University of Groningen
Severe maternal cardiovascular pathology and pregnancy
Lameijer, Heleen
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from
it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date:
2018
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Lameijer, H. (2018). Severe maternal cardiovascular pathology and pregnancy. Rijksuniversiteit Groningen.
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.
8
―
8
―
125
INTRODUCTION
Direct oral anticoagulants (DOACs) are increasingly used as anticoagulation treatment in patients with atrial fibrillation (AF), deep venous thrombosis (DVT) and pulmonary embolism (PE).1 2 Pregnancy is a known risk factor for both DVT
and PE.3 Moreover, in women of fertile age with heart disease, atrial fibrillation
is a common rhythm disorder that may warrant anticoagulation therapy. Earlier studies have shown that anticoagulation with the use of vitamin K antagonist can cause serious foetal malformations, especially when used in higher dosages between 6-12 weeks of pregnancy.4-7 Low molecular weight heparins (LMWH)
appear safe for the foetus as they do not cross the placenta, however, maternal anticoagulation may be suboptimal and the adequate methods and intervals for monitoring (via anti Xa blood sample measurements) is still discussed.4 6 8 Furthermore, LMWH are administered by daily injection, which causes pain
as well as other complications such as injection infiltrates and hematoma. A direct oral alternative exists: the DOAC. While DOACs are increasingly used for anticoagulation purposes outside pregnancy, their efficacy and safety during pregnancy is unknown due to exclusion of pregnant women in DOAC study protocols and current guidelines advise against DOAC use during pregnancy. Because pregnancy is a dynamic hypercoagulative state, the effectiveness of anticoagulation medication may not be adequate during pregnancy.
Additionally, the direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban are partly, and dabigatran mainly, eliminated by the kidneys. Given the markedly increase of glomerular filtration rate during pregnancy, anticoagulation with DOACs at regular dosages may be insufficient due to increased renal elimination, as has previously been reported with the use of low molecular weight heparins (LMWH).9 10
Furthermore, dabigatran inhibits clot formation by direct inhibition of factor IIa, thus decreasing the transition of fibrinogen into fibrin. During pregnancy fibrinogen levels are elevated, which is another reason that dabigatran, as well as other DOAC dosages could be insufficient in pregnant women.11 Women who
use LMWH during pregnancy are currently monitored and dose-adjusted by anti-Xa measurements.6 Whether or not dose adjustment according to anti-Xa
levels is useful for DOAC use, including pregnant women, is yet unknown. Furthermore, an antidote for dabigatran is commercially available but antidotes for the Xa inhibitors are still in the stage of clinical trial. Treatment of bleeding complications during pregnancy and delivery can therefore theoretically be challenging. Additionally, dabigatran, rivaroxaban and edoxaban, have been shown to cross the placenta in perfusion models. Therefore toxic effects on the foetus may possibly be a complication of the use of DOACs during pregnancy.12 13
8
―
126
To update current knowledge and evaluate the use of DOACs during pregnancy we systematically reviewed the current literature concerning the efficacy, safety and pregnancy outcome of the use of DOACs in pregnant patients.
METHODS
We systematically searched the PubMed/MedLine public database for all studies dated up to 04-07-2017. Search terminology was: ((((("Dabigatran"[Mesh]) OR "Rivaroxaban"[Mesh]) OR "edoxaban" [Supplementary Concept]) OR "apixaban" [Supplementary Concept]) OR "ximelagatran" [Supplementary Concept]) AND "Pregnancy"[Mesh]; Dabigatran AND pregnancy; Rivaroxaban AND pregnancy; Apixaban AND pregnancy; Edoxaban AND pregnancy; Ximelagatran AND pregnancy; ((Direct oral anticoagulants) OR DOAC) AND pregnancy; ((New oral anticoagulants) OR NOAC) AND pregnancy. We included all studies and study designs which reported the use of DOAC during pregnancy or within 1 month post-partum. We excluded studies not discussing DOAC use during pregnancy and guidelines or reviews when they did not report new cases or data. Studies could be included via cross-referencing. Duplicates were electronically removed. Collected data were type of DOAC and indication, timing of use during pregnancy, any described thrombotic complications, any described bleeding complications, and pregnancy outcome including occurrence of anomalies.
