Service de Médecine Interne, Hôpital La Rabta, Tunis.






tables 1;2;3;4;5;6




Indications for anticoagulation during pregnancy include treatment and prophylaxis of acute venous thromboembolism, prevention of systemic embolism in-patients with prosthetic valves or native valvular heart disease, and prevention of pregnancy loss in selected women with antiphospholipid antibodies. The use of anticoagulants in pregnancy is problematic, however, because they may produce complications in the fetus, as well as in the mother.



These drugs have been associated with adverse events in the mother and in the fetus because they cross the placenta. Their use needs precautions during pregnancy.

II-1- Adverse effects:

II-1-1- Risks to the fetus include three categories of deleterious effects:

  1. Terategenic effects consist on the " warfarin embryopathy syndrome ": (1,2)
  2. The most common features of this syndrome include nasal hypoplasia (due to failure of development of the nasal septum) and stippled epiphyses resembling a type of chondroplasia punctata (3,4). These embryopathies have been reported to in approximately 5 % of infants (5) exposed to warfarin between 6 and 12 weeks of gestation (1).
  3. The daily dosage of warfarin seems to have an importance in the occurrence of the embryopathy (6).

  4. Central nervous system (CNS) abnormalities:
  5. These abnormalities include dorsal midline dysplasia, Dandy-walker malformations and midline cerebellar atrophy, as well as, ventral midline dysplasia with optic atrophy and blindness (1).
  6. CNS abnormalities can occur after warfarin exposure at any point in gestation and they are more devastating and debilitating than the warfarin embryopathy syndrom (mental retardation, blindness, spasticity, seizures, deafness, scoliosis and death). Their incidence was estimated at less than 5 % (1,5). They are thought to be consecutive to intracranial hemorrhages in the fetus.

  7. Miscarriage:


First trimester exposure to warfarin appears to increase the rate of spontaneous abortion. But the incidence of abortion, still birth and neonatal deaths is increased (15 to 25 %) even when this therapy is restricted to the second and third trimester of pregnancy (5).

It’s worthy to note that fetal hypocoagulation and potential subsequent bleeding might occur in spite of the fact that maternal anticoagulation parameters are maintained in a therapeutic range (7).


II-1-2 Risk to the mother:

The long half-life of Vitamin K antagonist (VKA) is a handicap during labor and delivery since potential hemorrhagic complications are then difficult to control. Thus, their use should be avoided beyond 36 weeks of gestation and replaced with heparin (8).

Warfarin, which is safe for breast-needing infants (9) can be substituted after delivery.



Unfractioned heparin (UFH) and low-Molecular-weight-heparin (LMWH) do not cross the placenta and would not be expected to produce fetal complications (10,11). UFH is now the commonest mode of anticoagulation therapy in pregnant women. However their long-term use UFH requires monitoring and causes adverse effects in the mother (osteoporosis and heparin induced thrombocytopenia), this is why LMWH are attractive for use in pregnant women because they do not require monitoring in non pregnant patients and may cause less osteopenia (12).

III-1-Unfractioned Heparin (UFH):

III-1-1- Drug action:

Heparin is a heterogeneous sulfated long-chain acidic glycosaminoglycan that is extracted from beef or porcine lung or gut. It functions as a catalytic cofactor for an endogenous inhibitor of serine proteases called anti-thrombin. Heparin exerts its effect by complexing with and changing the molecular configuration of anti-thrombin, thereby increasing its ability to neutralize thrombin, factor Xa, factor IXa, factor XIa and factor XIIa (13).

III-1-2- Pharmacokinetics particularity during pregnancy:

Few pharmacokinetics studies evaluated heparin therapy during pregnancy and most of these investigations focused on subcutaneously administered UFH.

Brancazio and al (14) compared pregnant women in early third trimester and non-pregnant control patients that received a single dose of unfractionned heparin subcutaneously at 143 U/ Kg (8500 to 11500U). The pregnant women demonstrated a longer time to peak heparin concentration (222 ± 21 Vs 113 ± 20 min), longer peak activated partial thromboplastin time [ APTT] (230 ± 36 Vs 137 ± 31 sec), lower peak plasma heparin concentration (0,11 ± 0,017 U Vs 0,23 ± 0,036 U) and lower trough APTT (30 ± 1,7 sec Vs 50 ± 4 sec).

