The Annals of Anticoagulation: A description of maternal and foetal outcomes in pregnant women with mechanical prosthetic heart valves using warfarin only vs sequential therapy with unfractionated heparin or enoxaparin vs dose adjusted enoxaparin only at Inkosi Albert Luthuli Central Hospital, Kwa-Zulu Natal, South Africa

The Annals of Anticoagulation: A description of maternal and foetal outcomes in pregnant women with mechanical prosthetic heart valves using warfarin only vs sequential therapy with unfractionated heparin or enoxaparin vs dose adjusted enoxaparin only at Inkosi Albert Luthuli Central Hospital, Kwa-Zulu Natal, South Africa | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 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Data may be preliminary. 3 February 2025 V1 Latest version Share on The Annals of Anticoagulation: A description of maternal and foetal outcomes in pregnant women with mechanical prosthetic heart valves using warfarin only vs sequential therapy with unfractionated heparin or enoxaparin vs dose adjusted enoxaparin only at Inkosi Albert Luthuli Central Hospital, Kwa-Zulu Natal, South Africa Authors : Jenneker M 0000-0003-3368-777X [email protected] , Ramnarain H , Mchunu N , and Sebitloane H Authors Info & Affiliations https://doi.org/10.22541/au.173856612.26358251/v1 269 views 128 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Objective To retrospectively audit and describe maternal and foetal outcomes in pregnant women with prosthetic mechanical heart valves (MHV) using various formulations of anticoagulation, namely: (1) warfarin only versus (2) warfarin with sequential therapy with unfractionated heparin (UFH) or enoxaparin or (3) dose adjusted enoxaparin only. Design A 6-year single site retrospective audit from 2017 to 2022. Setting The study was conducted at a single site tertiary hospital, Inkosi Albert Luthuli Central Hospital in Durban, South Africa. Population All pregnant women with a history of mechanical valve replacement requiring lifelong anticoagulation. Methods A retrospective audit of all hospital records using keywords (warfarin, enoxaparin, pregnancy, mechanical heart valves) were used to identify and extract eligible participants for inclusion in the study. Main outcome measures The main outcome sought to describe maternal and foetal outcomes with a focus on maternal thrombo embolic complications, bleeding and foetal affectation in particular warfarin toxicity and fetal wastage. Results The study showed that 9% of pregnant women with MHV were at risk of thrombo embolic complications (TEC), with 9.8% in the warfarin group and 7.9% in the enoxaparin group (p= 0.69). There were higher rates of post-partum bleeding complications in the enoxaparin group (p= 0.035). In particular, individuals treated with enoxaparin had a 20% significantly higher likelihood of achieving live births compared to those treated with warfarin, (risk ratio (RR): 1.20; 95% CI: 1.06-1.07, p<0.001 Conclusion Pregnant women on therapeutic anticoagulation for mechanical heart valve prosthesis are at significant risk for adverse maternal morbidity. not-yet-known not-yet-known not-yet-known unknown The Annals of Anticoagulation: A description of maternal and foetal outcomes in pregnant women with mechanical prosthetic heart valves using warfarin only vs sequential therapy with unfractionated heparin or enoxaparin vs dose adjusted enoxaparin only at Inkosi Albert Luthuli Central Hospital, Kwa-Zulu Natal, South Africa M Jenneker1, 2 H Ramnarain1, 2 N Mchunu3 H Sebitloane1 1*Department of Obstetrics and Gynaecology, School of Clinical Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa 2Department of Obstetrics and Gynaecology, High Risk Obstetrics and Foetal Medicine Department, Inkosi Albert Luthuli Central Hospital, Cator Manor, Durban, South Africa 3 Biostatistics Department, South African Medical and Research council, Durban, South Africa Dr M. Jenneker1, 2 - Corresponding author’s e-mail: [email protected] Dr H Ramnarain1, 2 - e-mail: [email protected] Prof H Sebitloane1 - e- mail: [email protected] Contact no.: +27 64 207 9479 Short Title: The Annals of anticoagulation in pregnant women with mechanical heart valves Objective To retrospectively audit and describe maternal and foetal outcomes in pregnant women with prosthetic mechanical heart valves (MHV) using various formulations of anticoagulation, namely: (1) warfarin only versus (2) warfarin with sequential therapy with unfractionated heparin (UFH) or enoxaparin or (3) dose adjusted enoxaparin only. Design A 6-year single site retrospective audit from 2017 to 2022. Setting The study was conducted at a single site tertiary hospital, Inkosi Albert Luthuli Central Hospital in Durban, South Africa. Population All pregnant women with a history of mechanical valve replacement requiring lifelong anticoagulation. Methods A retrospective audit of all hospital records using keywords (warfarin, enoxaparin, pregnancy, mechanical heart valves) were used to identify and extract eligible participants for inclusion in the study. not-yet-known not-yet-known not-yet-known unknown Main