RESULTS
For inclusion, see figure 1. Six articles were included, of which 2 larger studies, with overlap in outcome data, and 4 case reports, presented in table 1. All studies were recently performed (2014-2016). Overall, the use of DOACs during pregnancy was reported in 276 cases of which 40 were double reported, resulting in 236 reported cases for analysis. Rivaroxaban was the most reported DOAC (n=178, 75%), followed by dabigatran (n=27, 11%), apixaban (n=21, 9%) and edoxaban (n=10, 4%). Indication for DOAC use was reported in 97 cases (41%). Reported indications were prophylaxis or treatment of DVT (n=91, 94%), AF (n=4, 4%), PE (n=1, 1%) and congenital thrombophilia (n=1, 1%).
Timing of discontinuation of the DOAC during pregnancy was known for 73 pregnancies (31% of total reported cases). In these pregnancies, DOACs were discontinued within the first 2 months of pregnancy in 61 women (84%), see table 2. The maximum reported duration of DOAC use during pregnancy was 26 weeks.14
8
―
127
Pregnancy outcomes were reported in 140 pregnancies (59%), and are reported in table 2. Of these pregnancies, 28% were electively terminated. Two studies reported the reasons for the elective terminations. In one study 8 elective terminations were observed; 6 for social reasons, 1 for fear of malformations and 1 for a complex foetal heart defect in a woman who previously had an electively terminated pregnancy for foetal heart defects while not using a DOAC.14 The
other study reported 13 known indications for 39 elective terminations, of which 7 for a social indication, 3 for fear of malformations, and 3 for non-DOAC related medical reasons.15 For ongoing pregnancies, the miscarriage rate was 31%
(ranging 14-44%), overall live birth rate was 68% (ranging 50-86%). There were no perinatal deaths.
The presence or absence of thrombotic and bleeding complications were reported for 42 pregnancies (18%) and consisted of 2 thrombotic complications (PE (n=1), DVT (n=1), 5%). Caesarean section occurred in 10 pregnancies, and bleeding post-partum or post abortion in 3 pregnancies (8%, including the woman who used a DOAC during the post-partum period). In two pregnancies, thrombocytopenia was reported.
Foetal and neonatal abnormalities were reported in 8 pregnancies in which rivaroxaban was used (8% of the 105 pregnancies with rivaroxaban use with sufficient data reported), during the 1st trimester of pregnancy. For details of reported
abnormalities see table 3. Of these, 4 (4%) are possibly related to the rivaroxaban use.16 No foetal and neonatal abnormalities were reported for other DOACs.
DISCUSSION
We reviewed two hundred and thirty six cases of DOAC use during pregnancy that were reported in recent literature (2014-2016). The data suggest a high miscarriage rate compared with a 20% miscarriage rate in the general population and raise concern about a possible association with foetal anomalies.17
Outcomes of pregnancies were only available in 59%. Elective terminations were performed in 28% of the pregnancies with sufficient outcome data. However, only once an elective termination was performed because of an anomaly and in this case a relation with the DOAC was unlikely. Reasons for elective terminations were underreported. The most reported reason for termination was a social indication. The high rate of termination for a social reason is understandable because patients with DOACs were probably advised against pregnancy, therefore their pregnancies might already were unplanned/unwanted in the first place. Fear for malformations was also reported and may have hypothetically also played a role in the cases with unknown reason for elective termination.
8
―
128
High miscarriage rate (31%) was observed in ongoing pregnancies. Increased miscarriage rate in animals using DOACs during pregnancy was previously reported by the United States Federal Drug Administration (FDA) and the European Medicines Agency (EMA) (table 4).18 19 The high miscarriage rate both
in animals and humans may be related to embryonic/foetal toxicity of DOACs. Moreover the bone and facial abnormalities observed in 4% of pregnancies during the use of rivaroxaban raises further concerns about foetal safety. Notably, this percentage may even be an underestimation because most women (84%) discontinued DOAC use within the first 2 months, before anomalies may have developed. The 4% cases that were possibly related to rivaroxaban use are comparable to the anomalies found in animal studies reported by the FDA and EMA (table 4).18 19 Interestingly, in 3 cases structural bone or facial abnormalities
were observed. Whether or not the growth retardation in one other case might also be related to DOAC use remains undetermined. Human and animal data suggest that bone structure formation is possibly affected by the use of DOACs during pregnancy, as is also observed with the use of vitamin K antagonists during pregnancy.20 No anomalies were reported with the use of other DOACs
(other than Rivaroxaban) during pregnancy, but this may well be related to the smaller patient cohorts.