Barbour and al showed in another study (15) that 4 of 9 pregnant women in the second trimester and only 4 of 13 in the third trimester achieved the desired mid interval heparin levels after receiving a prophylactic dose of subcutaneous UFH every 12 hours.
Then, these two studies suggest an apparent resistance to heparin in late pregnancy and that UFH should be administered more frequently than every 12 hours and at higher daily doses.


III-1-3-Adverse effects:

III-1-3-1- The fetus

Many studies showed that maternal heparin (that does not cross the placenta) is safe for the fetus. The incidence of adverse fetal outcomes associated with heparin therapy during pregnancy is similar to that in an untreated population (16)

III-1-3-2- The mother:

The main adverse effects are:

a)- Heparin induced thrombocytopenia (HIT):

It is a rare side effect occurring in 1 to 5% of cases depending on the route of administration, the type and the daily dosage of UFH. There are two types of HIT:


However, once a patient presents with clinical symptoms compatible with HIT, far example, greater than 50% decrease in platelet count and/or new thrombotic complications, heparin should be stopped immediately.

But, for a HIT patient with thrombosis in whom heparin has been discontinued, there is a very high risk for subsequent thrombosis with an incidence ranged from 5% to 10% per day (23).

Thus, a therapeutic dose for a compatible anticoagulant (either danaparoïd or lepirudin) should be given immediately to a patient with thrombosis and acute HIT. Treatment should never be delayed for laboratory confirmation in a patient strongly suspected of having HIT (17).


b)- Heparin –induced osteoporosis (HIO):

HIO was first reported in 1965 (24). Several studies have since reported that long term heparin treatment during pregnancy is associated with reduced bone density and vertebral bone fracture with an incidence as high as 2% (25, 26). However, pregnancy and breast feeding themselves may cause bone demineralization. It is therefore unclear what proportions of the reported decrease in bone density associated with long term treatment with heparin during pregnancy is attributable to pregnancy itself and what proportion may be caused by heparin. This is compounded by the fact that earlier studies reporting HIO during pregnancy used relatively imprecise radiological methods with suffer from poor sensitivity and reproducibility (25). Up to date, only two prospective studies using dual X-ray absorptiometry (DEXA) to assessing bone mineral density (BMD) in pregnant women treated by heparin, have been reported (29,30). These authors reported that during pregnancy, a

decrease in lumbar spine BMD of 2% (29) to 5% (30) was similar to the loss (3%) in untreated pregnant women.

c)- Bleeding:

Minor bleeding manifestations (ecchymoses at the site of injections, microscopic hematuria, bleeding from gems) can be controlled by withholding the next dose of heparin and reducing subsequent doses. If major bleeding occur protamine could be used (it is not avoided during pregnancy).

d)- Heparin-induced skin reaction:

It is a rare complication but may progress to skin necrosis. If a pruritic rash at the injection site occurs treatment must be withdrawn.

e)- Alopecia is uncommon:

Therapeutic monitoring

Use precautions and laboratory monitoring of heparin therapy in pregnant and non-pregnant patients are similar. However, as heparin requirement may increase and are highly variable during pregnancy measuring anti Xa activity may be useful to guide the therapy until appropriate clinical trials can determine optimal dosing in pregnant women (15).



LMWHs which have been recently introduced into clinical practice, have been demonstrated to be safe and affective for the prevention and treatment of acute deep vein thrombosis (31,32) and for the prevention of myocardial infarction in patients with instable angina (33). These agents are attractive for use in pregnant women because they don’t require monitoring as in non-pregnant patients. However, very little is known about the pharmacokinetic profile and appropriate dosing of the LMWHs in pregnant patients.

III-2-1- Pharmacology:

LMWHs are heparin fragments produced by chemical or enzyme depolymeryzation of UFH. They differ in preparation method, molecular weight distribution, specific activity, clearance routes and rates and optimal dosage; therefore we can not assume that specific clinical properties are common to different LMWH preparation (34). LMWH exerts its anticoagulant effect by binding to AT, where as potentiating the inhibition of factor Xa. The various commercially available LMWH preparations differ in their ratio of antiXa to antiIIa activity (Table 1)

Table1: Commercially available LMWH preparations

These drugs are readily absorbed from subcutaneous tissue and have a bioavailability of more than 90% as compared with 30% with UFH. They are eliminated primarly by the kidneys.

