Arch Gynecol Obstet (2006) 274: 141145

DOI 10.1007/s00404-006-0152-0

O R I GI N A L A R T IC L E

Snezana D. Plesinac Plecas V. Darko

Igor Z. Pilic Ivana R. Babovic

Anticoagulation therapy during pregnancy of patients with artificial

heart valves: fetomaternal outcome

Received: 7 February 2006 / Accepted: 6 March 2006 / Published online: 6 April 2006
Springer-Verlag 2006

Abstract Objectives: The major problem is the need for

anticoagulant therapy in patient with mechanical heart
valves. Study design: The aim of the study was to analyze
the course and outcome of pregnancies of patients with
articial mechanical heart valves with anticoagulant
therapy. Study included 43 pregnancies leaded and terminated at the Institute of Gynecology and Obstetrics
Clinical Center of Serbia in 20 years. We divided the
patients in two groups depending on the type of anticoagulation therapy. Group I included 21 patients who
were under Ethylbiscumacetate (Pelenthan) during the
rst 36 weeks of gestation, and intravenous Heparin in
the last 4 weeks and after the delivery. Group II included 22 patients who received oral anticoagulant
therapy all the time. Results: Worsening of the heart
functional status happened in 6 patients (13.9%). The
incidence of heart failure during the pregnancy was
13.9% and after the delivery 9.3%. The incidence of
hemorrhagic complications was 11.6% during pregnancy and 14% after the delivery. Four patients had
thromboembolic events before the pregnancy. The incidence of postpartal thromboembolic complications was
6.9% in group I. Two patients died due to the heart
failure 37 days after the vaginal delivery. Maternal
mortality was 4.6%. One neonatus died of hydrocephalus (2.5%) in group II. In our study there were no
fetuses with congenital heart disease. Conclusions:
Pregnancies of patients with mechanical heart valves
should be planned. We suggest ethylbiscumacetate in
combination with Heparin as anticoagulation therapy
during the pregnancy.

S. D. Plesinac (&) P. V. Darko I. Z. Pilic I. R. Babovic

Department of Fertility Control,
Institute of Gynecology and Obstetrics,
Clinical Center of Serbia, Koste Todorovica 26,
Belgrade 11000, Serbia and Montenegro
E-mail: plesinac@hotmail.com
Tel.: +381-16-41119755
Fax: +381-11-7824543

Keywords Pregnancy Articial heart valves

Fetus

Introduction
The steady decline in maternal mortality over the last
20 years has largely been due to a substantial reduction in
the number of deaths attributed to hypertensive disorders, hemorrhage, sepsis and abortions. In contrast, the
relative contribution of cardiac disease to maternal
mortality has remained unchanged and this is still one of
the leading causes of adverse maternal outcome worldwide. The frequency of cardiac disease in pregnancy
varies from 0.9 to 3.7%. Progress in the heart surgery
makes the life of women with articial heart valves longer
and reproduction safer and improves their functional
status. The history begins in 1963 with the rst implantation of the mechanical valve. The rst pregnancy
occurred in 1966 (DiSaia). These patients needed anticoagulant therapy throughout the pregnancy and delivery. This provoked many questions about the risks that
therapy carries for the fetus and the mother. There are
complications during pregnancy which come out of the
heart disease, valve itself and anticoagulant therapy. They
are endocarditis, heart failure, arrhythmia, hemorrhagic
complications, thrombosis and thromboembolic events.
The risk factors for developing thromboembolism are:
mitral mechanical valve, inadequate anticoagulant therapy, atrial brillation, hyperthrophy of the left atria,
design and material of the valve, cesarean section,
advanced age of the patient and previous thromboembolic events. Pregnancy carries additional risks of
thromboembolism, because of increased coagulation
activity and decreased venous blood ow due to the
pressure of the pregnant uterus. Anticoagulation therapy
has two regimens: one is oral anticoagulants and the other
is Heparin. There are two types of oral anticoagulant
therapy: coumarin derivates (dicumarol, Ethyl biscumacetate and warfarin) and indandione derivates (anisindion and pheindion). Oral anticoagulants carry the

