can heparin prevent adverse pregnancy outcome?

EditorialCan heparin prevent adverse pregnancy outcome?

Thrombosis of the uteroplacental circulation has beenimplicated as a mechanism of disease in many of the ‘greatobstetrical syndromes’1 responsible for adverse pregnancyoutcome, including pre-eclampsia, intrauterine growthrestriction (IUGR), fetal death and premature parturition.Consequently, much effort has been devoted during the last20 years to determine whether thromboprophylaxis withantiplatelet agents can improve pregnancy outcome.Meta-analyses of randomized clinical trials indicatethat aspirin administration can reduce the rate ofperinatal death by 14% and pre-eclampsia by 15%2,3.With the increased recognition of thrombophilic dis-orders and their proposed link to adverse pregnancyoutcome, the interest in the utilization of heparin inobstetrics has been rekindled. This Editorial will brieflyreview the evidence that thrombosis is a mechanism ofdisease in obstetrics, as well as the justification for testingwhether thromboprophylaxis with heparin will beeffective.

The hemostatic system

The hemostatic system maintains blood within the circula-tory system by sealing vascular leaks without compromisingblood fluidity. This is accomplished by the complex andbalanced interaction of the four components of thehemostatic system:

(1) The vessel wall and, in particular, the endothelium;

(2) Platelets;

(3) The soluble components of the coagulation system;

(4) The fibrinolytic system.

The endothelium maintains blood fluidity by inhibitingboth platelet aggregation and fibrin formation (coagu-lation), and by promoting fibrinolysis (degradation offibrin)4. Upon injury to the vessel wall, the sub-endothelium is exposed to circulating blood. Platelets‘adhere’ to the site and ‘aggregate’ to form a ‘primaryhemostatic plug’. The soluble components are acti-vated, leading to fibrin deposition within the plateletplug, while excessive fibrin deposition and thrombosis areprevented by the action of the fibrinolytic system(plasmin)5,6.

Pregnancy and the hemostatic system

Pregnancy poses substantial challenges to the hemostaticsystem. For example:

(1) Blastocyst invasion into the endometrium should occurwithout hemorrhage;

(2) Trophoblast invasion of the walls of the spiral arteriesmust take place without thrombosis or hemorrhage;

(3) Thrombosis within the intervillous space of theplacenta needs to be avoided despite the relative circu-latory stasis and direct contact between trophoblast(semi-allogeneic) and maternal blood;

(4) Placental separation must be accomplished withoutlethal hemorrhage.

Dramatic changes in local7–10 and systemic hemostasisduring pregnancy have been demonstrated11–22, and arethought to be adaptations which prevent bleeding. Normalpregnancy is characterized by excess thrombin genera-tion19–23 and a tendency of platelets to aggregate inresponse to agonists24–28. Hemostatic disorders (hem-orrhage and thrombosis) are leading causes of maternaldeath world-wide, underscoring the importance of thissystem for reproduction and survival.

Thrombosis as a mechanism of disease inobstetrics

Two broad lines of evidence suggest that excessive hemo-stasis is a mechanism of disease in pre-eclampsia, IUGR,fetal death, abruptio placentae and premature parturition:

(1) An excessive rate of thrombotic lesions has beenobserved by histologic examination of the placenta andof the spiral arteries of patients with these complica-tions of pregnancy29–41;

(2) Evidence of platelet activation and excessive thrombingeneration in the maternal circulation have beendemonstrated at the time of diagnosis in pre-eclampsia,IUGR and premature parturition42–86. That the activa-tion is related to placentation is inferred by theobservation that hemostatic abnormalities are moremarked in blood obtained from the uterine vein thanin the peripheral blood, at least in patients with

The Journal of Maternal–Fetal and Neonatal Medicine 2002;12:1–8

Correspondence: Roberto Romero, Perinatology Research Branch, NICHD, Wayne State University/Hutzel Hospital, Departm ent ofObstetrics and Gynecology, 4707 St. Antoine Boulevard, Detroit, MI 48201, USA

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pre-eclampsia87. Some data suggest that impairedfibrinolysis may also be involved in pre-eclampsia andIUGR58.