LMWH do not cross the placenta (11). Thus, LMWH may have some pharmacological advantages during pregnancy because of their long half-life, which may allow dosing one time per day, their increased bioavailability after subcutaneous injection, their more predictable anticoagulant response, which allows their use without laboratory monitoring.


III-2-2- Safety and efficacy of LMWH use during pregnancy:

Based on the results of large clinical trials in non-pregnant women that showed that LMWH are at least as effective and safe as UFH in the treatment of patients with acute proximal DVT (35) and in the prevention of DVT in patients who undergo both general or orthopedic surgery (36), several studies have evaluated the efficacy and safety of LMWH during pregnancy.

In one of these studies Chan and Rey (37) conducted in 1999 a systematic literature search of MEDLINE using the MeSH headings "Low molecular weight heparin" and "Pregnancy". Additional references from retrieved articles were also examined. The authors excluded case reports less than five patients. The results of their search are presented in Table 2

In total, more than 500 pregnant women received LMWH for the treatment of or prophylaxis against venous thromboembolism or recurrent pregnancy loss. Daltaparin and exoxaparin were the principle drugs used in these studies, although nadroparin and certoparin were also used.

In normal pregnancy, there is increased body mass and glomerular filtration rate, and one can suppose that higher doses of LMWH would be necessary in late pregnancy. The need for adjusted-dose was investigated by two authors. Nelson-Piercy and al (38) showed that antiXa levels remained relatively constant throughout pregnancy at a fixed LMWH dose. However, Hunt and colleagues (39) found that increasing dose adjustments with each trimester were needed, in accordance with declining antiXa levels. The need of weight-based dosing of LMWH during pregnancy was confirmed recently by Crowther and al (12) in a prospective cohort study of the pharmacokinetic characteristics of Rivaparin (a LMWH) administered throughout pregnancy.

Concerning the effectiveness of LMWH during pregnancy: although only 0,6% receiving "therapeutic" or prophylactic doses of these drugs showed venous thromboembolism complication, a definitive conclusion can not be given due to the non-randomized design of the studies and the heterogeneity of the risk of venous thromboembolism in the population studied (40).

Table 2 : Clinical studies of LMWH use during pregnancy


No women /


Indication for LMWH

LMWH type

LMWH dose

Achieved anti-Xa level (IU/ml)

Gillz 1992


VTE treatment or prophylaxis


40 mg (4000 U) od/bid


Melissari et al. 1992


VTE prophylaxis


2,500-22,500 U per day

0,1-0,3 (trough)



VTE prophylaxis


2,500-5,000 U od/bid


Ramussen 1994


VTE treatment or prophylaxis


2,500-5,000 U od/bid

0,2-0,5 at 2-6 hours postinjection

Kraub 1994


VTE prophylaxis for caesarian section or during tocolysis

Dalteparin vs UFH

LMWH 2,500-5,000 U od vs. UH 5,000 U bid


Sturridge 1994


VTE prophylaxis among SLE



(2,000-4,000 U) od

(+/- aspirin 75mg)


(mean level)

Wahlberg 1994


VTE prophylaxis


2,500 to 16,000 U od


Boda. 1996


VTE prophylaxis


2,050 to 4,000 U od

0,1-0,3 at 3-hours postinjection

Dulitzki 1996


VTE treatment or prophylaxis among patients with SLE or APLAS



(2,000-4,000U) od/bid

0,1-0,15 (trough)

Lima at al. 1996


APLAS or VTE prophylaxis


Not started. Also on aspirin 75 mg od

0,4 -0,6 at 2 hours postinjection and

0,15-0,2 (trough)

Hunt et al. 1997


VTE treatment

or prophylaxis for recurrent pregnancy loss


5,000 U od to 10,000 U bid +/- aspirin 75 mg/od

0,4 -0,6 at 2 hours postinjection and

0,15-0,2 (trough)

Nelson-Piercy 1997


VTE treatment or prophylaxis


20 mg (2,000 U) od to

40 mg (4,000 U ) bid


(interquartile steady state for 40 mg od daily)

and 0,02-0,6 (interquartile steady state for 20 mg od)

Scheinder 1997


VTE prophylaxis


3,000 U od/bid


Daskalakis 1997


VTE treatment


6,150 U od


*VTE, venous thromboembolism includes pulmonary embolism and deep-venous thrombosis ; NA, data not available ; SLE, systemic lupus erythematosus ; APLAS, Antiphospholipid antibody syndrome.

