Valvular Heart Disease in Pregnancy - Jennifer Lewey, MD, MPHa,*, Lauren Andrade, MDb, Lisa D. Levine, MD, MSCEc - BINASSS

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Valvular Heart Disease in Pregnancy - Jennifer Lewey, MD, MPHa,*, Lauren Andrade, MDb, Lisa D. Levine, MD, MSCEc - BINASSS
Val v u l a r H e a r t D i s e a s e i n
Jennifer Lewey, MD, MPHa,*, Lauren Andrade, MDb, Lisa D. Levine, MD, MSCEc

   Valvular heart disease  Pregnancy  Mitral stenosis  Aortic stenosis  Mechanical heart valve

   Pregnancy is well tolerated in most women with valvular heart disease. Cardiac output increases up
    to 50% and can lead to clinical decompensation in high-risk women.
   Women with mechanical heart valves need careful management of anticoagulation during preg-
    nancy to minimize maternal and fetal risks.
   Vaginal delivery with epidural anesthesia is recommended for most women with stable valvular
    heart disease.
   All women with valvular heart disease should be managed by a multidisciplinary Pregnancy Heart
    Team before and during pregnancy.

INTRODUCTION                                                                are pregnant or considering pregnancy should be
                                                                            managed by a multidisciplinary Pregnancy Heart
Cardiovascular (CV) disease complicates an esti-                            Team consisting of cardiologists and high-risk
mated 1% to 4% of all pregnancies and is the                                obstetricians.
leading cause of death in pregnant and post-                                   Hemodynamic changes start early in pregnancy.
partum women in the United States.1,2 Valvular                              Cardiac output increases 30% to 50% and peaks
heart disease is a common cause of CV disease                               between the second and third trimesters.7,8
that affects women of childbearing age.3,4                                  Changes in cardiac output are driven by an in-
Congenital heart disease is the leading cause of                            crease in stroke volume in the first half of preg-
valvular heart disease in the United States; howev-                         nancy followed by a gradual rise in heart rate. As
er, rheumatic heart disease is a prevalent condi-                           a result of placental maturation, systemic vascular
tion especially among immigrant populations.5,6                             resistance and blood pressure decrease in the first
Most women with valvular heart disease will do                              and second trimesters and returns to pre-
well during pregnancy, but high-risk conditions                             pregnancy levels in the third trimester. Women
such as severe mitral stenosis (MS) or aortic ste-                          with valvular heart disease, especially left-sided
nosis (AS), can be associated with significant                              obstructive lesions, may have limited cardiac
maternal morbidity and mortality. Management of                             reserve to accommodate these hemodynamic
anticoagulation of pregnant women with mechan-                              changes. As a result, close serial monitoring during
ical heart valves presents unique challenges to                             pregnancy is necessary to assess for clinical
reduce the risk of maternal and fetal complica-                             decompensation. The changes in flow can lead
tions. Women with valvular heart disease who

    Division of Cardiology, Department of Medicine, University of Pennsylvania Perelman School of Medicine,

  Perelman Center for Advanced Medicine, 3400 Civic Center Boulevard, 2-East Pavilion, Philadelphia, PA
  19104, USA; b Philadelphia Adult Congenital Heart Center, University of Pennsylvania, Children’s Hospital of
  Philadelphia, Perelman Center for Advanced Medicine, 3400 Civic Center Boulevard, 2- East Pavilion, Philadel-
  phia, PA 19104, USA; c Department of Obstetrics and Gynecology, Maternal and Child Health Research Center,
  University of Pennsylvania Perelman School of Medicine, 3400 Spruce Street, 2 Silverstein, Philadelphia, PA
  19104, USA
  * Corresponding author.
  E-mail address:

