Accepted Manuscript

Anticoagulation regimens during pregnancy in patients with mechanical heart valves:

a systematic review and meta–analysis

Zhe Xu, M.D. PhD., Jin Fan, M.D., Xin Luo, M.D. PhD., Wen–bo Zhang, M.D., Jun
Ma, M.D., Yu–bi Lin, M.D., Shao–hong Ma, M.D. PhD., Xin Chen, M.D., Zhi–ping
Wang, M.D. PhD., Jing–song Ou, M.D. PhD., Xi Zhang, M.D. PhD.
PII: S0828-282X(15)01581-0
DOI: 10.1016/j.cjca.2015.11.005
Reference: CJCA 1929

To appear in: Canadian Journal of Cardiology

Received Date: 30 April 2015

Revised Date: 30 October 2015
Accepted Date: 4 November 2015

Please cite this article as: Xu Z, Fan J, Luo X, Zhang W–b, Ma J, Lin Y–b, Ma S–h, Chen X, Wang
Z–p, Ou J–s, Zhang X, Anticoagulation regimens during pregnancy in patients with mechanical heart
valves: a systematic review and meta–analysis, Canadian Journal of Cardiology (2015), doi: 10.1016/
j.cjca.2015.11.005.

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 ACCEPTED MANUSCRIPT

Title: Anticoagulation regimens during pregnancy in patients with mechanical heart

valves: a systematic review and meta–analysis

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Authors: Zhe Xu M.D. PhD., *#Jin Fan M.D.,† # Xin Luo M.D. PhD.,† Wen–bo Zhang

M.D., * Jun Ma M.D.,*Yu–bi Lin M.D.,‡ Shao–hong Ma M.D. PhD.,* Xin Chen M.D.,

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†
Zhi–ping Wang M.D. PhD.,* Jing–song Ou M.D. PhD. *, Xi Zhang M.D. PhD.*

Affiliations:

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* Division of Cardiac Surgery, the First Affiliated Hospital of Sun–Yat–sen University

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Division of Obstetrics and Gynecology, the First Affiliated Hospital of Jinan

University

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Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences,

Guangdong General Hospital

Short Title: Anticoagulation for Pregnant Women with Mechanical Valves

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Word Count: 6200

Corresponding Authors:
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Xi Zhang M.D. PhD.

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Division of Cardiac Surgery

The First Affiliated Hospital of Sun–Yat–sen University

58 Zhong Shan Road II, Yue Xiu District

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Guangzhou, Guangdong, 510080

P.R.China
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Tel: 8620–87755766–8238

Fax: 8620–87755766–8238
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Cell: 86–13902279690

E–mail: himybox@126.com

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#
Zhe Xu and Jin Fan contributed equally to this work.
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Abstract

Background: Managing anticoagulation in pregnant women with mechanical heart

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valves remains challenging. Our aim was to evaluate the effectiveness and safety of

four regimens in these women.

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Methods: Relevant studies published before June 2015 were collected in several

databases and analyzed with RevMan 5.3 and SPSS 19.0. Four regimens were defined

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as follows: a regimen of a vitamin K antagonist (VKA) throughout pregnancy, an

H/VKA regimen using VKA except for unfractionated heparin (UFH) or

low–molecular–weight heparin (LMWH) during 6–12 weeks of pregnancy, a LMWH

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regimen of adjusted LMWH doses throughout pregnancy and a UFH regimen of

adjusted UFH doses throughout pregnancy. The low warfarin dose in the VKA

regimen was defined as 5 mg/day or less.

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Results: 51 studies comprising 2113 pregnancies in 1538 women were included. The

rate of fetal wastage (FW) was significantly higher in the high warfarin dose subgroup
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than the low dose one. Compared with the H/VKA regimen, the rate of maternal
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major thromboembolic event of low dose VKA regimen was significantly lower,

while the fetal outcomes were similar. Compared with H/VKA regimen, the rate of

FW in the LMWH regimen was significantly lower, while the maternal outcomes
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were similar. The UFH regimen presented the worst maternal and fetal outcomes.

Conclusion: In the absence of large prospective trials, this meta-analysis showed that:
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the VKA regimen should be best for pregnant women with low warfarin dose;

H/VKA regimen may be reasonable for those with high warfarin dose. The LMWH
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regimen could be used for those refusing VKA.