outcome measures The main outcome sought to describe maternal and foetal outcomes with a focus on maternal thrombo embolic complications, bleeding and foetal affectation in particular warfarin toxicity and fetal wastage. Results The study showed that 9% of pregnant women with MHV were at risk of thrombo embolic complications (TEC), with 9.8% in the warfarin group and 7.9% in the enoxaparin group (p= 0.69). There were higher rates of post-partum bleeding complications in the enoxaparin group (p= 0.035). In particular, individuals treated with enoxaparin had a 20% significantly higher likelihood of achieving live births compared to those treated with warfarin, (risk ratio (RR): 1.20; 95% CI: 1.06-1.07, p<0.001 Conclusion Pregnant women on therapeutic anticoagulation for mechanical heart valve prosthesis are at significant risk for adverse maternal morbidity. Funding: Discovery Foundation Keywords Mechanical prosthetic heart valves, Pregnancy, Warfarin, Heparin, Enoxaparin, Rheumatic heart disease Introduction Cardiac disease is an important contributor to maternal morbidity and mortality worldwide. Globally, there has been a paradigm shift to re-evaluate various causes, identify key avoidable risk factors and implement strategic health care interventions to lower maternal and neonatal mortality rates by 2030 (Sustainable Developmental Goal 3.1 and 3.2). 1 A paucity in prospective trials and a reliance on small retrospective studies and expert opinions have led to the development of registries such as the Registry of pregnancy and cardiac disease (ROPAC). 2 An important finding of this worldwide registry is that only 58% of women with mechanical heart valves (MHV) will have an uncomplicated pregnancy. 3 Furthermore, the incidence of rheumatic valvular heart disease (RHD) is higher in low to middle income countries (LMIC) which contributes about 56 -89% of cardiac disease in pregnancy as opposed to high income countries (HIC) where congenital heart disease comprises 75- 82% of cases. 4 Rheumatic heart disease, if left untreated eventually causes indolent progressive damage to heart valves, resulting in stenosis, severe pulmonary hypertension, arrhythmias, cardiac failure and death. Young women desiring fertility and requiring valve replacements should ideally be offered the option of either a bio prosthetic valve (BPV) or a mechanical heart valve (MHV). The risk associated with a BPV is that it is prone to degeneration and therefore has a shorter lifespan with a need for re-operation. 5, 6 MHV are preferred as they are more durable than their tissue counterparts. In LMIC, like South Africa, offering these options may not be economically feasible, sustainable or accessible, where there is a significant burden of cardiovascular disease on the health sector. The lack of resources such as the limited availability of quaternary cardiothoracic units, competing with issues of poverty as well as a large burden of non-communicable diseases further confound the problem. South Africa has approximately only 120 cardiothoracic surgeons with about 60 % of them in the private sector. 7 The large proportion of young women with RHD reside mainly in rural areas, with poor access to health facilities, even at the lowest level. As a result, they are offered MHV replacements and placed on lifelong Coumarin therapy, which is consequently used throughout their reproductive years. The main objective of the study was to describe maternal and foetal outcomes across regimens and describe the maternal complications in relation to the valve position, number and primary valvular pathology. Materials and methods 2.1 Study setting The study was conducted at Inkosi Albert Luthuli Central Hospital (IALCH), Cato Manor, Durban. It is a quaternary level hospital that delivers approximately 450 women per annum with 6% on anticoagulation for mechanical heart valve prosthesis. The hospital serves the greater Durban as well as areas to the south of Kwa- Zulu Natal and Eastern Cape. It has a high-risk obstetric unit which includes a foetal medicine pre diagnostic clinic run by certified foetal maternal subspecialists. The unit has access to cardiology, cardiothoracic surgeons, pulmonologists, neonatologists, intensivists, and anaesthesiologists. Study participants Over the study period there were approximately 450 deliveries, of which 155 were eligible for evaluation. The study population were pregnant women with valvular heart disease that subsequently had mechanical valve replacement on anticoagulation (of various formulations as already described), and who delivered at IALCH from 2017 to 2022. All data of pregnant women with a history of valvular heart disease with subsequent valve replacement surgery were analysed. Clinical data Maternal mortality was defined as a death during pregnancy or within 42 days post-partum. Miscarriage was defined as a pregnancy loss less than 24 weeks and foetal mortality or stillbirth as a foetal demise after 24 weeks gestation. Thromboembolic complications (TEC) included stuck valves, valve dysfunction, stroke and transient ischaemic attacks (TIA). Bleeding complications