Adverse fetal outcomes

The occurrence of adverse fetal outcomes in pregnancies with LMWH use depends on women conditions. In fact, in a total of 486 pregnancies in which LMWH was administered as the sole anticoagulant agent; abortion and still birth occurred at a notably higher rate : 13,4% in the group of women with comorbid conditions than in women without such conditions: 3,1% (Table 3) which is comparable to that seen in the normal population and confirming the fetal safety of LMWH (40).

Table3: Indication for LMWH use during pregnancy in subgroups with and without maternal comorbidity, number of adverse fetal/infant outcomes


Maternal systemic side effects

LMWH was seen to be rarely associated with maternal systemic side effects, such as bleeding, thrombocytopenia or osteoporosis (37,40,21).

Warkentin and al (21) compared the incidence of HIT in patients treated with LMWH or UFH. Heparin-induced thrombocytopenia occurred in 99 of 332 patients who received UFH and in none of 333 patients who received LMWH (2,7% vs 0%, P = 0,0018). Eight of the 9 patients with HIT also had one or more thrombotic events (venous in7 and arterial in1), as compared with 117 of 656 patients without HIT (88,9% vs 17,8%, P< 0,001). In the subgroup of 387 patients, the frequency of heparin-dependent IgG antibodies was higher among patients who received UFH (7,8% vs 2,2% among patients who received LMWH, P = 0,02). Then, HIT, associated thrombotic events and heparin-dependent IgG antibodies are more common in patients treated with UFH than in those treated with LMWH.

Monreal et al (41) compared bone densities in 80 non-pregnant, older patients randomized for treatment of venous thromboembolism with either UFH or LMWH. Although bone density measurements at the lumbar spine were similar in the two groups, more vertebral fractures were reported with UFH than LMWH (6 vs1). Small prospective studies of pregnant women treated with LMWH suggest that bone density is not adversely affected (30). But, because osteopenia may arise with LMWH use, compounded by the negative effects of pregnancy on bone turnover, adequate maternal intake of calcium and vitamin D should be encouraged throughout pregnancy.

The risk for major bleeding in the non-pregnant patient seems to be minimal with LMWH, and compared with UFH, is reduced by 35 to 68% (42). Wahlberg and Kher (43) reported a bleeding rate of 2,2% among a survey cohort of pregnant women on LMWH. Furthermore, HIT occurs less frequently with LMWH (21), and no such case in pregnancy has been published.

In conclusion, published experience suggests that LMWH are generally safe and effective when administered for thromboprophylaxis during pregnancy. Until prospective, randomized, controlled trials comparing them with UFH are performed, their benefits in pregnancy will remain inconclusive.



There are limited data regarding the efficacy of anticoagulants during pregnancy. Treatment recommendations, therefore, have largely been extrapolated from data in non-pregnant patients and case series of pregnant women.

IV-1- Treatment of acute venous thromboembolism:

IV-1-1- Initial therapy:

Initial therapy has traditionally consisted of a bolus of intravenous UFH followed by a continuous infusion adjusted to maintain a therapeutic activated partial thromboplastin time (APTT).

IV-1-2- After 5 –10 days:

On the basis from the results from two studies (16,44), intravenous heparin is discontinued and therapy with twice-daily subcutaneous UFH, in doses sufficient to achieve a therapeutic mid-interval APTT. The APTT should be checked every few weeks because UFH requirements might vary as the pregnancy progresses. Apparent heparin resistance during pregnancy is not uncommon and monitoring of heparin levels by anti-factor Xa assay has been suggested (14,15).

Although there is growing clinical experience with LMWH in pregnancy, good information on appropriate dosage regimens and the need for dose adjustment or laboratory monitoring is lacking.

