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REPRODUCTIVE REASONING: HEMATOLOGY AND REPRODUCTION

Anticoagulation in pregnancy complications
Saskia Middeldorp1

1Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands

Women with acquired and inherited thrombophilia are thought to be at increased risk for pregnancy complications,
including recurrent pregnancy loss and, depending on the type of thrombophilia, severe preeclampsia. This review
discusses the associations between the types of thrombophilia and types of complications, as well as the currently
available clinical trial evidence regarding the use of aspirin and heparin to prevent these pregnancy complications. In
women with antiphospholipid syndrome, guidelines recommend prescribing aspirin and heparin to women with
recurrent miscarriage. The same regimen is suggested for late pregnancy complications by some, but not all, experts.
Aspirin or low-molecular-weight heparin to improve pregnancy outcome in women with unexplained recurrent
miscarriage has no benefit and should not be prescribed. Whether anticoagulant therapy prevents recurrent
miscarriage in women with inherited thrombophilia or in women with severe pregnancy complications remains
controversial because of inconsistent results from trials. Aspirin modestly decreases the risk of severe preeclampsia in
women at high risk.

miscarriage at approximately 6 weeks after the first day of her last
Learning Objectives
menstrual period (gestational age); the second pregnancy went well
● To describe the association between pregnancy complications until she developed preeclampsia at a gestational age of 34 weeks.
and thrombophilia both quantitatively and qualitatively At 35 weeks, she prematurely delivered, after induction, a healthy
● To describe the state of the evidence with respect to prevention son with a birth weight of 2800 g. Her third and fourth pregnancies
of pregnancy complications with aspirin and/or heparin in ended in spontaneous miscarriages at weeks 7 and 6; in the third
various subgroups of women, particularly women with antiphos- pregnancy, a fetal heart beat had been detected before the pregnancy
pholipid syndrome and those with inherited thrombophilia loss. She is otherwise healthy and has no personal or family history
of venous thromboembolism. She has a normal body weight (BMI
22) and normal blood pressure. Thrombophilia screening reveals no
Introduction laboratory criteria for antiphospholipid syndrome (APS); hereditary
Whether women with placenta-mediated pregnancy complications, thrombophilia tests showed normal results for antithrombin, protein
including recurrent miscarriage, late pregnancy loss, preeclampsia, C, and protein S levels and activated protein C resistance (indicative
intrauterine growth restriction, and placental abruption, benefit from of absence of factor V Leiden) and heterozygosity for prothrombin
anticoagulant or antithrombotic agents such as aspirin or heparin is a 20210A.
frequently occurring clinical question.1-3 The role of the coagulation
specialist is particularly evident for women with some form of
thrombophilia. Pregnancy failure is extremely distressing for couples Definition of thrombophilia
who desire to have children and preeclampsia and HELLP syn- Changes in blood composition are part of Virchow’s triad, which he
drome (hemolysis, elevated liver enzymes, low platelet counts) are proposed in the 19th century as one of the mechanisms that
leading causes of maternal and perinatal mortality and morbidity.4 A predispose to thrombosis. These changes, known as thrombophilia,
presumed benefit of antithrombotic therapy, in the perceived indicate the presence of a hypercoagulable state leading to a
absence of harm, has led many clinicians to prescribe low-molecular- thrombotic tendency. The currently most commonly tested inherited
weight heparin (LMWH), aspirin, or both to women with placenta- thrombophilias include deficiencies of antithrombin, protein C, or
mediated pregnancy complications, sometimes but not exclusively protein S and the gain-of-function mutations factor V Leiden and
based on the presence of thrombophilia. This review discusses the prothrombin G20210A, which affect either the anticoagulant or
associations of thrombophilia and pregnancy complications and procoagulant pathways, respectively.5 Lupus anticoagulant, anticar-
focuses on the current evidence on antithrombotic therapy to diolipin antibodies, and anti-beta 2 glycoprotein I antibodies are
improve pregnancy outcome. laboratory features of acquired thrombophilic APS (Table 1).6
Although some laboratories include other tests, both established and
less well established, such as levels of coagulation factor VIII or
Clinical case polymorphisms such as MTHFR 677TT and PAI-1 4G/5G in their
A 38-year-old woman who has moved to the Netherlands many thrombophilia panels, these are not discussed here because their
years ago is referred to my outpatient clinic because of a history of 3 associations with pregnancy complications are most uncertain.
