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Cardiovascular medications in pregnancy
16.1
Introduction
Cardiovascular disease is the leading cause of death for women in the United States, and similarly in other countries with developed health systems. Heart disease is the leading cause of death worldwide for men and women. While it is common to think of noncongenital heart disease as one of older populations, women of childbearing age can be affected by any noncongenital cardiovascular condition. The leading cause of maternal death in the United States is cardiovascular disease [ ]. When combined with other cardiovascular causes of death, such as hypertensive disorders, thromboembolism, and cerebrovascular accidents (CVAs), nearly half of all maternal deaths in this country can be attributed to these causes [ ]. It is also important to understand that metaphorically maternal deaths are just the tip of the iceberg, for every death more women suffer severe morbidity or near misses.
Pregnancy care presents a unique challenge with any pharmacotherapy. Maternal needs have to be balanced with fetal safety and vice versa. This intricate balance is often challenging for those who do not routinely provide maternal healthcare. A similar challenge also applies to maternal healthcare providers in areas such as cardiology where they do not routinely provide care. Some medications used in the treatment of cardiovascular conditions have known adverse fetal effects. For many women with diagnosed cardiovascular disease, such as hypertension or conditions requiring anticoagulation, it may require a strategy of either changing medications starting with preconception care or as soon as pregnancy is known or prescribing alternative medications that are safer for women desiring pregnancy.
Another challenge in maternity care may be the first significant access to the health system as an adult, which means that obstetrical providers cannot rely solely on patient histories to provide care. Patients may have underlying cardiovascular disease that is not readily apparent, even with a physical exam.
For women with known cardiovascular disease (either congenital or noncongenital), the European Society of Cardiology (ESC) recommends that these patients receive an evaluation to include an electrocardiogram (ECG), echocardiogram, and exercise stress testing. If a patient has a known aortic issue, such as an aneurysm, the ESC Guidelines recommend Computerized Tomography (CT) or Magnetic Resonance (MR) Imaging [ ].
There are many known risk factors for various types of CVD. Current recommendations from both American College of Obstetricians and Gynecologists (ACOG) and ESC each have a directed screening algorithm that focuses on patient symptoms, abnormal vital signs, risk factors, and physical exam findings. The California Maternal Quality Care Collaborative (CMQCC) also has an algorithm and toolkit identifying which patients should see a cardiologist versus obstetrical provider management [ ]. An area to focus future research is determining if the directed screening is as effective as universal screening. Given the impact of cardiovascular disease on maternal health and lifespan health, it may be time to consider universal screening with a more focused approach to those at higher risk similar to current screening for gestational diabetes in the United States. The current body of literature does not support the practice of universal screening for cardiovascular conditions, instead, focusing on those with certain risk factors.
Electrocardiography and specifically 12-Lead ECG is a powerful diagnostic tool. Beyond the simple assessment of ischemia or infarction, a 12-Lead can provide a wealth of information [ ]. It is normal for an ECG to have changes as pregnancy progresses, notably a more leftward axis deviation due to the physical shifting of the heart due to the upward shifting of the uterus. It is important to note that having a baseline 12-Lead ECG increases the diagnostic value of subsequent ECGs.
Cardiovascular disease is a prime example of the medical reasons to focus on preventing unplanned pregnancy. In cases of severe congenital disease or cardiomyopathy with a low ejection fraction carrying a pregnancy not only to term gestation but even to the age of viability for a fetus could prove to be fatal to the woman [ ]. Even in patients with unknown cardiovascular disease, prepregnancy screening offers more diagnostic testing and treatment options than screening patients who are already pregnant. CT imaging and invasive cardiovascular testing utilize ionizing radiation, and MR imaging uses high-powered magnetic fields that are not recommended for routine use in pregnant patients. Most transcatheter interventions for heart problems, whether electrophysiology procedures, percutaneous coronary interventions, valvuloplasty, aortic aneurysm repairs, or others, require the use of ionizing radiation that is shown to be harmful to the fetus.
It should be noted that these interventions require the use of fluoroscopy, which emits higher doses of ionizing radiation than a single chest X-ray and, in some cases, CT imaging. Shielding of the abdomen is possible for some areas, and certain procedures like percutaneous coronary intervention can be completed through a radial approach minimizing radiation exposure to the fetus by shifting the brunt of the radiation exposure to the upper extremities and chest. Surgical interventions for cardiovascular problems often require cardiopulmonary bypass, which has evidence of increased risk of fetal mortality, but this could be attributed to the severity of maternal health [ ]. The bottom line is that these procedures are often challenging and complex enough without involving pregnancy. It would be ideal to identify these issues prior to pregnancy, where all of the focus can be on the mother's health and after treatment, and while these issues are being managed, women can be counseled on risks to be able to make an informed decision on whether to attempt pregnancy.