Nature of the hemostatic disorder leading tothrombosis

Thrombosis can occur at any site of the circulatory systemincluding arteries, veins and the microcirculation. Venousthrombosis tends to occur at the site of stasis, while arterialthrombosis is usually located at the site of vascular lesions(i.e. atherosclerosis). Even though thrombi containplatelets and fibrin, prevention of venous thrombosis innon-pregnant patients is clinically accomplished by anti-coagulation (e.g. heparin or coumadin administration),while prevention of arterial thrombosis in patients withatherosclerosis is attempted with antiplatelet agents88. Arepregnancy complications associated with endothelial/platelet activation, excessive thrombin generation and/ordefective fibrinolysis? Despite the apparent simplicity ofthis question and the implications of the answer (i.e. selec-tion of antithrombotic agent: antiplatelet and/or heparin),the answer is not clear. Some evidence of activation/dysfunction of each of the components of the hemostasicsystem or a combination of them has been reported inpatients with pre-eclampsia, IUGR and preterm parturitionat the time of diagnosis89–99.

Does alteration of hemostasis occur before orafter the clinical onset of disease?

For an antithrombotic strategy to prevent adversepregnancy outcome, activation/dysfunction of the hemo-static system should precede the development of thedisease. Support for activation of platelets in the preclinicalstages of pre-eclampsia has been available for more than 15years100–105 and was considered so persuasive as to justifythe enrollment of over 30 000 women in randomizedclinical trials of aspirin2. On the other hand, evidencesupporting the role of preclinical excessive thrombingeneration or defective fibrinolysis in pre-eclampsia,small-for-gestational-age (SGA) fetuses, abruptioplacentae and fetal death is currently less clear. One studynoted excessive thrombin generation in patients whosubsequently developed preterm premature ruptureof membranes106. Increased thrombin generation mayeven begin before pregnancy in patients with a historyof recurrent pregnancy loss107.

Does aspirin prevent adverse pregnancyoutcome?

The most recent systematic review from the CochraneCollaboration demonstrated a 15% reduction in the risk of

pre-eclampsia (32 trials with 29 331 women; relative risk(RR) 0.85, 95% confidence interval (CI) 0.78–0.92) and a14% diminution in fetal and/or neonatal death (30 trialswith 30 093 women; RR 0.86, 95% CI 0.75–0.99). Thisreduction in the death rate was greatest among high-riskwomen (4134 women; RR 0.73, 95% CI 0.56–0.96)2.Another systematic review3 concluded that the administra-tion of low-dose aspirin reduced the risk of IUGR by 18%(odds ratio (OR) 0.82, 95% CI 0.72–0.93). Despite theevidence from meta-analyses, some experts remainskeptical about the clinical importance of a modest butstatistically significant finding.

Thrombophilic disorders and adverse pregnancyoutcome

The term thrombophilia is generally used to describe acondition (inherited or acquired) that places a patient atincreased risk for thrombosis. A potentially thrombophilicpatient is one who has a laboratory abnormality associatedwith an increased risk of thrombosis, but has not had aclinically recognizable thrombotic episode (i.e. a patientwith the diagnosis of antithrombin III deficiency). Themost common inherited thrombophilic disorders are FactorV Leiden mutation, prothrombin promoter and mutation oftetrahydrofolic reductase108, while the most frequentacquired thrombophilic abnormality is the anti-phospholipid antibody syndrome. Are potentiallythrombophilic disorders associated with adverse pregnancyoutcome? An association between pre-eclampsia andinherited thrombophilias was first reported by Dekker andcolleagues in 1995109. Subsequently, a large number ofcase-controlled studies have examined the relationshipbetween maternal carriage of a thrombophilic mutationand adverse pregnancy outcome (pre-eclampsia, IUGR,abruptio placentae, fetal loss and recurrent early or latefetal losses)110–114. Although there is no consistency amongreports, the weight of the evidence suggests that there is anassociation between the maternal carriage of thrombophilicmutations (and some functional disorders such as activatedprotein C resistance) and adverse pregnancy outcome (for adetailed review, see references 110–114). The strength ofthe association varies with the type of thrombophilicmutation and the specific adverse pregnancy outcomeunder study. The reasons for this are complex and related tothe population rates of inherited disorders, severity of theconditions, biases, nature/strength of the association, etc.For instance, for pre-eclampsia, some of the larger studiesonly found an association between the presence ofthrombophilias and early-onset pre-eclampsia (delivery< 28 weeks’ gestation), and no relation betweenthrombophilias and third-trimester pre-eclampsia115. Alarge cohort study, including nearly 5000 patients andconducted by the National Institute of Child Health and

Editorial Romero et al.