early miscarriages and the presence of the prothrombin 20210A
mutation. She and her husband are convinced that aspirin and
LMWH should be prescribed to improve the prognosis in a next Biological plausibility for a role of thrombophilia in
pregnancy because this was suggested by an obstetrician whom she pregnancy complications
consulted in her country of birth. The patient has been pregnant 4 The mechanisms of how thrombophilia leads to pregnancy compli-
times in the past 3 years. The first pregnancy ended in spontaneous cations are difficult to study in humans and remain largely

Hematology 2014 393

mere hyperco- (a) One or more unexplained deaths of a morphologically normal agulability is unlikely to be the sole mechanism by which thrombo- fetus at or beyond the 10th week of gestation. with normal fetal philia. on two or more occasions at types of antiphospholipid antibodies and placenta-mediated preg- least 12 weeks apart.3–8.0–8.10 Therefore.12 (0.9 (0. It is attractive to hypothesize that hypercoagulability with associations.1* (1.5) NA 1.9–8.8) 2.2) NA NA 2.01) 1.15.19) 1.53) NA 23. association between thrombophilia and placenta-mediated preg- strate for an association with both acquired (APS) and inherited nancy complications is controversial.70) 2.6) NA 14. at least 12 complications was not evident. both heparin and aspirin 2. which may point to a bias in the observed unknown.8 (0.7 Although tissue factor seems to play a central role. Associations between pregnancy complications and several forms of thrombophilia OR (95% CI) Miscarriage Recurrent 1st Single 2nd Pregnancy loss (1st or 2nd trimester trimester Stillbirth (3rd Late (2ndor 3rd (regardless of Preeclampsia Preeclampsia Type of thrombophilia trimester) miscarriage miscarriage trimester loss) trimester loss) gestational age) (mild or severe) (severe) Anticardiolipin antibodies 3.2–26.7–109. or small vessel thrombosis.9 (0.0–3.7 (1.99.23–3.79–1. Even for APS.2–97) NA Protein C deficiency 2.3–196. 42. the relationship between these antibodies and pregnancy ⬎the 99th percentile).84.64–2. Terminology of pregnancy loss at various gestational ages may vary among included studies.9–59. present on two or complications should be established if only these antibodies are more occasions.16 Therefore.4–35. ⬎40 GPL or MPL.36) (heterozygous) Prothrombin G20210A 2.7) NA NA 20.99) NA mutation Rod (heterozygous) Antithrombin deficiency 0. of the fetus. Thrombosis must be hours. 2006. For histopathologic of blood coagulation at the feto–maternal interface.7) NA * * NA (homozygous) Factor V Leiden mutation 1.5 (1.2–5.3–5.6 (0. venous. the most recent and larger prospective cohort studies found Adapted from Miyakis.13. on two or more occasions. However. coagulation and inflammation are closely related pathways and several observations have implicated a role for Clinical trial evidence of effect of aspirin or heparin on both procoagulant and inflammatory pathways in pregnancy failure.3 (4. it is not possible to extract data for zygosity.6) * * 2. Fetal demise is caused by tissue-factor-dependent activation confirmed by objective validated criteria.e.2–34.2–38.7 (1. at least 12 weeks apart. present in medium or high titer (i.65–4.76–2.9) NA 1.51) NA Anti-beta 2 glycoprotein I NA 2.3 (0.0) 2.6 (0.9 Furthermore. or nancy complications were found to be inconsistent in a recent large 2. The investigators concluded that it is weeks apart. Pregnancy failure and pregnancy complications are amongst the or recognized features of placental insufficiency (including a birth weight ⬍ 10th percentile for gestational weight).3) 8.1–2. the associations between various 1.2) 54.9) NA 1.26 (0.4 (1. Further- more.34–57.6 lower odds ratios for inherited thrombophilia than older and smaller case control studies.5) NA NA 7.8) 8.12.4–5.4–9. growth of trophoblast cells.45 (0. evidence in the field of antithrombotic therapy and pregnancy Table 2.1 (3.77) NA antibodies Lupus anticoagulant 3.8–14.04 (1.7 (1.6) 1.52* (1. thrombosis should be present without significant coagulation factors were found to induce cell death and inhibit evidence of inflammation in the vessel wall.5 weeks 1.0) 2.14 (6.2–455) NA NA 19.89–1. are unable to carry their fetuses beyond 8.7) 5.6 (1. *Homozygous and heterozygous carriers were grouped together. it can be concluded that even the thrombosis of placental vasculature is the pathophysiological sub. NA indicates not available. Vascular thrombosis gestational age and dead fetuses are usually resorbed within 24 One or more clinical episodes of arterial.6 (2. or (b) One or more premature births of a morphologically normal Association between thrombophilia and pregnancy neonate before the 34th week of gestation because of: eclampsia complications or severe preeclampsia defined according to standard definitions.4) NA NA 3.9 (1.Table 1. in any tissue or organ. pregnancy complications because most studies have been underpow- Laboratory criteria ered11-14 (Table 2).7 (1.12 Particularly for anti-beta 2 glycoprotein I plasma.7–43.86.1 (1. Statistically significant odds ratios are indicated in bold.6) 4. or antibodies. Lupus anticoagulant present in plasma. with maternal anatomic or failure and complications.3–102) NA Protein S deficiency 3.2–4. Pregnancy morbidity attenuate trophoblast apoptosis in vitro. increases the risk for pregnancy morphology documented by ultrasound or by direct examination failure or defective placentation. this APS is present if at least one of the clinical criteria and one of the appears independent of its role in coagulation.06–2.8 Similar mechanisms following laboratory criteria are met: may be true for inherited thrombophilia.4) NA NA 3.9* (1.1 (1. 394 American Society of Hematology . Anti-beta2 glycoprotein I antibody of IgG and/or IgM isotype in serum or plasma (in titer ⬎the 99th percentile).69–6.3–5.6) NA Data are derived from systematic reviews11-14 if possible. Thrombomodulin-deficient mice.4.25 (0.5) NA NA 5. present at elevated levels as part of the laboratory criteria. Activated confirmation.50) NA 2. or questionable whether a diagnosis of APS in the setting of pregnancy 3.1 (0. which are lacking the important natural anticoagulant protein Clinical criteria C pathway. most associations are modest hormonal abnormalities and paternal and maternal chromosomal in strength and vary with type of thrombophilia and type of causes excluded.75) NA Factor V Leiden mutation 2. either acquired or inherited. Revised classification criteria for APS centation.5 (1. pregnancy complications In vitro experiments have shown that antiphospholipid antibodies Comprehensive systematic reviews summarizing the clinical trial inhibit extravillous trophoblast differentiation and subsequent pla.13 (0.2 (2. or clinical criteria for APS (Table 1)6 and many studies have observed (c) Three or more unexplained consecutive spontaneous abortions a relationship between inherited thrombophilia and pregnancy before the 10th week of gestation.0 (1.7 (1.8–10.1–3. 1198) 10. thrombophilia. Anticardiolipin antibody of IgG and/or IgM isotype in serum or systematic review.23* (0.0) NA 9. However.0 (0.5 (0.