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risk of hemorrhagic complications for mother and teratogenic eects on fetus. The principal problems confronting the fetus are: fetal warfarin syndrome, central
nervous system defects, spontaneous abortion, stillbirth,
prematurity and hemorrhage. The use of coumarin derivates during the rst trimester presents a signicant risk
to the fetus. Only about 70% of pregnancies are expected
to result in a normal infant. Exposure in the rst trimester
may produce a pattern of defects termed fetal warfarin
syndrome: nasal hypoplasia, growth retardation, eye defects, hypoplasia of extremities, seizures, scoliosis, congenital heart diseases and intrauterine death. Infants
exposed before and after this period had infrequent central nervous system defects which may be the result of
cerebral hemorrhage and scarring with impaired growth
of the brain. The use of Heparin from the 6th week till
12th week and again at term may lessen this adverse fetal
outcome. Heparin causes osteoporosis and decreased
number of platelets of the mother, but it has no eects on
the fetus because its large molecules do not pass the placenta and cannot be transferred to fetal circulation.

up position. Intermittent oxygen and analgesics were

provided whenever needed. The second stage of labor
was shortened, if necessary, by the use of outlet forceps
or vacuum extractor. Following delivery, injection frusemide (Lasix, Hoechst Marion Roussel, India) of 20 mg
was administered intravenously. Oxytocin was used for
control of postpartum hemorrhage. Women who had
been on anticoagulants were restarted on heparin within
4 h of vaginal delivery and 8 h of cesarean delivery. Oral
anticoagulants were resumed and heparin discontinued
when prothrombin time reached 1.52 times normal.
Statistical analysis was made by Students t test, chisquared test and analysis of variance. We looked for
maternal and fetal complications such as hemorrhage,
thromboembolic complications and heart failure during
pregnancy, delivery and puerperium. Neonatal evaluation was complete. It included gestational age, fetal
weight, APGAR score, intrauterine growth retardation,
anomalies and mortality. We showed peripartal and
postnatal neonatal outcome.

Results
Methods
The aim of the study has been to analyze the course and
outcome of pregnancies of patients with articial
mechanical heart valves with anticoagulant therapy.
There are several questions which seek answers. What
type of anticoagulation therapy should be administered,
and should it be changed during the pregnancy and
delivery? When should it be stopped before the delivery?
What are the most frequent complications? How does
the pregnancy inuence the course of heart disease?
Study included 43 pregnancies controlled and terminated at the Institute of Gynecology and Obstetrics,
Clinical Center of Serbia, in 20 years. The Institute of
Gynecology and Obstetrics is the tertiary center for
perinatology in Serbia. All patients were under control
of an obstetrician, cardiologist and cardiac surgeon. We
divided the patients in two groups according to the type
of anticoagulation therapy. Group I included 21 patients
who received Ethylbiscumacetate (Pelenthan) during the
rst 36 weeks of gestation, and intravenous Heparin in
the last 4 weeks and after delivery. Group II included 22
patients who received oral anticoagulant therapy during
whole pregnancy. All patients were under regular laboratory testing. Every 2 weeks laboratory checkups were
made and they included: hemoglobin levels, hematocrit,
red cells, platelets, coagulation time and APTT or INR
testing depending on the type of anticoagulants received.
Fetal evaluations were made every 34 weeks and they
included ultrasound examination and measurements and
biophysical prole. Labor was induced only for obstetric
indications. Oxytocin was used for induction of labor.
However, it was administered cautiously in a concentrated solution to avoid water overload. All patients
received antibiotics for prophylaxis against infective
endocarditis during labor. They were kept in a propped

The average age of the patients was similar in both

groups. Group I 29.8 years and group II 28.1 years (t1.2 is
0.5). There were 25 mitral, 16 aortic and 2 tricuspid
valves. Nine patients had two articial valves implanted
and one had three articial valves implanted. The difference between the groups was not signicant (t1.2 is 1.4).
In Tables 1 and 2 we can see that during the pregnancy 32 patients were NYHA class I (74%), 7 class II
(16.2%) and 4 were class III and IV, who were not advised to get pregnant, but came to hospital in advanced
pregnancy. Worsening of the heart functional status
happened in six patients (13.9%). There was no statistical dierence between the groups (P1.2 is 0.08).
The incidence of heart failure during pregnancy was
13.9%: two patients from group I and four patients from
Table l NYHA class during the pregnancy
NYHA class

Group I

Group II

Total

I
II
III
IV

16 (36.3%)
3 (6.8%)
1 (2.2%)
1 (2.2%)