Another key point from both ACOG and the ESC guidelines is that a single provider should not be managing pregnancy in patients with cardiovascular disease in isolation. Patients with these conditions require a team approach, including cardiology providers, obstetrical providers, maternal–fetal medicine specialists, and other specialties as needed. In the United States, there are cardiologists and cardiology providers who have a particular interest in sex-specific cardiovascular issues focused on women. Cardio-obstetrics is an area of growing interest in the cardiology and women's health communities [ ].
Vaginal delivery is preferred over cesarean when maternal hemodynamics are stable. In cases of hemodynamic instability, a cesarean is preferred [ ].
16.2
Resources for guidance
Clinical Guidelines provide the most up-to-date and comprehensive focus on this subject. As this topic is seeing increased research activity by both women's health providers and cardiology providers, these guidelines are likely to be updated again shortly. The ESC and ACOG both have clinical guidelines and practice bulletins published or updated very recently [ , ]. CQMCC has also developed a toolkit for Maternal Cardiovascular Disease that contains valuable clinical information [ ]. The CMQCC resource provides algorithms and guidance to help with screening and referral to cardiovascular providers. Pharmacology reference databases also provide updated information on each medication. It is the responsibility of the clinician to evaluate any resource for accuracy and applicability critically.
16.3
Cardiovascular changes in pregnancy
The maternal cardiovascular system is one of the most changed body systems in pregnancy. Blood and plasma volumes increase, creating more strain on the maternal cardiovascular system. Hemodynamics, cardiac outputs, peripheral vascular resistance, and heart rate all change during pregnancy [ , ]. During pregnancy a woman's heart is likely working harder than it will at any other point in her life [ ]. Fig. 16.1 shows graphs showing how each of these measures changes throughout pregnancy.
16.3.1
Sedation for invasive procedures and timing of procedures
While not directly cardiovascular related, Cardiac Catheterization, Pacemaker/Implanted Cardiac Defibrillator placement, and transesophageal echocardiogram are just a few examples of often invasive procedures performed with some degree of sedation [ ]. Commonly, this involves fentanyl and versed. Versed and all benzodiazepines are contraindicated in pregnancy, until birth [ ]. It may be possible to complete the procedure with fentanyl only or adding diphenhydramine. It may be helpful to consult or involve anesthesia, as this would allow for a greater number of sedation options [ ]. It is currently recommended to wait until the second trimester, if possible, for any procedures requiring the use of radiation to reduce risks to the fetus [ ].
16.4
Cardiovascular disease in pregnancy
16.4.1
Hypertension
Hypertension is the most common cardiovascular condition during pregnancy. While many think immediately of preeclampsia when thinking of elevated blood pressure in pregnancy, patients can have chronic hypertension existing before the pregnancy or develop gestational hypertension [ ]. Preeclampsia presents with hypertension, proteinuria, and other physical symptom manifestations [ ]. Gestational hypertension should not have any physical symptoms or abnormal lab work associated with it [ ]. It was once a common belief that preeclampsia was “cured” by delivering the placenta. Postpartum preeclampsia, by definition, completely discredits that belief. Current research is not only highlighting the immediate postpartum impacts of preeclampsia but lifelong cardiovascular impacts [ , , , ].
| Features | Pharmacologic goals | ||
|---|---|---|---|
| Chronic hypertension | Existing or hypertension diagnosed prior to 20 wks EGA First diagnosed in pregnancy in first 20 wks EGA and does not resolve postpartum |
Likely to require antihypertensive long-term following pregnancy. ACOG recommendation to evaluate liver enzymes, creatinine, potassium, blood urea nitrogen, and blood count. Either a spot protein/creatinine ratio or a 24 h urine can be considered Consider 12-Lead ECG and/or echocardiogram |
Maintain blood pressure in normal range, assess and adjust dosage throughout and after pregnancy |
| Gestational hypertension | Occurs after 20 wks EGA | No abnormal labwork or other features associated with preeclampsia other than elevated blood pressure. Should be monitored for hypertension following pregnancy, hypertension likely to resolve after pregnancy. Increased risk of hypertension later in life requires annual evaluation in primary care |
Maintain normal blood pressure. Reassess and evaluate for the efficacy of therapy and signs of preeclampsia |
| Preeclampsia | Occurs after 20 wks EGA | Labwork is abnormal and/or accompanied with features of preeclampsia | Pharmacological goals are to maintain blood pressures in a normal range until birth and the postpartum period. If pharmacological therapies are not effective in maintaining blood pressure in a safe range, consider emergent birth. Magnesium sulfate is used for preeclampsia and not other forms of hypertensive disorders in pregnancy |
Hypertension management is a crucial preventative measure in reducing the risk of several disease processes, including cardiovascular disease [ ]. Keeping blood pressure in a normal range has been shown to reduce the risk of renal disease, heart disease, stroke, and even dementia. Hypertension is one of the most common chronic conditions worldwide and most often requires lifelong management. Hypertension in nonpregnancy is divided into primary and secondary hypertension. The overwhelming majority of cases in the United States and worldwide are primary hypertension; that is, the hypertension is not caused by another medical condition. In secondary hypertension, the focus is on correcting the cause of the hypertension versus long-term management.