Thrombotic and bleeding complications were highly underreported, and no firm conclusions about their incidence can be made. However, the current data do not raise concern regarding bleeding complications since the percentage of bleeding complications is comparable to other studies with anticoagulation use during pregnancy.21 22
LIMITATIONS
The quality of our systematic review was limited by absence of high quality and randomised studies, small sample sizes, incomplete data and the probability of reporting and publication bias.
CONCLUSION
Safety and efficacy of the use of DOACs during pregnancy is not supported by current literature. The limited available evidence raises concern regarding embryo-foetal safety, because of a high incidence of miscarriages and a 4% rate of anomalies with the use of rivaroxaban. The current limited evidence justifies avoidance of DOACs in pregnant women. For most indications a switch to low molecular weight heparin will be appropriate while, depending on indication, dosage, and stage of pregnancy, vitamin K antagonists may also be used according to current guidelines.1 23
8
―
129
REFERENCES
1. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC guidelines for the manage-ment of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37: 2893-962.
2. Konstantinides SV, Torbicki A, Agnelli G,
et al. 2014 ESC guidelines on the
diagno-sis and management of acute pulmonary embolism. Eur Heart J 2014;35: 3033,69, 3069a-3069k.
3. James AH, Jamison MG, Brancazio LR,
et al. Venous thromboembolism during
pregnancy and the postpartum period: Incidence, risk factors, and mortality. Am
J Obstet Gynecol 2006;194: 1311-5.
4. D'Souza R, Ostro J, Shah PS, et al. Anti-coagulation for pregnant women with mechanical heart valves: A systematic review and meta-analysis. Eur Heart J 2017;38: 1509-16.
5. Hassouna A, Allam H. Limited dose war-farin throughout pregnancy in patients with mechanical heart valve prosthe-sis: A meta-analysis. Interact Cardiovasc
Thorac Surg 2014;18: 797-806.
6. European Society of Gynecology, Associ-ation for European Paediatric Cardiology, German Society for Gender Medicine, et
al. ESC guidelines on the management of
cardiovascular diseases during pregnan-cy: The task force on the management of cardiovascular diseases during preg-nancy of the european society of cardiol-ogy (ESC). Eur Heart J 2011;32: 3147-97. 7. Regitz-Zagrosek V, Gohlke-Barwolf C,
Iung B, et al. Management of cardiovas-cular diseases during pregnancy. Curr
Probl Cardiol 2014;39: 85-151.
8. Elkayam U, Goland S, Pieper PG, et al. High-risk cardiac disease in pregnancy: Part I. J Am Coll Cardiol 2016;68: 396-410. 9. Capeless EL, Clapp JF. Cardiovascular
changes in early phase of pregnancy.
Am J Obstet Gynecol 1989;161: 1449-53.
10. Katz R, Karliner JS, Resnik R. Effects of a natural volume overload state (preg-nancy) on left ventricular performance in normal human subjects. Circulation 1978;58: 434-41.
11. Szecsi PB, Jorgensen M, Klajnbard A, et
al. Haemostatic reference intervals in
pregnancy. Thromb Haemost 2010;103: 718-27.
12. Bapat P, Kedar R, Lubetsky A, et al. Transfer of dabigatran and dabigatran etexilate mesylate across the dually per-fused human placenta. Obstet Gynecol 2014;123: 1256-61.
13. Bapat P, Pinto LS, Lubetsky A, et al. Ri-varoxaban transfer across the dually perfused isolated human placental cot-yledon. Am J Obstet Gynecol 2015;213: 710.e1,710.e6.
14. Hoeltzenbein M, Beck E, Meixner K, et al. Pregnancy outcome after exposure to the novel oral anticoagulant rivaroxaban in women at suspected risk for thrombo-embolic events: A case series from the german embryotox pharmacovigilance centre. Clin Res Cardiol 2016;105: 117-26. 15. Beyer-Westendorf J, Michalski F, Tittl L,
et al. Pregnancy outcome in patients
ex-posed to direct oral anticoagulants - and the challenge of event reporting. Thromb
Haemost 2016;116: 651-8.