Keywords: Anticoagulation; Pregnancy; Heparin; Heart Valve Prosthesis;

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Meta–analysis

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Brief Summary

Managing anticoagulation in pregnant women with mechanical heart valves

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remains challenging. Our meta-analysis, which included 51 studies comprising 2113

pregnancies, evaluate the effectiveness and safety of four updated regimens in these

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women. Our study showed that: the vitamin K antagonist (VKA) regimen should be

best for women with low warfarin dose; H/VKA regimen may be reasonable for those

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with high warfarin dose. The low–molecular–weight heparin regimen could be used

for those refusing VKA.

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Text

Introduction

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Advances in prosthetic heart valve replacements have led to a growing number

of women of childbearing age with valvular heart disease as more young patients

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survive to adulthood [1]. Of the different prosthetic heart valves, many women of

childbearing age prefer mechanical prosthetic heart valves (MPHVs) due to their

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long–term durability. Because of the procoagulant nature of pregnancy, managing

anticoagulation in pregnant women with MPHVs remains challenging.

Of the current guidelines for anticoagulation therapy in pregnant women with

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MPHVs, the following four anticoagulation regimens are most often recommended:

(1) a regimen of a vitamin K antagonist (VKA) throughout pregnancy; (2) an H/VKA

regimen, which includes using VKA except for adjusted doses of unfractionated or
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low–molecular–weight heparin (LMWH) during 6–12 weeks of pregnancy; (3) a

LMWH regimen of adjusted LMWH doses throughout pregnancy; and (4) a UFH
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regimen of adjusted doses of unfractionated heparin (UFH) throughout pregnancy

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[2–4]. Chan ’s systematic review, including 976 women with 1234 pregnancies,

demonstrated that thromboembolic prophylaxis of pregnant women with MPHVs was

best achieved by the VKA regimen, although it increased the risk of fetal
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embryopathy; the H/VKA regimen reduced the risk of fetopathic effects but increased

the risk of a maternal major thromboembolic event (MTE) [5]. Two other systematic
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reviews containing cases with and without monitoring found that the risks of maternal

MTE using the LMWH regimen was 22% [6] and 8.64% [7]; maternal death occurred
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in 4% [6] and 0% [7]. To date, no large prospective trials have been conducted to

examine the efficacy of novel anticoagulants in pregnant women with MPHVs.

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Chan ’s review included studies with pregnancies occurring from 1964 to 1997;

thus, many (433/872) of the study participants had adopted old model and more

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thrombogenic heart valve prostheses that are not the standard prosthetic heart valves

used today. Furthermore, a large number of patients included in previous reviews had

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initiation doses that were sub therapeutic and had no monitoring. Little work has been

done to explore the contemporary prevalence of pregnancy among heart valve

recipients. As valve types and regimens change and improve, we performed a

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systematic review and meta–analysis of the effectiveness and safety of these regimens

for mothers and their fetuses.

Material and Methods

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This study was performed according to the Meta–analysis of Observational

Studies in Epidemiology (MOOSE) Guidelines [8].

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We searched MEDLINE, EMBASE, CENTRAL (Cochrane Central Register of

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Controlled Trials), the Cochrane Database of Systematic Reviews, and the Database

of Abstracts of Review of Effectiveness until June 2015 for the following medical

subject headings and search terms: "heart valve prosthesis", "pregnancy",

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"anticoagulants", "antithrombins", "coumarins", "warfarin", "heparin,

low–molecular–weight", "thromboembolism" and "hemorrhage". We also searched

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for conference articles (from the ISI Web of Knowledge Platform of ISI Proceedings),

unpublished theses and dissertations (from ProQuest Digital Dissertations).

