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Eur J Cardiothorac Surg 2002;22:223-227
© 2002 Elsevier Science NL

Pregnancy and mechanical heart valves replacement; dilemma of anticoagulation

Cardiothoracic Surgery Unit, Royal Hospital Muscat, Sultanate of Oman, PO Box 225, Code 115, Muscat, Oman

Received 4 February 2002; received in revised form 13 May 2002; accepted 20 May 2002.

* Corresponding author. Tel.: +968-605-721; fax: +968-694-120
e-mail: adilawati{at}yahoo.com

	Abstract

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion References

 
Objectives: To establish a uniform anticoagulation regimen for pregnant patients with mechanical heart valves taking into account the socio-economic background and to evaluate the incidence of anticoagulant related complications. Methods: A retrospective study on 63 pregnancies in 21 women with mechanical heart valves was evaluated. These pregnancies were divided into two groups: Group I (n=42) received oral anticoagulants throughout pregnancy and Group II (n=21) received subcutaneous heparin in the 1st trimester and oral anticoagulants for the rest of pregnancy period. Both groups received heparin at time of delivery. Results: There was no case of coumarin embryopathy seen and there was no maternal death. Life threatening valve thrombosis occurred in two patients who were both from Group II and needed emergency re-replacement. Group I had a higher incidence of spontaneous abortion than Group II although this was not statistically significant. Conclusions: The role of coumarin embryopathy has been overstated. We recommend the use of oral anticoagulants throughout pregnancy especially in countries with similar socio-economic background.

Key Words: Mechanical heart valves • Coumarin embryopathy • Anticoagulation • Low molecular weight heparin

	1. Introduction

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion References

 
There has been an increase in the prevalence of pregnancy in women having one or more mechanical heart valves. This prevalence is more in the developing countries due to the fact that there is still high incidence of valvular diseases in children and as a result a large number of young females undergo valve replacement and subsequently get pregnant. This is well observed in a country like Oman.

Pregnancy induces anatomic, physiologic and biochemical changes that alter the precarious haemostatic balance favoring thrombo-embolic complications [1]. Therefore it is obvious and mandatory to anticoagulate these women who represent a challenge to the medical professional looking after their pregnancy especially regarding the mode and method of anticoagulation.

There is a wide acceptance especially in the USA of a regimen using unfractionated heparin during 1st trimester and oral anticoagulants for the rest of pregnancy period until about 2 weeks short of expected date of delivery at which time the patient is switched back to heparin.

However, many studies from various parts of the world have shown that such a regimen is not entirely safe and infact carries a considerable risk to mother's life [2]. Whereas others have reported that the use of oral anticoagulants during the 1st trimester resulted in significantly less problem than what was originally thought [3,4].

In this report we evaluate our experience and the outcome of these pregnancies in our institution and assess the benefits and risks of each regimen hoping to establish a uniform anticoagulation method.

The cardiothoracic surgery unit at the Royal hospital – Muscat, Oman, is the only unit available in this country. It was established in Dec 1990. It provides services for a population of approximately 3 millions.

This unit performed 365 valve operations in the period Dec 1990–Dec 2001. Prior to Dec 1990 all patients needing cardiac surgical procedures were sent abroad.

All patients operated in our unit were followed up for one full year and then referred to their physicians either in our institution or elsewhere in the country for further follow up. Similarly their physicians and obstetricians followed up the group under study until time of delivery when they were referred to the Royal hospital where cardiac surgical service is available.

	2. Patients and methods

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion References

 
A retrospective study of 63 pregnancies in 21 women who had their valves replaced during the period 1983–1997 was carried out. The ages of these women ranged between 21 and 35 with a mean of 27 years. Most of them had multiple pregnancies (Table 1). 15 patients had mitral valve replacement, two had aortic valve replacement and four patients had both mitral and aortic valves replacement. The type of prostheses used was Bjork Shiley in 14 patients, St. Jude in seven patients and Medtronic in four patients. The choice of the prosthesis was according to what was in common use at the time of valve replacement.