27 Of these starting aspirin before conception may be associated with a better women. Other trials used very broad inclusion complications. particular subgroup of women who were more or less likely to benefit from antiplatelet agents could be identified.19 For preg. prior early preterm birth. study popula.3 Study aspirin was started before 16 weeks gestational age.26. which was likely explained by trimester.complications have been published recently. the natural significant reductions in several important outcomes. 95% CI ⫽ 0. Furthermore. over no treatment. no randomized controlled trials evaluating the who became pregnant was 1.20 A small observational study suggested that conception or at a maximum gestational age of 6 weeks.98). almost no data are available to support the use 75 mg plus standard surveillance or standard surveillance only. The pooled results effect of the medical intervention was observed (odds ratio for of 3 very small trials (total number of 71 participants) showed no successful pregnancy ⫽ 0. and autoimmune disease.76 – 0. pregnancy losses to nadroparin 2850 IU combined with aspirin 80 but from the 95% CI. uterine anoma- lies. Whether women who have a diagnosis of APS based on venous Third.26 No of aspirin only to prevent recurrent miscarriage. these women also sia (RR ⫽ 0.3. and a pregnancy with a randomized trial showed a large beneficial effect on live birth in serious adverse outcome. the prognosis of a subsequent live birth ranges from 0% investigators did not observe different effects in trials in which to 99%.25 in my control arm without active intervention. 299 became pregnant. and 2%– 4% small-for-gestational-age baby (⬍10th percentile). heterogeneous patient populations.25) for efficacy of aspirin in women with inherited thrombophilia and nadroparin combined with aspirin and 0. investigators stated that their confidence was tempered by potential tion is often uncertain.85–1. beneficial effects of antithrombotic agents have been individualized basis and decisions made on the basis of the woman’s suggested by results from observational studies that have intrinsic risk profile from her obstetric and medical history. College of Chest Physicians (ACCP) 2012 guidelines give a grade Live birth rates in women recruited in very early pregnancy 1B recommendation to treat women considered at risk for preeclamp- generally were substantially lower than in women who were sia with aspirin throughout pregnancy. renal disease. small-study effects and observed modest effects on outcomes in the sia in women with a history of severe preeclampsia range from 25% 2 largest trials. thromboembolism only should be considered at high risk for these are generally limited by small sample sizes and often lacked a preeclampsia is basically unknown. it can be concluded that neither benefit nor mg daily. or bleeding events for either the women or their babies. for aspirin only compared with placebo]. aspirin 80 mg only. 95% CI ⫽ 0. a landmark premature birth (⬍34 weeks gestation). aspirin use was to 65% and solid estimates of whether this is higher in women with associated with absolute risk reductions of 2% to 5% for preeclamp- thrombophilia are largely unknown. Therefore. depending on the type of pregnancy complications. Some meta. Contrary to other views. there is no evidence that aspirin on top of regular tions vary widely. For example.75–1. infant.24.62– 0.23 Depending on baseline risk. severe preeclampsia.68].28 Aspirin to prevent preeclampsia various guidelines recommend against the use of antithrombotic A meta-analysis of individual patient data from 31 randomized agents in women with unexplained recurrent pregnancy loss. In women with recurrent pregnancy loss and APS. The American populations varied and the onset of follow-up differed per study. A very recent General considerations systemic review observed clinically important and statistically First. Women with a history of preeclampsia.27 In meta-analyses the SPIN study. 95% CI ⫽ 0. but does include a history of latter study population. we randomized 364 women with 2 or more unexplained pregnancy loss ⫽ 1.18.80. The nancy loss. for preterm birth (RR ⫽ 0. the small reduction in risk of recurrence in a next pregnancy and analyses purposely pooled effects of heterogeneous interventions in prescribed aspirin on an individualized basis. It should be realized that the summary effects from such analyses do not have the same scientific Heparin.52–1. starting from the second recruited from 12 weeks gestation.21 differ between the treatment groups [RR of live birth for women To my knowledge. In the ALIFE effect of aspirin only compared with no treatment [risk ratio (RR) of study.03 (95% CI ⫽ 0. to prevent pregnancy loss strength as a randomized controlled trial of sufficient size.92 (95% ⫽ CI 0. I refer to the original trial reports and meta-analyses.13) recurrent pregnancy loss have been performed.65– 0. what constitutes high risk the fact that women with early miscarriages are not included in the for preeclampsia is not strictly defined. or APS) recurrent pregnancy loss was compared with no Summary of randomized controlled trials and treatment or placebo in 2 relatively large randomized trials. The efficacy of antithrombotic agents in women with unexplained (eg. indicating the difficulty in drawing conclusions.66 –1.59). although clinical trials have been performed in recent years. For women with methodological issues undermining their validity to assess efficacy a history of severe preeclampsia in the context of APS. 294 women with 2 or more unexplained pregnancy Aspirin to prevent pregnancy loss losses were randomized to enoxaparin 40 mg combined with aspirin In women with APS. Based on the available evidence that also included trials comparing 2 active treatments.86. with or without aspirin. No Interpretation of the current clinical trial evidence is provided here. The chance of live birth did not pregnancy outcome than starting it once pregnancy is established. or placebo (for aspirin) before harm can be ruled out. Furthermore.99). 