = magnetic resonance imaging Reproduced and modified with permission from Regitz-Zagrosek et.al.

89

3

Table 4: Recommendations for the management of congenital heart disease Classa Pre-pregnancy relief of stenosis (usually by balloon valvulotomy) should I be performed in severe pulmonary valve stenosis (peak Doppler gradient >64 mmHg). Individual follow-up schedules should be arranged; ranging from twice I during pregnancy to monthly. Symptomatic patients with Ebstein’s anomaly with cyanosis and/or heart I failure should be treated before pregnancy or advised against pregnancy. In symptomatic women with marked dilatation of the right ventricle due to I severe pulmonary regurgitation, pre-pregnancy pulmonary valve replacement (bioprosthesis) should be performed. In asymptomatic women with severely dilated right ventricle due to severe IIa pulmonary regurgitation, pre-pregnancy pulmonary valve replacement (bioprosthesis) should be considered. Anticoagulation treatment should be considered during pregnancy in IIa Fontan patients. In PAH anticoagulant treatment should be considered in patients with IIa suspicion of pulmonary embolism as cause (or partly cause) of the pulmonary hypertension. In patients who are already taking drug therapy for PAH before becoming IIa pregnant, continuation should be considered after information about the teratogenic effects. Women with pulmonary hypertension, or with an oxygen saturation below III 85% at rest, should be advised against pregnancy. Patients with TGA and a systemic right ventricle with > moderate III impairment of RV function and/or severe TR should be advised against pregnancy. Fontan patients with depressed ventricular function and/or moderate to III severe atrioventricular valvular regurgitation or with cyanosis or with protein losing enteropathy should be advised against pregnancy. a

Class of recommendation,

evidence B

37,78

b

recommendation for severe pulmonary valve stenosis is level of

, all others are level C

PAH = pulmonary arterial hypertension; RV = right ventricle; TGA = transposition of the great arteries; TR = tricuspid regurgitation, Reproduced and modified with permission from Regitz-Zagrosek et.al. 3

90

Table 5: Recommendations for the management of aortic diseases Classa, b Women with Marfan syndrome or other known aortic disease should be I counselled about the risk of aortic dissection during pregnancy and the recurrence risk for the offspring. Imaging of the entire aorta (CT/MRI) should be performed before pregnancy in I patients with Marfan syndrome or other known aortic disease. Women with Marfan syndrome and an ascending aorta >45 mm should be I treated surgically pre-pregnancy. In pregnant women with known aortic dilatation, (history of) type B dissection or I genetic predisposition for dissection strict blood pressure control is recommended. Repeated echocardiographic imaging every 4-8 weeks should be performed I during pregnancy in patients with dilatation of the ascending aorta. For imaging of pregnant women with dilatation of distal ascending aorta, aortic I arch or descending aorta, magnetic resonance (without gadolinium) is recommended. In women with a bicuspid aortic valve imaging of the ascending aorta is I recommended. Women with aortic dilatation or (history of) aortic dissection should deliver in a I centre where cardiothoracic surgery is available. Surgical treatment prepregnancy should be considered in women with aortic IIa disease associated with a bicuspid aortic valve when the aortic diameter is > 50mm (or >27 mm/m2 BSA). Prophylactic surgery should be considered during pregnancy if the aortic IIa diameter is ≥ 50 mm and increasing rapidly. Patients with (or history of) type B dissection should be advised against III pregnancy. a

Class of recommendation; b all recommendations have level of evidence C.