  Cardiol Clin 39 (2021) 151–161
  0733-8651/21/Ó 2020 Elsevier Inc. All rights reserved.
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152                 Lewey et al

             to increases in mitral and aortic transvalvular gra-                        with newly diagnosed or newly symptomatic
             dients and an overestimation of lesion severity.                            valvular heart disease and collaborative care be-
             Direct valve planimetry for patients with AS or                             tween MFM, cardiology, anesthesia, and other
             MS may more accurately reflect the degree of                                specialists is needed to reduce ongoing maternal,
             valve stenosis, especially for patients newly diag-                         obstetric, and fetal risk.
             nosed during pregnancy. The hypercoagulable
             state of pregnancy increases the risk of thrombo-                           RISK ASSESSMENT
             embolic events during pregnancy and the first 6
             to 12 weeks postpartum, further complicating the                            The most common maternal complications of
             anticoagulation management of women with me-                                valvular heart disease during pregnancy are heart
             chanical valves.9                                                           failure, arrhythmias, and thromboembolic compli-
                Labor and delivery is associated with sudden                             cations. Postpartum hemorrhage can be a com-
             hemodynamic changes and increases in oxygen                                 mon complication for women on anticoagulation.
             consumption. After delivery, dramatic changes in                            Cardiac symptoms can be managed in many
             hemodynamics occur as a result of autotransfu-                              women with diuresis, medical therapy, and
             sion of uterine blood volume, relief of caval pres-                         reducing level of physical activity. If symptoms
             sure, and mobilization of dependent edema. The                              are refractory to conservative management, valve
             sudden increase in preload can lead to clinical                             intervention during pregnancy may be necessary.
             decompensation and women with high-risk le-                                 Percutaneous balloon valvuloplasty performed by
             sions will need to be followed closely immediately                          experienced operators is preferred for stenotic le-
             after delivery and in the subsequent days post-                             sions. Ideally these interventions should be per-
             delivery.                                                                   formed after the fourth month in the second
                                                                                         trimester to minimize radiation exposure during
             PRECONCEPTION COUNSELING                                                    organogenesis.6 Valve surgery with cardiopulmo-
                                                                                         nary bypass performed during pregnancy is asso-
             Reproductive age women with valvular heart dis-                             ciated with rates of fetal death up to 30%,
             ease should undergo counseling before concep-                               especially when surgery is emergent and/or per-
             tion by a collaborative Pregnancy Heart Team                                formed at early gestational age.11,12 If surgery is
             consisting of a maternal fetal medicine (MFM)                               needed, however, the second trimester is the
             specialist and cardiologist with experience in car-                         preferred time frame with use of high flow on car-
             ing for pregnant women with heart disease.10                                diopulmonary bypass to provide adequate
             The goal of preconception counseling is to review                           placental perfusion.13
             and individualize the maternal and fetal risk of                               Maternal cardiac risk can be estimated using the
             pregnancy. Baseline cardiac function should be                              lesion specific modified World Health Organization
             assessed with an electrocardiogram and echocar-                             (WHO) classification (Table 1).6 Women with se-
             diogram to start. Exercise stress testing can be an                         vere MS and severe symptomatic AS are consid-
             important tool to assess exercise capacity, devel-                          ered to be at extremely high risk of maternal
             opment of arrhythmias and symptomatic                                       morbidity or mortality (WHO IV) and pregnancy is
             response, which may guide risk stratification and                           contraindicated. Most other types of valvular heart
             treatment before conception. Additional imaging                             disease in pregnancy are considered to be moder-
             modalities such as cardiac MRI or computed to-                              ate to high risk (WHO II-III). Those with regurgitant
             mography may be used to further assess valvular                             lesions such as aortic regurgitation and mitral
             function, anatomy of structures not well seen by                            regurgitation usually tolerate pregnancy well due
             echocardiogram, and associated aortopathies.                                to the decreased systemic afterload during preg-
                For women planning pregnancy, medications                                nancy. Individualized risk can be further estimated
             should be reviewed for safety during pregnancy.                             using pregnancy-specific risk indices developed in
             Angiotensin-converting enzyme inhibitors and                                large cohorts, including the CARPREG II and the
             angiotensin receptor blockers are teratogenic                               ZAHARA models.4,14,15 Contraception should be
             and can be changed to medications with a better                             discussed with all women with valvular heart dis-
             safety profile during pregnancy. Bosentan and sta-                          ease but highly effective contraception should be
             tins are also considered teratogenic and should be                          particularly recommended for women at high risk
             stopped before pregnancy. For women with me-                                of pregnancy complications. Estrogen-containing
             chanical valves taking warfarin, shared decision                            contraception increases the risk of venous and
             making will help guide the appropriate choice of                            arterial thrombosis and hypertension and should
             anticoagulation in the first trimester. Beta blockers                       be avoided in women with cardiac disease, espe-
             are generally considered safe in pregnancy.                                 cially those at increased thrombotic risk. In such
             Women may frequently present during pregnancy                               patients, long-acting progesterone-only methods