16 (36.3%)
4 (9%)
3 (6.8%)
0

32 (72.7%)
7 (15.9%)
4 (9%)
1 (2.2%)

P1.2 is 0.08
Table 2 NYHA class in delivery
NYHA class

Group I

Group II

Total

I
II
III
IV

13 (29.5%)
6 (13.6%)
2 (4.4%)
0

13 (29.5%)
2 (4.4%)
7 (15.9%)
0

26 (59%)
8 (18%)
9 (20.4%)
0

P1.2 is 0.24

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Table 3 Heart rhythm during delivery

Table 6 Complications of anticoagulant therapy during puerperium

Heart rhythm

Group I

Group II

Total

Sinus rhythm
Atrial premature
complex
Ventricular
premature complex
Pace maker

16 (36.3%)
4 (9%)

9 (20.4%)
8 (18%)

25 (56.8%)
12 (27.2%)

1 (2.2%)

4 (9%)

5 (11.3%)

1 (2.2%)

1 (2.2%)

Group I

Group II

Postpartal hemorrhage
Hemathoma of episiotomy

1
0

3
2

P1.2 is 0.004

P1.2 is 0.00026

Table 4 Heart rhythm in pregnancy

Heart rhythm

Group I

Group II

Total

Sinus rhythm
Atrial premature
complex
Ventricular
premature complex
Pace maker

13 (29.5%)
5 (11.3%)

12 (27.2%)
6 (13.6%)

25 (56.8%)
11 (25%)

3 (6.8%)

4 (9%)

7 (15.9%)

1 (2.2)

1 (2.2%)

P1.2 is 0.027

group II. The heart failure after delivery was registered

in 9.3% of cases: two patients from group I and two
patients from group II. The dierence between the
groups was not signicant (P1.2 is 0.05).
In Tables 3 and 4 we see that 17 patients had heart
rhythm disturbances: 18% in group I and 25% in group
II. One patient had pacemaker. Six patients (13.6%)
changed sinus rhythm during labor. Statistical dierence
between the groups was signicant. Majority of patients
(60%) from group II had disturbances of the heart
rhythm (P1.2 is 0.00026).
Ethylbiscumacetate (Pelenthan) was administered in
dosage of 1/4 of tablet per day (75 mg) or 1/2 of tablet
(150 mg). The average INR level in group I was 2.05,
and in group II 2.02. The optimal therapeutic range for
INR during oral anticoagulant therapy was 1.52.5. Our
results show that dosage was adequate. Dierence between the groups was not detected (Fx is 0.06).
Heparin of 1 ml (5,000 IU) was administered intravenously every 6 h or 1.5 ml (7,500 IU) every 6 h. The
average APTT was 13.3 s in group I and 12.65 s in
group II. There was no dierence between the groups (Fx
is 2.55).
The incidence of hemorrhagic complications is shown
in Tables 5 and 6. During pregnancy ve patients
(11.6%), all from group I, had various complications.
Table 5 Complications of anticoagulant therapy during the pregnancy
Complications

Group I

Group II

Vaginal bleeding
Epistaxis
Subcutaneal hemathoma

1
3
2

0
0
0

P1.2 is 0.007

Complications

After delivery the incidence was 14%, but 83% of them

happened in group II. Statistical analysis showed signicant dierence between the groups (P1.2 is 0.004).
One total and one subtotal hysterectomy were performed in patients with abundant postpartal uterine
hemorrhage.
Four patients had thromboembolic events before
pregnancy: two had cerebrovascular attacks, and two
thrombosis of the valve. Analysis of thromboembolic
complications during puerperium showed that one patient had pulmonary and two cerebral embolisms, all in
group I. The incidence of postpartal thromboembolic
complications was 6.9%.
Two patients died of heart failure 37 days after the
vaginal delivery.
Premature labor occurred in 23% of pregnancies.
Vaginal deliveries were 65% spontaneous, only ve were
induced with oxytocin. In six cases (13.9%) cesarean
section was performed. Forceps or vacuum during
delivery was applied in 24 cases (54.5%) in order to
shorten the second stage of labor. There was no statistical dierence between the groups (P1.2 is 0.23).
Analysis of neonatal morbidity showed that ten fetuses suered from peripartal asphyxia, seven had
intrauterine growth restriction and two suered birth
trauma. Birth trauma was the result of forceps delivery.
Analysis of APGAR score showed that 14% had APGAR score less than eight. Twenty percent of the newborns were delivered prematurely. The average birth
weight was 3,023 g in group I and 2,954 g in group II.
There was no statistical dierence between the groups
(t1.2 is 0.075).
One neonatus died of hydrocephalus (2.3%) in group
II, which can be explained by teratogenic eect of oral
anticoagulant therapy. In our study there were no fetuses with congenital heart disease.

