Anticoagulation of pregnant women with mechanical heart valve prosthesis. a systematic review (fi

Anticoagulation of pregnant women with mechanical heart valve prosthesis: current guidelines Ahmed Hassouna, MD. March 2012

It is generally accepted that (OA) provide efficientthromboprophylaxis for patients with (MPHV)however, pregnancy raises important concerns andaddresses still unresolved questions: 1- (OA) impose a true risk of embryopathies and, in this regards, heparin (H) is safe for being unable to cross the placental barrier. 2- However, the use of (H) is associated with a higher rate of (TEC), (VT) and maternal death. 3- There is a considerable rate of fetal wastage, regardless to the type of adopted regimen. In other words, OA appear to be safer to the mother while H appears to be safer to the fetus!

In the absence of a randomized clinical trial (RCT),AHA/ACC have recommended 3 regimen: 1- (OA) throughout pregnancy*. 2- (OA/H): OA are substituted with H between the 6th and 13th week of gestation. 3- (H) throughout pregnancy. In any of the above regimen it is advised to: 1- add a daily oral dose of 100 mg aspirin. 2- Shift to (H) therapy before delivery (2 weeks- 2 days) and, 3- Hospitalization for either normal or induced delivery at 36th month.

A Medline search was conducted of articles published in Englishlanguage between January 2000 and September 2009 using MESHheadings “PHV", "pregnancy,” and “anticoagulants.” Inclusion/exclusion criteria: Major adverse outcomes: -Complete reports of (MPHV) patients  Maternal adverse outcomes included : that defined any of the 3 PVT, TEC, major bleeding and death. anticoagulation regimen, as well as a 4th group of concomitantly reported  Fetal adverse outcomes included: fetal cases who stopped anticoagulants embryopathy/congenital malformation, against medical advice. spontaneous abortions, prematurity -Articles involving small case series of and total fetal wastage. less than 5 patients, reports to  Outcomes were expressed as questionnaire, duplicate data, letters to proportions of total pregnancies, the editor as well as data issued from except embryopathy and maternal editorials or review articles were death, which were related to the excluded from the analysis. numbers of live births and number of *The quality of given information was patients; respectively. appreciated by noting if eligible studies were clinical trials, prospective  Results were presented as pooled observational studies or else. estimates (+ 95% confidence interval).