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Valvular Heart Disease in Pregnancy                                      153

   Table 1
   Modified World Health Organization (WHO) classification of pregnancy risk

   WHO Classification                                                            Maternal Risk
   WHO I                                                                          Morbidity: little to no increased risk
    Mild pulmonary stenosis                                                       Mortality: no increased risk
    Small patents ductus arteriosus (PDA)
    Mitral valve prolapse with mild mitral
    Repaired simple lesions: ASD, VSD, PDA,
       anomalous pulmonary venous drainage
    Isolated atrial or ventricular ectopic beats
   WHO II                                                                         Morbidity: moderately increased risk
    Uncorrected ASD or VSD                                                        Mortality: mildly increased risk
    Repaired Tetralogy of Fallot
    Most arrhythmias
   WHO II-III                                                                    Risk varies based on individual patient
    Mild LV impairment (EF >45%)                                                  Morbidity: moderately to severely increased
    Hypertrophic cardiomyopathy                                                    risk
    Valvular heart disease not considered WHO                                     Mortality: intermediate increased risk
       I or IV
    Marfan syndrome, aorta
154                 Lewey et al

             Women with stable cardiac disease can undergo                               Women with moderate or severe stenosis (mitral
             full-term delivery at 39 weeks of gestation.1                               valve area (MVA)
Valvular Heart Disease in Pregnancy                                      155

Fig. 1. Cardiac complication of MS according to severity. (Adapted from Hameed A, Karaalp IS, Tummala PP, Wani
OR, Canetti M, Akhter MW, Goodwin M, Zapadinsky N, Elkayam U. The effect of valvular heart disease on
maternal and fetal outcome of pregnancy. J Am Coll Cardiol. 2001;37:893–899; with permission.)

atrium, large left atrium (60 mL/m2), or conges-                           special care unit for at least 24 hours after deliv-
tive heart failure.1 Rate control with beta blockers                        ery is recommended.
or digoxin should be used as an initial strategy,                              Careful preconception counseling of women
though many women will ultimately undergo elec-                             with MS is critical in order to identify severity of
trical cardioversion (which is considered safe in                           stenosis, symptoms, and need for intervention
pregnancy) due to ongoing symptoms, poor rate                               before pregnancy. Similar to non-pregnant pa-
control, or hemodynamic instability.                                        tients, the 2014 American Heart Association
   Women who remain severely symptomatic                                    (AHA)/American College of Cardiology (ACC)
despite adequate medical therapy and activity re-                           Valvular Heart Disease Guidelines recommends
striction may need to undergo mitral valve inter-                           PMBV, when feasible, in patients with severe
vention during pregnancy. Percutaneous mitral                               symptomatic MS (Class I recommendation) before
balloon valvotomy (PMBV) can be safely per-                                 pregnancy. In order to avoid clinical decompensa-
formed during pregnancy and result in improved                              tion and need for intervention during pregnancy.
valve area and gradients.11,22 Due to risk of                               The AHA/ACC Guidelines also recommend
ionizing radiation to the fetus, PMBV should be                             PMBV in patients with severe MS who are asymp-
avoided during the first trimester, if possible, and                        tomatic (Class I recommendation). The decision to
performed by experienced operators. Surgical                                intervene in asymptomatic women before preg-
mitral valve replacement may be considered in                               nancy should depend on valve area, exercise
women with refractory symptoms who are not                                  tolerance, and the presence of pulmonary hyper-
candidates for PMBV but is associated with high                             tension, especially among women who are not
rates of fetal mortality, estimated at 20% to                               candidates for PMBV.6,23,24
   Most women with MS can undergo a vaginal                                 Aortic Stenosis
delivery with regional anesthesia, with preference
                                                                            AS in pregnancy is most often caused by congen-
for epidural placement.23 An assisted second
                                                                            ital bicuspid aortic valve and less commonly other
stage should be considered for women with mod-
                                                                            congenital abnormalities or rheumatic heart dis-
erate to severe stenosis. Cesarean delivery is
                                                                            ease.24,25 Pregnancy is well tolerated in women
reserved for obstetric indications and decompen-
                                                                            with mild and moderate AS. Women with severe
sated heart failure. Due to the hemodynamic
                                                                            AS are at higher risk of developing cardiac compli-
shifts that occur postpartum, monitoring in a
                                                                            cations, such as heart failure or atrial arrhythmias,