IV-1-3- During delivery:

A prolonged anticoagulant effect at the time of delivery may increase the risk of bleeding or haematoma formation with epidural analgesia. Planned delivery is often advocated with discontinuation of subcutaneous UFH or LMWH 24 h prior to elective induction. Women at high risk of recurrent thromboembolism can be converted to an infusion of UFH that is discontinued 4-6h prior to delivery. Women with spontaneous onset of labour should discontinue injections immediately. The APTT must be checked to ensure it has normalized with discontinuation of UFH. If necessary, rapid reversal of heparinization in patients receiving UFH can be accomplished with protamine sulfate. The optimal approach in women who enter spontaneous labour while receiving therapeutic doses of LMWH remains controversial and depends upon the proximity of the last dose to the expected time of delivery, and, if available, the anti-factor Xa level. If a significant anticoagulant effect is expected or documented at the time of delivery, epidural analgesia should be avoided and protamine sulfate should be used judiciously.

IV-1-4-After delivery:

Therapeutic doses of UFH or LMWH should be reintroduced with adequate homeostasis. Warfarin can be started immediately and heparin discontinued once the international normalized ratio has been in the therapeutic range for two consecutive days. (45)

IV-2- Venous thromboembolism (VTE) prophylaxis in pregnant women:

Optimal management of VTE prophylaxis depends on the presence or no of women’s history with prior VTE and/or thrombophilia.

The main congenital causes of VTE (thrombophilia) are: deficiency in anti-thrombin (AT; previously named AT III), protein C (PC) or protein S (PS), activated PC (APC) resistance associated with factor V mutation and prothrombin 20210A variant. (46,47). Hyperhomocysteinaemia, homozygosity for methylene tetrahydrofolate reductase and increased levels for factor VIII may also be considered as risk factors.

In the absence of anticoagulant prophylaxis the risk of deep vein thrombosis or pulmonary embolism (exclusion of superficial vein thrombosis) related to pregnancy and post partum has been shown to be 24-28% in women with AT, PC or PS deficiency.(Table 4 ).

Table 4: Risk of deep vein thrombosis and pulmonary embolism related to pregnancy in women with AT, PC or PS deficiency

AT-deficient women have a high risk during pregnancy (14-40%) and post partum (11-26%), while PS-deficient women have a very low risk during pregnancy (0-6%) but at a greatly increased risk in the postpartum period (13-22%) (Table 5).

Table 5: Risk of deep vein thrombosis and pulmonary embolism related to pregnancy in women with AT, PC or PS deficiency

The optimal approach to VTE prophylaxis during pregnancy is not known, and the pattern of practice varies widely, from clinical surveillance to aggressive ante partum heparin therapy. There is no consensus among various expert panels, and many different approaches have been recommended. (48,49,50) (Table 6)

IV-3- Anticoagulation of pregnant women with mechanical heart valves

The management of women with prosthetic heart valves during pregnancy poses a particular challenge as there are no available controlled clinical trial to provides guidelines for effective antithrombotic therapy. Oral anticoagulants such as warfarin sodium cause fetal embryopathy; subcutaneous administration of heparin sodium has been reported to be ineffective in preventing thromboembolic complications.

Recently Chan and al (37) evaluated the risks of maternal and fetal complications in women with mechanical heart valves treated with different anticoagulation regimens during pregnancy. They performed a systematic review of the literature to determine pooled estimates of maternal and fetal risks associated with the 3 commonly used approaches: (1) oral anticoagulants (OA) throughout pregnancy, (2) replacing OA with heparin in the first trimester (from 6-12 week’s gestation), and (3) heparin use throughout pregnancy. Fetal outcomes included spontaneous abortions and fetopathic effects, and maternal outcomes were major bleeding, thromboembolic complications, and death. They found that the use of OA throughout pregnancy is associated with warfarin embryopathy in 6,4% of livebirths. The substitution of heparin at or prior to 6 weeks, and continued until 12 weeks, eliminated this risk. Overall risks for fetal wastage (spontaneous abortion, stillbirths and neonatal deaths) were similar in women treated with OA throughout, compared with women treated with heparin in the first trimester. Maternal mortality was 2,9%. Major bleeding events occurred in 2,5% of all pregnancies, most at the time of delivery. The regimen associated with the lowest risk of valve thrombosis (3,9%) was the use of OA throughout, using heparin only between 6 and 12 week’s gestation was associated with an increased risk of valve thrombosis (9,2%).

