Pregnancy and the Heart (and Vessels)

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Pregnancy and the Heart (and Vessels)

• Jorge Cheirif, MD, FACC, FASE

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Outline

• Thrombosis
• Valvular heart disease
• HTN
• Pregnancy related CMP

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Thromboses during Pregnancy

• Leading cause of maternal mortality.
• Levels of AT III, protein C and S fall throughout
  pregnancy. F VIII, IX, XI increase in pregnancy
• Prior DVT, emergency C section.
• AT III deficiency associated with 2-4 fold higher
  risk (14) than PC or PS.
• F V Leiden (PC resistance) and F II 20210A
  (inhibits fibrinolysis) combo increases risk of
  DVT. Heterozygous 4 risk. If Hx DVT and both
  factors present, 50 risk.
• AT deficiency and FV Leiden worse post-partum.
  Risk 41 homozygous,9.2 double homozygous

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Risk Stratification

• Predictive role of prior Hx DVT
• Age gt35
• Obesity
• Varicose veins
• Protein deficiencies. APLA

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Dx of DVT

• DVT 1-2/1000 pregnancies.
• Difficult to Dx, especially if pelvic veins are
  involved.
• Compression US If treat (occas false ). If
  ve, and still suspect DVT Venous duplex,
  impedance plethys-mography, venography or MRI,
  V/Q.
• In APL Syndrome, heparin/LMWH ASA

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Thromboses Management

• Heparin Osteopenia, HIT.
• LMWH Better tolerated than UFH, safe, ?
  Prosthetic heart valves effectiveness. No
  epidural.
• Coumadin crosses placenta. teratogenic (OK 2-3
  trimester), bleeding if not stopped 2-3 weeks
  prior to delivery.

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Outline

• Thrombosis
• Valvular heart disease
• HTN
• Pregnancy related CMP

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CV System and Pregnancy

• Increase up to 40-50 plasma volume
• Relative anemia
• Increases in CO (HR increases, SVR and PVR
  decrease, therefore wide PP)
• IVC obstruction (supine) abrupt decrease CO.
• In labor increase in CO 60-80. Post delivery
  increases in preload
• CV complications (13) poor FC, LVOT obstruction
  (gt30 mmHg), EF lt40, cyanosis, prior events or
  arrhythmias. Risk 27 with 1 risk factor, 70
  with gt2.
• Neonatal complications (20) FC, cyanosis, LVOT
  obstruction, anticoagulation, smoking, multiple
  prior pregnancies.

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Physical Exam

• Faster HR (10-20 beats), bounding pulses, widened
  PP, low N SBP, warm extremities.
• High normal JVP. Thyroid may be enlarged. S2
  widely split. S3 is common. I-II/VI SEM LUSB.
  Conti-nuous murmur. Diastolic M unusual. MS or AS
  M increase, AI or MR less.

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VHD associated with low Maternal and Fetal Risk

• Asymptomatic AS with low mg (lt50) with normal EF.
• NYHA FC I or II AI with N EF.
• NYHA FC I or II MR with N EF.
• MVP with no MR or mild to mod MR and N EF
• Mild to mod MS (MVA gt1.5 cm2, mg 5 mmHg) without
  pulmonary HTN.
• Mild to moderate PV stenosis

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VHD lesions associated with high Maternal and/or
Fetal Risk

• Severe AS with or without symptoms
• AI with NYHA FC III-IV.
• MS with NYHA FC II-IV.
• MR with NYHA FC III-IV.
• AVD or MVD with severe pulm HTN.
• AVD or MVD with EFlt 40.
• Mechanical prosthesis.
• AI in Marfan Syndrome

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CV System and Pregnancy

• Regurgitant lesions are well tolerated
• Stenotic lesions increase morbidity of mother and
  fetus. Higher incidence of CHF, arrhythmias,
  hospitalizations pre-term delivery, low birth
  weight.
• Correct, if possible VHD prior to conception.
• In MS BB, diuretics, anticoagulation, PBV if
  severe SXS.
• In AS Rx CHF, if severe PBV or AVR.

