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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 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. 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 LFT’s. 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. Marriot’s 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 16/56 29/56 11/56 PPCMP 1/10 1/10 8/10 BCKD DCMP PPCMP 30/56 0/10 21/56 2/10 Myosin DCMP PPCMP 18/56 1/10 27/56 1/10 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 Lymphoblastoid prolactin Viral infection Toxemia HTN 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 Percent of women 50 40 All women Group 1 Group 2 30 20 10 0 Index Postpartum Subsequent Last F/U 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 Contractile Reserve (D Vcfc in circ/sec) Prognosis Assessment 1.2 Dobutamine 1 0.8 0.6 0.4 0.2 0 0 20 30 40 50 60 70 Hemodynamics in PPCMP 40 % Change 30 20 10 Recovered Control 0 -10 -20 -30 HR CO PVR 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. TIA’s, acute abdomen: thrombosis SMA, bowel resection ileostomy. 158 days later!! Orthotopic heart transplant. Tandler R. EJCT Surg 1997;11:394