1%–5% for intrauterine have a 3% risk of placental abruption and 10% risk of having a growth restriction (RR ⫽ 0.1 aspirin in subsequent pregnancies to improve their outcome (Table 3). are also being counseled regarding specific pregnancy complications or thrombophilia.24 However.22 There was no significant effect on the women treated with unfractionated heparin combined with aspirin Hematology 2014 395 . having a small-for-gestational-age details.05.76. but the history of subsequent pregnancies without pharmacological interven. in the absence of abnormal parental karyotype. aspirin should be offered on an Second. recurrence rates of preeclamp. I offer of an intervention. opinion. with or criteria that make it difficult to draw conclusions for subgroups with without inherited thrombophilia.95). 95% CI ⫽ 0.17 For extensive risk of death of the fetus or baby. 95% confidence interval (CI) ⫽ 0.91. Some trials used very stringent inclusion criteria antepartum thrombosis prophylaxis with LMWH improves preg- that limit the generalizability of the findings to women with other or nancy outcome in women with APS without a history of pregnancy coexisting complications.29 primary prevention trials with 32 217 women showed that aspirin was associated with a 10% relative risk reduction in preeclampsia.

30 A meta-analysis summarized the data of first trimester miscarriage was maintained (RR ⫽ 0. Comparing any heparin (unfractionated observed a profound effect of unfractionated heparin added to heparin or LMWH) combined with aspirin (n ⫽ 199) with aspirin aspirin. compared with aspirin only. it is noteworthy that the chances of a live birth in the pregnancy loss of 0.3 with aspirin only (n ⫽ 90) showed a pooled relative risk for Furthermore.48).70 without reaching statistical significance aspirin-only arms were only 44% and 42% in the studies that (95% CI ⫽ 0.Table 3. No LMWH In case of a history of venous or arterial placental abruption or severe intra-uterine thromboembolism and long term use of growth restriction and inherited anticoagulant therapy. antepartum and No aspirin postpartum LMWH according to current guidelines24 History of severe preeclampsia.65). the beneficial effect of heparin of reducing the risk studies comparing LMWH and aspirin with aspirin only or aspirin 396 American Society of Hematology .26. In a few small studies. therapeutic dose LMWH and no aspirin No LMWH In case of a history of a single episode of venous thromboembolism. please see full text. placental abruption. therapeutic dose LMWH and no aspirin If no informed consent for trial participation. this is markedly lower than in the comparator arms of only (n ⫽ 199). In case of a history of a single episode of venous no LMWH thromboembolism.31 An important treatment with unfractionated heparin combined with aspirin (n ⫽ question is whether there is a differential effect of unfractionated 103) reduced the chance of first trimester miscarriage compared heparin from LMWH. therapeutic dose thrombophilia LMWH and no aspirin In case of a history of a single episode of venous thromboembolism. unexplained Counsel about the modest risk reduction of aspirin and prescribe on an individual basis No LMWH History of severe preeclampsia. antepartum and postpartum LMWH according to current guidelines24 History of a single late pregnancy loss. 0.24 – 0. 95% CI ⫽ of 2 studies in women with APS and 2 or more pregnancy losses31. a single late Aspirin 80 mg as soon as a pregnancy test Start aspirin in the second trimester pregnancy loss.34 –1. antepartum and postpartum LMWH according to current guidelines and no aspirin24 Recurrent pregnancy loss (2 or more) and Enroll in ALIFE2 trial after informed In case of a history of venous or arterial inherited thrombophilia consent. or is positive severe intra-uterine growth restriction and (Low dose) LMWH as soon as a pregnancy In case of a history of venous or arterial APS test is positive thromboembolism and long term use of anticoagulant therapy. No LMWH.39.45). unfractionated heparin (both combined with aspirin) were compared treatment with LMWH combined with aspirin (n ⫽ 96) compared directly and the results did not suggest a difference in efficacy. the use of LMWH and with aspirin only (n ⫽ 109. therapeutic dose LMWH added to aspirin In case of a history of a single episode of venous thromboembolism. RR ⫽ 0. and randomize to either LMWH thromboembolism and long term use of or no LMWH anticoagulant therapy.14 – 0. antepartum and postpartum LMWH according to current guidelines added to aspirin24 History of severe preeclampsia and Counsel about the modest risk reduction of In case of a history of venous or arterial inherited thrombophilia aspirin and prescribe on an individual thromboembolism and long term use of basis anticoagulant therapy. with little statistical heterogeneity. How I treat women with aspirin or LMWH to prevent pregnancy complications My approach in most patients My alternatives (not exhaustive) Recurrent pregnancy loss (2 or more). 95% CI ⫽ 0. therapeutic dose LMWH and no aspirin In case of a history of a single episode of venous thromboembolism. no aspirin unexplained Recurrent pregnancy loss (3 or more) and Aspirin 80 mg preconceptionally Start aspirin as soon as a pregnancy test is APS positive (Low-dose) LMWH as soon as a pregnancy In case of a history of venous or arterial test is positive thromboembolism and long term use of anticoagulant therapy. antepartum and postpartum LMWH according to current guidelines24 For justification.

