Outcomes in Pregnant Women with Valvular Heart Disease from Portuguese-Speaking African Countries Treated in Portugal through an International Agreement of Health Cooperation - (2024)

Introduction

Recent advances in surgical techniques and the medical management of valvular heart disease (VHD) in developed countries have permitted young patients to have an improved prognosis and quality of life, with a significant number of women having successful pregnancies []. VHD is primarily caused by rheumatic heart disease (RHD) in low-middle income countries (LMICs), and sub-Saharan Africa bears a significant portion of the global burden of the disease []. Most patients with VHD in Africa do not avail themselves of required surgery despite being symptomatic because of lack of cardiac surgical services []. Pregnant women with VHD in African countries have a high maternal morbidity and mortality due to the reduced accessibility to health care and the scarcity of skilled health care professionals []. Patients with VHD are a particular high-risk group in general, since the physiologic haemodynamic changes in pregnancy increase the risk of heart failure and arrhythmias, with potential adverse impact on both maternal and fetal outcomes [, , , , ]. Our group has previously reported on the data over a 10-year period with VHD and pregnancy []. For the surgical management of these patients in Africa, generally three models have existed. The first was the referral of some patients to high-income countries (HIC) through agreements or various channels. The second has been the surgical repair of these lesions by visiting teams to Africa at regular intervals []. The third is the development of local cardiac surgical capacity []. However, very little data exists in the public domain regarding outcomes in pregnant women with VHD followed in a HIC after they had been referred specifically for management of their condition.

Through a health agreement of international cooperation, Portugal provides medical and surgical treatments of cardiac disease for patients from Portuguese-speaking African countries, that include Angola, Mozambique, Guinea-Bissau, Cape Verde, and São Tomé and Príncipe. In 1992, these countries formed an interstate organization known as Países Africanos de Língua Oficial Portuguesa (PALOP). At least three countries (Guinea-Bissau, Cape Verde, São Tomé and Príncipe) have no facilities for either cardiac catheterization or cardiac surgery. Under this agreement, annually about 1000 patients with diverse medical and surgical conditions have access to the tax-funded universal access health system of Portugal—the Serviço Nacional de Saúde (SNS) []. These patients can be referred to various cardiology/cardiac surgery departments in Portugal for evaluation and management of mainly severe VHD, and our departments form part of the network that provides this service.

We performed a clinical audit of pregnant women with VHD from five African nations, followed at our tertiary centre, during a twenty-year period, evaluating maternal cardiovascular and pregnancy outcomes. Our aim was to determine if rigorous follow-up of patients with VHD, which is difficult in the LMIC that the patients originated from (including those with mechanical heart valve (MHV) on anticoagulation), would guarantee good maternal and fetal outcomes.

Materials and methods

Results

Discussion

In this retrospective descriptive clinical audit conducted at our tertiary centre, we reviewed the outcomes of 81 pregnancies in patients with severe VHD, initially transferred from five Portuguese-speaking African countries, but mainly Cape Verde, São Tomé, and Príncipe and Guinea-Bissau for management of their VHD as these countries have no cardiac surgical facilities.

In this cohort, the use of VKA was the single most important predictor of an unsuccessful pregnancy. The rate of live birth was higher in patients on heparin compared with those on VKA. Mirroring other experiences [, , ], in four pregnancies with a MHV an acute valve thrombosis occurred, all in patients on LMWH. The patient who died had a therapeutic anti-Xa level in the visit preceding her demise. Significant bleeding events occurred in 8.6% of the pregnancies, all anticoagulated, in immediate postpartum or puerperal period. The patients in our cohort were managed according to current international guidelines. The ESC [] and AHA/ACA guidelines [] recommend the use of VKAs until pregnancy is achieved. Given the known dose-dependent teratogenicity, continuation of VKAs should be considered during the first trimester in patients with a low daily dosing of a VKA (warfarin <5 mg/day or acenocoumarol <2 mg/day), ideally in a shared decision-making paradigm. Guidelines also recommend the sequential anticoagulation with heparin from 6–12 weeks, under strict monitoring, primarily in those who need a higher daily dose of VKA. Both guidelines recommend that VKAs should be used during the second and third trimesters, irrespective of dose, until approximately 36 weeks’ gestation.

