META-ANALYSIS
European Heart Journal (2017) 38, 1509–1516 doi:10.1093/eurheartj/ehx032
Anticoagulation for pregnant women with mechanical heart valves: a systematic review and meta-analysis Rohan D’Souza1,2*, Jackie Ostro3, Prakesh S. Shah2,4, Candice K. Silversides5, Ann Malinowski1, Kellie E. Murphy1,2, Mathew Sermer1, and Nadine Shehata2,6 1 Department of Obstetrics and Gynaecology, Division of Maternal and Fetal Medicine, Mount Sinai Hospital, University of Toronto, 700 University Avenue, Toronto ON M5G 1Z5, Canada; 2Institute of Health Policy, Management and Evaluation, University of Toronto, 155 College Street, Toronto ON M5T 3M6, Canada; 3Department of Medicine, Division of Hematology, University of Toronto, Toronto, Canada; 4Department of Paediatrics, Division of Neonatology, Mount Sinai Hospital, University of Toronto, 700 University Avenue, Toronto ON M5G 1Z5, Canada; 5Department of Medicine, Division of Cardiology, Obstetric Medicine Program, Mount Sinai Hospital, University of Toronto, 700 University Avenue, Toronto ON M5G 1Z5, Canada; and 6Departments of Medicine and Laboratory Medicine and Pathobiology, Mount Sinai Hospital, Division of Hematology, Mount Sinai Hospital, University of Toronto, 700 University Avenue, Toronto ON M5G 1Z5, Canada
Received 23 July 2016; revised 28 September 2016; editorial decision 7 January 2017; accepted 13 February 2017; online publish-ahead-of-print 9 March 2017
See page 1517 for the editorial comment on this article (doi: 10.1093/eurheartj/ehw673)
Aims
To review maternal and foetal outcomes in women with mechanical heart valves (MHVs) treated with vitamin-K antagonists (VKAs), first-trimester heparin followed by VKAs (sequential treatment), low molecular weight heparin (LMWH) and unfractionated heparin (UFH) during pregnancy, in order to inform practice.
................................................................................................................................................................................................... Methods Medline, Embase and Central were searched from inception until February 2016. Two reviewers independently screened 1786 titles, reviewed 110 full-texts and extracted data and assessed risk-of-bias from 46 articles. Pooled incidence (95% and results
confidence intervals) was calculated for maternal and foetal outcomes. Included studies had a moderate or high risk-ofbias. With VKAs, sequential treatment and LMWH, maternal mortality occurred in 0.9% (0.4–1.4), 2.0% (0.8–3.1) and 2.9% (0.2–5.7), thromboembolic complications in 2.7% (1.4–4.0), 5.8% (3.8–7.7) and 8.7% (3.9–13.4), livebirths in 64.5% (48.8–80.2), 79.9% (74.3–85.6) and 92.0% (86.1–98.0) and anticoagulant-related foetal/neonatal adverse events (embryopathy or foetopathy) in 2.0% (0.3–3.7), 1.4% (0.3–2.5) and 0%, respectively. When UFH is used throughout pregnancy, 11.2% (2.8–19.6) suffered thromboembolic complications. Foetal loss and adverse events occurred with first-trimester warfarin doses 5 mg/day.
................................................................................................................................................................................................... Conclusions VKAs are associated with fewest maternal complications but also with fewest livebirths. Sequential treatment does not eliminate anticoagulant-related foetal/neonatal adverse events. LMWH is associated with the highest number of livebirths. The safety of UFH throughout pregnancy and first-trimester warfarin 75% as having a high degree of heterogeneity.13 Although we considered performing a formal statistical comparison between treatment strategies using Student t tests and non-parametric tests, the significant clinical and methodological heterogeneity between studies meant that the
.. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. ..
assumptions of these tests were violated. We therefore restricted statistical comparisons only to those studies that reported more than one treatment strategy (see Supplementary material online, Table S4).