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156                 Lewey et al

             however the risk of maternal mortality and need for                         preload and systemic vascular resistance, which
             aortic valve intervention during pregnancy is low.                          may poorly tolerated.
             Women with congenital bicuspid valve or Marfan
             syndrome may have an associated aortopathy                                  MITRAL REGURGITATION AND AORTIC
             which further increases maternal risk and warrants                          REGURGITATION
             additional monitoring before and during preg-
             nancy. Pregnancy is contraindicated in women                                The most common causes of mitral regurgitation
             with bicuspid aortic valve when aortic dilation                             (MR) during pregnancy are rheumatic heart dis-
             is >50 mm and in women with Marfan syndrome                                 ease and mitral valve prolapse. Patients with pre-
             when aortic dilation is >45 mm.6                                            viously repaired (or unrepaired) AV septal defects
                In a Canadian cohort of 39 women representing                            may also have significant left-sided AV valve
             49 pregnancies, cardiac complications, including                            regurgitation. In contrast, aortic regurgitation (AR)
             heart failure or arrhythmias, were observed in                              is more commonly associated with congenital
             10% of women with severe AS. Only 1 woman                                   bicuspid aortic valve or aortopathy, and less
             required aortic valve intervention during preg-                             commonly rheumatic heart disease. Both MR
             nancy and no maternal deaths were reported.25                               and AR are well tolerated during pregnancy, even
             Other series have reported that heart failure oc-                           if severe, due to the fall in systemic vascular resis-
             curs in 3.8% to 44% of patients, with the highest                           tance and blood pressure. Surgical intervention
             rate observed in the smallest (n 5 12)                                      before pregnancy is reserved for women meeting
             cohort.19,26,27 Maternal complications are associ-                          routine indications for surgery, including severe
             ated with severity of AS, especially when symp-                             symptomatic valve disease. Exercise testing
             tomatic, and maternal age >30 years.26,27                                   before pregnancy can be considered to assess
             Maternal mortality in contemporary cohorts and                              for exercise tolerance and symptoms.29 Women
             need for valvular intervention during pregnancy is                          who develop heart failure symptoms or left ventric-
             low. Valve deterioration and need for aortic valve                          ular dysfunction can be treated with diuretics and
             intervention may be higher in women with severe                             vasodilators, such as hydralazine or nitrates, with
             AS after pregnancy, although the causes for this                            care to avoid hypotension which can lead to
             are not well-understood.25,26 Women with severe                             placental hypoperfusion. Angiotensin-converting
             AS experience higher rates of preterm delivery,                             enzyme inhibitors and angiotensin receptor
             low birth weight, and fetal death.19,26                                     blockers are contraindicated during pregnancy.