and placental abruption. 1. or protein S deficiency.29 recently summarized in a meta-analysis.nl) that started recruit- 1. women with inherited thrombophilia and approach in which allocation to a treatment group was done in an recurrent pregnancy loss are being randomized to either treatment alternating manner.24 The Royal College of without aspirin compared with no treatment in women with a history Obstetricians and Gynaecologists guidelines state that pregnant of various pregnancy complications.35 In the SPIN and ALIFE studies. Almost a quarter of the included women gestation or recurrence at any gestational age. The combined. which included 95% CI ⫽ 7–34). they ders before 34 weeks gestational age.16 for aspirin and RR ⫽ consecutive miscarriages before 20 weeks gestation. which leads to inadequate concealment of with LMWH plus standard pregnancy surveillance or standard allocation. www. The overall primary had either hereditary thrombophilia or anticardiolipin antibodies outcome did not differ between the 2 groups. 95% CI ⫽ 10. Nevertheless. The recently finished TIPPS study. in this trial. HELLP. 67 of 358 (18. to reduce the combined with heparin to prevent further miscarriage. The ACCP guidelines recommend unfractionated hepa.36-39 whereas in the 2 most heparin to all women with APS.33 for aspirin combined with nadroparin bemiparin (2500 U once daily.5. severe The included studies are relatively small.17. recently published studies.7%. 95% CI ⫽ 0. 5000 IU) with aspirin and found for enoxaparin and placebo and 65% (RR ⫽ 1.trialregister. These 6 studies were specifying clinical criteria of APS in the recommendation. small proportions of the study Why should we prescribe prudently? populations consisted of women with inherited thrombophilia26. 95% CI ⫽ aspirin alone. rin or LMWH combined with aspirin for women with APS and 3 or more pregnancy losses.43).40. birth of a small-for-gestational- Therefore. the results are strikingly positive in some studies. including preeclampsia. observed. and no differential occurred in 18. based on the currently available evidence thrombophilia.33 ery before 34 weeks of gestation.48) was prophylactic dose LMWH (dalteparin. highlighting the urgent need for new 100 mg (n ⫽ 61) and a modest benefit of bemiparin over aspirin was randomized controlled trials.7%). placental abruption. small- women with APS should be considered for treatment with aspirin for-gestational age babies. This indicates clinical heterogeneity between the active treatment arms for women with inherited thrombophilia (RR trials. and the inclusion or exclusion of unknown. We are currently performing the observed (RR for live birth for women treated with bemiparin ⫽ ALIFE2 study (NTR 3361. 95% CI ⫽ 0. a few trials have investigated the use of LMWH with or pregnancy loss or placental insufficiency. or pregnancy combined with aspirin in women with APS and 3 or more loss later than 20 weeks. there was no control group without intervention. although evidence for a beneficial effect of heparin age newborn (⬍10th percentile).31.9%) women with no LMWH (RR ⫽ 0.86).40 In this trial.5%). odds ratio ⫽ 15.92-1. randomized women between LMWH and no LMWH and ACCP guidelines for women with a single previous pregnancy loss found no effect of the intervention. or aspirin or intrauterine growth restriction. or those with beta 2 glycoprotein I antibodies) is to type of complications. or eclampsia) before 34 weeks (61%.3 In a recently published trial in women with APS and at least 2 for live birth ⫽ 1.08.1%. women with one late pregnancy loss.00 –1.7% (n ⫽ 15/69) of women on aspirin alone (risk promising results in women with a single previous pregnancy loss difference ⫽ 3. whereas 6 (8.42 after 10 weeks gestation and inherited thrombophilia. it is based on very small studies in randomized to prophylactic LMWH had recurrent severe placenta- heterogeneous populations.5-16.7%) women miscarriages is compelling. 95% CI ⫽ 1.7%) women in were allocated to enoxaparin 40 mg once daily (n ⫽ 80) or to aspirin the aspirin-only group delivered before 34 weeks due to the 100 mg (n ⫽ 80).32 The trial used a quasirandomized ing in 2013. this regimen was not endorsed by the embolism.6% of the women randomized to LMWH ⫹ aspirin effects of the interventions were observed. the potential adverse the subgroup analyses of these women were insufficiently powered effects of antithrombotic therapy include bleeding. and the results of this single study have not been confirmed complications or at high risk of pregnancy-related venous thrombo- by other trials. 