Arch Gynecol Obstet
DOI 10.1007/s00404-015-3768-0
MATERNAL-FETAL MEDICINE
Anticoagulant management of pregnant women with mechanical
heart valve replacement during perioperative period
Ce Bian1 • Xiaorong Qi1 • Li Li1 • Jitong Zhao1 • Xinghui Liu1
Received: 23 November 2014 / Accepted: 27 May 2015
Ó Springer-Verlag Berlin Heidelberg 2015
Abstract
Objective To investigate the morbidity of complications
and pregnancy outcomes in women with mechanical heart
valve replacement who received low-dose oral anticoagu-
lation treatment with warfarin throughout the pregnancy,
compare the prognosis and complications of patients who
were treated with single oral warfarin treatment or the
‘‘bridging’’ therapy treatment, investigate the influence of
using vitamin K1 before emergency cesarean section
delivery on postoperative warfarin anticoagulant effect and
to explore an appropriate anticoagulant regimen during
perioperative period for pregnant women with mechanical
heart valve replacement.
Method 46 pregnant women with mechanical heart valve
replacement who received low-dose oral anticoagulation
treatment from October 2008 to October 2014 treated at
West China Women’s and Children’s Hospital were ret-
rospectively reviewed. Eight patients received emergency
cesarean section (CS), while 38 patients received selective
CS, in which 17 patients received single oral warfarin and
21 patients received ‘‘bridging’’ anticoagulation treatment
during postoperative period. Morbidity of complications
and the time to achieve the target INR after operation were
compared.
Results The mechanical valves were at the mitral position
in 35 (76.09 %) patients, at the aortic position in 2
& Xinghui Liu
xinghui_liu@126.com
1
Department of Obstetrics and Gynecology, Sichuan
Provincial Key Laboratory of Gynecologic Oncology, Key
Laboratory of Obstetric and Gynecologic and Pediatric
Diseases and Birth Defects of Ministry of Education, West
China Women’s and Children’s Hospital, Sichuan University,
Chengdu 610041, Sichuan, People’s Republic of China
(4.35 %) patient and at both the mitral and aortic position
in 9 (19.57 %) patients. 46 full-term healthy babies were
delivered and no maternal thromboembolic was observed
during pregnancy. There was no significant difference of
the amount of uterine bleeding between single oral war-
farin group and ‘‘bridging’’ treatment group during post-
partum period. In single oral warfarin group, one valve
thrombosis was observed and led to sudden death. No
periphery thrombosis, hematoma, general hemorrhage or
other sign of over-anticoagulation was observed. The INR
increased more slowly in the group who received emer-
gency CS with preoperative application of vitamin K1 than
other two groups.
Conclusion The use of vitamin K1 preoperatively might
result in warfarin resistance and discontinuation of war-
farin therapy before selective CS might be more appro-
priate than application of vitamin K1. The ‘‘bridging’’
anticoagulation treatment which combines oral warfarin
and subcutaneous LMWH might be more effective and
safer than single oral warfarin therapy for patients with
mechanical heart valve replacement during postoperative
period, no matter selective or emergency CS. The safety of
low-dose oral warfarin therapy throughout pregnancy is
still under controversy.
Keywords Mechanical heart valve
Pregnancy

Anticoagulation
Warfarin
Vitamin K1
Perioperative
period
Introduction
Pregnancy prompts hypercoagulability state, which
increases the risk of mechanical heart valve thrombosis and
death [1], and effective anticoagulation should be
123