                                                                                         PULMONIC STENOSIS
             Management                                                                  Pulmonic stenosis (PS) is most commonly a result
             Women who become symptomatic should be                                      of congenital valve disease but may also occur as
             managed with activity restriction. Diuretics should                         a result of homograft calcification after a Ross pro-
             be carefully used in women who develop pulmo-                               cedure or prosthetic valve stenosis in patients with
             nary edema so as to avoid a sudden drop in pre-                             repaired tetralogy of Fallot. Mild and moderate PS
             load. Women who remain symptomatic despite                                  are well tolerated during pregnancy. Severe PS is
             conservative management may need valvular                                   associated with high rates of hypertensive disor-
             intervention during pregnancy with a preference                             ders, such as preeclampsia, preterm delivery,
             for percutaneous aortic balloon valvuloplasty if                            and thromboembolic complications.30 Although
             the valve anatomy is favorable and an experienced                           severe PS may be well tolerated during pregnancy,
             team is available. Percutaneous transcatheter                               some women may experience right ventricular
             aortic valve replacement for bicuspid severe AS                             heart failure or arrhythmias. As a result, women
             has been successfully performed during preg-                                with severe PS, even if asymptomatic, should be
             nancy, and may be preferred over valvuloplasty if                           considered for balloon valvuloplasty, surgical val-
             significant aortic regurgitation is present.28                              votomy, or percutaneous valve replacement
             Women who develop severe symptoms early in                                  before pregnancy.31
             pregnancy may consider pregnancy termination.
             Similar to patients with MS, vaginal delivery is                            PULMONIC REGURGITATION
             the preferred mode of delivery with an assisted
             second stage for women with moderate to severe                              Pulmonic regurgitation (PR) may be secondary to
             stenosis, though Cesarean delivery may be                                   prior tetralogy of Fallot repair, balloon valvulo-
             considered for patients with severe symptoms.6,24                           plasty for isolated PS, or develop in patients with
             Regional anesthesia with an epidural is preferred                           a prior right ventricle to pulmonary artery conduit.
             for pain control but hemodynamics should be                                 PR is generally well tolerated during pregnancy.
             monitored closely to avoid a sudden drop in                                 Similar to the systemic vascular resistance,

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Valvular Heart Disease in Pregnancy                                      157

pulmonary vascular resistance also decreases                                warfarin crosses the placenta and is associ-
during pregnancy. However, the increased plasma                             ated with an embryopathy, consisting of nasal
volume and CO associated with pregnancy can                                 hypoplasia, stippled epiphyses, and choanal
lead to right-sided heart failure symptoms in                               atresia, when exposure occurs between 6
women with severe PR, especially in the presence                            and 12 weeks of gestation.37 Later exposure
of underlying right ventricular (RV) dysfunction, RV                        is associated with central nervous system ab-
hypertrophy, or additional obstructive lesions such                         normalities and intracranial hemorrhage. The
as branch pulmonary artery stenosis.32,33 Right-                            most common fetal adverse even is miscar-
sided heart failure can often be treated with di-                           riage and fetal demise can occur at any gesta-
uretics and activity restriction. Valve intervention                        tional age.
is rarely needed during pregnancy.6 In women                                   Warfarin has a dose-dependent effect on fetal
with severe PR before pregnancy who are symp-                               outcomes with the highest risk associated with
tomatic or have progressive RV dilatation or                                daily warfarin doses >5 mg,38 though lower risk
dysfunction, pulmonary valve replacement is                                 with lower doses has not been demonstrated in
recommended.31                                                              all studies.36 In a 2017 meta-analysis, the rate
                                                                            of livebirths among women taking 5 mg
TRICUSPID REGURGITATION                                                     compared with >5 mg of warfarin daily was
                                                                            83.6% versus 43.9%, respectively.39 The rate
Isolated tricuspid regurgitation (TR) in young                              of embryopathy/fetopathy was 2.3% with lower
women is uncommon and, when present, occurs                                 dose (5 mg) and 12.4% with higher dose
in the setting of Ebstein anomaly, rheumatic heart                          (>5 mg) of warfarin. Women treated with low mo-
disease, or endocarditis. Patients with AV septal                           lecular weight heparin (LMWH) alone during
defects commonly have right-sided AV valve                                  pregnancy had the highest rate of livebirth at
regurgitation. The hemodynamic changes of preg-                             92%.
nancy are usually well tolerated in women with TR,                             LMWH does not cross the placenta and is
even if severe. Ebstein anomaly is associated with                          therefore not associated with congenital malfor-
atrial septal defect and Wolff-Parkinson-White                              mations. Weight-based dosing is administered
syndrome. As a result, pregnancy may be associ-                             twice daily and cleared by the kidneys. Dose
ated with progressive cyanosis and/or arrhythmias                           adjustment in response to peak anti-Xa levels is
in women at risk.34 Ebstein anomaly is also asso-                           needed due to changes in renal clearance and
ciated with increased risk of preterm delivery.35                           volume of distribution over the course of preg-
Secondary TR can occur as a result of RV pressure                           nancy.40 In contemporary studies, dose-
or volume overload as a result of left-sided heart                          adjusted LMWH is still associated with thrombo-
disease and pulmonary hypertension, cardiac                                 embolic complication in 4% to 17% of
conditions associated with significantly elevated                           pregnancies.39,41,42
maternal risk during pregnancy.                                                Thromboembolic       complications      occur
                                                                            throughout pregnancy and may be related to
PROSTHETIC VALVES                                                           sub-therapeutic anticoagulation during transition
                                                                            of anticoagulants, especially in the first
Pregnancy is a prothrombotic state and is associ-
                                                                            trimester, or sub-therapeutic LMWH levels.
ated with an increased risk of valve thrombosis in
                                                                            Fixed dose LMWH is associated with signifi-
women with prosthetic heart valves. Pregnant
                                                                            cantly higher thromboembolic complications
women with mechanical heart valves require care-
                                                                            compared with dose-adjusted regimens.43 The
ful anticoagulation management to prevent severe
                                                                            measurement of peak anti-Xa levels may not
maternal       morbidity      while      minimizing
                                                                            sufficiently assure adequate anticoagulation.
anticoagulation-related risk to the fetus. Although
                                                                            Among pregnant women with peak anti-Xa
hypercoagulability risk increases throughout preg-
                                                                            levels within the recommended range of 0.8 to
nancy and peaks in the immediate postpartum
                                                                            1.2 U/mL, 57% had sub-therapeutic trough
period, valve thrombosis frequently occurs in the
                                                                            levels (
158                 Lewey et al

