Plain language summary
Methods for administering subcutaneous heparin during pregnancy
There is no evidence from randomised controlled trials to evaluate the best method of administering subcutaneous heparin to pregnant women.
Pregnant women have an increased risk of venous thromboembolism (VTE) when compared with non-pregnant women because of changes in blood clotting. VTE includes deep vein thrombosis (DVT) and pulmonary embolism (PE). DVT is a clot in the deep veins of the leg blocking blood flow; parts of the clot may break away and be carried in the blood to the lungs, to form a PE. DVT is potentially, and PE is definitely, life-threatening for both mother and baby. Pregnant women with a history of VTE, antithrombin deficiency, or other risk factors for VTE are at an even greater risk and need heparin for prevention of VTE (prophylaxis). Although receiving subcutaneous heparin (either unfractionated heparin (UFH) or low molecular weight heparin (LMWH)) is the main option in the prevention of VTE during pregnancy, the management of thromboprophylaxis in pregnant women has mostly relied on the evidence from non-pregnant participants. Methods of receiving heparin subcutaneously include giving an injection at regular intervals, or using an indwelling catheter and an infusion pump. Women's satisfaction with receiving subcutaneous heparin is highly important as thromboprophylaxis in pregnancy involves a cost burden, inconvenience, and side effects as a result of a longer duration. Some women may not self-administer heparin and must rely on others to give them their injections otherwise they stop using the heparin, thus exposing themselves to an increased risk of VTE. However, this review found no randomised controlled trials to show which methods of receiving subcutaneous heparin are effective and safe for pregnant women.
Méthodes d'administration d'héparine sous-cutanée au cours de la grossesse
Il n'existe aucune preuve issue d'essais contrôlés randomisés permettant de déterminer la meilleure méthode d'administration d'héparine sous-cutanée aux femmes enceintes.
Les femmes enceintes présentent un risque accru de thromboembolie veineuse (TEV) comparé aux femmes non-enceintes en raison des changements concernant la coagulation. La TEV comprend la thrombose veineuse profonde (TVP) et l'embolie pulmonaire (EP). La TVP est provoquée par un caillot dans les veines profondes des jambes bloquant la circulation sanguine ; certaines parties du caillot peuvent se fragmenter, être transportées dans le sang jusqu'aux poumons et former une EP. La TVP est potentiellement mortelle et l'EP est clairement mortelle, tant pour la mère que pour le bébé. Les femmes enceintes ayant des antécédents de TEV, de carence en antithrombine ou d'autres facteurs de risque de TEV présentent un risque encore plus grand et ont besoin d'héparine pour prévenir la TEV (prophylaxie). Bien que l'administration d'héparine sous-cutanée (soit de l'héparine non-fractionnée (HNF) soit de l'héparine de bas poids moléculaire (HBPM)) soit la principale option pour la prévention de la TEV durant la grossesse, la prise en charge de la thromboprophylaxie chez la femme enceinte se fonde principalement sur des preuves provenant de participantes non-enceintes. Les méthodes d'administration d'héparine par voie sous-cutanée comprennent une injection à intervalles réguliers ou l'utilisation d'un cathéter à demeure et d'une pompe à perfusion. La satisfaction des femmes concernant l'administration d'héparine sous-cutanée est extrêmement importante, car la thromboprophylaxie pendant la grossesse implique un coût financier, un inconfort et des effets secondaires du fait d'une durée plus longue. Il est possible que certaines femmes ne puissent pas s'administrer elles-même l'héparine et qu'elles doivent avoir recours à d'autres personnes pour leurs injections ; dans le cas contraire, elles arrêtent d'utiliser l'héparine et s'exposent ainsi à un risque accru de TEV. Cependant, cette revue n'a trouvé aucun essai contrôlé randomisé montrant quelles méthodes d'administration d'héparine sous-cutanée sont efficaces et sûres pour les femmes enceintes.
Notes de traduction
Traduit par: French Cochrane Centre 22nd March, 2013
Traduction financée par: Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux pour la France: Minist�re en charge de la Sant�
Description of the condition
Pregnancy is associated with physiologic and anatomic changes that increase the risk of venous thromboembolism ((VTE) from the first trimester (James 2011). The true incidence of VTE associated with pregnancy is unknown, yet there is a strong clinical indication of an increased risk when compared with non-pregnant women (Bates 2004). The estimated incidence varies from 0.76 to 1.72 per 1000 pregnancies, which is four times greater than among the non-pregnant population (Marik 2008).