J ournal of Maternal–Fetal and Neonatal Medicine

A4336:AMA:First Revise 26 June 2002 Paper:Edit-Romero

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Human Development Network of Maternal–FetalMedicine Units (under the leadership of Dr DonnaDizon-Townson), is currently in the analysis stages. Thisstudy is expected to provide estimates of the rate of adverseoutcome with each thrombophilic state, as well as informa-tion about the relationship between these thrombophilicconditions and placental pathology. An important con-sideration when analyzing the association between poten-tially thrombophilic states and adverse pregnancy outcomeis the state of the fetus. Thrombosis is often found in thefetal vessels of the placenta (i.e. fetal stem vessel thrombo-sis) in a substantial number of patients with adverse preg-nancy outcome, and inherited and acquired thrombophiliascan affect the fetus, mother, or both (some are inheritedwith an autosomal dominant pattern)116. It is possible thatinteraction between maternal and fetal thrombophilicstates alters the risk of adverse pregnancy outcome. Themechanism by which inherited thrombophilic mutationslead to thrombosis is thought to be excess thrombin genera-tion, although impaired fibrinolysis and other mechanismsmay also be operative. One point is clear: carrying athrombophilic mutation by itself is not sufficient to have aclinically detectable thrombotic event. However, it ispossible that the increased demands imposed by pregnancyand placentation on the hemostatic system serve touncover hemostatic disorders that may otherwise remainquiescent. Pregnancy could be considered a stress to thehemostatic system just as it is to the pancreas. Thus,thrombotic events of the placenta and adverse pregnancyoutcome in potentially thrombophilic patients may be tothe hemostatic system what diabetes is to the endocrine/metabolic system controlling carbohydrate tolerance. Ifthis were to be generalized to other organ systems,pregnancy could be considered a stress test for organdysfunction later in life. The observation that women withpre-eclampsia are at increased risk for the subsequentdevelopment of cardiovascular disease117,118 supports thisinterpretation.

Are thrombophilic conditions associated withthrombotic lesions in the placenta?

Thrombotic lesions of the placenta have been documentedin patients with thrombophilic conditions and adversepregnancy outcome119. However, those lesions appear to beprimarily related to the occurrence of adverse pregnancyoutcome, rather than to the detection of a potentialthrombophilic state in the mother. One study found thatthe frequency of thrombotic lesions was higher in theplacenta of patients with thrombophilic disorders than inthose without detectable thrombophilic disorders (75 vs.40%)120. However, two studies have reported a high preva-lence of thrombotic lesions of the placenta in patientswith adverse pregnancy outcome, regardless of whether or

not they had detectable thrombophilic states39,40. Thereasons for this are unknown, but several possibilitiesshould be considered. First, it is unlikely that allthrombophilic states have been discovered and thereforethe current list of these disorders may be incomplete.Second, acquired thrombophilic states may develop duringthe course of other complications of pregnancy, leading tothrombosis and disease, but may not be detected whentesting for thrombophilias is limited to genetic conditions.Third, there is a possibility that gene–gene and gene–environmental interactions play a role in influencing thelikelihood of thrombosis. The factors determining whethera patient with a known thrombophilia will or will notdevelop thrombotic lesions of the placenta have not beenelucidated. For example, it is likely that an insult such asinfection/inflammation will be required for thrombosis tooccur in a potentially thrombophilic patient. Susceptibilitymay be modified if two thrombophilic states coexist and/orthe fetus has the condition116 and is exposed to an insultthat activates the hemostatic system. There is evidence ofthe coexistence of inflammatory lesions and thromboticlesions in the placentas of patients who deliver withpreterm premature rupture of membranes29. Other issuesthat should be addressed are the accuracy of placentalhistologic examination and the location and distributionof lesions. For example, thrombotic lesions involvingthe spiral arteries may be important, but their detectionrequires the study of placental bed biopsies. What is clear isthat thrombotic lesions of the placenta can occur inpatients with and without known thrombophilic states,and that further research is required to determine thereason for this.

Can heparin administration prevent adversepregnancy outcome?