were divided into ante-partum and post-partum bleeding complications. In view of the retrospective nature of the study, bleeding was defined based on documentation in the medical record and no fixed definition was set. Clinical management The pre- pregnancy and pregnancy regimens used for anticoagulation were documented. Our centre uses three anticoagulation regimens viz: • sequential therapy with either UFH or Enoxaparin in the first trimester with transition to Warfarin during the second and third trimesters • Enoxaparin throughout all trimesters • Warfarin predominantly (often the result of late antenatal booking and continued warfarin use, sometimes across all trimesters). All these regimens require bridging with UFH in the last 2 weeks prior to a planned delivery. In 2020, the authors published a flowchart depicting the clinical management and anticoagulation options in pregnant women with MHV. (Annexure 1) All mean INR, APTT and anti Xa levels were documented. All adverse events, obstetric complications, maternal, foetal, and neonatal outcomes in the ante partum and post-partum periods were assessed. 2.5 Data collection Study participants were identified after electronic maternity records were screened using search words: warfarin, enoxaparin, pregnancy and mechanical heart valves. Women with valvular disease not receiving anticoagulants were excluded. Information was retrieved using the in hospital electronic database. The information was then recorded on to a data collection sheet and later computed on to an excel spreadsheet for statistical analysis. Data included demographic information, baseline maternal and neonatal characteristics. The maternal characteristics included age, parity, weight, employment history and antenatal booking bloods: Rhesus, Syphilis, HIV status. Further enquiry into the past medical, surgical, obstetric and contraceptive history were sought. The socio-economic conditions of the women were noted. The neonatal characteristics included gestational age, birth weight, warfarin exposure and toxicity. Neonatal outcomes included prematurity, growth restriction, stillbirths, miscarriage and termination of pregnancy. Maternal outcomes included major adverse cardiac events (MACE), stuck valves, bleeding, death, number of high care and intensive care unit (ICU) hospital admissions. The valve position, number of valves and the primary valve pathology were also used to risk stratify these women. 2.6 Statistical analysis Descriptive statistics were used to summarize maternal and perinatal outcomes, as well as the demographic and clinical characteristics of the study population. Non-normally distributed quantitative data were described using medians with interquartile ranges (IQR) and compared using the Wilcoxon rank-sum test. Categorical data were presented as frequencies and percentages, and comparisons were conducted using the Chi-square test or Fisher’s exact test, as appropriate. A modified Poisson regression model with robust standard errors was used to assess factors associated with warfarin exposure. A similar analysis was conducted to assess the risk of experiencing TEC, bleeding complications and live births for individuals treated with enoxaparin versus warfarin. A two-tailed P-value of <0.05 was considered to indicate statistical significance. All statistical analyses were performed using Stata software version 18 (StataCorp. 2023. Stata Statistical Software: Release 18. College Station, TX: StataCorp LLC). The study was approved by the local ethics committee, University of Kwa-Zulu Natal Biomedical Research Ethics Committee, BREC/00003925/2022. Permission was also obtained from the institution and the provincial Department of Health. Results The baseline maternal characteristics are represented in Table 1. The mean age of women in the study population was 27.7 years with a median weight of 68kg. There were 57 (36.8%) women living with HIV, with 85.7% of whom had a suppressed viral load, (Table 1). The records indicated that all women were aware of their cardiac problem and need for anticoagulation. Despite this, only 19 (12.3%) were on contraception and only 14 (9 %) admitted to a planned pregnancy, with 7.2 % seeking pre pregnancy counselling, (Table 1). At least 114 (76%) had visited the cardiologist within 2 years of conception and 14.7% showed poor follow-up, being not seen by a cardiologist for more than 5 years, (Table 1). On average 38.7% of the pregnant women presented in the first trimester with the majority 61.3 % presenting in the second and third trimesters, (Table 1). Comorbid conditions of note were chronic hypertension (11.6%), history of an ischaemic event (4.5%) and a prior history of a bleeding disorder in 0.6% of women, (Table1). The past obstetric history on birth outcomes revealed 26 (16.8%) had a previous intra uterine fetal death (IUFD), while 40 (25.8%) had a previous miscarriage and 3.2% had terminated a previous pregnancy, (Table 1). The commonest primary valvular pathology was RHD 148 (95.5%), and congenital heart disease accounted for only 7 (4.5%) of cases, (Table 1). Most women had a single mitral