Dalteparin and Low-Dose Aspirin in the Prevention of Adverse by gjjur4356




Dalteparin and Low-Dose Aspirin in the
Prevention of Adverse Obstetric Outcomes in
Women With Inherited Thrombophilia
Line Leduc, MD,1 Emmanuelle Dubois, MD,1 Larissa Takser, MD, PhD,1 Evelyne Rey, MD, MSc,1
Michèle David, MD2
Department of Obstetrics and Gynecology, Sainte-Justine Hospital, University of Montreal, Montreal QC
Department of Pediatrics, Hematology service, Sainte-Justine Hospital, University of Montreal, Montreal QC
This study was presented at the 25th meeting of the Society for Maternal Fetal Medicine, February 2–7, 2004, New Orleans LA

Abstract                                                                     Résumé
    Objective: To evaluate the benefit of treatment with dalteparin and      Objectif : Évaluer les avantages du traitement à la daltéparine et à
      low-dose aspirin (ASA) in the prevention of obstetric complications      l’aspirine (AAS) à faible dose en matière de prévention des
      in women with inherited thrombophilia.                                   complications obstétricales chez les femmes qui présentent une
                                                                               thrombophilie héréditaire.
    Methods: A retrospective chart review identified women who had
      had at least one pregnancy complicated by severe early-onset           Méthodes : Une analyse de dossiers rétrospective a permis
      preeclampsia, placental abruption, fetal growth restriction (FGR),       d’identifier des femmes qui avaient connu au moins une
      or fetal death. The following inherited thrombophilias were              grossesse compliquée par une prééclampsie grave à début
      included: deficiencies of antithrombin, protein C, or protein S, and     précoce, un décollement placentaire, un retard de croissance
      mutations of factor V Leiden (G1691A), factor II (G20210A), or           intra-utérin (RCIU) ou un décès fœtal. Les thrombophilies
      methylenetetrahydrofolate reductase C677T.                               héréditaires suivantes ont été admises aux fins de l’étude :
                                                                               carences en antithrombine, en protéine C ou en protéine S et
    Results: The records of 43 women with 110 pregnancies were
                                                                               mutations du facteur V Leiden (G1691A), du facteur II (G20210A)
      included in the study. Anticoagulant prophylaxis was administered
                                                                               ou de la méthylènetétrahydrofolate réductase C677T.
      using dalteparin in 13 pregnancies, ASA with dalteparin in 26, and
      ASA alone in 11. Dalteparin alone and ASA alone showed                 Résultats : Les dossiers de 43 femmes ayant connu 110 grossesses
      equivalent effects in preventing preeclampsia and FGR. Combined          ont été admis à l’étude. Une anticoaguloprophylaxie avait été
      dalteparin and ASA significantly decreased the risk of                   administrée en faisant appel à la daltéparine dans le cas de
      preeclampsia (odds ratio [OR] 0.80; 95% confidence intervals [CI]        13 grossesses, à l’AAS et à la daltéparine dans le cas de
      0.70–0.91, P = 0.001) and FGR (OR 0.70; 95% CI 0.60–0.82,                26 grossesses et à l’AAS seul dans le cas de 11 grossesses. La
      P = 0.001).                                                              daltéparine seule et l’AAS seul ont exercé des effets équivalents
                                                                               en matière de prévention de la prééclampsie et du RCIU.
    Conclusion: Data from this retrospective cohort study suggest that
                                                                               L’utilisation concomitante de daltéparine et d’AAS a entraîné une
      combined treatment with dalteparin and ASA decreases the risk of
                                                                               baisse significative du risque de prééclampsie (rapport de cotes
      preeclampsia by 20% and the risk of FGR by 30% in women with
                                                                               [RC], 0,80; intervalle de confiance [IC] à 95 %, 0,70–0,91,
      inherited thrombophilia.
                                                                               P = 0,001) et de RCIU (RC, 0,70; IC à 95 %, 0,60–0,82,
                                                                               P = 0,001).
                                                                             Conclusion : Les données issues de cette étude de cohorte
                                                                               rétrospective semblent indiquer que le traitement concomitant à la
                                                                               daltéparine et à l’AAS entraîne une baisse de 20 %, en ce qui
                                                                               concerne le risque de prééclampsie, et de 30 %, en ce qui
                                                                               concerne le risque de RCIU, chez les femmes qui présentent une
                                                                               thrombophilie héréditaire
                                                                             J Obstet Gynaecol Can 2007;29(10):787–793

    Key Words: Thrombophilia, adverse pregnancy outcomes,
    anticoagulation therapy, low molecular weight heparin
    Competing Interests: None declared.
    Received on December 4, 2006
    Accepted on May 9, 2007