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Prosthetic Mechanical Valves

• Discontinue warfarin as soon as Dx of pregnancy
  is established.
• Start heparin (or if lawyers do not scare you,
  LMWH), S/Q to prolong PTT to therapeutic range.
• Replace heparin with warfarin (INR 2.5-3.5) at
  week 12 and continue to middle of 3rd trimester,
  then restart heparin.

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UNsafe drugs during Pregnancy
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Outline

• Thrombosis
• Valvular heart disease
• HTN
• Pregnancy related CMP

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HTN in Pregnancy

• 2nd leading cause of maternal mortality (15
  deaths).
• HTN disorders 6-8 pregnancies.
• Contributes to still-births and neo- natal
  morbidity and mortality.
• Abruptio placenta, DIC, cerebral hemorrhage,
  hepatic failure, ATN.
• Etiology unknown.
• Risk of CHF, encephalopathy PP.

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Classification of HTN

• Chronic HTN (gt140/90 mmHg).
• Pre-eclampsia-eclampsia (gt20 wks).
• Pre-eclampsia superimposed upon chronic HTN.
• Gestational HTN (lt20 weeks)
• - Transient, if no pre-eclampsia. BP
• returns to normal by 12 weeks
• - Chronic HTN if it persists.

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Pre-eclampsia

• Proteinuria gt 0.3 g protein in 24 hr. Correlates
  1 dipstick or 30 mg/dL.
• SBP gt160 or DBP gt110 mmHg.
• Proteinuria gt2g/day (1st time).
• Increase serum creatinine (gt1.2)
• Platelet ct lt100K and/or micro-angiopathic anemia
  (high LDH).
• High liver enzymes
• Persistent headache or cerebral/visual
  abnormalities.
• Persistent epigastric pain.
• Eclampsia seizures in pre-eclampsia.
• Edema no longer a criteria.

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Pre-eclampsia

• Can progress slowly or very fast (hrs).
• Maternal vasospasm, activation of coagulation
  system, perturbation in volume and BP control
  (sensitive AII, loss circadian rhythm). Oxidative
  stress and inflammatory-like responses.
• Pathologic changes ischemic and affect placenta,
  brain, kidney, liver.

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Pre-eclampsia

• Renal lesion glomeruli are swollen due to
  hypertrophy of endothelial and mesangial cells
  which encroach the capillaries (glomerular
  endotheliosis). Decrease 25 GFR and RBF,
  however since renal function increases 35-50 in
  pregnancy, a normal creatinine does not exclude
  pre-eclampsia. ATN. Hyperuricemia. Low calciuria.
  Low intra-vascular volume.

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Pre-eclampsia

• Thrombocytopenia (lt100K) rarely severe. Cause
  unknown (deposit at sites of endothelial damage
  and/or immunologic process). Fetuses born show no
  problems.
• Liver range from mild necrosis to ominous HELLP
  syndrome (hemolysis elevated enzymes, hepatic
  bleeding or rupture.

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Pre-eclampsia

• CNS Headache, visual disturbance (blurred
  vision, scotomata, cortical blindness), focal
  signs. Seizures (eclampsia) due to coagulopathy
  and/or HTN encephalopathy.
• High risk for it in pts with Hx HTN, previous
  gestation, multiparous, DM CVD, renal vascular or
  parenchymal disease, multi-fetal pregnancy.
• Sonogram to evaluate fetal growth 25-28 weeks.

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Pre-eclampsia superimposed on Chronic HTN

• Much worse prognosis.
• HTN without proteinuria lt20 weeks.
• Sudden increase in proteinuria.
• Sudden increase in BP, previously under control.
• Thrombocytopenia (lt100K).
• Increase in LFTs.

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Gestational HTN

• HTN first Dx in mid pregnancy.
• No proteinuria.
• BP returns to N by 12 weeks PP. If it persists,
  chronic HTN.

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Pregnancy Counseling

• If HTN severe prior to pregnancy (180/110)
  evaluate for 2ary causes. Stop ACE-I. If target
  organ damage (creatinine gt1.4), advise higher
  risk for fetus (loss 10 fold), may also
  exacerbate HTN if pregnancy occurs.
• No wt loss. Na restriction (2.4 g).
• Alcohol aggravates HTN. Tobacco risk placental
  abruption and fetal growth restriction.