Given the strength of the evidence that thrombotic lesionsof the placenta are associated with adverse pregnancyoutcome, and that platelet activation, excess thrombingeneration and/or altered fibrinolysis are present, a crucialquestion is whether the administration of heparin to at-riskpatients will improve pregnancy outcome. This is not a newquestion: heparin administration to patients with pre-eclampsia was attempted decades ago, mostly as isolatedcase reports or small series. In 1995, North and colleaguesreported that heparin administration reduced the rateof pre-eclampsia in women with renal disease121. Morerecently, two randomized clinical trials compared the useof low-dose aspirin and low-dose aspirin plus heparin inpatients with antiphospholipid antibody syndrome122,123.Three observational studies reported the use of low-molecular-weight heparin and aspirin in patients withknown thrombophilias and a history of previous adversepregnancy outcome, with encouraging results124–126. Thus,

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the time is right to determine whether low-molecular-weight heparin can improve pregnancy outcome.

Such a trial has now been designed. HEPAPO (HEparinto Prevent Adverse Pregnancy Outcome) will seek toidentify women with a previous history of severe pre-eclampsia, HELLP syndrome, small for gestational age,placental abruption, unexplained fetal death, and two ormore fetal losses. Eligible patients would be randomly allo-cated to either aspirin or aspirin and low-molecular-weightheparin. The primary goal of the trial is to determine ifadjunctive heparin can reduce the rate of fetal death.The frequency of other secondary outcomes will also beexamined. It is noteworthy that having a thrombophilic

state will not be a criterion for inclusion. DNA and func-tional coagulation studies will be conducted after the trialto determine if a thrombophilic state modifies the responseto treatment. Patients with antiphospholipid antibodysyndrome will be eligible to participate in the trial. Thisundertaking is an important one in that it attempts toprovide an answer to what is a pressing clinical question. Itis crucial that obstetricians resist the temptation to treatpatients with heparin until there is adequate evidence thatthis intervention is effective. The trial is planned to be aninternational collaboration. We welcome centers with alarge case load, interest and expertise to participate in thisendeavor.




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Dr Roberto Romero, Perinatology Research Branch, NICHD, Bethesda, MD, USADr Gustaaf Dekker, University of Adelaide, AustraliaDr Michael Kupferminc, Tel Aviv University, IsraelDr George Saade, University of Texas at Galveston, USADr Jeffrey Livingston, Carilion Medical Center, Roanoke, VA, USADr Alan Peaceman, Northwestern University, Chicago, IL, USADr Moshe Mazor, Ben Gurion University, Beer-Sheva, IsraelDr Bo Hyun Yoon, Seoul National University, Seoul, KoreaDr Jimmy Espinoza, Perinatology Research Branch, NICHD, Detroit, MI, USADr Tinnakorn Chaiworapongsa, Perinatology Research Branch, Detroit, MI, USADr Ricardo Gomez, Hospital Dr. Sotero del Rio, Santiago, ChileDr Fernando Arias, Toledo Hospital Center for Women’s Health, OH, USADr Baha Sibai, University of Cincinnati, OH, USA

Acknowledgements

The HePAPO consortium is a multi-disciplinary groupwhich includes hematologists, perinatal epidemiologists,genetic epidemiologists, pediatric pathologists, ethicists,nurses and patient representatives. Investigators who maybe interested in participating in the trial can contactDr Romero at [email protected], Dr Dekker([email protected]), Dr Kupferminc([email protected]) or Dr Sibai ([email protected]) for further information.

Dr Romero wishes to acknowledge the contribution ofDr Thomas Duffy of Yale University for constructivediscussions over the years about the role of the hemostaticsystem on the genesis of pre-eclampsia and other pregnancycomplications.

Note added at proof: A debate about whether or not heparinshould be administered to prevent adverse pregnancyoutcome in patients with a prior adverse outcome was heldat the last meeting of the International Society for theStudy of Hypertension in Pregnancy held in Toronto,Canada, June 2–5, 2002. The transatlantic debate featuredDr John Kingdom of the University of Toronto, Canadaand Professor Steven Robson of the University of Newcas-tle, United Kingdom. After the debate, an informal surveyof individuals attending the debate indicated that a major-ity agreed that heparin should not be administered toprevent adverse pregnancy outcome until further evidenceis available.

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can heparin prevent adverse pregnancy outcome?

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