valve replaced 117 (75.5%) with 32 (20.6%) cases having a dual valve replaced i.e. aortic and mitral valve, (Table 1). Warfarin was the anticoagulation regimen used in (n= 84/155) 54.2 % of cases, with enoxaparin only used in (n= 59/155), 38.1% of cases, the rest were sequential therapy, (Table 1). Table 2 shows the main maternal outcomes stratified by the regimen used, i.e. bleeding complications in the antepartum and postpartum period, and thrombo embolic complications (TEC) i.e. stuck valves, valve dysfunction, stroke and transient ischaemic attacks (TIA). Post-partum bleeding complications including post-partum haemorrhage (PPH), wound haematoma and pelvic haematoma were more common in the enoxaparin group i.e. 13.6%, 37.3% and 18.6% respectively, (Table 2) In particular, individuals treated with enoxaparin had a 56% significantly higher risk of bleeding complications compared to those on warfarin (Risk Ratio (RR)=1.56; 95% CI: 1.04-2.34, p= 0.030, Table 3). With regards TEC, there were 9.5 % of cases in the warfarin group compared to 8.5 % in the enoxaparin group, p= 0.83 . In particular, individuals treated with enoxaparin had a 19% lower risk of TEC compared to those on warfarin. However, this was not statistically significant, (RR=0.81, 95% CI: 0.28-2.32, p=0.696, Table 3). The live births in the enoxaparin predominant group were significantly higher than the warfarin predominant group 96, 6% compared to 82.1%, (p <0.001, Table 2). In particular, individuals treated with enoxaparin had a 20% significantly higher likelihood of achieving live births compared to those on warfarin, (risk ratio (RR)=1.20; 95% CI: 1.08-1.34, p=0.001, Table 3) . The main maternal outcomes are listed in Table 4. The outcomes focused mainly on thrombo embolic complications associated with mechanical heart valves and anticoagulation. These included stuck valves (3.9%), valve dysfunction (7.1%), transient ischaemic attack (TIA) (1.9%) and stroke (1.3%). There was 1 maternal death over the study period. She had the initial mitral valve replacement in 2006, which needed a repeat in 2007. In this pregnancy she presented at 24 weeks with a background of chronic atrial fibrillation controlled on a beta blocker. She had an uneventful antenatal course on warfarin, with 4 admissions for a sub therapeutic INR. She was admitted at 36 weeks for bridging to UFH. At 38 weeks, she went into spontaneous labour and had an emergency caesarean section for previous caesarean section X1 and a breech presentation. This patient deteriorated immediately post-delivery with rapid atrial fibrillation and subsequently went into cardiac failure. Echocardiography revealed a stuck prosthetic valve, systolic function of 16% and severe pulmonary hypertension. Despite thrombolysis, she developed a massive thrombus to the middle cerebral artery with infarction. The final cause of death was a left cerebral vascular accident with mass effect and ventricular fibrillation. The perinatal outcomes are represented in Table 5. The median gestational age at delivery was 38 weeks with an interquartile range between 36 and 38 weeks (Table 4). The modes of deliveries are depicted in the flow chart (Figure 1), where majority of the deliveries were an emergency caesarean section (51.0%, Figure 1). Induction of labour was offered to 33 women, n= 20 (61%) had a failed induction and an emergency caesarean section and n= 13 (39%) had a successful normal vaginal delivery. Of importance is the high rates of warfarin exposure i.e. 81.9% of cases, with a warfarin embryopathy rate of 19.3%. Features of warfarin embryopathy were suspected either on abnormal antenatal scan in 34.2% of cases, abnormal neonatal cranial ultrasounds (CRUSS) in 15% of cases or abnormal babygrams in 3.8% of cases, (Table 5). The prematurity rate (spontaneous or iatrogenic) was 24.8%. The study showed a total of 14 stillbirths and 6 cases of spontaneous miscarriage, 2 fetocides and 2 terminations of pregnancy. The study also aimed to risk stratify women by valve position, number and primary valvular pathology (Table 6 and Table 7). The single aortic valve was associated with the least complications in comparison to the mitral valve. These findings were not statistically significant. On average, women with rheumatic heart disease spent more days in high care compared to those with congenital heart disease with a median stay of 5 and 4 days respectively (Table 6). In addition, women who had an aortic valve replacement spent more days in high care compared to those who had mitral valve replacement and dual valve replacement (Table 7). When assessing factors related to warfarin exposure. Mothers with warfarin exposure had a 6% risk of experiencing prematurity compared to those that were not exposed (RR=1.06; 95% CI: 0.87-1.30, p=0.547, Table 8). Discussion Rheumatic heart disease is a common cause of preventable heart disease in LMIC. The rate of this disease is 3.4/100, 000 in non-endemic areas vs 444/ 100, 000 in endemic areas of the world. 