2.1.1. Group I (42)
Oral anticoagulants (DuPont Pharma; Warfarin Sodium USP; Tablets 1, 2, 5 mg) were given throughout pregnancy including the 1st trimester with a target international normalised ratio (INR) at 2.5–3.5. In all pregnancies the dose of warfarin required to keep the target INR was less than 5 mg with the exception of four pregnancies in two patients who required a dose of 6 mg/day.

The INR was measured at each follow up ‘once a month’. There was no significant oscillation in INR measurement noticed in this group.

The larger number of pregnancies in this group reflects late presentation, which means that the patient first presented herself at or just before the completion of 1st trimester and so there was no question of switching over to heparin.

2.1.2. Group II (21)
In the remaining 21 pregnancies oral anticoagulants were replaced by subcutaneous heparin (Heparin Leo; Leo Pharmaceutical Products; 1000/ml, 5000 IU/ml, 25 000/ml; 5 ml ampoules) when pregnancy was confirmed. The dose of heparin was started at 10 000 units every 12 h that was later adjusted according to measurements of activated partial thromboplastin time (APTT), which was kept at twice the control level. We do not have the actual APTT value for all patients as many of them were done in different hospitals but for those done at the Royal hospital the actual APTT was in the range of 80–90. At the completion of 12 weeks heparin was stopped and oral anticoagulants restarted.

At the time of delivery oral anticoagulants were stopped 2 weeks before the expected date in both groups and subcutaneous heparin was commenced with a target APTT kept at twice the control level.

The mode of delivery was a normal vaginal delivery in all but one pregnancy, which required a caesarian section to deliver the baby.

Oral anticoagulant was recommenced 24 h after delivery when bleeding stopped and the patients were kept in the hospital for few more days until INR is within therapeutic range.

	3. Results

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion References

 
Fig. 1 shows the outcome of these pregnancies as a whole while Fig. 2 shows the results of each group separately.

View larger version (69K): [in this window] [in a new window]   Fig. 1. Shows the outcome of all pregnancies.

View larger version (48K): [in this window] [in a new window]   Fig. 2. Shows the outcome of pregnancies in each group.

There was 46 babies delivered alive; 31 was from Group I forming 73.8% of the total number in this group, whereas the other 15 were from Group II forming 71.4% of the total number in this group.

Fourteen pregnancies spontaneously aborted their contents; 11 were from those who were exposed to warfarin during the 1st trimester forming 26.2% of this group and the other three were from the heparin group forming 14.3% of the total number in this group.

3.1. Maternal complications
There was no maternal mortality in this series but there were the following complications.

3.2.1. Post-partum hemorrhages
There were three primary post-partum hemorrhages; one from Group I and two from Group II.

Two pregnancies were complicated by secondary post-partum hemorrhages both from Group I. The cause of bleeding was retained placenta in one and retained clots in the other. All responded well to conservative management.

3.3.2. Thrombo-embolic complications
There were major thrombo-embolic complications in two patients who were both from Group II. Both presented with blocked valves at week 14, i.e. 2 weeks after the 1st trimester got over when heparin treatment was completed.

The 1st patient was 22 years old woman who presented with a blocked Medtronic Hall prosthesis at mitral position during her 3rd pregnancy. She underwent emergency Re-replacement to save her life. The end result was a stillborn baby at week 32.

The 2nd patient was 27 years old woman who had a blocked Bjork Shiley prosthesis at mitral position during her 4th pregnancy. Emergency Re-replacement was carried out to save her life and again this pregnancy terminated in a stillborn baby at week 32.

Both of them presented early in pregnancy to the antenatal clinics and they were switched to heparin during 1st trimester but they were poorly compliant to heparin treatment. However they kept a regular follow up.

3.4. Fetal complications
3.4.1. Coumarin embryopathy
There was no case of coumarin embryopathy seen in this series of pregnancies. No complete genetic evaluation was carried out but clinically no signs of abnormality were seen in these babies as evaluated by a neonatologist well versed with coumarin embryopathy.