The main reason for the increased risk of VTE in pregnancy is the hypercoagulability that occurs and which protects women from haemorrhaging at the time of miscarriage or childbirth (James 2009). The most important risk factors for VTE in pregnancy are personal history of thrombosis and thrombophilia (a hereditary or acquired predisposition to thrombosis) (James 2006; RCOG 2009). Other risk factors include medical comorbidities (e.g. heart or lung disease, cancer), over 35 years of age, obesity, hypertension, smoking and having a delivery by caesarean section (Bauersachs 2007; RCOG 2009).
VTE includes deep vein thrombosis (DVT) and pulmonary embolism (PE). DVT is the result of an occlusive clot formation in the deep veins of the leg, from which parts of the clot frequently embolise to the lungs resulting in PE (Fauci 2008). From 75% to 80% of pregnancy-associated VTE comes in the form of DVT, while 20% to 25% is PE (James 2006). Because DVT is potentially, and PE is definitely, life-threatening for both mother and fetus, those pregnant women with a high risk of VTE require anticoagulation medications in order to prevent the incidence or recurrence of thrombosis.
Caution is advised in the use of anticoagulation therapy in pregnancy with especial regard to the health of both mother and fetus. Hepain compounds are the preferred anticoagulants in pregnancy (James 2011). Administering heparin carries the risk of bleeding, osteoporosis and heparin-induced thrombocytopenia (HIT) (Bates 2004). However, James 2009 reported that the rate of recurrent VTE in women who did not receive anticoagulation with heparin varies from 2.4% to 12.2%, while the rate of recurrent VTE in women who did receive anticoagulation ranges from 0% to 2.4%. This shows that receiving heparin as an anticoagulant significantly reduced the risk of recurrent VTE during pregnancy.
The signs and symptoms of DVT, such as swelling, pain, redness, superficial venous dilatation, and Homan's sign (a pain in the calf or behind the knee on dorsiflexion of the ankle), are non-specific (Fauci 2008). This is because some of the symptoms of DVT are similar to common symptoms that manifest themselves during pregnancy (Barbour 2001). Clinical suspicions are confirmed in 10% of pregnant women, compared with 25% of non-pregnant participants (Ginsberg 1998).
As regards DVT, compression ultrasonography carries no risk and is the preferred initial test in pregnant women with suspected VTE (Marik 2008). When the results are negative or equivocal and iliac venous thrombosis is suspected, additional confirmatory testing with magnetic resonance imaging (MRI) is recommended (Nijkeuter 2006); MRI does not involve radiation exposure and is not harmful to the fetus (Fraser 2002; Rodger 2006). The use of D-dimer testing in pregnancy is potentially limited by the level of D-dimer which increases with the progression of a normal pregnancy, thus, a combination of the D-dimer level test with other tests is recommended (Nijkeuter 2006).
The signs and symptoms of PE, such as dyspnoea, pleuritic chest pain, cough, and haemoptysis, are also non-specific. Ventilation-perfusion scanning is a reasonable first choice for diagnosing PE in pregnancy that gives less radiation exposure to maternal breast tissue and fetus (Chunilal 2009). Computed tomographic (CT) scanning is also the test of choice with relatively low radiation exposure for the fetus, yet concerns about maternal breast radiation exposure remain (James 2011). Women with suspected PE should be informed that these tests carry the risk of potential radiation exposure.
Although maternal mortality from PE can be reduced by conducting a clinical investigation among symptomatic women and by anticoagulation regimens in women with an increased risk of DVT, PE, or both, it is controversial because a clinical evaluation (e.g. a lung scan) exposes the fetus to radiation, and long-term anticoagulation medications may be inconvenient and painful for women.
Description of the intervention
The anticoagulant, unfractionated heparin (UFH) is administered subcutaneously or intravenously and low molecular weight heparin (LMWH) is usually administered subcutaneously. These are the anticoagulants of choice during pregnancy, due to their established efficacy (Bates 2004) that has been demonstrated in pregnant women with DVT (Fauci 2008). Unlike other anticoagulants such as vitamin K antagonists (e.g. warfarin), both UFH and LMWH have no placental transfer (Bates 2008).
The potential risks of administering heparin - bleeding, osteoporosis and HIT - differ between UFH and LMWH. In one study (Ginsberg 1989), the rate of major bleeding in pregnant women receiving UFH was 2%, which is consistent with the reported rates of bleeding associated with administering heparin in non-pregnant women (Hull 1982a) and with warfarin therapy (Hull 1982b) when used for the treatment of DVT. In contrast, complications resulting from bleeding in pregnant women receiving LMWH are uncommon. Moreover, there was no statistically significant difference in bone loss between those who received LMWH and those who were untreated, suggesting that bone loss associated with prophylactic LMWH therapy is no different from the normal physiologic losses that occur during pregnancy (Carlin 2004). However, bone density was significantly lower in those receiving UFH compared with both those who were not treated and those who received the LMWH dalteparin (Monreal 1994). The risk of HIT with heparins is also low and may be lower with LMWH than with UFH, although as yet the actual risk is still unclear (Bates 2008). LMWHs are now commonly used for prophylaxis of maternal thromboembolism (Bates 2012) because they are at least as effective as and safer than UFH (RCOG 2009).