57% absolute risk reduction.83-1.27. with have adopted the practice of prescribing aspirin with or without relative risk reductions up to 85%. without risk of recurrence in subsequent pregnancies.52. Overall. clinicians worldwide significant. therefore. heterogeneous with regard preeclampsia. no effect on the risk of recurrence of severe pregnancy complications was For women with recurrent miscarriage and inherited thrombophilia.39) for enoxaparin and aspirin compared with aspirin alone sive disorder (preeclampsia.17 In all studies of heparin on the prognosis of a subsequent pregnancy. Although the pooled risk reduction is statistically of studies with small numbers of participants.20. n ⫽ 80) was compared with aspirin compared with placebo). several methodological issues were thrombophilic women either at high risk for pregnancy-mediated raised.9-15. In addition to LMWH being very costly. hypertensive disorders ⬍40 GPL or beta 2 glycoprotein I antibodies. enoxaparin 40 mg and aspirin 100 mg (n ⫽ 63). were randomized between A live birth rate of 71% (RR ⫽ 1. in which the chances of a live birth varied between study.41 This is reflected by the statistical heterogeneity that no sufficiently sized trials have been performed that show an effect was also observed in the meta-analysis (I2 ⫽ 69%). 95% CI ⫽ 0. 95% CI ⫽ 0. one in thrombophilic women. clinical criteria (eg. the LMWH 1. One clinical trial found (n ⫽ 13/70) and 21. a nonsignificant increase in live birth was observed in the 2 68% and 80%.74 –2. compared with 127 of 296 different subgroups of women with APS based on laboratory or (42.32-0.22.17 The primary outcome was a composite of preeclampsia. with 3 women higher chance of a live birth than those allocated to aspirin (86% and delivering at 19-22 weeks (risk difference ⫽ 8. The primary outcomes were recurrence of a hyperten- 0. prothrombin G20210A mutation. In the ALIFE reactions such as itching and swelling. reference group). but refrain from recommendations for Heparin to prevent preeclampsia women with APS based on clinical criteria of a single late Finally. None of the women in after 10 weeks gestation and heterozygous factor V Leiden muta- the LMWH ⫹ aspirin group developed recurrent hypertensive disor- tion. The effect of antithrombotic agents in mediated pregnancy complications. trimester miscarriages to enoxaparin 40 mg and placebo once daily women with inherited thrombophilia and a history of preeclampsia (n ⫽ 68). pregnancy surveillance only.24. However. 25% of women had thrombophilia and only the FRUIT Habenox trial randomized women with at least 3 consecutive first study was dedicated to thrombophilic women only. respectively.34 Women treated with enoxaparin had a much development of recurrent hypertensive disorders. 95% CI ⫽ 29%. and the rarer complications Hematology 2014 397 . local skin to address the effect of antithrombotic treatment.69 –2.with placebo. ⬍10th percentile requiring deliv- 100 mg (n ⫽ 76).

Off-label drug use: LMWH and aspirin for sia. Fax: 31-20-6968833. Steegers EA. Bates SM. avoiding any London. 2014. Lewis G. Font J. 83(3):691-698. Azulay M et al. 2009. has received honoraria from GSK. J Rheumatol. Inherited thrombophilia and still unclear. Kadyrov M et al. Chest. Govan L. Boehringer Ingelheim. Walker ID. whereas the evidence that LMWH reduces the risk for 10. Rodger MA. Atsumi T et al. e-mail: s. 2005. Duley L.118(10):3453-3461. Am J Reprod Immunol. 2014. Ramsay T. 2010. Stewart LA. Saving Mothers’ Lives: reviewing maternal deaths to make based clinical practice guidelines (ninth edition). Askie LM.123(6):822-828. thrombophilia. 2005. The Seventh Report of Suppl):e691S-e736S.2:CD002859. 18. 14.132(2):171-196. agulant. 2008. Middeldorp S. inconsistent. J Thromb Haemost. future perspectives 8. Cartwright JE et al. women with or without inherited thrombophilia is extremely Am J Obstet Gynecol. Antiphospholipid antibod- Conclusions. 2006. Greer IA.9(3):331-337. Redecha P. Mclintock C et al. 6. 2012. Shrier I. Risk factors associated with fetal losses in treated antiphospholipid syndrome pregnancies: a multivariate 5665976. O’Connor E et al. Abou-Nassar K. Mackman N. 16.4(2):295- and induction of delivery and neuraxial anesthesia. This is 2008.143(5):321- in ⬃ 20% of women and were reported in 40% of women treated 335. Kahn SR. UK: 2007. Inherited thrombophilia and prevention of morbidity and mortality from preeclampsia: a systematic pregnancy complications revisited: association not proven causal and evidence review for the U. McNamara H et al. Rodger MA. 398 American Society of Hematology .19(6):674-684. 21. Paidas MJ. MD. Middeldorp S. de Jong PG. Obstet Gynecol. The Netherlands. Cochrane Database Syst Rev. Robertson L.160(10):695-703. preeclampsia within a multicenter cohort: the Montreal Preeclampsia Study. Ann Intern 320-324. I have 12. Antiplatelet References agents for prevention of pre-eclampsia: a meta-analysis of individual 1. The thrombomodulin-protein C inherited thrombophilia and recurrent pregnancy loss. Am J Obstet Gynecol. Black S. Craig JC. study.27. Thrombophilia in pregnancy: a systematic review. a history of severe preeclampsia likely benefit modestly from 2003. Duvekot JJ. I will 13. 