There is not an antihypertensive medication that is free from potential fetal effects. With that said, there are also significant issues relating to hypertension in pregnancy [ ]. Maternal risks from hypertension include the risk of CVAs and renal disease in cases of severe hypertension [ ]. Preeclampsia has a very different pathology from hypertension and can have even more severe and sudden physiological impacts [ ]. Hypertensive disorders of pregnancy can be fatal. From 2011 to 2016, 6.9% of maternal deaths in the United States were due to hypertensive disorders [ ]. The fetus is not isolated from maternal hypertension, and preterm birth and fetal growth restriction are only two common fetal impacts from maternal hypertension. In the general population and in the peripartum, severe hypertension or hypertensive emergency has immediate health implications, including hemorrhagic stroke or hypertensive bleeding [ ]. Observation of blood pressure in pregnancy has become more common as we are watchful for preeclampsia. In the general population, mild–moderate hypertension chronically shows little short-term impacts, but the chronic impacts are immense. Hypertension has long been called, “the silent killer” because patients are often asymptomatic until they start to show effects of long-term hypertension or blood pressure reaches severe ranges [ ]. Pregnancy treatment for mild to moderate hypertension is essential, but care should be made to avoid dropping blood pressures so low that they interfere with placental perfusion [ , ].
Currently, ACOG recommends labetalol or nifedipine as the first-line medications for chronic and gestational hypertension, with hydralazine being recommended only for acute hypertension [ , ].
Both ACOG and ESC recommend keeping maternal blood pressure below 140/90 and to consider blood pressure severe at 160/110. This applies to both the systolic and diastolic. ACOG recommends using the trend of two blood pressures at least 4 hours apart. In sudden onset of hypertension over 160/110, prompt administration of antihypertensives is indicated [ , ]. Hypertensive emergency/crisis, or malignant hypertension, is an abrupt increase in blood pressure. For nonpregnant patients, it is recommended to decrease pressure, but should aim for a target of 160–100. IV antihypertensives are recommended for this purpose [ , ].
In patients with chronic hypertension in pregnancy, antihypertensive treatment is proven to help reduce the occurrence of severe hypertension during pregnancy [ ].
For nonpregnant patients, there has been some debate regarding guidelines for hypertension. Some have suggested a more relaxed guideline, and others, specifically the American Heart Association and American College of Cardiology guidelines recommended tighter blood pressure control. While these guidelines have some disagreement, provided a patient is not symptomatic, evidence shows tighter blood pressure control has positive benefits in terms of cardiovascular disease risk reduction.
| Guideline and year updated | JNC-8 (2014) | AHA/ACC (2017) | EHA/ESC |
|---|---|---|---|
| BP where medication is initiated | Ages 60+: 150/90 Under 60: 140/90 Also considers lower thresholds for diabetes and CKD |
130/80 Lower thresholds based of CVD risk |
Based on disease staging and 4-step grading of hypertension 130/85 for those with severe disease 160/100 in those with no risk factors |
| Has race-specific guidelines | Yes | Yes | Yes (extrapolates on US data) |
16.5
Mechanism of action for hypertensive medications
Hypertension is an abnormally elevated blood pressure caused by alterations in the body's standard physiological systems for maintaining homeostasis. The body has several ways to regulate and adjust blood pressure, and pharmacological methods have been developed to alter these processes to achieve modification of the blood pressure to acceptable ranges [ ]. The heart's contractile force, rate, and the compliance of arteries and blood vessels all factor in the maintenance of normal blood pressure. The amount of circulating volume can be increased or reduced through hormonal actions to further balance blood pressure.