Methods of administering heparin subcutaneously include giving an intermittent injection, or using an indwelling catheter and an infusion pump. For prophylaxis with intermittent subcutaneous injections, UFH is usually given in fixed doses of 5000 U two or three times per day in non-pregnant participants. With these low doses, it is unnecessary to monitor coagulation, but monitoring is required when it is given for treatment (Fauci 2008). However, there is concern that this low dose may be insufficient in high-risk groups, including pregnant women with prior VTE, because it does not reliably produce detectable heparin (UFH) levels (Bates 2008).
The duration and doses of subcutaneous LMWH during pregnancy vary depending on guidelines and studies. For prophylaxis, several dose regimens of LMWHs have been used, including administering subcutaneous enoxaparin 40 mg per 24 hours (Gates 2004), dalteparin 5000 U per 24 hours (Pettila 1999; Rey 2000), and an adjusted dose of LMWH to achieve a peak anti-Xa level of 0.2 to 0.4 U/mL (Blomback 1998; Dulitzki 1996).
Rey 2000 reported that dalteparin 5000 U per 24 hours was suitable for most pregnant women and did not need to be modified in the third trimester because anti-Xa activity levels did not vary significantly throughout pregnancy. In contrast, with the same regimen, where 5000 U of dalteparin was administered once daily, the mean anti-Xa level at 12, 24, and 36 week's gestation was significantly reduced at two hours post-injection when compared with postpartum (Sephton 2003). This suggests that there are inter- and intra-individual handling differences as pregnancy progresses.
The Duke protocol (James 2005) reflects the increasing requirements for both UFH and LMWH as pregnancy progresses: UFH 5000 U subcutaneously per 12 hours before eight weeks, 7500 U subcutaneously per 12 hours from eight to 28 weeks, then 10,000 U subcutaneously per 12 hours after 28 weeks; or enoxaparin (LMWH) 30 mg twice-daily before 28 weeks, then 40 mg twice daily after 28 weeks. Although higher dosages ranging from UFH 13,000 to 40,000 per 24 hours (mean 19,100 U per 24 hours) with 25 weeks of the average duration of prevention have been given, a 2.7% (five out of 184) recurrence of thrombotic events was recorded in spite of the high-dose prophylaxis (Dahlman 1993). Barbour 1995 also concluded that the adjusted high dose of UFH 7500 U to 10,000 per 12 hours may be reasonable in the second and third trimester as long as the activated partial thromboplastin time (aPTT) is not significantly elevated, while prophylaxis with low-dose anticoagulation is recommended for pregnant women with a history of thrombosis (Bates 2004).
One study (Anderson 1993) has investigated the comparative effectiveness and safety of using an indwelling Teflon catheter and a subcutaneous injection. Teflon catheters were inserted over an introducer steel needle at a 30o angle into the subcutaneous tissues of the abdomen by means of a sterile technique. After removal of the needle, the catheter was fixed in place with an adhesive foam pad. UFH was injected slowly, twice daily, through an external port at the proximal end of the indwelling Teflon catheter by means of an insulin syringe and a 25-gauge needle. The entire catheter was 3.5 cm in length with the Teflon portion that was inserted subcutaneously being 2 cm in length. Catheters were changed weekly to reduce the risk of infection. There were no differences in the mean heparin dose or aPTT between the two methods of heparin administration. The study also used a questionnaire to obtain information from women about their preferred route of heparin administration. Of the 12 women interviewed, 11 reported that the catheter caused less pain and bruising than the subcutaneous injections given twice daily, although five women developed urticarial reactions at the sites of the injections and these reactions tended to be more severe when the catheter was used.
Another method of subcutaneous heparin delivery, using a programmable external infusion pump, has been compared with the use of an intermittent subcutaneous injection. In a retrospective study (Floyd 1991), the mean daily dose of UFH when using a subcutaneous infusion pump was higher (29,445 versus 13,822 U), resulting in smoother, more therapeutic heparinisation (mean aPTT, 20.6 versus 10.4 seconds above control) among the subcutaneous infusion pump group when compared with the intermittent subcutaneous injection group. There were two complications (haematoma, site infection) in the intermittent subcutaneous injection group, while none occurred in the subcutaneous infusion pump group. Although the results showed that there was no statistical significance in the smaller number of complications among the subcutaneous infusion pump group, when used in concert with weekly home visits, the subcutaneous infusion pump method nevertheless allowed the administration of the prevention to be more evenly controlled than did the use of intermittent subcutaneous injections.