Subgroup and sensitivity analyses Subgroup analysis for VKAs were conducted based on PT or INR targets, the use of VKAs until planned caesarean delivery and the first-trimester dose of VKAs. Studies describing sequential therapy were categorized according to whether the heparin was UFH or LMWH. In addition, subgroup analyses for all categories were conducted including studies that reported outcomes with bileaflet and single-tilting disc valves. Sensitivity analyses were performed according to risk-of-bias scores and the country’s economic status based on the 2015 World Bank report on income level.14
1512
0 0 INR, international normalized ratio; LMWH, low molecular weight heparin; NA, not applicable; UFH, unfractionated heparin. Estimates are presented as proportions per 100 affected pregnancies with 95% confidence intervals. a Of these 7/407 [0.8% (0.0, 1.7)] represent embryopathy and 5/197 [2.1% (0.1, 4.1)] represent foetopathy. b All cases represent foetopathy.
0
NA 7.6 (0.1, 15.0)b
1.4 (0.3, 2.5)b 5/431
0/103 4/44 8 4
19 79.9 (74.3, 85.6) 61
92.0 (86.1, 98.0) 0 69.5 (37.8, 100) 87 68/74 33/51
381/475 18
7 3 0 0
29 5.8 (3.8, 7.7)
8.7 (3.9, 13.4) 11.2 (2.8, 19.6) 13/127 7/52
44/530 20
9 3 2.9 (0.2, 5.7) 0 3.4 (0, 7.7) 0 10 4
2.0 (0.8, 3.1) 0 11/530 20 Sequential treatment
LMWH alone UFH alone
1/132 2/64
24 2.0 (0.3, 3.7)a 11 64.5 (48.8, 80.2) 95 369/531 10 0 2.7 (1.4, 4.0) 22/581 11 0.9 (0.1, 1.6) 0 7/581 Vitamin K antagonists 11 (INR target 2.5-3.5)
I2 (%) Studies
Events
Estimate (%) I2 (%)
Estimate (%) Events Studies
12/407
I2 (%) Estimate (%) Events
.............................................................
Studies
I2 (%) Estimate (%) Events
Anticoagulant-related foetal/ neonatal adverse events
..............................................................
Livebirth rate
............................................................
Thromboembolism
.........................................................
Maternal mortality
Anticoagulation regimen
The use of VKAs with standard (2.5–3.5) INR targets throughout pregnancy was associated with the lowest pooled proportions of maternal mortality and TECs followed by sequential treatment and LMWH respectively (Table 1). In contrast, LMWH throughout pregnancy was associated with the highest number of livebirths followed by sequential treatment and VKAs with standard (2.5–3.5) INR targets throughout pregnancy. Anticoagulant-related embryopathy and foetopathy was seen in approximately 2% of the foetuses exposed to VKAs throughout pregnancy. Although embryopathy was eliminated in foetuses on sequential treatment, 1.4% of these foetuses encountered foetopathy. Similarly, although embryopathy was eliminated in foetuses exposed to LMWH and UFH, 4/44 neonates on UFH had intraventricular
Primary maternal and foetal outcomes
Primary outcomes
Table 1
The literature search identified 1786 publications, and five publications were found through citation tracking (Figure 1). After screening titles and abstracts, 110 publications were selected for full-text review, of which 63 were excluded because they did not fulfil the eligibility criteria. The characteristics of the 46 included publications, all of which were non-randomized prospective and retrospective studies involving at least five pregnancies are described in Supplementary ma terial online, Table S1. Excluded studies are described in Supplementary material online, Table S2. The included studies described 2468 pregnancies in at least 1874 women. Of the 46 included studies, 37 studies reported on valve type and 44 on valve position. Of the studies that described valve types, 458/ 1555 (29%) of the replaced valves were ball-and-cage valves, 1070/ 1555 (69%) were single-tilting disc or bileaflet valves and no information was available on 27 (2%) of the valves. Of the studies that described valve positions, 1071/1569 (68%) were in the mitral position, 255/1569 (16%) in the aortic position, 238/1569 (15%) were in more than one position (196 mitral þ aortic, three mitral þ tricuspid and the remainder were not described) and 5/1569 (0.3%) were in the tricuspid position. Only 12 studies reported whether the primary valvular lesion was rheumatic or congenital, of which rheumatic valvular disease was described in 183/236 (78%) and congenital valvular disease in 53/236 (22%). Outcomes were not reported by valve type, position or primary valvular disease. Of the 30 studies (1373 pregnancies) that reported the use of VKAs throughout pregnancy, 11 (581 pregnancies) used a standard INR target of 2.5–3.5. Twenty studies (530 pregnancies) reported the use of sequential treatment, 10 (132 pregnancies) used LMWH throughout pregnancy either adjusted to the woman’s bodyweight, peak anti-Xa levels, or to both peak and trough anti-Xa levels and four studies (64 pregnancies) used UFH throughout pregnancy adjusted to an aPTT of 1.5–2.5 times normal. The included studies varied with respect to the risk of bias. As no RCTs were identified, none of the studies were deemed to be at a low risk of bias. Twenty six studies were at high risk of bias and 20 were at moderate risk of bias, from failing to report compliance with the anticoagulation regimen, the absence of the outcome of interest at the start of the study, the method of outcome assessment, adequacy of follow up and/or the lack of adjustment for confounding factors (see Supplementary material online, Figure S3).