16.5.1
Medications affecting the renin angiotensin aldosterone system (the kidney–lung pathway)
The kidneys and the lungs are two areas of the body that are sensitive to blood pressure changes. The kidneys especially need adequate perfusion to function. The kidneys produce a substance called renin, which has no significant effect on blood pressure. Renin is converted into Angiotensin I by angiotensinogen, which is produced by the liver. Angiotensin I also has no significant systemic effects. The lungs create Angiotensin-Converting Enzyme (ACE) that converts the relatively inert Angiotensin I into Angiotensin II, a potent vasoconstrictor. Angiotensin II binds with receptors in the arteries causing this vasoconstriction [ ]. This pathway is the target of many hypertension medications (ACE Inhibitors, Angiotensin II Receptor Blockers (ARBs), and Direct Renin Inhibitors); however, all of the medications altering this pathway are contraindicated in pregnancy due to risk for fetal renal and other congenital issues [ ]. Direct renin inhibitors bind to the renin and prevent angiotensinogen from converting it to Angiotensin I [ ]. ACE Inhibitors prevent the ACE from converting the inert Angiotensin I to the potent Angiotensin II. Finally, ARBs block the binding sites where Angiotensin II would bind to induce vasoconstriction. While these medications are not used in pregnancy, they are some of the first-line medications used in hypertension in the general population [ , ]. Drugs in these classes can be used in postpartum/breastfeeding, but it is suggested to observe the infant for signs of hypotension. As ACE Inhibitors are a common first-line medication for the treatment of hypertension, it is possible for someone with an unplanned pregnancy to be on one before pregnancy is diagnosed [ , ]. While a patient should be transitioned to another class of medication promptly, data suggest no significant risk of harm in these cases [ ].
16.5.2
Beta-Blockers
Beta-Blockers or Beta-Adrenergic Blocking agents are a family of medications that block the receptor site of naturally occurring beta-adrenergic agonists, such as epinephrine [ ].
Beta-blockers, as a class, provide multiple therapeutic effects. The heart beats more slowly and with less force, and there is also a vasodilatory property [ , ]. Beta-blockers also are divided into two categories: selective and nonselective. Our bodies have three different types of beta-adrenergic receptors: B1, B2, and B3 [ ]. B1 receptors are located primarily in the heart and kidneys. B2 Receptors are located in most other parts of the body, but most notably in the lungs. B3 receptors are found in adipose tissue, and while they are found in the cardiovascular system, their role is not fully understood. Most selective Beta-blockers target B1 only, while nonselective beta-blockers affect all beta-receptors or at least B1 and B2 [ ].
One of the most commonly used antihypertensives in pregnancy is labetalol (Trandate) [ ]. Labetalol is a nonselective beta-blocker that also has an alpha-receptor blocking effect. ACOG Guidelines recommend labetalol as a first-line drug to manage both chronic and gestational hypertension [ ]. ESC guidelines suggest a Beta-1 Selective Beta-Blocker due to the lack of effects on uterine beta receptors [ ].
Carvedilol is currently one of the preferred beta-blockers for the treatment of heart failure and is considered safe in pregnancy.
Breastfeeding: Labetalol and Propranolol are the preferred beta-blockers for use in breastfeeding as both of these medications are significantly bound to plasma proteins and are not found in high levels in breast milk compared to some other beta-blockers such as metoprolol.
16.5.3
Calcium Channel Blockers
Calcium Channel Blockers are commonly used in pregnancy. They provide smooth muscle relaxation in the arteries and decrease vascular resistance [ ]. Some calcium channel blockers can be used outside of hypertension management to relax the uterine muscle for tocolysis as well [ ]. The uterine relaxation could be to delay labor or to allow for relaxation for an external cephalic version [ ].
Calcium channel blockers are also a fantastic option for long-term management instead of ACE Inhibitors or ARBs in women with chronic hypertension desiring future pregnancy. Many formulations also have extended release options that can increase compliance by reducing the number of times per day a patient needs to take medication to be effective [ ]. In situations where immediate blood pressure control is needed, IV administration is preferred (hydralazine or labetalol). Oral nifedipine can be used, but only immediate release versions should be used for emergent hypertension management [ ]. Following pregnancy, maternal heart rate returns to a normal baseline from the sight tachycardia that is common in late pregnancy. Most calcium channel blockers do not affect heart rate as significantly as beta-blockers, making them an excellent choice for long-term postpregnancy use in women who have a normal baseline heart rate. In both the JNC-8 and AHA/ACC Guidelines, calcium channel blockers are an option for initial therapy in patients of African descent. ACE Inhibitors are not as effective as thiazide diuretics or calcium channel blockers in studies examining black populations in the United States [ , ]. The EHA/ESC guidelines are cautious about this recommendation, as they based their race-specific recommendation on extrapolation from United States' data. They specifically cite several differences in the black populations in Europe compared to the United States, including a socioeconomic difference [ ]. The concerns in the EHA/ESC Guideline are a valid consideration in non-United States populations, and clinicians should use their best judgment when selecting medications.
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