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Treatment HTN

• Mild chronic HTN does not need Rx during
  pregnancy. Rx if gt150/100 persists. Methyldopa
  preferred (N placental flow and F/U in kids up to
  7 years. Labetalol good alternative. Limited data
  Nifedipine SR OK. Hydralazine.
• Diuretics effective. Theoretical risk.
• ACE-I contraindicated.
• All anti-HTN can appear in breast milk.
  Methyldopa and hydralazine OK. Labetalol and
  propranolol OK. ?CaB. Diuretics may suppress
  lactation. No ACE-I.
• No proven value of low dose ASA for most, of Ca
  Mg, fish oil. Vit C and E, encouraging results.

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Pre-eclampsia Rx

• Vaginal delivery preferred.
• MgS04 for seizures.
• Acute HTN Hydralazine (IV or IM) 5 mg bolus 1-2
  min, subsequent doses in 20 min. Labetalol IV
  20-40 mg bolus, then 1 mg/Kg infusion. Nifedipine
  used, but not approved, careful when Mg used.
• Recurrence rate (particularly if lt week 30) up to
  40 (higher if multiparous) subsequent
  pregnancies, if HELLP, 5.

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Outline

• Thrombosis
• Valvular heart disease
• HTN
• Pregnancy related CMP

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As a Cardiologist, I worry when

• 90 of the reports of PPCMP are published in
  non-cardiology journals.
• Tremendous variability in definitions, response
  to treatment and outcomes in various reports.
• No controlled randomized studies.
• The NIH decides to hold a panel of experts to
  shed light on a rare and catastrophic disease

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NIH Expert Panels

• Meetings in Bethesda.
• Attempts to reach consensus. After all, they
  are supporting the meeting
• Reimbursement for
• meals/day 25. Marriots breakfast
• 19.907 26.90
• Hotel 100. Actual cost 187
• Airfare 495. Actual cost 980

ABILITY TO IMPRESS YOUR GRANDMA..PRICELESS
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Perspective

• 4.6 million people Rx for CHF.
• 550,000 new annual cases.
• 1 and 5 year survival rates 76/35.
• Numerous clinical (older age, NYHA, LVEF, RVEF),
  biochemical (NE, BNP), EPS (VT, AF) and
  hemodynamic variables (MVO2) influence survival.
• Underlying ischemia (59 Vs 69) 5 yr survival.

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Perspective (cont.)

• HIV and amyloid related CHF have high mortality.
• Inflammatory cytokines and oxidative stress
  potential mediators.
• Gouley first described PPCMP in 1937.

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Spectrum of DCMP

• At least 75 specific diseases of heart muscle.
• However, Rx, Px utility of identifying them is
  unknown.
• 1,278 pts with DCMP (82-98) at JH.
• Endomyocardial biopsy in all (0.2 mortality),
  and cath, if risk factors present. 50 cases
  idiopathic.

Felker M. Medicine 199978270
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Spectrum of DCMP

• 50 of PPCMP pts showed evidence of myocarditis.
  (previous pathologic studies also found evidence
  of it).
• Resolution of myocarditis, with or without
  immunosupression correlates with improved
  function. Rx only if seen shortly after SXS
  onset, and if no spontaneous recovery.
• Anticoagulation unless contraindicated.

Felker M. Medicine 199978270
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Causes of DCMP and Survival

• 1230 pts. (1982-1997) with CHF underwent Bx for
  unexplained CMP.
• RHC (and LHC if CAD suspected).
• Idiopathic, peripartum, CAD, HTN, HIV,
  infiltrative, myocarditis, substance abuse, CTD,
  doxorubicin.
• 614/1230 specific cause, rest idiopathic. Bx
  specific Dx 15. Complication 8, 0.2 mortality.

Felker GM. NEJM 342151077
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Causes of DCMP and Survival

• F/U 4.4 yrs 417 pts died, 57 underwent
  transplantation.
• In comparison to idiopathic DCMP, PP better Px (5
  yr survival of 94,HR 0.14, plt.001), worse for
  infiltrative (4.79, plt.001), HIV (4 plt.001),
  doxorubicin (2.64, p.005), IHD (2.01, plt.001).
  Same for HTN, myocarditis, substance abuse, CTD.
• 26/51 with PPCMP had myocarditis by Bx.