Real world data back up the guidelines with some important nuances. In a study by Mazibuko and colleagues from South Africa, 29 (50%) patients were on warfarin ≤ 5 mg in the first trimester and no congenital fetal anomalies occurred, replicating reports from India, Oman and Lebanon [, , ]. In the meta-analysis by D’Souza et al. [], the often-quoted ceiling dose of 5 mg was established for warfarin beyond which the fetal adverse events increased. However, the ROPAC registry [] could not confirm this margin of safety. Fetal complications can occur even with daily doses < 5 mg [, ]. VKAs come packaged with their own logistical constraints particularly in LMICs. In Ethiopia, Chalachew et al. [] have shown that the educational level of primary school or less, long distance from follow-up medical facility, infrequent check-up visits and unreliable source of free warfarin supply were associated with sub-optimal control of INR. These conditions were also noted in Nigeria, the most populous nation in Africa, making a VKA a difficult choice for a patient with a MHV that can portend a disastrous outcome [].

LMWH is often advocated as an option in HIC for the first trimester. Under rigorous monitoring, some institutions even have protocols that use LMWH throughout pregnancy []. Although the use of LMWH with peak and trough levels of anti-Xa levels monitoring seems a promising approach, the risk of MHV thrombosis is still a heavy burden. A recent study from India found that healthcare access, costs, compliance with parenteral therapy, limited training in administration and availability of monitoring techniques were significant challenges []. The risk of valve thrombosis with LMWH persists, even when with therapeutic anti-factor Xa activity levels [, ].

The newer oral anticoagulants are not an option in those with MHV and all the studies (including iNVICTUS []) excluded pregnant patients. This leaves VKAs as the best option to protect the mother albeit at risks of fetal embryopathy.

In our study, 42% of pregnancies occurred in multiparous women and four patients were responsible for approximately 25% of the total pregnancies. However, in each woman, about half of pregnancies were successful. This underscores the need for multiple pregnancies to obtain favourable fetal outcomes, mainly when anticoagulated. Notwithstanding this fact, the increased number of pregnancies per woman was not associated with major maternal adverse cardiac events. The majority (79.0%) were in NYHA functional class I or II at the onset of gestation. A symptomatic deterioration in NYHA functional class was the most important cardiac complication (42.0%) and 9.9% needed to initiate or intensify cardiac medication. APE was rare (4.9%) and effectively reverted with medical therapy. The relative paucity of APE in our cohort could be due to early pregnancy assessment, adequate medical therapy and the absence of significant number of patients with untreated mitral stenosis which is the commonest cause of APE in LMIC. In the absence of severely regurgitant lesions, APE is rare. Our findings are in line with the CARPREG II study where a decrease in the incidence of APE was documented over two different time periods [].

In our study, the rate of live births was 69.1%, miscarriage and stillbirth occurred in 23.5% and 7.4% of pregnancies, respectively. A CS was performed in 28.3%, a higher value compared to that in the normal population as recorded in an European registry [], although an absolute cardiac indication was present in only 6.6%. However, this may be related to clinician preference as seen in a comparison between two European obstetric cardiac centres, where the rate of CS was 74% in one centre and 28% in another for patients with MHV, demonstrating varying practice patterns [].

In our experience, management of these patients with a MHV is resource-intensive and, every attempt at valve repair, although particularly difficult, should be attempted. Truth be told, the paucity of these patients on the regular cardiac surgical list of a surgeon in a developed country precludes the attainment of adequate expertise, as evidenced in a Korean study where just two cases were performed per surgeon per year []. Valve repair provides the opportunity for women to possibly go through their pregnancy without anticoagulation and its complications. In most cases, though, a durable repair—even in expert hands—lasts for approximately a little more than a decade []. Bioprosthetic valves are prone to rapid structural deterioration, especially during pregnancy, as described in a study from Rwanda []. Patients may present late, precluding repair and cardiac surgical facilities are sparse in Africa.