BSA = body surface area ; CT = computed tomography; MRI = magnetic resonance imaging. Reproduced and modified with permission from Regitz-Zagrosek et.al. 3

91

Table 6: Recommendations for the management of valvular heart disease

a b

Mitral stenosis In patients with symptoms or pulmonary hypertension, restricted activities and β1-selective blockers are recommended. Diuretics are recommended when congestive symptoms persist despite beta-blockers. Patients with severe MS should undergo intervention before pregnancy. Therapeutic anticoagulation is recommended in case of atrial fibrillation, left atrial thrombosis, or prior embolism. Percutaneous mitral commissurotomy should be considered in pregnant patients with severe symptoms or systolic pulmonary artery pressure >50 mmHg despite medical therapy. Aortic stenosis Patients with severe AS should undergo intervention prepregnancy if: they are symptomatic or LV dysfunction ( LVEF <50%) is present Asymptomatic patients with severe AS should undergo intervention prepregnancy when they develop symptoms during exercise testing. Asymptomatic patients with severe AS should be considered for intervention prepregnancy when a fall in blood pressure below baseline during exercise testing occurs. Regurgitant lesions Patients with severe aortic or mitral regurgitation and symptoms or impaired ventricular function or ventricular dilatation should be treated surgically pre-pregnancy. Medical therapy is recommended in pregnant women with regurgitant lesions when symptoms occur.

Classa

Levelb

I

B

I

B

I

C

I

C

IIa

C

I I

B C

I

C

IIa

C

I

C

I

C

Class of recommendation. Level of evidence.

AS = aortic stenosis; LVEF = left ventricular ejection fraction; MS = mitral stenosis Reproduced and modified with permission from Regitz-Zagrosek et.al. 3

92

Table 7: Recommendations for the management of mechanical valves Mechanical valves OAC are recommended during the 2nd and 3rd trimesters until the 36th week. Change of anticoagulation regimen during pregnancy should be implemented in hospital. If delivery starts while on OAC, caesarean delivery is indicated. OAC should be discontinued and dose-adjusted UFH (a PTT ≥2× control) or adjusted-dose LMWH (target anti-Xa level 4–6 hours post-dose 0.8-1.2 U/ml) started at the 36th week of gestation. In pregnant women managed with LMWH post-dose anti-Xa level should be assessed weekly. LMWH should be replaced by intravenous UFH at least 36 hours before planned delivery. UFH should be continued until 4–6 hours before planned delivery and restarted 4–6 hours after delivery if there are no bleeding complications. Immediate echocardiography is indicated in women with mechanical valves presenting with dyspnoea and/or an embolic event. Continuation of OAC should be considered during the first trimester if warfarin dose required for therapeutic anticoagulation is <5 mg/day , after patient information and consent Discontinuation of OAC between weeks 6 and 12 and replacement by adjusted-dose UFH (a PTT ≥2× control; in high risk patients applied as intravenous infusion) or LMWH twice daily (with dose adjustment according to weight and target anti-Xa level 4-6 hours post-dose 0,8-1,2 U/ml) should be considered in patients with a warfarin dose required of > 5 mg/day. LMWH should be avoided, unless anti-Xa levels are monitored. a

Class of recommendation.

b

all recommendations have the level of evidence C.

Classa,b I I I I I I

I IIa IIa

III

aPTT = activated partial thromboplastin time; LMWH = low molecular weight heparins; LVEF = left ventricular ejection fraction; OAC = oral anticoagulants; UFH = unfractionated heparin. Reproduced and modified with permission from Regitz-Zagrosek et.al. 3

93

Table 8: Recommendations for the management of coronary artery disease. Classa,b ECG and troponin levels should be performed in case of chest pain in a I pregnant woman. Percutaneous coronary intervention is the preferred reperfusion therapy for I STEMI during pregnancy. A conservative management should be considered for non ST-elevation IIa ACS without risk criteria. An invasive management should be considered for non ST-elevation ACS IIa with risk criteria (including NSTEMI). a

Class of recommendation, b all recommendations have the level of evidence C.