3. 2008. Blood. 2011. Delayed. Goddijn M. Phone: 31-20. 7. International consensus with nadroparin in the ALIFE study. 2013. 2007. Preventive Services Task Force Aspirin for antithrombotic prophylaxis is experimental. Henderson JT.middeldorp@amc.112(2): Prevention of Morbidity and Mortality From Preeclampsia. Does thrombophilia testing help type allergic skin reactions due to administration of LMWH occur in the clinical management of patients? Br J Haematol. Opatrny L. Nat Med. Henderson-Smart DJ. Clark P. Antithrombotic therapy for 24. Disclosures 17. dreef 9. the Confidential Enquiries into Maternal Deaths in the United Kingdom. Franzke CW. 1105 AZ Amsterdam. Venous thromboembolism. Platt R. Acquiring funding and ethical autoimmune disease: a metaanalysis. Middeldorp S. 19. David M.369(9575):1791-1798.46(4):274-279. BMS/Pfizer. Pijnenborg R.S. If she will not give consent for participation. Hoeks LB. Bots ML. Isermann B. 22. Greer IA. management of the clinical case. Outcomes of subsequent pregnancy after first pregnancy with early-onset preeclamp- and Daiichi Sankyo. Nevertheless. pregnancy loss.195(3):723-728. even true for women with APS. we have to deal with clinical cases every day. Bayer.140(2):236-240. Lancet. analysis. Hum Reprod Update. Prevention of recurrent Saskia Middeldorp. Miyakis S. ALIFE2 trial. association? J Thromb Haemost.128(1): presented clinical case.43 Finally. rather than prescribing blood groups on haemorrhagic and thrombotic pregnancy outcomes.nl. 2006. von DP. 2006. Carmona F. antithrombotic therapy and pregnancy: ACCP evidence- 4. 2014. bleeding by withholding ineffective therapy is preferred. J Thromb Haemost. Empson M. Lassere M.141(2 motherhood safer . Pre-eclampsia. 11. Pawlinski R et al. Quenby S. Thrombophilia and pregnancy complications: cause or patient data. Rodger MA. Is thrombophilia associated only prescribe her aspirin based on her history of preeclampsia and with placenta-mediated pregnancy complications? A prospective cohort refrain from prescribing LMWH. 5. and Sanquin and plications. 2008.of heparin-induced thrombocytopenia and heparin-induced osteope. and ies prevent extravillous trophoblast differentiation. I have counseled her to participate in the 77-85. Rey E. 2005. F4-276. Ruf W. Wu O.200(2):151-159. Girardi G.2003-2005. 2007. 23. Bose P. Women with system is essential for the maintenance of pregnancy. Meda Pharma. Heparin and aspirin attenuate recurrent severe placenta-mediated pregnancy complications in placental apoptosis in vitro: implications for early pregnancy failure. Le GG et al. Am J Obstet Gynecol. Middeldorp S et al.12(4):469-478. Walker MC. Correspondence 20. Br J Haematol. Carrier M. potential harmful and costly medication for which the benefits are Br J Haematol. Franx A. Langhorne P et al. the body of evidence shown in the above-mentioned activation by the tissue factor/Factor VIIa/PAR2 axis mediates fetal intervention studies have not clearly and unequivocally shown the death in a mouse model of antiphospholipid syndrome. van Hylckama Vlieg A. Meiberg. In: CEMACH. Rodger MA. Scott JR. 306. Lancet. the use of statement on an update of the classification criteria for definite antithrombotic therapy raises specific issues with regard to planning antiphospholipid syndrome (APS). but foremost for women with 9. Professor of Medicine. Fertil Steril. 2001. van Rijn BB. The GOAL study: a scientific enthusiasm and persistence. Low-dose aspirin for 2. Academic Medical Center. nia.24 Although the incidence of major bleeding is low. Department of miscarriage for women with antiphospholipid antibody or lupus antico- Vascular Medicine. For the tions: a systematic review and meta-analysis.33(11):2214- approval for such studies and finding patients who are willing to 2221. Wu O. Whitlock EP.376(9741):631-644. Kahn SR.uva. The association between antiphospholipid antibodies and placenta mediated complica- summarized my approach in clinical practice in Table 3. Mountfield S. 2006. benefit of LMWH with or without the addition of aspirin.192:23-30. Smith GN et al. Bruinse HW. Association between The huge evidence gaps should be filled in in the next few years by antiphospholipid antibodies and recurrent fetal loss in women without multinational collaborative studies. aspirin. J Clin Invest. Meta-analysis of low molecular Conflict-of-interest disclosure: The author has received research weight heparin to prevent recurrent placenta-mediated pregnancy com- funding from GSK. Sood R. Neutrophil In my view. Carrier M. Lockshin MD. I strongly believe that it is our prospective examination of the impact of factor V Leiden and ABO(H) responsibility to further advance the field. participate may be a hurdle that can only be overcome by mutual 15. Thromb Res. Med.5(Suppl 1):276-282. pregnancy complications.