Studies
Results
.................................................................................................................................................................................................................................................................................................
R. D’Souza et al.
1513
Anticoagulation for pregnant women
haemorrhage. There were no cases of anticoagulant-related embyropathy or foetopathy in foetuses exposed to LMWH. Maternal and foetal complications were highest when UFH was used throughout pregnancy.
Secondary outcomes Secondary maternal outcomes – major bleeding, cardiac events and adverse drug events – were lowest with the use of VKAs throughout pregnancy, while foetal and neonatal complications including intrauterine foetal loss, preterm birth and small for gestational age infants were lowest with the use of heparins throughout pregnancy or sequential treatment (see Supplementary material online, Table S3).
Subgroup and sensitivity analyses Of the studies involving VKAs, nine studies (391 pregnancies) used lower (1.5–2.5) INR targets and six (298 pregnancies) used stratified INR targets based on the type, position and number of MHVs (Table 2). These targets were associated with comparable maternal complications and a higher numbers of livebirths but an increase in foetal anomalies. The use of stratified INR targets reduced TECs without affecting maternal mortality or foetal outcomes. Six studies (240 pregnancies) did not change to peripartum heparin, choosing to discontinue VKAs 24 h prior to a planned caesarean section. Among these studies, there were no maternal deaths and comparable foetal outcomes, but lower TECs were reported than with studies that changed to peripartum heparin [1.6% (1.2–4.3%) vs. 2.7 (1.4–4.0%)]. Ten studies (312 pregnancies) reported foetal outcomes when the daily warfarin dose was 5 mg (Table 3). The use of
European Heart Journal (2017) 38, 1509–1516 doi:10.1093/eurheartj/ehx032
Anticoagulation for pregnant women with mechanical heart valves: a systematic review and meta-analysis Rohan D’Souza1,2*, Jackie Ostro3, Prakesh S. Shah2,4, Candice K. Silversides5, Ann Malinowski1, Kellie E. Murphy1,2, Mathew Sermer1, and Nadine Shehata2,6 1 Department of Obstetrics and Gynaecology, Division of Maternal and Fetal Medicine, Mount Sinai Hospital, University of Toronto, 700 University Avenue, Toronto ON M5G 1Z5, Canada; 2Institute of Health Policy, Management and Evaluation, University of Toronto, 155 College Street, Toronto ON M5T 3M6, Canada; 3Department of Medicine, Division of Hematology, University of Toronto, Toronto, Canada; 4Department of Paediatrics, Division of Neonatology, Mount Sinai Hospital, University of Toronto, 700 University Avenue, Toronto ON M5G 1Z5, Canada; 5Department of Medicine, Division of Cardiology, Obstetric Medicine Program, Mount Sinai Hospital, University of Toronto, 700 University Avenue, Toronto ON M5G 1Z5, Canada; and 6Departments of Medicine and Laboratory Medicine and Pathobiology, Mount Sinai Hospital, Division of Hematology, Mount Sinai Hospital, University of Toronto, 700 University Avenue, Toronto ON M5G 1Z5, Canada
Received 23 July 2016; revised 28 September 2016; editorial decision 7 January 2017; accepted 13 February 2017; online publish-ahead-of-print 9 March 2017
See page 1517 for the editorial comment on this article (doi: 10.1093/eurheartj/ehw673)
Aims
To review maternal and foetal outcomes in women with mechanical heart valves (MHVs) treated with vitamin-K antagonists (VKAs), first-trimester heparin followed by VKAs (sequential treatment), low molecular weight heparin (LMWH) and unfractionated heparin (UFH) during pregnancy, in order to inform practice.