One of the biggest contributions HIC can make is in the training of professionals from African countries. Tefera et al. [] reported the experiences of local surgeons and the visiting surgeons in Ethiopia. Local surgeons mentioned few cases performed under supervision and the lack of sufficient training provided by visiting surgeons, who also considered it an ineffective model for skill transfer. Improvement of cardiac surgical services can be possible through collabouration but will only be successful if real efforts are made to train local personnel and introduce sustainability measures [].

All the patients had cardiac surgery in Portugal and continued to live here of their own volition with a relatively good functional status. Concerns such as access to medications, medical care in the case of complications, the ability to make independent health choices, and the understanding that better obstetric care will be available within a multi-disciplinary unit convinced some women to remain behind in Portugal. Traditional beliefs and cultural contexts around childbearing can be discussed, allowing women to make informed decisions regarding their care and contraception. Choosing a method of contraception for women with VHD requires consideration of safety, effectiveness, patient preference and the risk of an unplanned pregnancy. The use of the CHC has an increased risk of thromboembolism which is particularly relevant in those with MHVs.

These factors call for increased coverage of interventions to control and manage RHD to accelerate progress towards its eradication in African countries []. Despite decades of clinical experience with penicillin in streptococcal pharyngitis to prevent rheumatic fever and RHD, rates of untreated pharyngitis remain very high among school-aged children in most LMIC []. Clinical decision-models that are simple can help prevent rheumatic fever and RHD in the countries that our patients were referred from and represent the low hanging fruit that should be plucked easily [].

Limitations

This is an analysis of data from a 20-year period. Some elements were missing from the earliest patients in the cohort. History of rheumatic fever was either self-reported or communicated by referring physician implying limitations in the fidelity of this information. In our series, no arrhythmic events occurred during pregnancy. However, we cannot exclude the possibility that these patients presented to other hospitals in the SNS network and electronic health platforms with access to the limited information across the different networks became available only recently. Most patients in this cohort received an MHV, which could also indicate the difficulty of repair in RHD, late referral and the relative inexperience of cardiac surgeons in HIC for this pathology. It is possible that better fetal outcomes would have been possible in this same cohort if repair was the primary approach. However, we emphasise that in our experience patients are often referred very late from these countries, precluding a durable repair. The health care systems of some of these nations are rudimentary for cardiac services and diagnosis is often delayed due to lack of imaging. The process of referral is also very convoluted in those countries with a panoply of bureaucratic procedures hindering timely transfer of patients. The sample size of the study population reflects the limitations of a single-centre experience, and a potential selection bias cannot be excluded. The confidence intervals in the univariate and multivariate analysis are wide due the small number of patients.

Conclusions

Pregnant women with VHD from five Portuguese-speaking African countries managed in a tertiary care centre in Portugal, through an intergovernmental agreement, can achieve successful pregnancies with low maternal cardiovascular complications. Significant fetal complications arise, despite vigilant control. VKA therapy was the only independent predictor of an unsuccessful pregnancy. Despite the relative success of such a care model, its applicability is limited due to logistic constraints for pregnant women with VHD in many countries of the African subcontinent. Valve repair should be pursued to hopefully avoid anticoagulation during pregnancy.

Data Accessibility Statements

The data underlying this article are available in the article and in its online supplementary material.

Additional File

The additional file for this article can be found as follows:

Supplementary Data

Tables S1 to S3. DOI: https://doi.org/10.5334/gh.1183.s1

Acknowledgements

The authors wish to thank Prof. Manuel Antunes from the University of Coimbra, Portugal for discussing the benefits of repair in mitral valve disease; Dr. Manuel Pedro Magalhães from Hospital Cruz Vermelha Portuguesa, Lisbon, Portugal for insights into surgical management of RHD; Prof. R Krishna Kumar from the Amrita Institute of Medical Sciences, Kochi, India for discussing the continuing challenge of RHD in LMIC; Dr. Endale Tefera from the University of Botswana at Gaborone for extensive revision of the manuscript and for enlightening us about the challenges of surgical missions to Ethiopia; and Dr. Ana Mocumbi from the National Public Health Institute, Maputo, Mozambique for information regarding the development of a cardiac surgical program in Africa.