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Furthermore, relevant trials were identified using a manual search of secondary

sources, including the references of the initially identified articles and recent review

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articles [9]. Two investigators (ZX, JF) independently screened the titles and abstracts

and retrieved eligible articles if they met the following criteria: (1) the study designs

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were case series (≥6 pregnancies), cohort studies or randomized control trials (RCTs)

of pregnancies in women with MPHVs; (2) the anticoagulation regimens were clearly

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specified and did not change during the whole pregnancy; and (3) at least one

outcome of interest was reported. Studies were excluded if they met the following

criteria: (1) the study was not written in English, (2) the study did not follow all

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pregnancies until completion, (3) the anticoagulation regimen was not consistent with

standards of care and the data from patient subgroups whose regimens were in line

with the standards could not be extracted, (4) the data had already been included and
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cited in any previously selected studies, or (5) the anticoagulation intensity was not

consistent with standards of care (international normalized ratio (INR): 2.0–4.5; active
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partial thromboplastin time (aPTT): two to three times the normal value; or peak
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anti–Xa level: 0.5–1.2 IU/ ml). The original article’s authors were contacted for

clarification if any uncertain issues arose. Any disagreements were further discussed

between the investigators. For each eligible study, we extracted data in a standardized
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manner. The anticoagulation regimens were classified as shown above. LMWH and

UFH should be started before 12 weeks of pregnancy in LMWH and UFH regimens.
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We extracted the low and high warfarin dose subgroups in the VKA regimen; and low

doses of warfarin were defined as 5 mg/day or less. We systematically assessed study

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quality using the Newcastle–Ottawa Scale [10].

The primary outcomes included maternal MTE, FW and maternal death, and we

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measured maternal major antenatal hemorrhagic events (MAHE) and congenital fetal

anomaly (CFA) as secondary outcomes. All of the outcomes are described below [4, 5,

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9] :

(1) Maternal MTE: including fatal thromboembolism, prosthetic valve thrombosis

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requiring thrombolysis or emergency surgery, documented evidence of central

nervous system embolization, documented evidence of peripheral limb and visceral

embolization requiring surgery, and any other related events requiring hospitalization;

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(2) MAHE: major hemorrhagic events in the antenatal period, including death due to

hemorrhage, intracranial bleeding or documented cardiac tamponade requiring

intervention, hemorrhage requiring transfusion, and any other related events requiring
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inpatient treatment;

(3) Maternal death: any maternal antenatal death from any causes;
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(4) FW: spontaneous abortion, therapeutic abortion, stillbirth and neonatal death;
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(5) CFA: any fetal anomaly associated with VKA during pregnancy. Classic warfarin

embryopathy includes hypoplasia of nasal bridge, laryngomalacia, pectus carinatum,

congenital heart defects, ventriculomegaly, agenesis of the corpus callosum, stippled

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epiphyses, telebrachydactyly, and growth retardation. Neurological sequelae related to

VKA include the Dandy–Walker malformation, microcephaly, mental retardation,

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spasticity, hypotonia, ventral midline dysplasia with corpus callosum agenesis, and

dorsal midline dysplasia with optic atrophy.

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Data Synthesis

All of the data were based upon the anticoagulation regimens and adverse

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maternal and fetal outcomes in the selected studies. The reported frequencies of the

various outcomes of interest from different studies were pooled, and the 95%

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confidence intervals (CI) were calculated [11]. To compare among the different

regimens, RevMan 5.3 and SPSS 19.0 were utilized for the statistical analysis.

Heterogeneity was examined with the I2 test. The inverse of variance method with the

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random effects model was used by default independently of any heterogeneity

(I2≥50%) between studies because we pooled data from studies with different designs.

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Publication bias was examined using a funnel plot with Begg’s test and Egger’s test

[12, 13]. Subgroup analyses were conducted to explore the potential sources of

heterogeneity among the included studies. Sensitivity analyses were performed to

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evaluate the effects of removing every single study from the analysis on pooled risk

estimates. Heterogeneity was considered statistically significant at P<0.1. For all other
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calculations, statistical significance was defined as P<0.05. All of the tests were
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two–tailed.

Results

After an extensive literature search and review, we were able to include 51 studies
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(54 records), of which 37 studies (39 records) used a VKA regimen [14–52]. Eleven

included studies reporting results in the low dose subgroup of a VKA regimen [32, 33,
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35, 37, 39, 40, 42–44, 47, 49], while seven included studies that reported high dose

subgroup results [32, 35, 37, 40, 44, 47, 49]. Thirteen studies (14 records) used the
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H/VKA regimen [30, 35, 38–41, 45– 49, 51, 53, 54], 12 studies (13 records) used the

LMWH regimen [45, 47, 54–63] and eight used the UFH regimen [32, 38, 41, 51, 54,

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64– 66]. Figure 1 shows the study’s selection processes and the reasons for excluding

studies. Of the 51 retrieved studies, there were 2113 total pregnancies among 1538

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women observed between 1964 and 2014 (See Supplemental Table S1, parts A and

B).