................................................................................................................................................................................................... Methods Medline, Embase and Central were searched from inception until February 2016. Two reviewers independently screened 1786 titles, reviewed 110 full-texts and extracted data and assessed risk-of-bias from 46 articles. Pooled incidence (95% and results
confidence intervals) was calculated for maternal and foetal outcomes. Included studies had a moderate or high risk-ofbias. With VKAs, sequential treatment and LMWH, maternal mortality occurred in 0.9% (0.4–1.4), 2.0% (0.8–3.1) and 2.9% (0.2–5.7), thromboembolic complications in 2.7% (1.4–4.0), 5.8% (3.8–7.7) and 8.7% (3.9–13.4), livebirths in 64.5% (48.8–80.2), 79.9% (74.3–85.6) and 92.0% (86.1–98.0) and anticoagulant-related foetal/neonatal adverse events (embryopathy or foetopathy) in 2.0% (0.3–3.7), 1.4% (0.3–2.5) and 0%, respectively. When UFH is used throughout pregnancy, 11.2% (2.8–19.6) suffered thromboembolic complications. Foetal loss and adverse events occurred with first-trimester warfarin doses 5 mg/day.
................................................................................................................................................................................................... Conclusions VKAs are associated with fewest maternal complications but also with fewest livebirths. Sequential treatment does not eliminate anticoagulant-related foetal/neonatal adverse events. LMWH is associated with the highest number of livebirths. The safety of UFH throughout pregnancy and first-trimester warfarin 75% as having a high degree of heterogeneity.13 Although we considered performing a formal statistical comparison between treatment strategies using Student t tests and non-parametric tests, the significant clinical and methodological heterogeneity between studies meant that the
.. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. ..
assumptions of these tests were violated. We therefore restricted statistical comparisons only to those studies that reported more than one treatment strategy (see Supplementary material online, Table S4).
Subgroup and sensitivity analyses Subgroup analysis for VKAs were conducted based on PT or INR targets, the use of VKAs until planned caesarean delivery and the first-trimester dose of VKAs. Studies describing sequential therapy were categorized according to whether the heparin was UFH or LMWH. In addition, subgroup analyses for all categories were conducted including studies that reported outcomes with bileaflet and single-tilting disc valves. Sensitivity analyses were performed according to risk-of-bias scores and the country’s economic status based on the 2015 World Bank report on income level.14
1512
0 0 INR, international normalized ratio; LMWH, low molecular weight heparin; NA, not applicable; UFH, unfractionated heparin. Estimates are presented as proportions per 100 affected pregnancies with 95% confidence intervals. a Of these 7/407 [0.8% (0.0, 1.7)] represent embryopathy and 5/197 [2.1% (0.1, 4.1)] represent foetopathy. b All cases represent foetopathy.
0
NA 7.6 (0.1, 15.0)b
1.4 (0.3, 2.5)b 5/431
0/103 4/44 8 4
19 79.9 (74.3, 85.6) 61
92.0 (86.1, 98.0) 0 69.5 (37.8, 100) 87 68/74 33/51
381/475 18
7 3 0 0
29 5.8 (3.8, 7.7)
8.7 (3.9, 13.4) 11.2 (2.8, 19.6) 13/127 7/52
44/530 20
9 3 2.9 (0.2, 5.7) 0 3.4 (0, 7.7) 0 10 4
2.0 (0.8, 3.1) 0 11/530 20 Sequential treatment
LMWH alone UFH alone
1/132 2/64
24 2.0 (0.3, 3.7)a 11 64.5 (48.8, 80.2) 95 369/531 10 0 2.7 (1.4, 4.0) 22/581 11 0.9 (0.1, 1.6) 0 7/581 Vitamin K antagonists 11 (INR target 2.5-3.5)
I2 (%) Studies
Events
Estimate (%) I2 (%)
Estimate (%) Events Studies
12/407
I2 (%) Estimate (%) Events
.............................................................
Studies
I2 (%) Estimate (%) Events
Anticoagulant-related foetal/ neonatal adverse events
..............................................................
Livebirth rate
............................................................
Thromboembolism
.........................................................