ACS = acute coronary syndrome; ECG = electrocardiogram; NSTEMI = Non ST-elevation myocardial infarction; STEMI = ST-elevation myocardial infarction. Reproduced and modified with permission from Regitz-Zagrosek et.al. 3

Table 9: Recommendations for the management of cardiomyopathies and heart failure in pregnancy Classa, b 1. Anticoagulation is recommended in patients with intracardiac I thrombus detected by imaging or with evidence of systemic embolism. 2. Women with heart failure during pregnancy should receive heart I failure treatment as for non-pregnant patients, respecting contraindications for some drugs in pregnancy 3. Women with dilated cardiomyopathy should be informed about the I risk of deterioration during gestation and peripartum. 4. In patients with a past history or family history of sudden death close I surveillance with prompt investigation is recommended if symptoms of palpitations or presyncope are reported. 5. Therapeutic anticoagulation with LMWH or oral Vitamin K I antagonists according to stage of pregnancy is recommended for patients with hypertrophic cardiomyopathy with atrial fibrillation. 6. Delivery should be performed with β-blocker protection in women I with hypertrophic cardiomyopathy. 7. In hypertrophic cardiomyopathy, cardioversion should be considered IIa for persistent atrial fibrillation. 8. Due to high metabolic demands of lactation and breastfeeding, IIb preventing lactation should be considered in peripartum cardiomyopathy. 9. Subsequent pregnancy is not recommended if left ventricular III ejection fraction does not normalize in women with peripartum cardiomyopathy. a

Class of recommendation, b recommendation 1 has the level of evidence A160 and recommendation 2

the level B149, all others have the level of evidence C. Reproduced and modified with permission from Regitz-Zagrosek et.al. 3

94

Table 10: Recommendations for the management of arrhythmias in pregnancy Management of Supraventricular tachycardia (SVT) For acute conversion of paroxysmal SVT vagal manoeuvre followed by i.v. adenosine is recommended. Immediate electrical cardioversion is recommended for acute treatment of any tachycardia with haemodynamic instability. For long-term management of SVT oral digoxinc or metoprolol/propranololcd is recommended. For acute conversion of paroxysmal SVT i.v. metoprolol cd or propranolold should be considered. For long-term management of SVT oral sotalole or flecainidef should be considered if digoxin or a beta-blocking agent fail. For acute conversion of paroxysmal SVT i.v. verapamil may be considered. For long-term management of SVT oral propafenonef, or procainamide may be considered as last option if other suggested agents fail and before amiodarone e is used. For long-term management of SVT oral verapamil may be considered for rate regulation if the other AV nodal blocking agents fail. Atenolol d should not be used for any arrhythmia.

Classa,b I I I IIa IIa IIb IIb IIb III

Management of Ventricular tachycardia (VT) The implantation of an ICD, if clinically indicated, is recommended prior to pregnancy but is also recommended whenever indicated, during pregnancy. For long-term management of the congenital long QT syndrome, βblocking agents are recommended during pregnancy and also postpartum when they have a major benefit. For long-term management of idiopathic sustained VT oral metoprolol cd, propranolol cd or verapamil cf is recommended. Immediate electrical cardioversion of VT is recommended for sustained, unstable and stable VT. For acute conversion of VT that is sustained, haemodynamically stable, and monomorphic, i.v. sotalol e or procainamide should be considered. Implantation of permanent pacemakers or ICDs (preferably one chamber) should be considered with echocardiographical guidance, especially if the fetus is beyond 8 weeks gestation. For acute conversion of VT that is sustained, monomorphic, haemodynamically unstable, refractory to electrical cardioversion or not responding to other drugs, i.v. amiodarone e should be considered. For long-term management of idiopathic sustained VT oral sotalole , flecainidef , propafenone f should be considered if other drugs fail. Catheter ablation may be considered in the case of drug-refractory and poorly tolerated tachycardias.