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Effects of Interventions

The frequencies of adverse fetal events with different anticoagulation regimens

are summarized in Table 1. The prevalence of CFAs in the live births in patient using

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the VKA regimen was 2.13% (95% CI: 1.34%–3.33%). The prevalence was reduced

to 0.74% (95% CI: 0.19%–2.33%) in the H/VKA regimen. There were no fetal

anomalies in the LMWH regimen or the UFH regimen. The most common CFA
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associated with VKA was typical warfarin embryopathy (11/ 21).

The overall risk of FW in the VKA regimen was 32.53% (95% CI: 29.65%–
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35.55%). Compared with the low dose subgroup in the VKA regimen, the rate of FW
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was significantly higher in the high dose subgroup (RR: 7.440, 95% CI: 4.617–11.989,

P<0.001, Table 5). The low dose VKA regimen had a low risk of FW, which was

19.23% (95% CI: 15.73%–23.28%); this risk was similar to those of the H/VKA
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regimen (22.65%, 95% CI: 18.38%–27.55%) and the LMWH regimen. The pooled

odds ratio (OR) estimate of the four included studies also revealed that the risk of FW
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did not significantly differ between the H/VKA regimen and the low dose VKA

regimen (OR 0.79, 95% CI: 0.47–1.34; P = 0.38, I2=0%, Figure 2). In receiving the
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LMWH regimen, the FW rate dropped to 12.24% (95% CI: 6.76% – 20.78%), which

was significantly lower than that of the H/VKA regimen (Table 4). However, the FW

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rate was the highest in the UFH regimen (53.62%, 95% CI: 41.28%–65.55%).

The maternal complications are listed in Table 2. MTE was observed to be 2.79%

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(95% CI: 2.01%–3.84%) in the VKA regimen, and 7.42% (95% CI: 4.95%–10.90%)

in the H/VKA regimen. The pooled results showed that the MTE rate significantly

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increased in the H/VKA regimen compared with the patients subjected to the low

dose VKA regimen (Table 3). In the group subjected to the LMWH regimen, the

MTE rate was 4.42% (95% CI: 1.64%–10.52%), which was a little bit lower than that

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of the H/VKA regimen but significantly higher than that of the VKA regimen (low

dose group) (Table 4, Supplemental Table S5). The prevalence of MTE (29.85%, 95%

CI: 19.60%–42.43%) in the UFH regimen was the highest. The most common MTE
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was mechanical valve thrombosis (MVT) (52/89). Among the 52 cases of MVT, data

on 26 patients were retrievable, 88.46% of which involved mitral valve thrombosis.

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The maternal deaths were reported at 0.89% (95% CI: 0.48%–1.60%) in the VKA
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regimen and 0.86% (95% CI: 0.22%–2.70%) in the H/VKA regimen. The pooled OR

estimate of the ten included studies showed no difference in all–cause mortality

between the H/VKA regimen and the low-dose VKA regimen (Table 3). Maternal
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mortality was 1.77%(95% CI: 0.31%–6.88%) in the LMWH regimen and 0.88% (95%

CI: 0.05%–5.51%) in the UFH regimen. The most common causes of death were
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MVTs (11/18) and related complications.

The pooled frequency of MAHEs reported from all studies was 17 (1.08%) across
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all 1568 pregnancies. Most MAHEs were associated with obstetric pathologies, such

as placenta previa and placental abruption.

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There were five studies that used a VKA or an H/VKA regimen along with aspirin

[30, 33, 42, 45, 47]; nine of the included studies used a VKA or H/VKA regimen

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without aspirin [16, 18, 20–22, 24, 28, 47, 51]. After pooling the studies

(Supplemental Table S2), we found no difference in maternal adverse outcomes

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between the two groups. Compared with studies without aspirin, the rates of FW and

spontaneous abortion were significantly lower in the studies using aspirin.

