Pregnancy and the Heart (and Vessels)

Jorge Cheirif, MD, FACC, FASE

Outline

Thrombosis Valvular heart disease HTN Pregnancy related CMP

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

Risk Stratification

Predictive role of prior Hx DVT Age >35 Obesity Varicose veins Protein deficiencies. APLA

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 plethysmography, venography or MRI, V/Q. In APL Syndrome, heparin/LMWH + ASA

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.

Outline

Thrombosis Valvular heart disease HTN Pregnancy related CMP

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 (>30 mmHg), EF <40%, cyanosis, prior events or arrhythmias. Risk 27% with 1 risk factor, 70% with >2. Neonatal complications (20%): FC, cyanosis, LVOT obstruction, anticoagulation, smoking, multiple prior pregnancies.

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. Continuous murmur. Diastolic M unusual. MS or AS M increase, AI or MR less.

VHD associated with low Maternal and Fetal Risk

Asymptomatic AS with low mg (<50) 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 >1.5 cm2, mg 5 mmHg) without pulmonary HTN. Mild to moderate PV stenosis

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 EF< 40%. Mechanical prosthesis. AI in Marfan Syndrome

CV System and Pregnancy

Regurgitant lesions are well tolerated Stenotic lesions increase morbidity of mother and fetus. Higher incidence of CHF, arrhythmias, hospitalizations preterm 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.

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.

UNsafe drugs during Pregnancy

Drug Warfarin Amiodarone Nitroprusside ACE-I Diuretics Effects

Fetal hemorrhage embryopathy, CNS abnormalities IUGR, prematurity, hypothyroidism

Thiocyanate toxicity, fetal loss Skull ossification defect, IUGR, PDA, LBW, ATN, anemia, death Placental hypo-perfusion, low platelets, jaundice, low Na+ & HR

Outline

Thrombosis Valvular heart disease HTN Pregnancy related CMP

HTN in Pregnancy

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

Classification of HTN

Chronic HTN (>140/90 mmHg). Pre-eclampsia-eclampsia (>20 wks). Pre-eclampsia superimposed upon chronic HTN. Gestational HTN (<20 weeks): - Transient, if no pre-eclampsia. BP returns to normal by 12 weeks - Chronic HTN if it persists.

Pre-eclampsia

Proteinuria: > 0.3 g protein in 24 hr. Correlates 1+ dipstick or 30 mg/dL. SBP >160 or DBP >110 mmHg. Proteinuria >2g/day (1st time). Increase serum creatinine (>1.2) Platelet ct <100K 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.

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.

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 preeclampsia. ATN. Hyperuricemia. Low calciuria. Low intra-vascular volume.

Pre-eclampsia

Thrombocytopenia (<100K) 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.

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.

Pre-eclampsia superimposed on Chronic HTN

Much worse prognosis. HTN without proteinuria <20 weeks. Sudden increase in proteinuria. Sudden increase in BP, previously under control. Thrombocytopenia (<100K). Increase in LFTs.

Gestational HTN

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

Pregnancy Counseling

If HTN severe prior to pregnancy (180/110) evaluate for 2ary causes. Stop ACE-I. If target organ damage (creatinine >1.4), 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.

Treatment HTN

Mild chronic HTN does not need Rx during pregnancy. Rx if >150/100 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.

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 < week 30) up to 40% (higher if multiparous) subsequent pregnancies, if HELLP, 5%.

Outline

Thrombosis Valvular heart disease HTN Pregnancy related CMP

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

NIH Expert Panels

Meetings in Bethesda. Attempts to reach consensus. After all, they are supporting the meeting: Reimbursement for:
meals/day: $25. Marriots breakfast: 19.90+7= $26.90 Hotel: $100. Actual cost: $187 Airfare: $495. Actual cost: $980
ABILITY TO IMPRESS YOUR GRANDMA:..PRICELESS

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.

Perspective (cont.)

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

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 1999;78:270

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 1999;78:270

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 342;15:1077

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, p<.001), worse for infiltrative (4.79, p<.001), HIV (4 p<.001), doxorubicin (2.64, p.005), IHD (2.01, p<.001). Same for HTN, myocarditis, substance abuse, CTD. 26/51 with PPCMP had myocarditis by Bx.

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 2000;283:1183

NIH Workshop

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

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.

Serum levels of Antibodies

Antibody titers Group <1:20 1:20-1:160 ANT >1:160

DCMP
PPCMP DCMP PPCMP DCMP PPCMP

16/56
1/10 30/56 0/10 18/56 1/10

29/56
1/10 BCKD 21/56 2/10 Myosin 27/56 1/10

11/56
8/10 5/56 8/10 11/56 8/10

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 2550%, half of them in first 3 months. 10% of them with myocarditis at Bx. Immunosuppressive Rx helpful?

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.

PATHOGENESIS Genetic Factors Twin Pregnancy Stress Micro adenoma Cocaine

Prolactin

Selenium deficiency

Decidual prolactin Toxemia HTN

Lymphoblastoid prolactin

Viral infection

Auto immunity
Ventricular dysfunction

Modified from Kothari S. IJC 1997;60:111

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.

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?

Clinical and Therapeutic Aspects

Multiparity, twin births, advanced maternal age, pre-eclampsia, gestational HTN, AA. About 50% recover completely. Persistence of CMP > 6 months = poor prognosis. Risk for recurrence is high in subsequent pregnancies.
Mehta NJ. Angiology 2001;52:759

Maternal and Fetal Outcomes post PPCMP

Retrospective study of 44 women with 60 subsequent pregnancies. Gp 1 (n=28) had normal LVEF. Gp 2 (n=16) 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 344;21:1567

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 > 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 < EF (46 to 43 Vs. 49 to 42) Premature delivery in 3 Gp 1 and 6 Gp 2. No fetal death.
Elkayam U. NEJM 344;21:1567

MEAN EF IN PPCMP
60 50

Percent of women

40 30 20 10 0 Index Postpartum Subsequent Last F/U All women Group 1 Group 2

Elkayam U. NEJM 344;21:1567

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!!!

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 1997;176:189

Prognosis Assessment
Contractile Reserve (D Vcfc in circ/sec)
1.2 1 0.8 0.6 0.4 0.2 0 0 20 30 40 50 60 70

Dobutamine

Hemodynamics in PPCMP
40 30

% Change

20 10 0 -10 -20 -30 HR CO PVR Recovered Control

Prognosis

28 women; 8 SXS ante-partum; 20 postpartum. 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 1997;176:182.

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.

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 2001;7:30

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 1999;73:47

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; 344:1629

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 1997;11:394