mandatory [2]. Oral anticoagulation offers the best pro-
tection for mothers, with a lower incidence of valve
thrombosis than unfractionated heparin (UFH) and low-
molecular-weight heparin (LMWH), whose application, on
the other hand, is associated with fetal malformation and
pregnancy loss [3]. Coumarin derivatives cross the placenta
and their use in the first trimester can result in embryopathy
in 0.6–10 % of cases [4–7]. UFH and LMWH do not cross
the placenta and embryopathy does not occur. But more
evidence shows that the hypercoagulable risk of coumarin
derivatives may be dose dependent [6, 8]. Therefore, low-
dose oral anticoagulation therapy throughout pregnancy
may be a simple, safe and more acceptable regimen.
Because of the discontinuation of warfarin, the hyper-
coagulable state, and patients presenting no or sluggish
increase of INR during postpartum warfarin resumption,
patients are more susceptible to mechanical valve throm-
bosis during the perioperative period. Therefore, the regi-
men during this period must be more effective.
The purpose of this study was to retrospectively inves-
tigate the morbidity of complications in women with
mechanical heart valve replacement who received low-
dose oral anticoagulation treatment with warfarin
throughout the pregnancy, compare the prognosis and
complications of patients who were treated with single oral
warfarin treatment or the ‘‘bridging’’ anticoagulation
treatment during perioperative period, investigate the
influence of using vitamin K1 before emergency cesarean
section (CS) on postoperative warfarin anticoagulant effect
and to explore an appropriate anticoagulant regimen during
perioperative period for pregnant women with mechanical
heart valve replacement.
Materials and methods
We conducted a retrospective review of all patients iden-
tified with mechanical heart valve replacement in West
China Women’s and Children’s Hospital from October
2008 to October 2014. Eligible patients in this analysis
were women received low-dose oral anticoagulation ther-
apy throughout pregnancy and terminated pregnancy by
CS. Women with spontaneous delivery, abortion and
incomplete clinical data were ineligible. Out of the popu-
lation, 46 consecutive patients with mechanical heart valve
replacement were identified from the obstetric database.
Clinical information regarding preoperative characteristics
including age, reproductive history, underlying heart dis-
ease, position of the mechanical valve, age at valve
replacement and gestational weeks were obtained from
patients’ records. Written informed consent was obtained
from all participants and this study was approved by the
Institutional Ethics Committee of Sichuan University.
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Arch Gynecol Obstet
Patients were advised to contact the outpatient clinic as
soon as they miss a period, and to perform pregnancy tests
every 3 days until positive or menstruation. Upon confir-
mation of pregnancy, every pregnant woman should be
informed that oral anticoagulation offers the best protection
against thrombosis, but is associated with an appreciable risk
of fetal malformations and pregnancy loss. On the other
hand, substitution of oral anticoagulation with LMWH or
UFH reduces the risk of fetal damage, but increases the risk
of valve thrombosis, even when administered in adjusted
doses. Each pregnant patient completed written informed
consent. The international normalized ratio (INR) was esti-
mated on a weekly basis at our outpatient clinic and recorded
along with prescribed warfarin doses to maintain the target
INR between 1.6 and 2.2. Echocardiographic follow-up was
performed monthly to evaluate cardiac and prosthetic func-
tion. Patients were followed up by cardiologists and obste-
tricians at biweekly intervals until the 36th week of gestation,
when they were estimated weekly. Selective CS was typi-
cally planned at 38 weeks of gestation. Warfarin therapy was
discontinued 2 days before surgery. During the preoperative
period, LMWH was not routinely administered, as was col-
legially considered not necessary for a warfarin discontinu-
ation within just 3 days [9], and INR was checked daily.
Echocardiography was done before the operation. The
maternal thrombotic, hemorrhagic complications and preg-
nancy outcomes were investigated from patients’ database.
During postoperative period, patients of selective
cesarean section received single oral warfarin or the
‘‘bridging’’ anticoagulation treatment. Single oral warfarin
group reinitiated warfarin (2.5 mg/day), 4–12 h after
delivery, depending on the degree of uterine bleeding; and
the ‘‘bridging’’ treatment group reinitiated warfarin, and
administered subcutaneous LMWH twice daily to maintain
anti-Xa levels of 1–1.2 IU/ml until the target INR was
reached. The uterine bleeding of the two groups during 24,
24–48, 48–72 h after surgery and the morbidity of post-
operative complications such as maternal valve thrombosis,
periphery thrombosis, general hemorrhage and other over-
anticoagulation were compared.
For the patients who needed emergency cesarean section
delivery, vitamin K1 (10 mg) was given intravenously, and
INR was checked every 2–4 h until INR reached normal.
Depending on the degree of uterine bleeding, ‘‘bridging’’
treatment was administered 4–12 h after delivery and the
INR level was examined daily. The time to achieve the
target INR after the emergency and selective cesarean
section was compared.
Statistical analysis
Statistical analysis was performed using SPSS version 19.0
(SPSS Inc., Chicago, IL, USA). Uterine bleeding and time
Arch Gynecol Obstet