Sensitivity Analyses

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While the subgroups of pregnant women enrolled in prospective studies were

analyzed separately, the primary results in Supplemental Table S3 were consistent

with the pooled analysis in Tables 1 and 2. Subgroup analyses showed no

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heterogeneity after excluding the retrospective studies. The pooled OR estimate of the

three prospective studies showed that the rate of maternal MTE (OR 0.36, 95% CI:
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0.15–0.86; P =0.02, I2=43%) significantly reduced in the VKA regimen compared

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with the H/VKA regimen (Figure 3). Compared with later studies (1986–2014) [33,

34, 38, 39, 41–48, 52], earlier studies (1963–2000) [14–32, 35, 36, 40, 51] had fewer

"newer" generation mechanical valve. Compared with earlier studies, the later studies
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had significantly lower rates of adverse fetal events, even though the maternal

outcomes were similar (Supplemental Table S4). We also performed sensitivity

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analyses by repeating the analyses following the removal of each study one at a

time.The results were all stable and consistent.

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Risk of Publication Bias

No significant evidence of substantial publication bias was observed in our

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analysis (Supplemental Funnel Plots 1, 2).

Discussion

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Due to the hypercoagulable state in pregnancy, pregnant women with MPHVs

have an increased risk of thromboembolism. The need for effective anticoagulation

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therapy is, therefore, imperative for these patients [2–4, 67, 68]. However, no data

have been available from large prospective trials until now. Only a few, and mostly

small, series on this topic have been reported and their results were controversial

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[14–66]. To the best of our knowledge, this study is the largest systematic review and

meta–analysis to date regarding the effectiveness and safety of the four updated

anticoagulation regimens in pregnant women with MPHVs. Our study includes data
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from 51 studies and 1538 women with 2113 pregnancies in a five-decade span. This

study characterizes contemporary anticoagulation practice.

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The analytical results of this systematic review reveal that the VKA regimen is
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the best option for mothers with maintenance warfarin doses of 5 mg/d or less,

especially for pregnant women with high thromboembolic risk factors, such as older

valve designs, position (mitral and tricuspid valve), atrial fibrillation, or history of
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thromboembolism [2–4, 68]. Compared with the high dose subgroup (Table 5), the

rate of warfarin embryopathy was significantly lower in the low dose subgroup. These
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data suggested that the toxic effect of VKA on the fetus is significantly lower when

the maintenance warfarin doses are 5 mg/d or less. The maintenance warfarin dose
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could be reduced by adopting relatively low INR levels (median INR<2.5) in pregnant

women with a mechanical bileaflet valve, especially the lowest thrombogenic risk

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bileaflet (St. Jude Medical, Carbomedics and On–X Prosthetic Heart Valve) [69].

Three reports adopting low INR levels (1.5–2.5) in pregnant women with MPHVs

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have shown good maternal and fetal results [70–72]. However, further study is needed

to determine the optimal INR levels because of the small number of reported cases

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and the hypercoagulable state in pregnancy. In addition, it may not be prudent to

maintain a low dose of VKA for a sub therapeutic INR.

For pregnant women whose maintenance warfarin doses are higher than 5 mg/d,

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an H/VKA regime may be a reasonable choice. Previous studies have shown that

exposure to VKA in the first 6 to 12 weeks of pregnancy led to a significantly

increased risk to the fetus, including spontaneous abortion, CFA. Substitution of VKA
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with UFH or LMWH during the first trimester of pregnancy could lower the risk of

adverse fetal outcomes to ignorable levels because LMWH and UFH do not cross the
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placental barrier [2–4]. However, pregnant women adopting the H/VKA regimen face
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the risk of increasing maternal MTE. Thus, the H/VKA regimen is recommended for

pregnant women with high VKA maintenance doses, with the caveat of appropriate

therapeutic initiation doses of UFH or LWMH and close monitoring for

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approximately 6–13 weeks.

After pooling the included studies adopting a VKA and H/VKA regimen with
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and without aspirin (Supplemental Table S2), we found that low-dose aspirin did not

improve pregnancy outcomes. There was no difference in maternal adverse outcomes

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between the two groups. The difference in fetal adverse outcomes between the two

groups may not be explained by aspirin use, but could be better explained by the

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proportion of mechanical valve types. More pregnancies in patients with cage and ball

valves will lead to higher INR levels and doses of VKA of these patients and poorer

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fetal outcomes.