How the intervention might work
Heparin (UFH and LMWH) acts as an anticoagulant by activating antithrombin and accelerating the rate at which antithrombin inhibits clotting enzymes, particularly thrombin and factor Xa (Fauci 2008). The administration of heparin (UFH and LMWH) protects pregnant women against the risk of producing a thrombosis that can develop into thromboembolism (DVT or PE).
Why it is important to do this review
First, although administering subcutaneous heparin (UFH or LMWH) is the main option in the prevention of VTE during pregnancy, the management of thromboprophylaxis in pregnant women has mostly relied on the evidence from non-pregnant participants.
Second, thromboprophylaxis in pregnancy involves a cost burden, inconvenience and side effects as a result for a longer duration. Pregnant women who require anticoagulation therapy, especially those with a history of VTE and those on lifelong anticoagulation, will require a switch from the administration of warfarin to heparin-related compounds (UFH and LMWH) (James 2007; James 2011) when conception has occurred and been detected, because of the effects of warfarin on the fetus. Heparin is more expensive than warfarin (Brill-Edwards 2000) and LMWH is even more expensive than UFH (James 2011). There is a report that LMWH is at least 10 times the cost of low-dose heparin in North America (Etchells 1999). It is clear that women who receive insufficient medical cost coverage face financial burdens. Furthermore, women in a region or country where self-administration is not allowed may need to be hospitalised for the management of administering heparin throughout pregnancy. Others who self-administer as outpatients require self-management to inject several times a day depending on agents and dosage used, yet those who do not self-administer heparin must rely on others to give them their injections otherwise they discontinue the administration, thus exposing themselves to an increased risk of VTE (Anderson 1993). Although bleeding in pregnant women receiving LMWH is uncommon, skin complications (Bank 2003) may occur due to repeated and long-term injections.
Having considered the disadvantages and adverse effects of administering subcutaneous heparin (UFH or LMWH), women's satisfaction is highly important, since the effectiveness and safety of administering subcutaneous heparin (UFH or LMWH) during pregnancy using different methods is still not clear. This underscores the importance of conducting a systematic review to investigate the effectiveness and safety of different methods of administering subcutaneous heparin (UFH or LMWH) in this high-risk of VTE group of pregnant women.
To compare the effectiveness and safety of different methods of administering subcutaneous heparin (UFH or LMWH) to pregnant women.
Description of studies
Results of the search
The search of the Cochrane Pregnancy and Childbirth Group's Trials Register retrieved two reports relating to one trial that we subsequently excluded because the study was a randomised, multiple, cross-over study (Anderson 1993). There are no included studies in this review.
Risk of bias in included studies
There are no included studies in this review.
Effects of interventions
There are no included studies in this review.
It is disappointing that no randomised controlled trials are available to assess the effectiveness and safety of different methods of administering subcutaneous heparin (UFH or LMWH) to pregnant women.
The lack of relevant studies identified by the review reflects the ethical concerns that emerge in this population requiring heparin (UFH or LMWH) prophylaxis during pregnancy. Random allocation of women at risk of VTE to one method of administering subcutaneous heparin (UFH or LMWH) or another may not be acceptable to women or their families, and therefore, informed consent of the study would be difficult. Although VTE and thrombophilia are not rare, it may be difficult to complete such a trial, because of the difficulty of recruiting pregnant women with a previous VTE or with thrombophilia.
In a randomised, multiple, cross-over study that has been excluded in this review, women alternated every two weeks between having heparin administered through the indwelling Teflon catheter and receiving heparin via subcutaneous injections. Ten of the 12 women in this trial preferred to have subcutaneous heparin administered through an indwelling Teflon catheter rather than by twice-daily injections (P = .04), and 11 women reported that the catheter caused less pain and bruising than twice-daily injections (P < .01). Although the interpretation of the result is limited by the small number of participants, it does indicate that the bioavailability of heparin is not affected by repeated injections into the same subcutaneous site (Anderson 1993).
The risk of severe adverse pregnancy outcomes is lower under the management of heparin prophylaxis during pregnancy but the potential adverse pregnancy outcomes are serious due to discontinuation of heparin prophylaxis. Therefore, large trials would be required to demonstrate that effectiveness and safety of different methods of administering subcutaneous heparin (UFH or LMWH) during pregnancy is assured.
The authors would like to acknowledge the help received from the Cochrane Pregnancy and Childbirth Group.
As part of the pre-publication editorial process, this review has been commented on by three peers (an editor and two referees who are external to the editorial team) and the Group's Statistical Adviser.
Contributions of authors
This review was drafted by Hatoko Sasaki (HS), which was edited by Naohiro Yonemoto (NY), Nobutsugu Hanada (NH) and Rintaro Mori (RM).