for anticoagulation therapy to CS were compared using pregnancy and regularly followed up by cardiologists. The
one-way ANOVA and serial changes in INR levels were usage of warfarin was all less than 5 mg/day and daily dose
compared by RM-ANOVA. p value \ 0.05 was considered was 1.25–4.375 mg, the INR was controlled between 1.6
significant. and 2.2. No maternal thromboembolic was observed during
pregnancy. Sixteen patients (34.78 %) suffered from gen-
eral bleeding, in which subcutaneous ecchymosis occurred
Results in nine patients (19.57 %), epistaxis occurred in five
patients (10.87 %), and gingival bleeding occurred in two
From October 2008 to October 2014, 46 patients with patents (4.35 %). Heart failure occurred during CS in one
mechanical heart valve replacement received low-dose oral patent (2.17 %), but recovered after emergency treatment.
anticoagulation therapy throughout pregnancy and termi- Other cardiac complications occurred in 15 patients
nated pregnancy by CS in West China Women’s and (32.61 %), in which 7 patients (15.22 %) suffered from
Children’s Hospital. The baseline characteristics of the atrial fibrillation and 8 patients (17.39 %) suffered from
patients are shown in Table 1. All patients were primipara ventricular premature beat. 46 full-term babies were born
with a mean age of 30.54 years old (range 20–42) and age and the mean birth weight was 2978.65 g (range
at valve replacement was 25.04 years old (range 12–39). 2180–4000). In these 46 neonates, there were two low birth
The termination time of pregnancy was 38.33 weeks (range weight infants, their weight were 2180 g and 2290 g,
37.1–40.3). respectively, and were transferred to department of
In these 46 patients, 44 (95.65 %) cases suffered from neonatology after birth. Apgar scores of 46 neonates at
rheumatic heart disease while the other 2 (4.35 %) cases birth were more than 7 points, with no neonatal or fetal
suffered from congenital heart diseases. The mechanical death, no stillbirth, no congenital abnormalities or neuro-
valves were at the mitral position in 35 (76.09 %) patients, logical dysfunctions. No warfarin embryopathy, charac-
at the aortic position in 2 (4.35 %) patient and at both the terized by nasal hypoplasia, stippled epiphyses, or both,
mitral and aortic position in 9 (19.57 %) patients. Valve was observed.
replacement was conducted 5.48 years (range 1–17) before Thirty-eight patients received selective CS, in which 17
pregnancy, and warfarin anticoagulation was routinely patients received single oral anticoagulation treatment and
used after the surgery. All patients received low-dose oral 21 patients received ‘‘bridging’’ anticoagulation treatment
anticoagulation therapy throughout pregnancy and were during postoperative period. There was one maternal
regularly monitored coagulation functions during thromboembolic event in the oral therapy group and led to
death. The patient was a 21-year-old woman with a history
Table 1 Baseline characteristics of patients with mechanical heart of rheumatic heart disease and received mitral valve
valve replacement replacement at the age of 12. She was treated with warfarin
3.75 mg/day. Her INR level ranged from 1.6 to 2.2
Characteristics (n = 46)
throughout pregnancy and received a selective CS at the
Maternal age (years) 38?2 weeks of gestation. Echocardiography before the
Mean 30.54 operation demonstrated no valve thrombosis but pulmonary
Range 20–42 artery hypertension. The operation went smoothly, and the
Age at valve replacement (years) warfarin was reverted 8 h after the operation. On the third
Mean 25.04 day after the operation, the patient felt chest discomfort,
Range 12–39 and in the meanwhile, her INR level was 0.89. Thereafter,
Primigravida (n, %) 46 (100 %) she acutely became short of breath, cardiac arrest and died
Gestational age (weeks) soon. The autopsy demonstrated mitral mechanical valve
Mean 38.33 thrombosis of approximately 16 mm 9 14 mm.
Range 37.1–40.3 The time for reinitiating anticoagulation therapy after
Underlying heart disease (n, %) CS was 7.65 h (range 4–11) in single oral warfarin group
Rheumatic 44 (95.65 %) and 7.48 h (range 4–11) in ‘‘bridging’’ treatment group,
Congenital 2 (4.35 %) where no statistically significant difference was found
Position of the mechanical valve (n, %) between two groups (p = 0.961). There was no significant
Mitral 35 (76.09 %) difference in the amount of uterus bleeding during 3 days
Aortic 2 (4.35 %) after surgery between two groups. No late postpartum
Mitral ? Aortic 9 (19.57 %) hemorrhage, periphery thrombosis, general hemorrhage or
any other over-anticoagulation complication were observed