Competing Interests

The authors have no competing interests to declare.

References

1. Lawley CM, Algert CS, Ford JB, Nippita TA, Figtree GA, Roberts CL. Heart valve prostheses in pregnancy: Outcomes for women and their infants. J Am Heart Assoc. 2014; 3: 1–8. DOI: https://doi.org/10.1161/JAHA.114.000953

2. Zühlke L, Karthikeyan G, Engel ME, et al. Clinical outcomes in 3343 children and adults with rheumatic heart disease from 14 low-and middle-income countries: Two-year follow-up of the Global Rheumatic Heart Disease Registry (the REMEDY Study). Circulation. 2016; 134: 1456–1466. DOI: https://doi.org/10.1161/CIRCULATIONAHA.116.024769

3. Vervoort D, Meuris B, Meyns B, Verbrugghe P. Global cardiac surgery: Access to cardiac surgical care around the world. J Thorac Cardiovasc Surg. 2020; 159: 987–996.e6. DOI: https://doi.org/10.1016/j.jtcvs.2019.04.039

4. Liaw J, Walker B, Hall L, Gorton S, White AV, Heal C. Rheumatic heart disease in pregnancy and neonatal outcomes: A systematic review and meta-analysis. PLoS One. 2021; 16: 1–19. DOI: https://doi.org/10.1371/journal.pone.0253581

5. Hui C, Lili M, Libin C, et al. Changes in coagulation and hemodynamics during pregnancy: A prospective longitudinal study of 58 cases. Arch Gynecol Obstet. 2012; 285: 1231–1236. DOI: https://doi.org/10.107/s00404-011-2137-x

6. Bremme KA. Haemostatic changes in pregnancy. Best Pract Res Clin Haematol. 2003; 16: 153–168. DOI: https://doi.org/10.1016/s1521-6926(03)00021-5

7. Gilson GJ, Samaan S, Crawford MH, Qualls CR, Curet LB. Changes in hemodynamics, ventricular remodeling, and ventricular contractility during normal pregnancy: A longitudinal study. Obstet Gynecol. 1997; 89: 957–962. DOI: https://doi.org/10.1016/S0029-7844(97)85765-1

8. Abbas AE, Lester SJ, Connolly H. Pregnancy and the cardiovascular system. Int J Cardiol. 2005; 98: 179–189. DOI: https://doi.org/10.1016/j.ijcard.2003.10.028

9. Poppas A, Shroff SG, Korcarz CE, et al. Serial assessment of the cardiovascular system in normal pregnancy. Role of arterial compliance and pulsatile arterial load. Circulation. 1997; 95: 2407–2415. DOI: https://doi.org/10.1161/01.CIR.95.10.2407

10. Monteiro AV, Rebelo J, Patricio L, Campos A, Borges A, Ferreira RC. Ten years’ experience of pregnancy outcomes in women with cardiac valvulopathies: Are valve prostheses worst? J Heart Valve Dis. 2015; 24: 368–375.

11. Tefera E. Treatment of children with rheumatic heart disease in Sub-Saharan Africa by overseas’ medical missions: Challenges left behind. Res J Cardiol. 2014; 2: 1–6.

12. Mocumbi AO. African experiences of humanitarian cardiovascular medicine: the Mozambican experience. Cardiovasc Diagn Ther. 2012; 2(3): 246–251.

13. Strategic plan in health cooperation of the community of Portuguese-speaking countries (PECS-CPLP). PECS 2018–2021. https://www.cplp.org/id-2370.aspx. (Accessed 13 May 2022).