95

I I I I IIa IIa IIa

IIa IIb

For drug dosing information please refer to three published guidelines on the management of patients 112 163 167 with atrial fibrillation, supraventricular arrhythmias, and ventricular arrhythmias . a Class of recommendation b all recommendations have the level of evidence C c AV nodal blocking agents should not be used in patients with pre-excitation on resting ECG. d β-blocking agents should be used with caution in the first trimester e Class III drugs should not be used in cases with prolonged QTc f Consider AV nodal blocking agents in conjunction with flecainide and propafenone for certain atrial tachycardias. AV = atrioventricular; ECG, electrocardiogram; ICD = implantable cardioverter-defibrillator; i.v. = intravenous; SVT = supraventricular tachycardia; VT = ventricular tachycardia Reproduced and modified with permission from Regitz-Zagrosek et.al.

3

Table 11: Recommendations for the management of hypertension in pregnancy Classa,b Non-pharmacological management for pregnant women with SBP of 140-150 mmHg or DBP of 90-99 mmHg is I recommended. In women with gestational hypertension or pre-existing hypertension superimposed by gestational hypertension or with hypertension and subclinical organ damage or symptoms at any time during pregnancy, initiation of drug treatment is I recommended at BP of 140/90 mmHg. In any other circumstances, initiation of drug treatment is recommended if SBP ≥ 150 mmHg or DBP ≥ 95 mmHg. SBP ≥ 170 mmHg or DBP ≥ 110 mmHg in a pregnant woman is I an emergency, and hospitalization is recommended. Induction of delivery is recommended in gestational hypertension with proteinuria with adverse conditions such as I visual disturbances, coagulation abnormalities or fetal distress. In pre-eclampsia associated with pulmonary oedema, nitroglycerine given as an intravenous infusion, is I recommended. In severe hypertension, drug treatment with intravenous I labetalol or oral methyldopa or nifedipine is recommended. Women with pre-existing hypertension should be considered to continue their current medication except for ACE inhibitors, IIa angiotensin II antagonists and direct renin inhibitors under close BP-control.

a

Class of recommendation

b

all recommendations have the level of evidence C

BP = blood pressure; DBP = diastolic blood pressure; SBP = systolic blood pressure Reproduced and modified with permission from Regitz-Zagrosek et.al.

96

3

Table

12:

Recommendations

for

the

prevention

and

management

of

venous

thromboembolism in pregnancy and puerperium Classa,b In all women who are pregnant or consider pregnancy assessment I of risk factors for VTE is recommended. Mothers should be informed about the signs and symptoms of VTE in pregnancy and the necessity to contact the physicians if they occur. High risk patients should receive antenatal prophylaxis with LMWH as well as postpartum for the duration of 6 weeks. In intermediate risk patients postpartum prophylaxis with LMWH should be given for at least 7 days or longer, if > 3 risk factors persist. In low risk patients early mobilisation and avoidance of dehydration is recommended. Graduated compression stockings are recommended antepartum and postpartum in all women at high risk. D-Dimer measurement and compression ultrasonography is recommended in patients with suspected VTE during pregnancy. For treatment of acute VTE during pregnancy UFH is recommended in high-risk and LMWH in non-high risk patients. Graduated compression stockings should be considered in women with intermediate risk during pregnancy and postpartum. In intermediate risk patients antenatal prophylaxis with LMWH should be considered.

a

Class of recommendation

b

all recommendations have the level of evidence C.

I I I

I I I I IIa IIa

LMWH = low molecular weight heparin, VTE = venous thromboembolism. Reproduced and modified with permission from Regitz-Zagrosek et.al. 3

15 Figure legends Figure 1 a Transabdominal sonographic presentation of a normal fetus with a normal skull in the left area of the figure . Brain structures are depicted in a regular manner. Pexus chorioideus is visible as a large clear structure. Cortex is still extremly thin. 13th pregnancy week. Sagittal section b Transabdominal sonographic presentation of a fetus with acrania. The right area of the figure exhibits the atypical profile of the head. The irregular contur is caused by the freely floating brain without calvarium, which will be destroyed in later follow up by amnioc fluid leading to the picture of anencephalus. 13th pregnancy week. Sagittal section

97

Figure 1:

a

b

98