From the results of our analysis, the authors argue that the LMWH regimen could

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be used for pregnant women refusing VKA, especially those without high risk

thromboembolic factors. Compared with the H/VKA regimen, the rates of FW and

spontaneous abortion in the LMWH regimen are both significantly lower, while

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maternal outcomes were similar. Although the risk of adverse fetal events can be

reduced by adopting the H/VKA regimen, using VKA during the second and third

trimesters of pregnancy still causes significant fetal toxicity. Previously published

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data on the use of the LMWH regimen in pregnant women with MPHVs were limited

to poor management of LMWH and isolated case reports with severe complications
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[5–7, 57]. Such complications were generally attributable to inadequate initiation

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doses of LMWH, no monitoring and patient noncompliance [6, 7, 9, 67]. Thus, cases

with inadequate doses and no monitoring were excluded from this study. Because

many pregnant women with MPHVs refuse to use VKA after they learn about the
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toxic effects of VKA on their babies, a LMWH regimen may be a good alternative to

VKA and H/VKA regimens. Goland S et al. showed that adjusted dose LWMH that
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achieved guideline–recommended peak anti–Xa levels (0.7-1.2 U/mL) was associated

with sub therapeutic trough levels [67]. Thus, further studies are needed to determine
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the optimal target anti–Xa levels and LMWH dosing methods. Our study confirms

previous studies that the UFH regimen presented with an unacceptable high risk of

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maternal and fetal complications [5, 9]. Compared with LWMH, UFH was attributed

to an increased risk of excessive bleeding, heparin–induced osteoporosis, and

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thrombocytopenia [6, 73].

To achieve the optimal anticoagulation effect, it is critical that patients in their

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designated regimen are strictly compliant with their treatment plan and are closely

monitored [2–4, 7–9]. The factors that could interfere with achieving the optimal

anticoagulation effects include patients' financial situations and educational levels and

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the mechanism of delivering the anticoagulant. Therefore, in clinical practice, these

factors need to be addressed before the specific anticoagulation regimen is decided.

Limitations
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Several limitations may affect the validity of our review, analysis, and evaluation.

First, although our search was comprehensive, it was possible that some published
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and unpublished studies may have been missed. Therefore, the results may represent
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an overestimation of the true treatment effect. Second, the use of data from

observational studies may lead to methodological and interpretational concerns [8].

Because an appropriately sized prospective trial is not available, this pooled analysis
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of 1538 women with 2113 pregnancies helps to explain and quantify variations in the

results among different regimens. To minimize potential publication bias, only case
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series (≥6 pregnancies) and cohort studies were included in our study.

Conclusions
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Effective anticoagulation is mandatory for pregnant women with MPHVs. In the

absence of large prospective trials, our meta–analysis show that the VKA regimen

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should be best for pregnant women with low maintenance warfarin doses, especially

those with high-risk thromboembolic factors; the H/VKA regimen may be reasonable

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for pregnant women with high maintenance warfarin doses, and the LMWH regimen

could be used for pregnant women refusing VKA.

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Acknowledgments: We thank Yana Wang and Fang Huang for their assistance in

writing this article.

Funding Sources: Supported by Medical Scientific Research Foundation

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(B2013103) of Guangdong Province, China and the National Clinical Key Specialty

Fund of China.

Disclosures: The authors have no potential conflicts of interest to disclose.

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Tables and Figures

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Table 1. Frequency of Fetal Complications Reported With Various
Anticoagulation Regimens
Table 2. Frequency of Maternal Complications Reported With Various
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Anticoagulation Regimens
Table 3. Comparison between VKA Regimen (Low Dose) and H/VKA Regimen
Table 4. Comparison between H/VKA Regimen and LMWH Regimen
Table 5. Comparison between Low and High Dose Subgroup Studies Adopting
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VKA Regimen
Figure 1. Flowchart of Search Results
Figure 2. Anticoagulation Effects of Fetal Wastage from Random–effects Model
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Figure 3. Anticoagulation Effects of Maternal Major Thromboembolic Events

in Prospective Studies
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Table 1. Frequency of Fetal Complications Reported With Various

Anticoagulation Regimens

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Anticoagulation Number (%) of pregnancies[95% Confidence Interval]
Regimen Fetal Wastage Congenital Fetal Anomaly