14. Van Hagen IM, Roos-Hesselink JW, Ruys TPE, et al. Pregnancy in women with a mechanical heart valve: Data of the European Society of Cardiology Registry of Pregnancy and Cardiac Disease (ROPAC). Circulation. 2015; 132: 132–142. DOI: https://doi.org/10.1161/CIRCULATIONAHA.115.015242

15. 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. DOI: https://doi.org/10.1016/j.jacc.2017.03.605

16. Mazibuko B, Ramnarain H, Moodley J. An audit of pregnant women with prosthetic heart valves at a tertiary hospital in South Africa: A five-year experience. Cardiovasc J Afr. 2012; 23: 216–221. DOI: https://doi.org/10.5830/CVJA-2012-022

17. Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J, Blomström-Lundqvist C, Cífková R, De Bonis M, et al. ESC Guidelines for the management of cardiovascular diseases during pregnancy. European Heart Journal. 2018; 39: 3165–3241. DOI: https://doi.org/10.1093/eurheartj/ehy340

18. Mehta LS, Warnes CA, Bradley E, Burton T, Economy K, Mehran R, et al. Cardiovascular considerations in caring for pregnant patients: A scientific statement from the American Heart Association. Circulation. 2020; 141(23): e884–e903. DOI: https://doi.org/10.1161/CIR.0000000000000772

19. Geelani MA, Singh S, Verma A, Nagesh A, Betigeri V, Nigam M. Anticoagulation in patients with mechanical valves during pregnancy. Asian Cardiovascular and Thoracic Annals. 2005; 13(1): 30–33. DOI: https://doi.org/10.1177/021849230501300107

20. Al-Lawati AA, Venkitraman M, Al-Delaime T, Valliathu J. Pregnancy and mechanical heart valves replacement; dilemma of anticoagulation. Eur J Cardiothorac Surg. 2002 Aug; 22(2): 223–227. DOI: https://doi.org/10.1016/s1010-7940(02)00302-0

21. D’Souza R, Ostro J, Shah PS, Silversides CK, Malinowski A, Murphy KE, et al. Anticoagulation for pregnant women with mechanical heart valves: a systematic review and meta-analysis. Eur Heart J. 2017 May 14; 38(19): 1509–1516. DOI: https://doi.org/10.1093/eurheartj/ehx032

22. Dhillon SK, Edwards J, Wilkie J, Bungard TJ. High-versus low-dose warfarin-related teratogenicity: A case report and systematic review. J Obstet Gynaecol Can. 2018; 40(10): 1348–1357. DOI: https://doi.org/10.1016/j.jogc.2017.11.020

23. McLintock C. Thromboembolism in pregnancy: Challenges and controversies in the prevention of pregnancy-associated venous thromboembolism and management of anticoagulation in women with mechanical prosthetic heart valves. Best practice & research Clinical obstetrics & gynaecology. 2014; 28(4): 519–536. DOI: https://doi.org/10.1016/j.bpobgyn.2014.03.001

24. Chalachew T, Yadeta D, Tefera E. Factors associated with sub-optimal control of anticoagulation in patients with prosthetic heart valves taking oral anticoagulants in a sub-Saharan African setting. Cardiovasc J Afr. 2019 May 24; 30(6): 1–5. DOI: https://doi.org/10.5830/CVJA-2019-024

25. Nwiloh J, Oludara M, Adebola P, Edaigbini S, Danbauchi S, Sowunmi A. Experience with prosthetic valve replacement in indigents with rheumatic heart disease in Nigeria: 10-year follow-up. World Journal of Cardiovascular Surgery. 2015; 5: 75–81. DOI: https://doi.org/10.4236/wjcs.2015.58013

26. Elkayam U. Anticoagulation therapy for pregnant women with mechanical prosthetic heart valves: How to improve safety? J Am Coll Cardiol. 2017 Jun 6; 69(22): 2692–2695. DOI: https://doi.org/10.1016/j.jacc.2017.04.034