16. The use of the WHO–UMC system for standardised case causality assess-ment. accessed from: Https://www. who-umc.org/media/2768/standard-ised-case-causality-assessment.pdf. last accessed oktober 2017. 2017. 17. C Nice. NICE Clinical guideline [CG154]
Ectopic pregnancy and miscarriage: di-agnosis and initial management https://
www.nice.org.uk/guidance/cg154
febru-ari 2017(last accessed may 2018). 18.
Https://www.accessdata.fda.gov/drug-satfda_docs/. last accessed oktober 2017. . 19. Http://www.ema.europa.eu/ema/. last
8
―
130
20. van Driel D, Wesseling J, Sauer PJ, et al. Teratogen update: Fetal effects after in utero exposure to coumarins overview of cases, follow-up findings, and pathogen-esis. Teratology 2002;66: 127-40. 21. Roos-Hesselink JW, Ruys TP, Stein JI,
et al. Outcome of pregnancy in patients
with structural or ischaemic heart dis-ease: Results of a registry of the euro-pean society of cardiology. Eur Heart J 2013;34: 657-65.
22. van Hagen IM, Roos-Hesselink JW, Ruys TP, et al. Pregnancy in women with a mechanical heart valve: Data of the eu-ropean society of cardiology registry of pregnancy and cardiac disease (ROPAC).
Circulation 2015;132: 132-42.
23. European Society of Gynecology, Associ-ation for European Paediatric Cardiology, German Society for Gender Medicine, et
al. ESC guidelines on the management of
cardiovascular diseases during pregnan-cy: The task force on the management of cardiovascular diseases during preg-nancy of the european society of cardiol-ogy (ESC). Eur Heart J 2011;32: 3147-97.
8
―
131
Table 1. Current literature describing the use of direct oral anticoagulants (DOACs) during pregnancy or in the postpartum period.
AF = atrial fibrillation, DVT = deep venous thrombosis, LOE = level of evidence, PE = pulmonary embolism.
Tables:
Study and
Year Type of study DOAC type DOAC indication Missing data Remarks
Beyer-Westendorf et al. 201615 Combined analysis of: - Review of 2 studies (n=40)14 24 - FDA cases (n=2) - Cohort of 4 pharmacovigilance databases (n=301) - Case series (n=15) After correction for double inclusion: n=233 Rivaroxaban (n= 176) Dabigatran (n=26) Apixiban (n= 21) Edoxaban (n= 10) DVT (n=86) DVT Prophylaxis (n=4) AF (n=4) DOAC indication n=135 (58%) Missing outcome data n=96 (41%) Overlap with 2 other studies14 24 Pooled analysis of different DOACs Possible reporting bias by including data from manufacturers Hoeltzenbein et al. 201614 Pharmacovigilance database survey: Prospective cohort (n=37) Retrospective case series (n=2) Rivaroxaban DVT (n=35) AF (n=1) DOAC indication n=3 (8%) Data included in study of Beyer-Westendorf15 Konigsbrugge et al. 201424 Case report
(n=1) Rivaroxaban Recurrent DVT and
PE Data included in study of Beyer-Westendorf15 Myers et al.
201625 Case report (n=1) Rivaroxaban PE pre-pregnancy
Rudd et al.
201526 Case report (n=1) Rivaroxaban DVT post-partum
Vausse et al.