             Comparing Anticoagulation Strategies                                        pregnancy offers the lowest risk of maternal
                                                                                         thromboembolic complications but carries a
             Four anticoagulation strategies were compared in
                                                                                         higher risk of miscarriage and embryopathy, as
             a meta-analysis of contemporary studies repre-
                                                                                         described previously. The 2014 ACC/AHA Valvular
             senting 800 pregnancies between 1974 and
                                                                                         Heart Disease Guidelines and the 2018 ESC Preg-
             2014.42 Studies were excluded if fixed dose
                                                                                         nancy and Heart Disease Guidelines recommend
             LMWH or unfractionated heparin (UFH) were
                                                                                         continuing warfarin at doses 5 mg/d during the
             used or if ball-in-cage valves were present in
                                                                                         first trimester and transitioning to dose-adjusted
             greater than 10% of reported pregnancies.
                                                                                         LMWH or intravenous (IV) UFH when the daily
             Maternal risk was lowest in women using vitamin
                                                                                         dose is >5 mg/d, as summarized in Table 3.6,45
             K antagonist (VKA) throughout pregnancy and 3-
                                                                                         Regardless of anticoagulant choice in the first
             times-higher in women using alternative strate-
                                                                                         trimester, treatment with warfarin is usually recom-
             gies, see Table 2. Maternal deaths were rare and
                                                                                         mended in the 2nd and 3rd trimesters. Discontinu-
             adverse events were driven by systemic thrombo-
                                                                                         ation of warfarin and starting IV UFH before
             embolism or valve thrombosis. Fetal risk was
                                                                                         planned vaginal delivery is recommended. Women
             lowest in women using LMWH throughout preg-
                                                                                         who are therapeutically anticoagulated on warfarin
             nancy or LMWH plus VKA. Differences in fetal out-
                                                                                         and need to be delivered should undergo Cesar-
             comes were driven by spontaneous abortions;
                                                                                         ean delivery to minimize traumatic fetal
             congenital defects were uncommon. Women tak-
             ing low-dose VKA throughout pregnancy had
                                                                                            The AHA/ACC guidelines recommend targeting
             similar fetal outcomes compared with women tak-
                                                                                         a peak anti-Xa level of 0.8 to 1.2 U/mL 4 to 6 hours
             ing LMWH or LMWH plus VKA. A similar meta-
                                                                                         after dosing for women treated with LMWH during
             analysis (see Table 2) demonstrated that women
                                                                                         pregnancy. Given the higher risk of thromboem-
             treated with VKA throughout pregnancy had the
                                                                                         bolic complications in women with sub-
             lowest proportion of livebirths compared with
                                                                                         therapeutic anticoagulation, aiming for peak levels
             women treated with LMWH (64.5% vs 92%) but
                                                                                         in the 1.0 to 1.2 U/mL range with trough levels
             had a lower risk of thromboembolic complications
                                                                                         greater than 0.6 U/mL may be reasonable, and is
             (2.7% vs 8.7).39
                                                                                         recommended in the 2018 ESC pregnancy and
                                                                                         heart disease guidelines (see Table 3).6 Because
                                                                                         the safety profile of low-dose warfarin is based
             Women with bioprosthetic and mechanical valves                              on a small number of studies and the risk of fetal
             should be treated with a baby aspirin during the                            loss is present throughout pregnancy, even at
             second and third trimesters. For women with me-                             lower warfarin doses, some investigators advo-
             chanical valves, warfarin continued throughout                              cate for using LMWH throughout pregnancy with