8 Pronounced decreasing trends of death and disability due to RHD were observed worldwide from 1990 to 2019, indicating progress in the current management and treatment of RHD. 8 This potentially indicates increased rates of treatment and valve replacements. The Modified WHO classification of maternal cardiovascular risk classifies a pregnancy with MHV as category III which places these women at significant risk for maternal morbidity and mortality with reported rates of 19% to 27% for maternal adverse events. 9 The study showed that the majority of women were multiparous, of poor socio-economic backgrounds and of sober habits. We found that women treated with warfarin, had a higher risk of experiencing TEC compared to those on enoxaparin Significantly, the rates of postpartum bleeding complications were higher in the enoxaparin group the latter being associated with more live births, and less foetal wastage. These women require a multidisciplinary team approach in an expert center for pregnancy and cardiac disease. Furthermore, it recommends that these women should be offered pre pregnancy counselling, planning and early booking. 9 The study showed higher rates of a prior history of poor obstetric outcomes. It is unsure if this was warfarin related. O ur study also showed that despite a hundred percent awareness of their cardiac problem, contraceptive uptake, pregnancy planning and early booking was poor with 25% of study participants presenting in the 2 nd and 3 rd trimesters. Moreover, the institution only introduced dose adjusted enoxaparin in the latter part of 2018, with the availability of Anti Xa testing. These factors led to high rates of warfarin use and exposure and consequently warfarin embryopathy and foetal wastage. A systematic review by Chan et al analyzed maternal and fetal risks associated with different anticoagulation regimens during pregnancy. The authors reported that the use of oral anticoagulants throughout pregnancy was associated with warfarin embryopathy in 6.4% (95% confidence interval, 4.6%-8.9%) of live births. There were 2 fetocides offered and accepted due to severe warfarin embryopathy: Case 1: Severe ventriculomegaly with distorted brain anatomy, nasal hypoplasia and an intra cranial bleed at 28 weeks gestation. Case 2: Severe intracranial haemorrhage with distortion of brain anatomy and midline shift at 30 weeks gestation. Fetus developed anaemia with cardiac decompensation because of the bleed A delicate balance between risk and benefit to both mother and foetus can be achieved with dose adjusted Enoxaparin. Historically, however, there were FDA warnings citing concerns regarding its use during pregnancy in women with mechanical prosthetic valves. 11 Additionally, the inability to monitor anti-Xa factor as a measure of its safety margin limits its use in many settings. It is noteworthy that as our use of dose adjusted enoxaparin continues to grow in patient years so too does our confidence in its safety of use, if used correctly. Our center monitors these women 2 weekly to achieve anti Xa levels between 1.0 IU/L and 1.2 IU/L (target therapy as per European Society of Cardiology/ ESC guidelines. 12 In contrast, warfarin is an affordable, easily accessible, oral anticoagulant that is advocated for the management of MHV outside of pregnancy. 13 This drug confers adequate maternal benefit but is associated with warfarin embryopathy and other adverse perinatal outcomes. 13 It is for this reason that more studies are needed to elucidate the maternal benefits of the Heparins e.g. dose adjusted Enoxaparin that offers 100% safety to the developing embryo and fetus. Our study confirmed that Enoxaparin is associated with higher live birth rates, 96.6% compared to other regimens. D’ Souza et al. 2015, reported similar livebirths for the Enoxaparin group but lower rates in the Warfarin group than our study. The Meta analysis showed live births in 64.5 % (48.8–80.2), 79.9% (74.3–85.6) and 92.0% (86.1–98.0) for Warfarin only, sequential therapy and Enoxaparin only respectively. 14 With respect to maternal outcomes, a focus on TEC and bleeding risk remains a grave concern for the attending physician managing these patients. Our study showed that TEC occurred more in the warfarin group in comparison to the enoxaparin group. This contrasts with what has historically been reported for enoxaparin. Furthermore, our study showed no cases of stuck valves in the Enoxaparin group. In a study conducted in South Africa by Rhemtula et al in 2024, there were no cases of stuck valves reported in women managed with dose adjusted Enoxaparin. 15 On evaluating the cases of stuck valves, the data shows that there was an underlying arrhythmia in 2/3 of cases and 1/3 of cases had a history of an ischaemic event or cerebral vascular accident. These are known predictors for increasing thrombogenicity of valves and valvular dysfunction. 16 Hence this may confound the increased incidence noted. Furthermore, the unit risk stratifies women based on baseline ECG and echocardiography features and may opt to use warfarin instead of enoxaparin in women with high- risk predictors. Notably, now that our experience with dose adjusted Enoxaparin increases, this approach is slowly declining. Bleeding is a known complication for people on anticoagulation. 