Thromboembolic prophylaxis of women with mechanical heart valves during pregnancy is best achieved with OA; however, this increases the risk of fetal embryopathy. Substituting OA with heparin between 6 and 12 weeks reduces the risk of fetopathic effects, but with an increased risk of thromboembolic complications. The use of low-dose heparin is definitely inadequate; the use of adjusted-dose heparin is warrants aggressive monitoring and appropriate dose adjustment. Large prospective trials to determine the best regimen for these women are needed.

Table 6: Consensus Panel Recommendations for Venous Thromboembolic Prophylaxis during pregnancy

Consensus panel

During pregnancy


American College of Chest Physiancs

Prior VTE secondary to transient risk factor:

Clinical surveillance

Prior idiopathic VTE or thrombophilia with no prior VTE:
Clinical surveillance or

low-dose heparin (5000U/12h) or

adjusted to produce a heparin level of 0,1-0,2U/ml.

Prior VTE and thrombophilia:

Adjusted-dose subcutaneous heparin

Prior VTE secondary to transient risk factor:

Warfarin for 4-6 weeks

Prior idiopathic VTE or thrombophilia with no prior VTE:

Warfarin for 4-6 weeks

Prior VTE and thrombophilia:

Warfarin for 4-6 weeks

British Society for Haematology Guidelines

UFH 5000U of sc heparin every 12 hours during the 1st and 2nd trimesters, with an increase in dosage sufficient to prolong the midinterval aPTT to 1,5´ control in the 3rd trimester or 10,000U of UFH sc every 12 hours throughout pregnancy unless heparin level > 0,3U/mL


Maternal and Neonatal Haemostasis working Party of the Haemostasis and Thrombosis Task

Prior VTE not associated with pregnancy:

Prophylaxis throughout pregnancy if previous episode severe or during 3rd trimester if not severe (7500U of UFH sc every 12 hours until 36 weeks gestation and 10,000U every 12 hours from 36 weeks to term)

Prior VTE associated with pregnancy or post partum:

UFH as above, starting 4-6 weeks before thrombosis occurred

Prior VTE not associated with pregnancy:

Warfarin for at least 6 weeks





Prior VTE associated with pregnancy or post partum:

Warfarin for at least 6 weeks



IV-4- Management of pregnant women with Antiphospholipid antibodies (APLA) and multiple pregnancy losses: (51)

Antiphospholipid antibodies (APLA) can be detected using clotting assays (lupus anticoagulant) or immunoassays (anticardiolipin antibodies) and have been reported to occur in systemic lupus erythematosus, with certain drugs, and in apparently healthy individuals. There is convincing evidence that the presence of antiphospholipid antibodies is associated with an increased risk of thrombosis and pregnancy loss. Thus, pregnant individuals with APLA should be considered at risk for both pregnancy loss and thrombosis. The management of these patients is problematic because few large clinical trials evaluating therapy have been performed. Regimens that have been evaluated include aspirin alone or in combination with prednisone or UFH and intravenous gamma globulin.

A relatively large, placebo-controlled , randomized trial has recently been published that shows no benefit to the use of aspirin and prednisone in pregnant women with prior pregnancy losses and one or more auto-antibodies. Approximately 40% of the women in this study had APLA. Two recent trials compared aspirin and heparin to aspirin alone and showed improved fetal survival with heparin and aspirin. These trials suggest that the combination of aspirin and heparin is the regimen of choice for the prevention of pregnancy loss in pregnant women with APLA and multiple previous pregnancy losses.

Based on current evidence, women with APLA and a history of multiple pregnancy losses are candidate for heparin plus aspirin. Pregnant women with APLA, no pregnancy losses, and previous venous thrombosis should also be considered to be candidates for heparin therapy. Women with APLA and no previous venous thrombosis and no pregnancy losses should be considered to have an increased risk of VTE and should be managed either with low-dose heparin or clinical surveillance for VTE.



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