                Table 2
                Comparison of maternal and fetal risk with different anticoagulation strategies among women with
                mechanical valves

                                                                      Steinberg et al42                                     D’Souza et al39
                                                               Maternal                  Fetal                  Maternal TE                   Livebirths,
                Anticoagulation Strategy                       risk,a %                  risk,b %               event,c %                     %
                VKA only                                       5                         39                     2.7                           64.5
                Low-dose VKA only                              5                         15                                                   83.6
                LMWH 1 VKA                                     16                        16                     8.3                           89.5
                UFH 1 VKA                                      16                        34                     6.1                           72.4
                LMWH only                                      15                        14                     8.7                           92.0

             Abbreviations: LMWH, low molecular weight heparin; TE, thromboembolic; UFH, unfractionated heparin; VKA, vitamin K
                 Maternal death, systemic TE, or valve failure resulting in heart failure, arrhythmia, or surgery.
                  Spontaneous abortion, fetal death, or congenital defect.
                 Valve thrombus or extravalvular TE event.
               Data from D’Souza R, Ostro J, Shah PS, Silversides CK, Malinowski A, Murphy KE, Sermer M, Shehata N. Anticoagulation
             for pregnant women with mechanical heart valves: a systematic review and meta-analysis. Eur Heart J. 2017;38:1509–1516
             and Steinberg ZL, Dominguez-Islas CP, Otto CM, Stout KK, Krieger EV. Maternal and Fetal Outcomes of Anticoagulation in
             Pregnant Women With Mechanical Heart Valves. J Am Coll Cardiol. 2017;69:2681–2691.

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Valvular Heart Disease in Pregnancy                                      159

   Table 3
   Recommendations regarding anticoagulation strategy for mechanical valves during pregnancy

                                              1st Trimester                       2nd and 3rd Trimesters                        Peripartum
   AHA/ACC guidelines
   Warfarin dose 5 mg             Warfarin (IIa) or          Warfarin (I)                     IV UFH (I)
                                   LMWH (IIb) or
                                   IV UFH (IIb)
   Warfarin dose >5 mg             LMWH (IIa) or              Warfarin (I)                     IV UFH (I)
                                   IV UFH (IIa)
    Aspirin is routinely recommended starting in 2nd trimester
    Target anti-Xa peak level: 0.8–1.2 U/ml 4–6 h post-dose (I)
   ESC guidelines6
   Warfarin dose 5 mg             Warfarin (IIa) or          Warfarin (I)                     IV UFH (I)
                                   LMWH (IIb) or
                                   IV UFH (IIb)
   Warfarin dose >5 mg             Warfarin (IIb) or          Warfarin (IIa) or                IV UFH (I)
                                   LMWH (IIa) or              LMWH (IIb)
                                   IV UFH (IIa)
    Aspirin is not routinely recommended
    Target anti-Xa peak level: 1.0–1.2 U/mL (mitral and right-sided valves) or 0.8–1.2 U/mL (aortic valves)
     4–6 h post-dose (I). Target anti-Xa trough level: >0.6 U/mL (IIb)
Both LMWH and IV UFH refer to dose-adjusted rather than fixed dosing.
  Abbreviations: AHA/ACC, American Heart Association/American College of Cardiology; IV UFH, intravenous unfractio-
nated heparin; LMWH, low molecular weight heparin.
  Data from Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J, et al. 2018 ESC Guidelines for the management of car-
diovascular diseases during pregnancy. Eur Heart J. 2018;39:3165–3241 and Nishimura RA, Otto CM, Bonow RO, et al. 2014
AHA/ACC Guideline 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. J Am Coll Cardiol. 2014;63:e57–e185.