201627
Prospective cohort study, with DOAC case (n=1) Dabigatran (n=1) DOAC indication (n=1) Cohort of women with prosthetic heart valves, indication DOAC unclear
8
―
132
All DOACs14 15 24-27 Rivaroxaban 14 15 24-26 Dabigatran1 5 27 Apixaban15 Edoxaban15 Pregnancies with sufficient outcome data (n,% of all pregnancies) 140 (59%) 105 (59%) 13(48%) 12 (57%) 10 (100%)Cases with known duration of exposure (n, %) 73 (52%) * * * * Maximum duration of exposure 1 month (n=22) 2 months (n=39) 3 months (n=2) 4 months (n=3) 5 months (n=3) 6 months (n=1) * 1 week (n=1) 10 weeks (n=36) 15 weeks (n=1) 25 weeks (n=1) 26 weeks (n=1) Post-partum (n=1) * 10 weeks (n=1) * * Elective abortion (n,%) 39 (28%) 26 (25%) 7 (54%) 3 (25%) 3 (30%) Ongoing pregnancies (n, %) 101 (72%) 79 (75%) 6 (46%) 9 (75%) 7 (70%) Missing offspring outcome (n,%) ** 1 (1%) 0 1 (17%) 0 0 Live birth (n,%) ** 69 (68%) 55 (69%) 3 (50%) 5 (56%) 6 (86%) Miscarriage (n,%) ** 31 (31%) 24 (30%) 2 (33%) 4 (44%) 1 (14%) Perinatal death (n,%) ** 0 0 0 0 0
Table 2. Outcomes of pregnancies with sufficient outcome data in the current literature in women who use a DOAC during pregnancy.
DOAC = direct oral anticoagulant. * incomplete or unknown because of pooled analysis of all DOACs in the study of Beyer-Westendorf.15 ** Elective abortions excluded to demonstrate the natural course of ongoing pregnancies in women with DOAC use during pregnancy.
Study Trimester of
Rivaroxaba n use
Pregnancy
outcome Abnormality WHO-UMC causality
category16
Beyer-Westendorf et
al.15
1st Live birth Renal pelvis dilatation
Facial dimorphism Unlikely Possible
1st Live birth Mild hip dysplasia Possible
1st Live birth Septum pellucid cyst Unlikely
1st Miscarriag
e
Anhydramnios Unlikely
1st Miscarriag
e Intra-uterine growth retardation Possible
Hoeltzenbein et al.14
Beyer-Westendorf et
al.15
1st Elective
termination Complex foetal heart defect Unlikely
1st Miscarriag
e Abnormal limbs (‘crumpled’) Possible
Table 3. Abnormalities reported as possibly associated with the use of Rivaroxaban during pregnancy.
8
―
133
Study Trimester of Rivaroxaba n use Pregnancy outcome Abnormality WHO-UMC causality category16 Beyer-Westendorf et al.151st Live birth Renal pelvis dilatation
Facial dimorphism
Unlikely Possible
1st Live birth Mild hip dysplasia Possible
1st Live birth Septum pellucid cyst Unlikely
1st Miscarriag
e Anhydramnios Unlikely
1st Miscarriag
e Intra-uterine growth retardation Possible
Hoeltzenbein et al.14
Beyer-Westendorf et
al.15
1st Elective
termination Complex foetal heart defect Unlikely
1st Miscarriag
e
Abnormal limbs (‘crumpled’)
Possible
Table 3. Abnormalities reported as possibly associated with the use of Rivaroxaban during pregnancy. DOAC* FDA pregnancy category (animals only)
FDA and EMA information on embryo-foetal toxicity in animal studies18 19
Rivaroxaban C At clinically relevant plasma concentrations.
- post-implantation loss
- retarded/progressed ossification
- hepatic multiple light coloured spots
- increased incidence of common malformations
- placental changes
At 4x human exposure dose: - increased resorptions
- decreased number of live foetuses
- decreased foetal body weight
Apixaban B No increased risk
Edoxaban C At 20-65x human exposure dose:
- increased post-implantation loss
- increased spontaneous abortion
- decreased live foetuses
- decreased foetal weight
- absent or small foetal gallbladder
Dabigatran C At 2.6-4.6 x human exposure dose:
- increased pregnancy loss
- increased the number of dead offspring
- increased incidence of delayed or irregular
ossification of skull bones and vertebrae At 13.3x human exposure dose:
- increased incidence of resorptions
- decrease in viable foetuses
- decrease in foetal weight
Table 4. United States Federal Drug Administration (FDA) and European Medicines Agency (EMA) information on embryo-foetal toxicity in female animals using DOACs during pregnancy (no human studies available).
Abnormalities corresponding to abnormalities found in human foetuses in our review are presented in Italics. DOAC = direct oral anticoagulant. * Ximelagatran is not EMA and FDA approved and therefore not described.