3.4.2. Prematurity/low birth weight
Fourteen babies out of those who were born alive had a low birth weight ranged between 1.6 and 2.4 kg but they were otherwise healthy; nine of them were from Group I and the other five were from Group II.

3.4.3. Fetal death
There were three stillborn as mentioned early; two were from the two women who blocked their prostheses during pregnancy. The cause of death of the 3rd baby was not clear.

	4. Discussion

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion References

 
Pregnancy with mechanical heart valves poses a special problem.

Pregnancy induces definite derangements of the haemostatic mechanism predisposing women to thrombo-embolic complications. There is a marked elevation of fibrinogen level, which in late pregnancy approaches double the level of that in non-pregnant women. In the 3rd trimester there is increased concentration of factors VII, VIII, IX, X and XII while the level of antithrombin III decreases. In addition to that there is an increase in blood volume, plasma viscosity, intra-abdominal pressure and venous compression.

At the same time the presence of mechanical heart valves is associated with the highest thrombo-embolic risks, although modern valves have better design and materials make them less thrombogenic.

Therefore it is obvious and essential that pregnant women must receive a good anticoagulation treatment throughout pregnancy period to avoid the hazardous outcome. Yet there is no agreement on what could be the best regimen to select in this high-risk subgroup of patients.

There is a general acceptance especially in the USA that warfarin is contraindicated during the 1st trimester of pregnancy due to it's teratogenic effects and high rate of abortion and that it should be replaced by heparin. But heparin has several disadvantages.

It is difficult to achieve adequate and constant anticoagulation level with subcutaneous heparin due to its narrow therapeutic margin. This makes it very difficult to control it and its short duration of action would leave few hours every day without proper protection [5,6]. The therapeutic target has never been agreed and therefore neither the dose nor the frequency of administration has been agreed. Earlier a target APTT of 1.5 was thought to be adequate [7]. This was subsequently changed to a minimum of 2 to maintain adequate anticoagulation [8]. Yet major thrombo-embolic episodes that ended patient's life have been reported [2] with an APTT of up to 2.5. In a retrospective study designed to obtain information from major European centers, Sbarouni and Oakley [9] reported 13 valve thrombosis (four fatal) and eight embolic events (two fatal) among 133 pregnant women with mechanical valves; ten out of the 13 were taking heparin, two were on warfarin and the last took no anticoagulants. In a review of literatures to determine maternal and fetal risks associated with different regimens of anticoagulation, Chan and associates concluded that thromboembolic prophylaxis in pregnant women with mechanical heart valves is best achieved with oral anticoagulants [10].

In our series, two women presented with thrombosed prosthesis. Both had heparin treatment during their 1st trimester with an APTT within therapeutic values. Their lives were saved only after an emergency redo-replacement with its entire potential hazardous outcome. Both pregnancies ended in stillbirth.

Furthermore in this country and in countries of similar socio-economic backgrounds, not all patients comply well with heparin treatment. The fact that heparin require two to three injections every day makes it difficult if not impossible for a villager to travel a long distance to get it and it would be more practical for her to have a supply of tablets available and ready to use.

At the same time the outcome of pregnancy is not favorable when heparin is substituted for warfarin as the incidence of fetal wastage from spontaneous abortion, prematurity and stillbirth is similarly high.

Hall reported the delivery of healthy full term babies in only 86 out of 135 pregnancies ‘63.7%’ [11]. Lee and colleagues reported an incidence of 50% spontaneous abortion when heparin was used [12]. Salazar [2] had an incidence of 37.5% of spontaneous abortion in his series although he partly attributed this high figure to warfarin as his patients became pregnant while receiving warfarin until the 6th week when they switched over to heparin. Pavankumar [4] and his group in India found that the rate of spontaneous abortion (4.2%), prematurity (6.4%) and stillbirth (2.1%) among their patients were comparable with or less than that from the general population (all their patients received warfarin through entire pregnancy period). Meschengieser [6] observed no significant statistical difference (P=0.571) in fetal loss from women on warfarin (15/61, 25%) than those used heparin during 1st trimester (six/31, 19%). We had a similar observation in our series as we had 26.2% spontaneous abortion from warfarin group and 14.3% in the heparin group with a calculated P value 0.454.