Maternal mortality
Anticoagulation regimen
The use of VKAs with standard (2.5–3.5) INR targets throughout pregnancy was associated with the lowest pooled proportions of maternal mortality and TECs followed by sequential treatment and LMWH respectively (Table 1). In contrast, LMWH throughout pregnancy was associated with the highest number of livebirths followed by sequential treatment and VKAs with standard (2.5–3.5) INR targets throughout pregnancy. Anticoagulant-related embryopathy and foetopathy was seen in approximately 2% of the foetuses exposed to VKAs throughout pregnancy. Although embryopathy was eliminated in foetuses on sequential treatment, 1.4% of these foetuses encountered foetopathy. Similarly, although embryopathy was eliminated in foetuses exposed to LMWH and UFH, 4/44 neonates on UFH had intraventricular
Primary maternal and foetal outcomes
Primary outcomes
Table 1
The literature search identified 1786 publications, and five publications were found through citation tracking (Figure 1). After screening titles and abstracts, 110 publications were selected for full-text review, of which 63 were excluded because they did not fulfil the eligibility criteria. The characteristics of the 46 included publications, all of which were non-randomized prospective and retrospective studies involving at least five pregnancies are described in Supplementary ma terial online, Table S1. Excluded studies are described in Supplementary material online, Table S2. The included studies described 2468 pregnancies in at least 1874 women. Of the 46 included studies, 37 studies reported on valve type and 44 on valve position. Of the studies that described valve types, 458/ 1555 (29%) of the replaced valves were ball-and-cage valves, 1070/ 1555 (69%) were single-tilting disc or bileaflet valves and no information was available on 27 (2%) of the valves. Of the studies that described valve positions, 1071/1569 (68%) were in the mitral position, 255/1569 (16%) in the aortic position, 238/1569 (15%) were in more than one position (196 mitral þ aortic, three mitral þ tricuspid and the remainder were not described) and 5/1569 (0.3%) were in the tricuspid position. Only 12 studies reported whether the primary valvular lesion was rheumatic or congenital, of which rheumatic valvular disease was described in 183/236 (78%) and congenital valvular disease in 53/236 (22%). Outcomes were not reported by valve type, position or primary valvular disease. Of the 30 studies (1373 pregnancies) that reported the use of VKAs throughout pregnancy, 11 (581 pregnancies) used a standard INR target of 2.5–3.5. Twenty studies (530 pregnancies) reported the use of sequential treatment, 10 (132 pregnancies) used LMWH throughout pregnancy either adjusted to the woman’s bodyweight, peak anti-Xa levels, or to both peak and trough anti-Xa levels and four studies (64 pregnancies) used UFH throughout pregnancy adjusted to an aPTT of 1.5–2.5 times normal. The included studies varied with respect to the risk of bias. As no RCTs were identified, none of the studies were deemed to be at a low risk of bias. Twenty six studies were at high risk of bias and 20 were at moderate risk of bias, from failing to report compliance with the anticoagulation regimen, the absence of the outcome of interest at the start of the study, the method of outcome assessment, adequacy of follow up and/or the lack of adjustment for confounding factors (see Supplementary material online, Figure S3).
Studies
Results
.................................................................................................................................................................................................................................................................................................
R. D’Souza et al.
1513
Anticoagulation for pregnant women
haemorrhage. There were no cases of anticoagulant-related embyropathy or foetopathy in foetuses exposed to LMWH. Maternal and foetal complications were highest when UFH was used throughout pregnancy.
Secondary outcomes Secondary maternal outcomes – major bleeding, cardiac events and adverse drug events – were lowest with the use of VKAs throughout pregnancy, while foetal and neonatal complications including intrauterine foetal loss, preterm birth and small for gestational age infants were lowest with the use of heparins throughout pregnancy or sequential treatment (see Supplementary material online, Table S3).
Subgroup and sensitivity analyses Of the studies involving VKAs, nine studies (391 pregnancies) used lower (1.5–2.5) INR targets and six (298 pregnancies) used stratified INR targets based on the type, position and number of MHVs (Table 2). These targets were associated with comparable maternal complications and a higher numbers of livebirths but an increase in foetal anomalies. The use of stratified INR targets reduced TECs without affecting maternal mortality or foetal outcomes. Six studies (240 pregnancies) did not change to peripartum heparin, choosing to discontinue VKAs 24 h prior to a planned caesarean section. Among these studies, there were no maternal deaths and comparable foetal outcomes, but lower TECs were reported than with studies that changed to peripartum heparin [1.6% (1.2–4.3%) vs. 2.7 (1.4–4.0%)]. Ten studies (312 pregnancies) reported foetal outcomes when the daily warfarin dose was 5 mg (Table 3). The use of