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 Arch Gynecol Obstet

Table 2 The comparisons between single oral warfarin group and ‘‘Bridging’’ treatment group
Group n Time for Therapy to CS (h) Uterine Bleeding (ml) Valve Thrombosis Periphery Thrombosis
24 h 24–48 h 48–72 h

Bridging 21 7.48 241.67 147.24 83.10 0 0

Oral 17 7.65 235.00 140.59 79.41 1 0
p 0.787 0.661 0.699 0.561

in two groups. The comparisons between two groups are

shown in Table 2.
Due to premature rupture of membranes and patients
refused to choose natural childbirth, eight patients received
emergency cesarean Section. 10 mg vitamin k1 was given
intravenously, and operation was underwent until INR
reached normal. ‘‘Bridging’’ treatment was administered
7.50 h (range 4–10) after delivery and the INR level was
examined daily. Serial changes in INR levels during
postpartum period were compared between vitamin K1
treatment group, single oral warfarin group and ‘‘bridging’’
treatment group. There was no significant difference in
time to reinitiated anticoagulation therapy between these
three groups. The INR levels in vitamin K1 treatment
group increased more slowly than other two groups, which
need 6.38 ± 1.06 days to achieve the target range. The
‘‘bridging’’ treatment group and oral anticoagulation group
needed 6.42 ± 0.81 days and 4.71 ± 0.92 days, respec-
tively. Significant difference is shown between ‘‘vitamin
K1 treatment’’ group and the other two groups (p \ 0.05),
Fig. 1 The comparison of serial changes in INR between single oral
with no significant difference between the other two groups warfarin group, ‘‘bridging’’ treatment group and vitamin K1 treatment
(p = 0.767). The comparison of serial changes in INR group
levels between three groups is shown in Fig. 1.

anticoagulation strength is the important reason of post-

Discussion
Pregnancy induces a series of haemostatic changes, with an
increase in concentration of coagulation factors, fibrinogen,
and platelet adhesiveness, as well as diminished fibrinol-
ysis, which lead to hypercoagulability and an increased risk
of thromboembolic events. In addition, obstruction to
venous return by the enlarging uterus causes stasis and a
further rise in risk of thromboembolism. Therefore, anti-
coagulation therapy is important for pregnant women who
had received mechanical heart valve replacement. To avoid
intraoperative and postoperative hemorrhage, the coagula-
tion function of the patients should be maintained normal.
In addition, the high maternal complication rate including
valve thrombosis and resultant death should not be ignored
either. Therefore, an effective anticoagulation therapy,
after the bleeding tendency, is particularly important. Since
the mid 1980s, heart surgeon has recognized that excessive
operative bleeding and reduced the anticoagulation
strength. The value of PTR has dropped to 1.5–2.0 from 3.0
to 4.0 and INR was dropped to 2.0–3.0 from 4.0 to 6.0. In
this strength, the rate of bleeding was 1.4–2.4 % and the
embolism was 2.0–3.8 % in western countries [10]. But in
the same standard of anticoagulant strength, Chinese
patients showed higher bleeding rate (0.68–10.4 %) and
lower embolism rate (0.3–1.48 %) [11]. This shows that
because of the difference between the races, it is necessary
to use low intensity of anticoagulant in Chinese patients.
And some studies also showed low-intensity anticoagula-
tion was safe and effective for Chinese patients [8, 12]. So,
the patients in our study received oral low-dose warfarin
anticoagulation throughout pregnancy, with INR controlled
between 1.6 and 2.2, and no complications happened, such
as embolism and severe bleeding. It shows that the oral
anticoagulant treatment of warfarin for pregnant women is
safe and effective.