 1. Rowan JA, McCowan LM, Raudkivi PJ, North RA. Enoxaparin treatment in women with mechanical heart valves during pregnancy. Am J Obstet Gynecol. 2001;185(3):633–637. 2. Hassouna A, Allam H. Oral anticoagulation therapy during pregnancy in patients with mechanical mitral valves: a prospective study. Cardiovasc Surg. 2001;9(5):478–481. 3. Ashour ZA, Shawky Abdel Fattah H, Hassan HM. Outcome of pregnancy in women with mechanical valves. Tex Heart Inst J. 2002;27:240–245. 4. Geelani MA, Singh S, Verma A, Nagesh A, Betigeri V, Nigam M. Anticoagulation in patients with mechanical valves during pregnancy. Asian Cardiovasc Thorac Ann. 2005;13(1):30–33. 5. Yamak B, Emir M, Ulus TA, et al. Pregnancy with St. Jude medical mitral valve prosthesis. Asian Cardiovasc Thorac Ann. 2000;8:127–129. 6. Ayhan A, Yucel A, Bildirici I, Dogan R. Feto-maternal morbidity and mortality after cardiac valve replacement. Acta Obstet Gynecol Scand. 2001; 80(8):713–718. 7. Al-Lawati AA, Venkitraman M, Al-Delaime T, Valliathu J. Pregnancy and mechanical heart valves replacement; dilemma of anticoagulation. Eur J Cardiothorac Surg. 2002;22(2):223–227. 8. Cotrufo M, De Feo M, De Santo LS, et al. Risk of warfarin during pregnancy with mechanical valve prostheses. Obstet Gynecol. 2002;99:35–40. 9. Srivastava AK, Gupta AK, Singh AV, Husain T. Effect of oral anticoagulant during pregnancy with prosthetic heart valve. Asian Cardiovasc Thorac Ann. 2002;10(4):306–309. 10. Bhutta SZ, Aziz S, Korejo R. Pregnancy following cardiac surgery. J Pak Med Assoc. 2003;53:407. 11. Vural KM, Ozatik MA, Uncu H, et al. Pregnancy after mechanical mitral valve replacement. J Heart Valve Dis. 2003;12(3):370– 376. 12. Nassar AH, Hobeika EM, Abd Essamad HM, Taher A, Khalil AM, Usta IM. Pregnancy outcome in women with prosthetic heart valves. Am J Obstet Gynecol. 2004;191:1009–1013. 13. De Santo LS, Romano G, Della Corte A, Tizzano F, Petraio A, Amarelli C. Mitralmechanical replacement in young rheumatic women: analysis of longterm survival, valve-related complications, and pregnancy outcomes over a 3707-patient-year follow-up. J Thorac Cardiovasc Surg. 2005;130(1):13–19. 14. Plesinac SD, Darko PV, Pilic IZ, Babovic IR. Anticoagulation therapy during pregnancy of patients with artificial heart valves: fetomaternal outcome. Arch Gynecol Obstet. 2006;274(3):141–145. 15. Akhtar RP, Abid AR, Zafar H, Cheema MA, Khan JS Anticoagulation in pregnancy with mechanical heart valves: 10-year experience. Asian Cardiovasc Thorac Ann2007;15(6):497–501. 16. Kawamata K, Neki R, Yamanaka K, et al. Risks and pregnancy outcome in women with prosthetic mechanical heart valve replacement. Circ J. 2007; 71(2):211–213. 17. Khamooshi AJ, Kashfi F, Hoseini S, Tabatabaei MB, Javadpour H, Noohi F. Anticoagulation for prosthetic heart valves in pregnancy. Is there an answer? Asian Cardiovasc Thorac Ann. 2007;15(6):493–496. 18. Kim KH, Jeong DS, Ahn H. Anticoagulation in pregnant women with a bileaflet mechanical cardiac valve replacement. Heart Surg Forum. 2007; 10(4):E267–E270. 19. Lee JH, Park N, Keum DY, Choi SY, Kwon KY, Cho CH. Low molecular weight heparin treatment in pregnant women with a mechanical heart valve prosthesis. J Korean Med Sci. 2007;22:258–261.

Distribution of mechanical prosthetic heart valves Number Number of Number Type of mechanical prosthesis Position of implantation of patients/ of Cage Tilting bileaflet undefined mitral Aortic Mitral + tricuspid studies* pregnancies prostheses & ball disc aortic 14 745/988 866 134 272 220 240 515 107 122+122 - (82.3%) (77.8%) 3 147/243 247 - 110 121 16 156 34 25+25 7 (17.7%) (22.2%) 17 892/1231 1113 134 382 341 256 671 141 147+147 7 (12%) (34.3%) (30.6%) (23%) (60.3%) (12.7%) (26.4%) (0.6%) *= A total of 19 studies were included in our review (974 patients/ 1343 pregnancies) however, 2 studies (1- Bhutta SZ, Aziz S, Korejo R.Pregnancy following cardiac surgery. J Pak Med Assoc. 2003;53:407. 2- De Santo LS, Romano G, Della Corte A, Tizzano F, Petraio A, Amarelli C.Mitral mechanical replacement in young rheumatic women: analysis of long-term survival, valve-related complications, and pregnancyoutcomes over a 3707-patient-year follow-up. J Thorac Cardiovasc Surg. 2005;130(1):13–19.) do not appear in this table because noinformation was available to correlate both: the exact number and positions of implanted MPHV.