Discussion
The most important fact for advising the patient to get
pregnant is NYHA status before pregnancy. Heart
functional status of our patients was satisfactory in 74%
of cases. Worsening of the heart functional status happened in six patients (14%). Casanegra [4] noticed one
worsening of the HYHA class among 14 patients. Vitali
[19] found no changes of NYHA status.
The incidence of heart failure during pregnancy was
13.9% and after delivery 9.3%. Javares [10] noticed one
heart failure among 46 patients. Matoras [13] had two

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among 59 patients. Pajszczyk [15] had two heart failures

among 27 patients. Mazhar [14] noticed 7% heart failure
and Malhorta [12] 5.1%.
Heart rhythm disturbances during pregnancy and
labor were detected in 18 patients (23%). Sareli [18]
noticed four heart rhythm disturbances in his study of 50
patients and Ayhan [2] had 17.5% of arrhythmias
among 64 patients.
The majority of hemorrhagic complications during
pregnancy and after delivery happened in group II. The
patients who received Heparin during the last 4 weeks
and after delivery rarely suered from hemorrhagic
complications. One patient had total hysterectomy because of postpartal hemorrhage. Matoras [13] had one
postpartal hemorrhage in 59 deliveries of patients with
oral anticoagulant therapy. Ismail [10] had seven postpartal hemorrhages among 76 patients. Ayhan [2] had
20% and Avila [1] 23% of hemorrhagic complications in
his study.
Analysis of thromboembolic complications during
pregnancy and puerperium showed that one patient
had pulmonary and two cerebral embolism after
delivery. They were all in group I. Ethylbiscumacetate
had better eect in prevention of thromboembolic
events. The incidence of postpartal thromboembolic
complications was 7.5%. Salazar [17] registered 3
valve thromboses and 14 cerebral embolisms in patients who received oral anticoagulant therapy with
Kumarin, and 1 patient had cerebral insult under
Heparin therapy. Ismail [9] found 2 thromboembolic
complications among 76 pregnancies who received
Heparin therapy. Pavankumar [13] studied 47 pregnancies with oral anticoagulant therapy and found 2
valve thromboses.
Two patients died of heart failure 37 days after the
vaginal delivery. Maternal mortality was 4.6%. Mazhar
[14] found maternal mortality rate of 7.1%. Avila [1] had
a lower rate of 2.7%.
Premature labor occurred in 23% of pregnancies.
Bhutta [3] found 7% of premature labors. Javares [10]
noticed one premature labor among 46 pregnancies and
Pavankumar [16] three among 47 pregnancies.
Cesarean section was performed in six (13.6%) cases.
Mazhar [14] had 10% of Cesarean sections. Kaemmarer
[11] had greater percentage of operative delivery, 21%,
and Faiz [6] had 3.6%.
Twenty percent of the newborns were delivered prematurely. Kaemmerer [11] found the same percentage.
Avila [1] had lower degree of 13%.
One neonatus died of hydrocephalus (2.5%), which
can be explained by teratogenic eect of oral anticoagulant therapy. Harrison [7] noticed 3 embriopathies of
55 pregnancies. Casanegra [4] had one fetus out of nine
with anomalies. Vitali [19] had incidence of 4.2% of
anomalies. Javares [10] found in his study 3 growth restricted fetuses among 33. Pajszczyk [15] noticed 9
growth restricted fetuses out of 45 pregnancies. Mazhar
[14] had 5% of fetal intrauterine death, Bhutta [3] 2%
and Kaemmerer [11] 1 fetus. In our study there were no

fetuses with congenital heart disease. Kaemmerer [11]

noticed 5.4% of them in his study.
Malhorta [12] analyzed women who were operated on
for heart disease and those who had no heart surgery
and found that operation improved maternal morbidity
and mortality but fetal outcome remained unchanged.
Horstkotte [8] showed great suspicion about anticoagulant therapy during pregnancy, according to the adverse maternal and fetal changes. De Santo [5] found no
maternal or fetal complications during warfarin therapy
in pregnancy.