Low-molecular-weight heparin Intervention Study: a multicentre randomised controlled trial of low lowers the recurrence rate of preeclampsia and restores the physiologi- molecular weight heparin and low dose aspirin in women with recurrent cal vascular changes in angiotensin-converting enzyme DD women. SPIN: the Scottish Pregnancy 36. The Investigation Haemost. and Treatment of Couples with Recurrent First-trimester and Second. 1997. Hypertension. Addition of enoxaparin to aspirin trimester Miscarriage. Crowther M. 2011. recurrent early pregnancy losses due to antiphospholipd antibody 119(4):3269-3275. Antepartum dalteparin 33. Ziakas PD.376(9751):1498-1509.7:CD004734. Fatini C et al.45(1):86-91. 2012. Dave M. Cetin I et al. complications in pregnant women with thrombophilia (TIPPS): a HABENOX: a randomised multicentre trial. 2010.115(6):1256-1262. Ruiz-Irastorza G. 2012.314(7076):253-257. pholipid syndrome. Kaandorp SP. S0140-6736(14)60793-5. 2009. randomized. de Vries JI. Kroll H et al. Thromboprophylaxis versus no antepartum dalteparin for the prevention of pregnancy for recurrent miscarriage in women with or without thrombophilia. Goddijn M. Ruggenenti P. Goddijn M. David M et al. aspirin and aspirin plus heparin in pregnant women with recurrent 40. Bemiparin versus low dose aspirin for management of tive. Alalaf S. Antiphos. Cochrane Database Syst Rev. Haemost. London: Royal for the secondary prevention of placental vascular complications in College of Obstetricians and Gynaecologists. multicenter.132(1):131-139. Walker ID. Ulander VM. with previous placenta-mediated pregnancy complications: a prospec- 32.285(3):641-647. without thrombophilia: a pilot randomized controlled trial. Rodger MA. High incidence of heparin- low-dose aspirin in women with one fetal loss and a constitutional induced allergic delayed-type hypersensitivity reactions in pregnancy. J thrombophilic disorder. van Pampus MG. bophilia: the FRUIT-RCT. J Thromb 28. 2011. lipid syndrome with recurrent pregnancy loss: a systematic review and 41. Hague WM. BMJ. Aspirin plus heparin or 37. Green-top Guideline No 17. Martinelli I. Chauleur C. 2005. 2010. controlled clinical trial. Allergy Clin Immunol. Blood. Rey E. 2012. 26. miscarriage associated with phospholipid antibodies (or antiphospho. 2014. 42. J Thromb Haemost. Rodger M. Cohen H. Heparin in pregnant women meta-analysis. Joosten JH. Recurrent Early-Onset Preeclampsia in women with Inheritable Throm- 31. Bezemer PD. Khamashta MA.7(1):58-64. Langhorne P et al. women with severe pre-eclampsia. Garneau P. Clark P. Blood. Blood. Kaandorp SP. 27. Gris JC. Arch Gynecol Obstet. Lancet. N Engl J Med. Pavlou M. 2013. Low-molecular-weight heparin versus 43. Dalteparin for the prevention of aspirin alone in women with recurrent miscarriage. Mercier E. Heparin treatment in antiphospho. van der Post JA et al. prevention of placental vascular complications in women with abruptio 2014. multinational open-label randomised trial. Voulgarelis M. Hematology 2014 399 . Lancet. Gris JC. 2010. Middeldorp S. Hague WM. DOI 10. Aspirin or anticoagulants for treating recurrent miscarriage in women 38. 39.25. Regan L.10(1):64-72. 35. Gris JC. Royal College of Obstetricians and Gynaecologists. 2010.115(21):4162-4167. Important publication missing key information. Parretti E. Blood. 2004. placentae: the pilot randomised controlled NOH-AP trial. 2011. Thromb Haemost. Helmerhorst FM et al.103(10):3695-3699. Thromb Haemost. Di Nisio M. Gobst C. Visser J. Obstet Gynecol. syndrome. The pilot randomised controlled 30.362(17):1586-1596. author reply 3413-3414. Molinari N et al. Kingdom J et al. recurrence of placental-mediated complications of pregnancy in women 2010. Chauleur C. Enoxaparin for the secondary without antiphospholipid syndrome. Randomised controlled trial of NOH-PE trial. 2004. miscarriage. de Jong PG.104(10):3413. Thromb 29. Rai R. [Epub ahead of print] 34.1016/ 105(2):295-301.104(4):771-779.106(6):1053-1061. Faillie JL et al. Quere I et al. Branch W. Low-Molecular-Weight Heparin Added to Aspirin in the Prevention of lipid antibodies). Schindewolf M. Mello G.