Anticoagulation regimens adopted / compared per study. Oral anticoagulation regimen* Number of Number of Number of studies patients pregnancies A) Studies adopting a single regimen1- OA 4 (21%) 154 (15.8%) 182 (13.6%)2- OA/H 1 (5.3%) 45 (4.6%) 64 (4.8%)3- Heparin 2 (10.5%) 23 (2.4%) 30 (2.2%)total 7 (36.9%) 222 (22.8%) 276 (20.6%) B) Studies comparing different regimens4- OA versus OA/H 5 (26.3%) 434 (44.5%) 593 (44%)5- OA versus Heparin 2 (10.5%) 104 (10.7%) 148 (11%)6- OA versus OA/H versus Heparin 2 (10.5%) 60 (6.2%) 123 (9.2%)7- OA versus OA/H versus none 1 (5.3%) 21 (2.15%) 21 (1.6%)8- OA versus Heparin versus none 1 (5.3%) 101(10.4%) 136 (10.1%)9- OA vs. OA/H vs. Heparin vs. none 1 (5.3%) 32 (3.3%) 46 (3.4%)total 12 (63.1%) 752 (77.2%) 1067 (79.4%) Overall total 19 974 1343

Distribution of anticoagulation regimen

Adverse fetal outcomes Anticoagulation regimen* OA OA/H Heparin None (559/833) (258/322) (96/157) (27/31)Embryopathy/ 21/559 (3.7%) 1/258 (0.4%) 0/96 0/27malformations [1.9-4.8] [0.2-2.7] [0-3.1] [0-11.1]Prematurity 62/833 (7.4%) 26/322 (8.1%) 15/157 (9.5%) 3/31 (9.7%) [2.1-9.6] [3.4-12.8] [3-23.6] [2.6-22.8]Spontaneous 194/833 (23.3%) 42/322 (13%) 34/157 (21.6%) 2/31 (6.4%)abortion [13.8-31.6] [7-21.6] [10.1-29.8] [1.8-20.7]Fetal wastage 274/ 833 (32.9%) 64/ 322(19.9%) 61/157 (38.8%) 4/31 (12.9%) [25.7-49.2] [15.9-31.4] [32-46.8] [5-28.4]

Adverse maternal outcomes Anticoagulation regimen* OA OA/H Heparin None (559/833) (258/322) (96/157) (27/31)PVT 10/833 (1.2%) 17/322 (5.3%) 16/157 (10.2%) 8/31 (25.8%) [0.7-2.2] [3-10.8] [6.9-16.5] [0.2-88.2]TEC 24/833 (2.9%) 23/322 (7.1%) 21/157 (13.4%) 9/31 (29%) [1.9-4.1] [4.7-10.3] [9.7-20.5] [0.5-98.7]Maternal 35/833 (4.2%) 11/322 (3.4%) 17/157 (10.8%) 2/31 (6.4%)bleeding [1.4-6.8] [2.3-6.6] [2.8-27.3] [1.8-20.7]Maternal 7/605 (1.1%) 4/236 (1.7%) 5/107 (4.7%) 0/26mortality [0.5-2.2] [0.8-4.5] [2.2-10.7] [0-11.5]

Adverse outcomes reported in prospective studiesAdverse outcomes Anticoagulation regimen OA OA/H Heparin (182/215) (87/100) (47/80)A) Fetal:Embryopathy/congenital (0.5%) 0 0malformationsPrematurity (14.9%) (13%) (1.2%)Spontaneous abortion (10.2%) (8%) 20 (25%)Fetal wastage due to any (15.3%) (13%) (41.2%)causeB) MaternalPVT 0 (1%) (7.5%)TEC (2.3%) (4%) (12.5%)Maternal bleeding (3.2%) (2%) (1.2%)Maternal mortality 0 (1%) (7.8%)

Questions to be answered 1- OA induced embryopathy: was it overstated or is it actually decreasing? 2- Does Heparin really improve fetal wastage, even on the expense of mothers? 3- Is pregnancy becoming safer for patients with MPHV?