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Arch Gynecol Obstet
In our study, we observed that even though the warfarin
was reinitiated as soon as possible, the INR level still
needed 4.71 ± 0.92 days to reach the target range. Patients
who discontinued warfarin preoperatively were in the
‘unprotecting’ state, which were subjected to high risk of
mechanical valve thrombosis until their postoperative INR
reached the target range. In the single oral warfarin group,
there was one patient suffered from mitral valve throm-
bosis and resulted in death. Therefore, single oral warfarin
therapy might be insufficient for anticoagulation during
perioperative period. LMWH works fast, and it takes only
3 h after subcutaneous injection that the peak concentration
in serum is reached with almost 100 % bioavailability.
Moreover, it is easier to achieve stable anticoagulation and
evaluation. Moreover, LMWH is reported to have lower
incidence of osteoporosis and thrombocytopenia compared
with unfractionated heparin [13]. The ‘‘bridging’’ antico-
agulation treatment reinitiates warfarin, and administers
subcutaneous LMWH twice daily to maintain anti-Xa
levels of 1–1.2 IU/ml until the target INR is reached. In our
study, one out of 17 patients without postoperative
‘‘bridging’’ therapy died due to valve thrombosis and
instead of increasing the morbidity of postpartum hemor-
rhage, late postpartum hemorrhage and general hemor-
rhage, the ‘‘bridging’’ treatment effectively prevented the
occurrence of mechanical valve thrombosis, periphery
thrombosis and stoke. Therefore, ‘‘bridging’’ treatment
might be more effective and safer than single oral warfarin
therapy for patients with mechanical heart valve replace-
ment after selective CS. Since LMWH does not influence
APTT, not only INR but also anti-Xa levels should be
checked daily during postoperative period.
Because the anticoagulant effect of warfarin can be
antagonized by vitamin K1, it is a common way to use high
dose of vitamin K1 to correct coagulant disturbance when
postoperative patients who received valve replacement are
in over-anticoagulant state or before emergency operation.
However, high doses of vitamin K1 might induce ‘‘war-
farin resistance’’ [14], which could influence anticoagulant
effect of warfarin even during postoperative period. In our
study, it is obvious that the postoperative increase of INR
in the vitamin K1 treatment group was significant more
slow than other two groups. Hence, for the selective CS,
the warfarin therapy should be discontinued 2 days before
surgery instead of vitamin K1 application via intravenous
infusion. For the emergency CS, due to the use of vitamin
K1 and ‘‘warfarin resistance’’, the ‘‘bridging’’ treatment
might be more appropriate and effective than single oral
warfarin therapy during postoperative period until the tar-
get INR is reached.
Warfarin provides the most effective control of antico-
agulation with mechanical heart valves. In addition, it is
considered to be the best method to prevent maternal
thrombotic events [15]. However, the best prophylaxis
becomes questionable during pregnancy, for being unsafe
to the fetus. Warfarin could cross the placenta and affect
the fetus, which lead to ‘‘warfarin embryopathy’’, miscar-
riage and stillbirth [16]. Since 1991, Cotrufo et al. sup-
ported that those complications could be dose related, and
suggested that warfarin would be safe as long as its use
during pregnancy was limited to 5 mg/day [17]. However,
the safety of low-dose oral warfarin therapy during first
trimester is still under controversy [18]. In our study war-
farin was continuously used throughout pregnancy and no
warfarin embryopathy or over-anticoagulation in the fetus
was observed, but since the objects and including criteria,
this result might not reflect the real impact of warfarin on
the fetus.
However, there are several limitations to our study that
must be considered. First, this is a retrospective, single-
center study with a limited ability to reliably determine
heart function and complications during pregnancy by
patients’ records. Second, due to the limitations of
knowledge and conditions, we did not use prothrombin
complex concentrates but vitamin K1 to normalize the INR
values prior to emergency cesarean section, which might
increase the risk of patients. Third, we did not follow-up
the neonatal outcomes, such as nervous system develop-
ment, mental development, so this study could not reflect
the impact of long-term development of fetus. Forth, the
overall patient population is certainly limited, and the
subgroup undergoing ‘‘vitamin K1 treatment’’ is even
smaller. These limitations might be solved by increasing
number of cases and participation of more research centers
in future, and our study results could be confirmed by the
larger sample study. And the use of prothrombin complex
concentrates prior to emergency cesarean section could
improve the safety of pregnant women with mechanical
heart valve replacement.
The discontinuation of warfarin during perioperative
period increases the risk of mechanical valve thrombosis
and death. The use of vitamin K1 preoperatively might
result in warfarin resistance and discontinue warfarin
therapy before selective CS might be more appropriate than
application of vitamin K1. The ‘‘bridging’’ anticoagulation
treatment which combines oral warfarin and subcutaneous
LMWH might be more effective and safer than single oral
warfarin therapy for patients with mechanical heart valve
replacement during postoperative period, no matter selec-
tive or emergency CS. The safety of low-dose oral warfarin
therapy throughout pregnancy is still under controversy,
the role of us is to continue the discussion of the pros and
cons of available regimens and, ultimately, help the patient
and her family to decide which drug to take. We consider
that the most important is the mother’s life, second is the
baby’s life or avoiding embryopathy.
123

Conflict of interest The authors declare that they have no conflict
of interest.
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