closely monitored anti-Xa levels.46 Favorable clin-                         bioprosthetic valves. Younger age at bio-
ical outcomes have been demonstrated in women                               prosthetic valve implantation is associated
treated with this strategy, but high levels of medi-                        with accelerated valve degeneration, which
cation adherence and patient engagement are                                 further shortens durability in women of repro-
needed. This strategy may be desirable for women                            ductive   age.48     Preconception   counseling
who are at otherwise low risk of thromboembolic                             regarding valve choice and implications for
complications (eg, mechanical valve in aortic posi-                         maternal and fetal risk in future pregnancies,
tion) or women who place higher value on avoiding                           especially for mechanical valves, is critically
potential fetal risk than maternal complications.                           important and should be performed by a cardi-
   Valve thrombosis during pregnancy should be                              ologist familiar with treating pregnant patients
confirmed with transesophageal echocardiogram                               with heart disease.
and treated first with heparin and, if needed,
thrombolytic therapy for women with small
thrombus and mild symptoms. Tissue-type plas-                               SUMMARY
minogen activator is associated with hemorrhagic                            Pregnancy in the setting of mild to moderate
complications but has been successfully used in                             valvular heart disease is often well tolerated. Pa-
pregnant women.47                                                           tients with severe mitral or severe symptomatic
   Women presenting with large thrombus burden                              AS are at increased risk of severe maternal
and more severe symptoms may require emergent                               morbidity and mortality and pregnancy may be
surgery, which is associated with adverse                                   prohibitively high risk unless valve intervention is
maternal and fetal outcomes.                                                performed. Care by a multidisciplinary Pregnancy
                                                                            Heart Team consisting of MFM specialists and
Choosing Prosthetic Valve Type Before
                                                                            cardiologists can improve preconception coun-
                                                                            seling and coordinated pregnancy and post-
Mechanical heart valves offer superior hemody-                              partum care to minimize maternal and fetal
namic profile and durability compared with                                  complications.

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160                 Lewey et al

             CLINICS CARE POINTS                                                          9. Kamel H, Navi BB, Sriram N, et al. Risk of a throm-
                                                                                             botic event after the 6-week postpartum period.
                 Women with severe mitral stenosis and symp-                                N Engl J Med 2014;370:1307–15.
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                  of poor outcomes and should be evaluated for                               Heart Association Council on Clinical Cardiology;
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                 Mitral and aortic regurgitation are well toler-                            Vascular Biology; Council on Cardiovascular and
                  ated during pregnancy.                                                     Stroke Nursing; and Stroke Council. Cardiovascular
                 For women with mechanical valves, warfarin                                 Considerations in caring for pregnant patients: A
                  offers the lowest risk of maternal thromboem-                              Scientific Statement from the American Heart Asso-
                  bolic complications, whereas low molecular                                 ciation. Circulation 2020;141:e884–903.
                  weight heparin offers the lowest fetal risk.                           11. de Souza JA, Martinez EE, Ambrose JA, et al. Percu-
                 Cardiac indications for Cesarean delivery                                  taneous balloon mitral valvuloplasty in comparison
                  include symptomatic heart failure and pulmo-                               with open mitral valve commissurotomy for mitral
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             ACKNOWLEDGMENTS                                                             12. John AS, Gurley F, Schaff HV, et al. Cardiopulmonary
                                                                                             bypass during pregnancy. Ann Thorac Surg 2011;
             This study was supported by grants K12
             HD085848 (Lewey) and R56 HL136730 (Levine)
                                                                                         13. Canobbio Mary M, Warnes Carole A, Aboulhosn J,
             from the National Institutes of Health.
                                                                                             et al. Management of pregnancy in patients with
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