The issue of teratogenicity is one of the major concerns that led to this continuing controversy in the management of anticoagulation in pregnant women.

Heparin has large molecules that can not cross the placental barrier and so it's use was advocated in the early weeks of pregnancy to avoid the development of a range of fetal abnormalities collectively known as coumarin embryopathy which were noticed when warfarin was used [13]. A larger series of various fetal abnormalities came in reports from the USA [14] where a large dose of warfarin was used to prolong the prothrombin time to the therapeutic level. In Europe (and other parts of the world) such a large dose of warfarin was found unnecessary [15,16] because European thromboplastin prolong prothrombin time (PT) more than the thromboplastin used in USA and consequently much lower dose is needed to maintain adequate anticoagulation. It was then noticed that once the dose of warfarin is kept at 5 mg/day or less, the incidence of coumarin embryopathy had significantly decreased to an acceptable level or perhaps had been eliminated [17–19]. This probably explain why in later reports many have supported the view that the incidence of fetal abnormality has been exaggerated and that warfarin can be probably safely used even during the 1st trimester. Many of these reports came from places where the occurrence of Rheumatic Heart Diseases is still high.

Pavankumar [4] had no congenital abnormalities in their live born infants. Ben Ismail [3] in Tunisia similarly reported no case in his series. Salazar and his group in Mexico observed one/38 typical coumarin embryopathy in their 1st series and two/35 in the 2nd series [20,21] giving a combination rate of 4.1%. Sbarouni and Oakley [9] reported no case in 46 pregnancies exposed to warfarin and similarly Meschengieser [6] reported no fetal abnormality among the 45 live born babies in their series. In our series there was no abnormality in the 46 live born infants including those who were exposed to warfarin.

The incidence of bleeding has not been found outside the acceptable range for both drugs, as the need for massive blood transfusion has not been reported. Some, however, reported marked difference between warfarin and heparin [9] with a P value <0.05 in favor of the former. In contrast Ginsberg and Dahlman [22] had bleeding rate of 2% or less when heparin is used. Similarly Salazar [2] and Meschengieser [6] each had one case of massive bleeding in their series. We had no case of excessive bleeding needed more than usual blood transfusion in either group. It seems that if the level is kept within the therapeutic range the risk of excessive uncontrollable bleeding will be diminished.

Lastly, much optimism have been put on low molecular weight heparins as an alternative to subcutaneous heparin as those agents do not cross the placenta, have less side effects and more important that they have more consistent protection against thromboembolism. Although they sound promising and infact some have used them with success [23,24], individual cases have been reported on their failure [25] and a formal and comprehensive study indicating their safety during pregnancy is lacking, and until such an experience becomes available, we would be reluctant to use or recommend them for use in pregnant women with prosthetic valves.

In conclusion, there is to date no anticoagulant regimen that can be said entirely safe for use during pregnancy as there is a degree of risk with each regimen. But if we balance the benefit against the risk of each of the available anticoagulant agents the selection would fall on using warfarin throughout pregnancy including the 1st trimester, as there is almost the same degree of risks to the fetus with either regimen but with greater risks to the mother's life if heparin is used.

In countries with socio-economic background similar to our country, reliability on patient's compliance is another determining point that needs to be considered before selection. The choice would again fall on using warfarin because patient's compliance is definitely superior with it as compared to subcutaneous heparin.

	Footnotes

 
Presented at the 14th Annual Meeting of the European Association for Cardio-thoracic Surgery, Frankfurt, Germany, October 7–11, 2000.

	References

Top Abstract 1. Introduction 2. Patients and methods 3. Results 4. Discussion References

 

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