27. Keepanasseril A, et al. Alternatives to low molecular weight heparin for anticoagulation in pregnant women with mechanical heart valves in middle-income countries: A cohort study. Global Heart. 2021; 16(1): 68. DOI: https://doi.org/10.5334/gh.1011

28. Yinon Y, Siu SC, Warshafsky C, Maxwell C, McLeod A, Colman JM, et al. Use of low molecular weight heparin in pregnant women with mechanical heart valves. Am J Cardiol. 2009 Nov 1; 104(9): 1259–1263. DOI: https://doi.org/10.1016/j.amjcard.2009.06.040

29. Connolly SJ, Karthikeyan G, Ntsekhe M, Haileamlak A, El Sayed A, El Ghamrawy A, et al; INVICTUS investigators. Rivaroxaban in rheumatic heart disease-associated atrial fibrillation. N Engl J Med. 2022 Sep 15; 387(11): 978–988. DOI: https://doi.org/10.1056/NEJMoa2209051

30. Silversides CK, Grewal J, Mason J, et al. Pregnancy outcomes in women with heart disease: The CARPREG II study. J Am Coll Cardiol Elsevier. 2018; 71: 2419–2430. DOI: https://doi.org/10.1016/j.jacc.2018.02.076

31. Roos-Hesselink JW, Ruys TPE, Stein JI, et al. Outcome of pregnancy in patients with structural or ischaemic heart disease: Results of a registry of the European Society of Cardiology. Eur Heart J. 2013; 34: 657–665. DOI: https://doi.org/10.1093/eurheartj/ehs270

32. Santos F Dos, Baris L, Varley A, et al. Mechanical heart valves and pregnancy: Issues surrounding anticoagulation. Experience from two obstetric cardiac centres. Obstet Med. 2021; 14: 95–101. DOI: https://doi.org/10.1177/1753495X20924937

33. Kim WK, Kim HJ, Kim JB, et al. Clinical outcomes in 1731 patients undergoing mitral valve surgery for rheumatic valve disease. Heart. 2018; 104: 841–848. DOI: https://doi.org/10.1136/heartjnl-2017-312249

34. Antunes MJ. Repair for rheumatic mitral valve disease. The controversy goes on! Heart. 2018; 104: 796–797. DOI: https://doi.org/10.1136/heartjnl-2017-312674

35. Rusingiza EK, El-Khatib Z, Hedt-Gauthier B, Ngoga G, Dusabeyezu S, Tapela N, et al. Outcomes for patients with rheumatic heart disease after cardiac surgery followed at rural district hospitals in Rwanda. Heart. 2018 Oct; 104(20): 1707–1713. DOI: https://doi.org/10.1136/heartjnl-2017-312644

36. Tefera E, Nega B, Yadeta D, Chanie Y. Humanitarian cardiology and cardiac surgery in Sub-Saharan Africa: Can we reshape the model? World J Pediatr Congenit Heart Surg. 2016; 7: 727–731. DOI: https://doi.org/10.1177/2150135116668834

37. Coates MM, Sliwa K, Watkins DA, Zühlke L, Perel P, Berteletti F, et al. An investment case for the prevention and management of rheumatic heart disease in the African Union 2021-30: A modelling study. Lancet Glob Health. 2021 Jul; 9(7): e957–e966. DOI: https://doi.org/10.1016/S2214-109X(21)00199-6

38. Pearce S, Bowen AC, Engel ME, de la Lande M, Barth DD. The incidence of sore throat and group A streptococcal pharyngitis in children at high risk of developing acute rheumatic fever: A systematic review and meta-analysis. PloS one. 2020; 15(11): e0242107. DOI: https://doi.org/10.1371/journal.pone.0242107

39. Engel ME, Cohen K, Gounden R, et al. The Cape Town clinical decision rule for streptococcal pharyngitis in children. Pediatr Infect Dis J. 2017; 36(3): 250–255. DOI: https://doi.org/10.1097/INF.0000000000001413