18 There were significantly more cases of bleeding in the enoxaparin group than any other regimen. In particular, in the post-partum period. Other studies also showed increased rates of bleeding associated with enoxaparin. 18 Finally, when interpreting the results by valve position and primary valve pathology, our study showed that RHD was 20 times more prevalent as the underlying primary valvular pathology compared to congenital causes. Furthermore, maternal risk stratified by primary valvular pathology showed a higher incidence in adverse outcomes in cases of RHD than CHD. Since, RHD commonly affects the mitral valve it is therefore not surprising that this valve position was the commonest position, replaced with 75.5% of cases. It was associated with more maternal complications in comparison to a single aortic valve. This finding has been reported in other studies. 19 Limitations and Strengths The strength of the study is in its 6- year experience at a quaternary hospital with expert care in anticoagulation and mechanical heart valves. Furthermore, the experience gained using dose adjusted enoxaparin since 2018 has increased. Dose adjusted enoxaparin is slowly proving that it can provide maternal benefit and safety and simultaneously protect fetuses from the potential teratogenic effects of warfarin. The study limitation is mainly linked to its retrospective nature. For this reason, definitions for bleeding complications were not standardized and relied on visual estimation by the attending physicians at the time. A higher n number in the enoxaparin group will provide more information on its potential maternal safety. Recommendations 1. With more studies confirming the safety of use of low molecular weight heparins (LMWH) in pregnant women with mechanical valves, future studies should be designed to show non inferiority between the coumarins and enoxaparin, particularly in LMIC. 2. This study highlights the need for contraceptive counselling in all disciplines of medicine, in particular women in their reproductive age with chronic medical disorders. 3. Education of women with MHV, on the need to plan their pregnancies, attend pre conceptual clinics and attend antenatal clinics at their first missed period to allow for early bridging to heparin 4. Women should not stop their warfarin while attempting pregnancy as this puts them at undue risk of thrombosis and death 5. These women should be managed at expert cardio obstetric centers with the skill and knowledge to navigate their anticoagulation needs throughout pregnancy 6. More studies are needed to evaluate dose adjusted enoxaparin with respect to its maternal benefit vs warfarin Conclusion Individuals treated with enoxaparin had a 56% significantly higher risk of bleeding complications compared to those on warfarin. Furthermore, individuals treated with enoxaparin had a 19% lower risk of TEC and a 20% significantly higher likelihood of achieving live births compared to those on warfarin. Dose adjusted enoxaparin is safe and a major contender as an anticoagulation of choice in pregnant women with MHV. More studies are needed to further elucidate its benefits and risks. The study presents a 6-year experience of pregnant women on anticoagulation with MHV. The paucity of data on this subject and the high burden of RHD in LMIC makes this an important contribution to the current body of evidence. This research will add to the current body of knowledge with regards options of management for anticoagulation in pregnant women with MHV making it possible for future generations to manage the many clinical dilemmas associated with this condition. References 1. United Nations. Sustainable Development Goals: 3.1 and 3.2. Available from: https://sdgs.un.org/goals 2. Roos-Hesselink JW, Ruys TP, Stein JI, Thilen U, Webb GD, Niwa K, et al. Outcome of pregnancy in patients with structural or ischemic heart disease: Results of a registry of the European Society of Cardiology. Eur Heart J. 2013;34(9):657-665. 3. van Hagen IM, Roos-Hesselink JW, Ruys TP, 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(2):132-142. 4. Zühlke L, Engel ME, Watkins D, Mayosi BM. Incidence, prevalence, and outcome of rheumatic heart disease in South Africa: A systematic review of contemporary studies. Int J Cardiol. 2015; 199:375-383. 5. Pieper PG, Balci A, Van Dijk AP. Pregnancy in women with prosthetic heart valves. Neth Heart J. 2008 Dec;16(12):406–411. doi: 10.1007/BF03086187. PMCID: PMC2612108 , PMID: 19127317 . 6. Barbarash L, Rutkovskaya N, Barbarash O, Odarenko Y , Stasev A, Uchasova E. Prosthetic heart valve selection in women of childbearing age with acquired heart disease: a case report. J Med Case Rep. 2016 Mar 8;10:51. doi: 10.1186/s13256-016-0821-y. 7. Schewitz I. Cardiothoracic surgery in South Africa: a history. J Thorac Dis. 2022 Apr;14(4):1275–1281. doi: 10.21037/jtd-21-1117. PMCID: PMC9096323 , PMID: 35572888 . 8. Watkins DA, Johnson CO, Colquhoun SM, Kwan GF, Engel ME, Zühlke LJ, et al. Global, regional, and national burden of rheumatic heart disease, 1990–2015. N Engl J Med. 2017;377(8):713–22. 