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NIH Workshop

• April 97, Cardio, OB, Immunologists and
  Pathologists.
• Definition
• CHF 1 month pre-delivery 5 months after.
• Absence of identifiable cause.
• Absence of prior recognizable HD.
• LV systolic dysfunction.

Pearson G. JAMA 20002831183
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NIH Workshop

• Risk factors multiparity, advanced maternal age,
  pre-eclampsia, gesta- tional HTN, African
  American.
• Etiology myocarditis, abnormal immune response
  to pregnancy, hemodynamic stress,
  stress-activated cytokines, prolonged tocolysis.
  ? Familial CMP.

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NIH Workshop

• Myocarditis Reported from a few cases to 76 (Bx
  ASAP and borderline criteria). Time between SXS
  and Bx, histologic criteria. Pregnant mice
  susceptible to viruses
• Abnormal immune response occurrence of chimerism
  of the hematopoietic lineage cells from the fetus
  to the mother.
• What the h___ is that?
• Fetal cells pass into the maternal circulation,
  colonize the heart and remain without being
  rejected till immunogenicity returns.

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Serum levels of Antibodies
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Definition and Epidemiology

• Unexplained LV failure in the last month of
  pregnancy or within 5 months post partum.
• Incidence 1 in 1500 to 1 in 15,000.
• Early studies, mortality rates 25-50, half of
  them in first 3 months.
• 10 of them with myocarditis at Bx.
• Immunosuppressive Rx helpful?

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Etiology

• Unknown. However, some interesting findings
• Incidence 1/15000-1/1300 USA and 1 in Nigeria.
  Blacks, twin pregnancies, toxemia, post-partum
  HTN.
• Prolactin HTN and cardiomegaly seen in 1/5
  cases of prolactinoma increases throughout
  pregnancy. Receptors on B and T lymphocytes and
  NK cells. Requires selenium for action. Low
  levels of selenium in Africa and some areas of
  China where PPCMP is common.

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PATHOGENESIS
Genetic Factors Twin Pregnancy Stress Micro
adenoma Cocaine
Prolactin
Selenium deficiency
Decidual prolactin
Lymphoblastoid prolactin
Toxemia HTN
Viral infection
Auto immunity
Ventricular dysfunction
Modified from Kothari S. IJC 199760111
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Diagnosis and Management

• Symptoms and signs of CHF, new murmurs.
• Exclusion of other causes of CMP.
• Diuretics, hydralazine, digoxin ACE only
  post-partum and if not breast feeding.
• BB not contraindicated in pregnancy.
• Heparin before delivery, then Coumadin.
• ?IV gamma globulin.
• Heart transplant if failure with all else.

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To Bx or not to Bx

• Confirm the presence of myocardial infiltration
  (amyloid, hemochrom), myocarditis, transplant
  rejection.
• Non specific findings (hypertrophy, fibrosis,
  necrosis) and sampling.
• Presence or absence of myocarditis results in
  similar mortality (fulminant in young people?).
• Alters medical management?

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Clinical and Therapeutic Aspects

• Multiparity, twin births, advanced maternal age,
  pre-eclampsia, gestational HTN, AA.
• About 50 recover completely.
• Persistence of CMP gt 6 months poor prognosis.
• Risk for recurrence is high in subsequent
  pregnancies.

Mehta NJ. Angiology 200152759
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Maternal and Fetal Outcomes post PPCMP

• Retrospective study of 44 women with 60
  subsequent pregnancies. Gp 1 (n28) had normal
  LVEF. Gp 2 (n16) abnormal.
• Mean age 29. Dx pre-delivery in 7, 1st month post
  in 28, 2-6 months in 9. 10 had pre-eclampsia, 4
  HTN. 3/7 had myocarditis on Bx.
• Subsequent pregnancy (1 in 33, 2 in 6, 3 in 5) 27
  months, F/U 90

Elkayam U. NEJM 344211567
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Maternal and Fetal Outcomes post PPCMP

• 6/28 pts in Gp 1, and 7/16 in Gp 2 had CHF in
  subsequent pregnancy.
• 21 and 25 respectively had a gt 20 EF drop, and
  14 and 31, respectively had a decreased EF at
  last F/U.
• None of Gp 1 pts died. 3 of Gp 2 died after
  subsequent pregnancy.
• In 9 women abortions induced, had lt EF (46 to 43
  Vs. 49 to 42)
• Premature delivery in 3 Gp 1 and 6 Gp 2. No fetal
  death.