Was fetal embryopathy overstated or is it actually decreasing? In their excellent large meta-analysis that reviewed the subject over the last 3 decades of the 20th century, Chan and colleagues have shown pooled risks of embryopathy of 6.4% and 3.4% in patients following OA and OA/H regimen; respectively (Arch Intern Med. 2000;160(2):191–196). In our study, the calculated pooled risk has dropped to 3.7% in patients on (OA), and became negligible (0.4%) in patients on OA/H. Twenty years ago, Cotrufo and co-workers have suggested that warfarin can be safe if the dose can be restricted to 5mg/day (Eur J cardiothorac Surg. 1991;5:300–305), yet it is unclear and hence doubtful if the patients reported in Chan review have benefited from this information.

 On the contrary, most of our authors have clearly indicated adopting this strategy. Consequently, we find it legitimate to suppose that the risk of warfarin embryopathy may be actually decreasing; even if actual doses/success in adopted strategy are not usually reported. Playing the same tune, this awareness can also explain the very low risks of 0.5% and 0% recorded in our prospective subgroup of patients.

Does heparin improve fetal wastage?The salutary effect of introducing heparin during the 1st trimester is lost/reversed whenever its use is extended till parturition.

Is pregnancy becoming safer for patients with MPHV? Compared to older reviews, maternal complications (mainly TEC) appear to be decreasing by nearly 50% which may reflect the improving valve technology (40% vs. 12% cage and balls valves). However, the use of heparin was associated with the same crescendo pattern; which was also reported in prospective studies.

The dilemma of using heparin The inherent problem of small series: Out of the 1,343 pregnancies and the 19 series in this review, only 11.7% of patients were following heparin throughout pregnancy in as many as 42% of our eligible series. In this review, the largest series of pregnant women who were kept on UFH and LMWH did only include 66 and 14 pregnancies; respectively. This modest representation may be due to a tendency for the publication of case reports, which we automatically excluded from our analysis. On the other hand, the reluctance to include many patients in those studies may suggest a probable loss of confidence in the safety of heparinotherapy.

The dilemma of using heparin (cont.) Two unfinished clinical trials are likely to overshadow any serious decision: Salazar and co- workers reported the interruption of their trial on UFH because of the unacceptable maternal mortality due to TEC and the manufacturer of Lovenox launching a warning against its use during pregnancy in patients with PHV because of its association with serious maternal and fetal complications, even if this was soon rephrased to ‘‘use of Lovenox for thromboprophylaxis in pregnant women with mechanical PHV has not been adequately studied’’

The dilemma of using heparin (cont.) There is an overall inadequate reporting of data concerning key elements, namely patient compliance, adequate dosing, and regular adjustment. In the largest series, which included 42% of pregnancies on Heparin, UFH was given in a small dose of 5,000 IU/8 h to 10000 IU/12 h, and the activated PTT was never checked [Ashour et al; Tex Heart Inst J. 2002]. The other 7 series reported between 2-18 pregnancies managed with UFH, LMWH, or IVIH, with only one prospective study on LMWH [Rowan et al; Am J Obstet. Gynecol. 2001], which respected and, fortunately, reported the recommended levels of pre- and 4-h postdose anti-Xa monitoring.

CONCLUSION This study shows that (OA) and (OA/H) are still competing alternatives for pregnant ladies with (MPHV), especially with an apparently decreasing rate of fetal embryopathy. (Heparin) does not ensure better fetal outcomes and is still associated with the worst adverse maternal outcomes, including mortality. To the best of our knowledge, still the literature do not supply enough data to judge the adequacy of dose adjustment of heparin or to evaluate the protective effect of an adjuvant low-dose aspirin in conjunction with either therapy.

Anticoagulation of pregnant women with mechanical heart valve prosthesis. a systematic review (fi

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