9. European Society of Cardiology (ESC). 2018 ESC Guidelines for the management of cardiovascular diseases during pregnancy. Eur Heart J. 2018;39(34):3165–241. 10. Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature. Arch Intern Med. 2000 Jan 24;160(2):191-6. doi: 10.1001/archinte.160.2.191. 11. Food and Drug Administration (FDA). Lovenox (enoxaparin sodium) injection label. Silver Spring, MD: FDA; 2002. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/020164s129lbl.pdf 12. Regitz-Zagrosek V, Blomstrom Lundqvist C, Borghi C, Cifkova R, Ferreira R, Foidart JM, et al. ESC guidelines on the management of cardiovascular diseases during pregnancy. Eur Heart J. 2011;32(24):3147–97. 13. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP, Fleisher LA, et al. 2017 AHA/ACC Focused Update on the Management of Patients With Valvular Heart Disease. Circulation. 2017;135(25):e1159-95. doi: 10.1161/CIR.0000000000000503. 14. D’Souza R, Ostro J, Shah PS, Silversides CK, Malinowski AK. Anticoagulation for pregnant women with mechanical heart valves: A systematic review and meta-analysis. Eur Heart J. 2017;38(19):1509–16. 15. Rhemtula N, Moodley J, Anthony J. Enoxaparin use in pregnant women with mechanical prosthetic valves in a tertiary South African hospital: a retrospective review. S Afr Med J. 2024;114(1):20–8. 16. Roudaut R, Serri K, Lafitte S. Thrombosis of prosthetic heart valves: diagnosis and therapeutic considerations. Heart. 2007;93(1):137-142 17. Greer IA. Thrombosis in pregnancy: maternal and fetal issues. Lancet. 1999;353(9160):1258–65. doi: 10.1016/S0140-6736(98)09333-8 18. Zühlke L, Engel ME, Watkins D, et al. Rheumatic heart disease in Africa: the Mosi-o-Tunya call to action. Lancet Glob Health. 2017;5(8):e843–5. doi: 10.1016/S2214-109X(17)30240-7 19. Sliwa K, Barros ACF, Bantje T, et al. Cardiac disease in pregnancy: a global perspective. Eur Heart J . 2015;36(18):1078–1083. doi:10.1093/eurheartj/ehv020. Gestational age (in weeks) at first visit 34 4 (2.6%) 56 (36.1%) 12 (7.7%) 42 (27.1%) 36 (23.2%) 5 (3.2%) Cardiac condition known before the pregnancy 155 (100.0%) Prior Contraception 19 (12.3%) Pregnancy planning 14 (9.0%) Pre pregnancy counselling 11(7.2%) Genetic counselling 5 (3.3%) Mean age (SD), in years 27.7 (6.2) Median weight (kg) Parity Primi gravida Multiple gravida Grand gravida (5+) 46 (29.7%) 108 (69.7%) 1 (0.6%) Rhesus positive 151 (97.4%) Rapid syphilis positive 4 (2.6%) Human immunodeficiency virus (HIV) positive 57 (36.8%) CD4 count 497.0 (337.0-656.5) Viral load (<50 copies/ml) 48 (85.7%) Previous IUFD 26 (16.8%) Previous miscarriages 40 (25.8%) Previous TOP 5 (3.2%) If Prosthetic valve: type/position/number MVR AVR DVR 117 (75.5%) 6 (3.9%) 32 (20.6%) If Valve disease : Primary valvular pathology RHD CHD 148 (95.5%) 7 (4.5%) Regimen used Warfarin Enoxaparin Sequential Therapy UFH Sequential Therapy Enoxaparin UFH 84 (54.2%) 59 (38.1%) 5 (3.2%) 4 (2.6%) 3 (1.9%) Warfarin exposed 127 (81.9%) Warfarin exposure until GA (weeks) 8.0 (6.0-10.0) Start dose of enoxaparin (mg/kg) 1.0 (1.0-1.0) End dose of enoxaparin (mg/kg) 1.4 (1.3-1.6) Time interval between first antenatal visit and last cardiology visit, in years 5 114 (76.0%) 14 (9.3%) 22 (14.7%) Chronic Hypertension 18 (11.6%) Prior history of ischaemic event 7 (4.5%) Prior history of bleeding disorder 1 (0.6%) Table 1: Baseline maternal and cardiac characteristics ( IUFD= Intra uterine fetal death, TOP= Termination of pregnancy, MVR= Mitral valve replacement, AVR= Aortic valve replacement, DVR= Dual valve replacement, RHD= Rheumatic heart disease, CHD= Congenital heart disease), SD= Standard deviation Table 2: Thrombo embolic complications and bleeding complications stratified by anticoagulant regimen Bleeding complications (post-partum) 27 (32.1%) 30 (50.8%) 1 (20.0%) 0 (0.0%) 0(0.0%) 58 (37.4%) 0.035 Bleeding complications (ante partum) 2 (2.4%) 5 (8.6%) 1 (20.0%) 0 (0.0%) 0 (0.0%) 8 (5.3%) 0.27 Postpartum haemorrhage 10 (11.9%) 8 (13.6%) 1 (20.0%) 0 (0.0%) 0(0.0%) 19 (12.3%) 0.85 Wound haematoma 19 (22.6%) 22(37.3%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 41 (26.5%) 0.075 Pelvic haematoma 8 (9.5%) 11(18.6%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 19 (12.3%) 0.34 Stuck Valves 6 (7.1%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 6 (3.9%) 0.26 Valve dysfunction 7 (8.3%) 3 (5.1%) 1 (20.0%) 0 (0.0%) 0 (0.0%) 11 (7.1%) 0.67 Stroke 1 (1.2%) 1 (1.7%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 2 (1.3%) 0.99 Transient ischaemic attack (TIA) 1 (1.2%) 2 (3.4%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 3 (1.9%) 0.89 not-yet-known not-yet-known not-yet-known unknown Table 3: Risk Ratios for clinical outcomes for enoxaparin group versus warfarin group TEC 0.81 [0.28 – 2.32] 0.696 Bleeding complications 1.56 [1.04 – 2.34] 0.030 Live births 1.20 [1.08 – 1.34] 0.001 Table 4: Maternal Outcomes N=155 Livebirths 135 (87.1%) MACE 7 (4.5%) Arrhythmia 18 (11.6%) TIA 3 (1.9%) Stuck Valves 6 (3.9%) Heart Failure 6 (3.9%) Valve dysfunction 11 (7.1%) Infective endocarditis 3 (1.9%) Sepsis 17 (11.0%) Maternal death 1 (0.6%) ICU