Elkayam U. NEJM 344211567
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MEAN EF IN PPCMP
Percent of women
Elkayam U. NEJM 344211567
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Prognosis

• Depends on normalization of LV function. Demakis,
  half of 27 women had persistent dysfunction and
  mortality was 85. In the ones that recovered, no
  mortality. Sutton, 6/14 pts with no recovery
  died. Survivors had higher EF (23 vs. 11).
• Better to be rich and healthy than sick and
  poor!!!

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Prognosis

• 21 pts with PPCMP (85-93). 18 with serial echo
  F/U. After baseline echo, dobutamine and
  methoxamine used to determine contractile
  reserve. 7/10 with reserve improved, none
  without. Matched controls.
• Increased intravascular volume, cardiac output
  and HR and lower SVR
• Contractility normally remains unaltered during
  pregnancy.

Lampert M. AJOBGYN 1997176189
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Prognosis Assessment
Dobutamine
Baseline contractility line
Contractile Reserve (D Vcfc in circ/sec)
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Hemodynamics in PPCMP
Change
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Prognosis

• 28 women 8 SXS ante-partum 20 post-partum. 19
  with pre-eclampsia or HTN Hx.
• 13 premature deliveries. Perinatal mortality
  36/1000 births.
• ECG LVH (14), NSSTT (7).
• 1 recovered completely 2 died early, 3 in follow
  up, 3 required transplant and 18 had
  stabilization of symptoms.
• 6 had subsequent pregnancies, and 4 had relapses
  of their PPCMP.
• Other reports, 50 have good prognosis.

Witlin A. AJOBGYN 1997176182.
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War Time Joke

• During a French-British war, a French officer
  asked a British one How come you guys wear red
  coats? It makes it so easy to identify you!!!
• The British answered, we do it so that if we get
  injured, our soldiers will not see us bleed and
  panic.
• Since then, the French were brown pants.

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Effect of New Pregnancies

• 44 pts with Hx PPCMP. Nine pregnant again. Two
  lost F/U.
• All 7 tolerated pregnancy relatively well and
  delivered healthy babies.
• 4 pts with FC II, and 2 with III, no change. One
  from III to II.
• EDD was same (61 to 58 mm), ESD (50 to 47 mm,
  p.008), FS (19 to 23).

De Souza JL J Card Fail 2001730
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Course of Subsequent Pregnancy

• 34 pts (mean 26 yrs).
• 5 in FC II, 1 in FC III, 28 in FC IV.
• All advised against new pregnancies.
• 12 (35.3) became pregnant. 6 (Gp 1) had normal
  heart size, 6 had persistent cardiomegaly (Gp 2).
• 5/6 in Gp 1 did well pre- post- pregnancy. All Gp
  2 tolerated pregnancy well, however 2/6
  deteriorated and died 8 13 years after.
• 3 year interval post recovery LVEF safe.

Filho A. Arq Bras Cardiol 19997347
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Summary

• Outcome highly variable. Regardless of initial
  severity, some pts clinical and echo status
  improve rapidly, and others deteriorate rapidly
  and need transplantation or die. Others have
  persistent dysfunction and over years improve.
• Hemodynamic stress of pregnancy can unmask
  impaired reserve.
• Anticoagulants, ACE. IABP in severe cases

Reimold SC. NEJM 2001 3441629
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If worse comes to worse.would transplant work?

• Case reports.
• 22 yo with multi-organ failure post partum. CI
  1.9 L/min, IABP, Novacor LVAD. Bx severe
  non-inflammatory lesions c/w DCMP. TIAs, acute
  abdomen thrombosis SMA, bowel resection
  ileostomy. 158 days later!! Orthotopic heart
  transplant.

Tandler R. EJCT Surg 199711394