Conclusion
Pregnancies of patients with mechanical heart valves
should be planned. Oral anticoagulant therapy should
be replaced with heparin during the rst 12 weeks, and
the last 4 weeks. In the middle of pregnancy oral anticoagulants should be given. We suggest ethylbiscumacetate, because of little fetal adverse eects. The dosage
regimen must be carefully controlled by adequate laboratory tests. Heparin should be stopped 46 h before
delivery and continued 1224 h after delivery. During
heparin therapy there were less hemorrhagic but
more thromboembolic complications, and during oral
anticoagulant therapy there were more hemorrhagic
complications and one fetal anomaly, but no thromboembolic events.

References
1. Avila WS, Ross EG, Ramires JA et al (2003) Pregnancy in
patients with heart diseaseexperience with 1000 cases. Clin
Cardiol 26(3):135142
2. Ayhan A, Japar EG, Nazbi N et al (1992) Pregnancy and its
complications after cardiac valve replacement. Int J Gynecol
Obstet 35:117122
3. Bhutta SZ, Aziz S, Korejo R (2003) Pregnancy following cardiac surgery. J Pak Med Assoc 53(9):407413
4. Casanegra P, Aviles G, Maturana G et al (1975) Cardiovascular management of pregnant women with a heart valve
prosthesis. Am J Cardiol 36:802806
5. De Santo LS, Romano G, Della Corte A et al (2005) Mitral;
mechanical replacement in young rheumatic women: analysis a
long term survival, valve related complications and pregnancy
outcomes over a 3707 patient year follow up. J Thorac Cardiovasc Surg 130(1):1319
6. Faiz SA, AlMesham AA, Sporrong BG (2003) Pregnancy and
valvular heart disease. Saudi Med J 24(20):10981101
7. Harrison E, Roschke E (1975) Pregnancy in patients with
cardiac valve prostheses. Clin Obstet Gynecol 18:107123
8. Horstkotte D, Fassbender D, Piper C (2003) Congenital heart
disease and acquired valvular lesions in pregnancy. Hertz
28(3):227239
9. Ismail M, Abid F, Trabelsi S et al (1986) Cardiac valve prostheses, anticoagulation and pregnancy. Br Heart J 55:101105
10. Javares T, Coto E, Rincon A et al (1984) Pregnancy after heart
valve replacement. Int J Cardiol 5:731739
11. Kaemmerer H, Bauer U, Stein JI et al (2003) Pregnancy in
congenital cardiac disease an increasing challenge for cardiologist and obstetriciana prospective multicenter study. Z
Kardiol 92(1):1623

145
12. Malhorta M, Sharma B, Arora P, Batra S, Sharma S, Arrora R
(2003) Mitral valve surgery and maternal and fetal outcome in
valvular heart disease. Int J Gynecol Obstet 81(2):151156
13. Matoras R, Reque JA, Larrea L et al (1985) Prosthetic heart
valve and pregnancy. Gynecol Obstet Invest 19:2131
14. Mazhar SB, Gul-e-Irim (2005) Fetomaternal outcome in
pregnancy with cardiac disease. J Coll Psysicians Surg Pak
15(8):476480
15. Pajszczyk-Kieszkiewicz T, Zaslonka J, Zaslonka A et al (1986)
Pregnancy in women with valvular prostheses. Z Kardiol
75:308311
16. Pavankumar P, Venugopal P, Airon B et al (1988) Pregnancy in
patients with prosthetic cardiac valve. Scand J Thorac Vasc
Surg 22:1922

17. Salazar E, Zajarias A, Iturbe I et al (1984) The problem of

cardiac valve prostheses, anticoagulants and pregnancy. Circulation 70:11691177
18. Sareli P, England MJ, Berk MR et al (1989) Maternal and fetal
sequele of anticoagulation during pregnancy in patient with
mechanical heart valve prostheses. Am J Cardiol 63:14621465
19. Vitali E, Donatelli F, Quaini E et al (1986) Pregnancy in patients with mechanical prosthetic heart valves. J Cardiovasc
Surg 27:221227