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325/999(32.53) 20/938(2.13)
VKA Regimen
[29.65-35.55] [1.34-3.33]
85/442(19.23) 3/442(0.68)
Low dose subgroup
[15.73-23.28] [0.18-2.14]
77/340(22.65) 3/404(0.74)
H/VKA Regimen
[18.38-27.55] [0.19-2.33]

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12/98(12.24) 0/99(0)
LMWH Regimen
[6.76-20.78] [0-4.69]
37/69(53.62) 0/105(0)
UFH Regimen
[41.28-65.55] [0-4.41]

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VKA: Vitamin K antagonist, H: Heparin, UFH: Unfractionated Heparin
LMWH: Low- Molecular- Weight Heparin

Table 2. Frequency of Maternal Complications Reported With

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Various Anticoagulation Regimens
Anticoagulation Number (%) of pregnancies[95% Confidence Interval]
Regimen MTEs MAHEs Death(All causes)
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39/1398 (2.79) 5/1027 (0.49) 12/1353(0.89)

VKA Regimen
[2.01-3.84] [0.18-1.21] [0.48-1.60]
4/351(1.14) 3/442(0.68) 1/325(0.31)
Low dose subgroup
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[0.37-3.09] [0.18-2.14] [0.02-1.97]

25/337(7.42) 2/329(0.61) 3/348(0.86)
H/VKA Regimen
[4.95-10.90] [0.11-2.42] [0.22-2.70]
5/113(4.42) 4/98(4.08) 2/113(1.77)
LMWH Regimen
[1.64-10.52] [1.31-10.71] [0.31-6.88]
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20/67(29.85) 6/114(5.26) 1/114(0.88)

UFH Regimen
[19.60-42.43] [2.15-11.57] [0.05-5.51]
MTEs: major thromboembolic events, MAHEs: major antenatal hemorrhage events
VKA: Vitamin K antagonist, H: Heparin, UFH: Unfractionated Heparin
LMWH: Low- Molecular- Weight Heparin
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Table 3. Comparison between VKA Regimen (Low Dose) and

H/VKA Regimen

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Items Regimen VKA Regimen H/VKA P value
(Low Dose)
Maternal Death(All causes) 1/325(0.31%) 3/348(0.86%) 0.665

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Major Thromboembolic
4/351(1.14%) 25/337(7.42%) <0.001
Events
MAHEs 3/442(0.68%) 2/329(0.61%) 1.000
Fetal Wastage 85/442(19.23%) 77/340(22.65%) 0.249
Congenital fetal anomalies 3/442(0.68%) 3/404(0.74%) 1.000
Spontaneous abortion 55/364(15.11%) 35/275(12.73%) 0.423

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MAHEs: major antenatal hemorrhage events, VKA: Vitamin K antagonist, H: Heparin

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Table 4. Comparison between H/VKA Regimen and LMWH

Regimen
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Items H/VKA Regimen LMWH Regimen P value
Maternal Death(All
3/348(0.86%) 2/113(1.77%) 0.774
causes)
Major Thromboembolic
25/337(7.42%) 5/113(4.42%) 0.383
Events
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MAHEs 2/329(0.61%) 4/98(4.08%) 0.085

Fetal Wastage 77/340(22.65%) 12/98(12.24%) 0.024
Congenital fetal
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3/404(0.74%) 0/99(0) 0.895

anomalies
Spontaneous abortion 35/275(12.73%) 5/98(5.10%) 0.036
MAHEs: major antenatal hemorrhage events, VKA: Vitamin K antagonist, H: Heparin,
LMWH: Low- Molecular- Weight Heparin
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Table 5. Comparison between Low and High Dose Subgroup Studies

Adopting VKA Regimen

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Items Low Dose Subgroup High Dose Subgroup P value
Number of pregnancies 442 97 ▬
Maternal Death(All
1/325(0.31%) 0/69(0%) 1.000

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causes)
Major Thromboembolic
4/364(1.10%) 1/60(1.67%) 0.536
Events
MAHEs 3/442(0.68%) 0/97(0%) 1.000
Fetal Wastage 85/442(19.23%) 62/97(63.92%) <0.001
Warfarin

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2/442(0.45%) 8/97(8.25%) <0.001
Embryopathy
VKA: Vitamin K antagonist, MAHEs: major antenatal hemorrhage events

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