admission 9 (5.8%) Number of days spent in ICU 6.5 (2.5-10.5) Number of days spent in high care 5.0 (3.0-8.0) Cardiac Intervention in pregnancy 6 (3.9%) Stroke 2 (1.3%) Preeclampsia 12 (7.8%) Chronic hypertension 6 (3.9%) Gestational hypertension 6 (3.9%) FGR 14 (9.0%) SGA 5 (3.2%) Gestational Diabetes 12 (7.7%) Antepartum Haemorrhage 7 (4.5%) Postpartum haemorrhage 19 (12.3%) Retained products of conception 13 (8.4%) Preterm labour 42 (27.3%) PROM 1 (0.6%) Spontaneous rupture of membranes 46 (29.7%) Table 4: Maternal Outcomes ( MACE= Major adverse cardiac event, TIA= Transient ischaemic attack, ICU= Intensive care unit, FGR= Foetal growth restriction, SGA= Small for gestational age, PROM= Premature rupture of membranes) Table 5: Perinatal outcomes, N=155 Gender Female Male 81 (56.6%) 62 (43.4%) Congenital heart disease 7 (5.1%) Neonatal sepsis 15 (11.0%) Neonatal jaundice 14 (10.4%) Prematurity 42 (27.3%) Warfarin exposed 127 (81.9%) Respiratory complication 14 (9.9%) Neonatal cranial ultrasound Normal Abnormal 113 (85.0%) 20 (15.0%) Baby gram Normal Abnormal 128 (96.2%) 5 (3.8%) Warfarin embryopathy 28 (19.3%) Neonatal mortality 1 (0.7%) Miscarriage 6 (3.9%) Fetocide 2 (1.3%) Termination of Pregnancy 3 (1.9%) Livebirths 135 (87.1%) Foetal mortality 14 (9.03%) Ultrasound Normal Abnormal 102 (65.8%) 53 (34.2%) Maternal outcomes stratified by primary valve pathology MACE 7 (4.7%) 0 (0.0%) 7 (4.5%) 0.56 Arrhythmia 18 (12.2%) 0 (0.0%) 18 (11.6%) 0.33 TIA 3 (2.0%) 0 (0.0%) 3 (1.9%) 0.70 Stuck Valves 6 (4.1%) 0 (0.0%) 6 (3.9%) 0.59 Heart Failure 6 (4.1%) 0 (0.0%) 6 (3.9%) 0.59 Valve dysfunction 11 (7.4%) 0 (0.0%) 11 (7.1%) 0.45 Infective endocarditis 3 (2.0%) 0 (0.0%) 3 (1.9%) 0.70 Sepsis 17 (11.5%) 0 (0.0%) 17 (11.0%) 0.34 Cardiac arrest 1 (0.7%) 0 (0.0%) 1 (0.6%) 0.83 Maternal death 1 (0.7%) 0 (0.0%) 1 (0.6%) 0.83 ICU admission 9 (6.1%) 0 (0.0%) 9 (5.8%) 0.76 Median number of days in ICU 6.5 (2.5-10.5) 6.5 (2.5-10.5) Median number of days in high care 5.0 (4.0-9.0) 4.0 (3.0-5.0) 5.0 (3.0-8.0) 0.13 Cardiac Intervention in pregnancy 6 (4.1% 0 (0.0%) 6 (3.9%) 0.59 Livebirth 130 (87.8%) 5 (71.4%) 135 (87.1%) 0.21 Miscarriage 5 (3.4%) 1 (14.3%) 6 (3.9%) 0.15 Prematurity 33 (25.0%) 1 (20.0%) 34 (24.8%) 0.80 FGR 14 (9.5%) 0 (0.0%) 14 (9.0%) 0.39 Table 6: Maternal outcomes stratified by primary valve pathology ( RHD= Rheumatic heart disease, CHD= Congenital heart disease, MACE= Major adverse cardiac event, TIA= Transient ischaemic attack, ICU= Intensive care unit, FGR= Foetal growth restriction) Maternal outcomes stratified by valve position and number MACE 6 (5.1%) 0 (0.0%) 1 (3.1%) 7 (4.5%) 0.77 Arrhythmia 14 (12.0%) 0 (0.0%) 4 (12.5%) 18 11.6%) 0.66 TIA 3 (2.6%) 0 (0.0%) 0 (0.0%) 3 (1.9%) 0.61 Stuck Valves 4 (3.4%) 0 (0.0%) 2 (6.2%) 6 (3.9%) 0.67 Heart Failure 5 (4.3%) 0 (0.0%) 1 (3.1%) 6 (3.9%) 0.84 Valve dysfunction 8 (6.8%) 0 (0.0%) 3 (9.4%) 11 (7.1%) 0.70 Infective endocarditis 2 (1.7%) 1 (16.7%) 0 (0.0%) 3 (1.9%) 0.023 Sepsis 13 (11.1%) 1 (16.7%) 3 (9.4%) 17(11.0%) 0.87 Cardiac arrest 1 (0.9%) 0 (0.0%) 0 (0.0%) 1 (0.6%) 0.85 Maternal death 1 (0.9%) 0 (0.0%) 0 (0.0%) 1 (0.6%) 0.85 ICU admission 7 (6.0%) 0 (0.0%) 2 (6.2%) 9 (5.8%) 0.90 Median number of days in ICU 5.0 (1.0-8.0) 18.5 (7.0-30.0) 6.5 (2.5-10.5) Median number of days in high care 5.0 (3.0-8.0) 11.0 (6.0-13.0) 4.0 (3.0-7.0) 5.0 (3.0-8.0) 0.18 Cardiac Intervention in pregnancy 4 (3.4%) 0 (0.0%) 2 (6.2%) 6 (3.9%) 0.68 Table 7: Maternal outcomes stratified by valve position and number ( MVR= Mitral valve replacement, AVR= Aortic valve replacement, DVR= Dual valve replacement, MACE= Major adverse cardiac event, TIA= Transient ischaemic attack, ICU= Intensive care unit) Table 8: Factors associated with warfarin exposure RR 95% CI P-value Prematurity 1.06 0.87-1.30 0.547 Fetal growth restriction 0.9 0.64-1.27 0.55 Abnormalities on Ultrasound 0.86 0.73-1.01 0.064 Abnormalities on Neonatal Cranial ultrasound 0.99 0.78-1.25 0.917 Figure 1: Mode of delivery of study participants Annexure 1 Information & Authors Information Version history V1 Version 1 03 February 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords maternal medicine medical disorders in pregnancy Authors Affiliations Jenneker M 0000-0003-3368-777X [email protected] Inkosi Albert Luthuli Central Hospital View all articles by this author Ramnarain H Inkosi Albert Luthuli Central Hospital View all articles by this author Mchunu N South African Medical Research Council Durban View all articles by this author Sebitloane H University of KwaZulu-Natal Department of Obstetrics and Gynaecology View all articles by this author Metrics & Citations Metrics Article Usage 269 views 128 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Jenneker M, Ramnarain H, Mchunu N, et al. The Annals of Anticoagulation: A description of maternal and foetal outcomes in pregnant women with mechanical prosthetic heart valves using warfarin only vs sequential therapy with unfractionated heparin or enoxaparin vs dose adjusted enoxaparin only at Inkosi Albert Luthuli Central Hospital, Kwa-Zulu Natal, South Africa. 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