                                                                                                      OCTOBER JOGC OCTOBRE 2007 l              787

INTRODUCTION                                                     prophylaxis was then offered in subsequent pregnancies to
     he development and maintenance of adequate placental        affected women. We initiated this exploratory retrospective
T    circulation is essential to successful pregnancy out-
                                                                 cohort study to evaluate the benefit of LMWH and
                                                                 low-dose ASA in the prevention of recurrent vascular
come. In some circumstances, abnormal placental
                                                                 obstetric complications, such as severe preeclampsia, FGR,
vasculature and disturbances of hemostasis result in inade-      placental abruption, and stillbirth in our population of
quate maternal-fetal circulation. This placental                 women with inherited thrombophilia.
vasculopathy is associated with gestational complications,
such as preeclampsia, placental abruption, fetal growth          METHODS
restriction, and intrauterine fetal death.1,2 These vascular
complications are known to contribute significantly to           From a retrospective chart review, we identified the records
maternal and fetal morbidity and mortality.3                     of women who had received antithrombotic prophylaxis
Dekker and colleagues were the first to report an associa-       during pregnancy between 1997 and 2001 for a history of
tion between the presence of a thrombophilia and                 previous pregnancy complicated by severe preeclampsia,
early-onset preeclampsia.4 Some obstetric vascular compli-       placental abruption, FGR, second or third trimester fetal
cations have also been associated with hereditary                loss, and associated hereditary thrombophilia. Individual
thrombophilias.5 Data from recent meta-analyses are con-         obstetrical data were collected for each case. Patients with
sistent with an association between hereditary                   recurrent miscarriages alone or with previous
thrombophilias and the development of severe                     thromboembolic disorders were not included in the study.
preeclampsia and early and late fetal losses.6,7                 Severe early onset preeclampsia (at < 34 weeks’ gestation)
                                                                 was defined according to the Canadian classification.12 Fetal
A rational approach to these pre-thrombogenic conditions         growth restriction was diagnosed when birth weight was
is to administer thromboprophylaxis during pregnancy.            below the third percentile according to the Canadian birth
Until recently, anti-platelet drugs, mostly low-dose aspirin     weight growth curves.13 Placental abruption was defined as
(ASA), were acknowledged to reduce to some extent the            vaginal bleeding in the second or third trimester after exclu-
incidence of recurrent preeclampsia in subsequent pregnan-       sion of placenta previa, with either clinical symptoms or
cies.8 Administration of LMWH was found to be superior           signs of abruption on ultrasound examination or the pres-
to low-dose ASA in women with one fetal loss and inherited       ence of an organized clot lying within a cup-shaped depres-
thrombophilia in a prospective randomized trial.9 Further-       sion on the maternal surface of the placenta at delivery. Mis-
more, it has been suggested that treatment with heparin and      carriage was defined as the first trimester fetal loss of a preg-
ASA is beneficial in improving the maternal-fetal outcomes       nancy that had been well documented by ultrasound. Unre-
in women with antiphospholipid antibody syndrome.10              lated causes of fetal demise had been previously excluded
In our centre, in accordance with the recently published         by standard investigations.
guideline from the Seventh American College of Chest Phy-
sicians Conference on Antithrombotic and Thrombolytic            All patients were followed and investigated for
Therapy,11 women with recurrent pregnancy loss, a second         thrombophilia in our tertiary care centre. A systematic eval-
trimester miscarriage, a history of intrauterine death, severe   uation for inherited thrombophilias consisted of assays of
fetal growth restriction, or severe or recurrent preeclampsia    antithrombin, protein C, and protein S, and genomic DNA
were screened for thrombophilias. Antithrombotic                 analysis for mutations of factor V Leiden (G1691A), factor
                                                                 II (G20210A), and MTHFR C677T. Blood samples were
                                                                 collected at least three months post partum. Antithrombin
                                                                 was assayed using amidolytic assay (Stachrom ATIII ).14
                         ABBREVIATIONS                           Protein C was assayed using an amidolytic assay (Stachrom
                                                                 Protein C). Protein S was measured as functional Protein S
 CI       confidence interval
                                                                 using a procoagulant assay (Staclot Protein S) until 1999,
 FGR      fetal growth restriction
                                                                 and subsequently as free Protein S using a commercial
 HELLP hemolysis, elevated liver enzyme levels and
       low platelet count                                        ELISA (Corgenix Inc.).15 Plasma homocysteine levels were
 IUFD     intrauterine fetal demise                              quantified by high pressure liquid chromatography on a
 LMWH low molecular weight heparin
                                                                 fasting overnight blood sample as described by
 MTHFR methylenetetrahydrofolate reductase
                                                                 Infante-Rivard et al.16 Factor V G1691A, factor II
 OR       odds ratio
                                                                 G20210A, and MTHFR C677T mutations were also evalu-
                                                                 ated as previously described.16,17 Patients with
 SD       standard deviation
                                                                 antiphospholipid antibodies were excluded.

                    Dalteparin and Low-Dose Aspirin in the Prevention of Adverse Obstetric Outcomes in Women With Inherited Thrombophilia

                  Table 1. Characteristics of the study population

                                                                 Dalteparin            ASA          Dalteparin + ASA   deliveries

                  Number of pregnancies                               13                11                     26          60
                  Mean maternal age, years (± SD)                30.4 ± 6.1        29.0 ± 4.4           32.8 ± 3.2      26.3 ± 5.0
                  Mean gestational age at delivery,              36.4 ± 4.0        36.1 ± 2.3           35.0 ± 7.7      34.5 ± 5.0
                  weeks (± SD)
                  Mean birth weight in grams (± SD)              2801 ± 966        2624 ± 566          3083 ± 727      2193 ± 1101

                  Deliveries were not compared in this table because the data were not independent measures.

Antithrombotic regimens included oral low-dose ASA                            RESULTS
(80mg daily), subcutaneous administration of the LMWH                         We identified 43 women with 110 pregnancies who were
dalteparin, or a combination of both. Patients who were                       eligible for inclusion in the study. Identified inherited
homozygous for the MTHFR C677T mutation also                                  thrombophilias included heterozygous factor V Leiden
received folic acid and vitamin B complex supplementation                     G1691A (n = 16) and factor II G20210A (n = 6), homozy-
throughout pregnancy. Data collected from the patient                         gous MTHFR C677T mutation (n = 7), protein S deficiency
records included demographic data and information about                       (n = 6), or a combination of these (n = 8). No women with
complications of pregnancy, maternal chronic diseases such                    antithrombin deficiency or protein C deficiency were iden-
as chronic hypertension, previous thromboembolic dis-                         tified in this population. Thirty-five women had a single
eases, smoking, family history of thromboembolic diseases,                    defect, six women had two defects, one had three, and one
and the use of multivitamin supplements.                                      had four. Low-dose ASA alone had been given in 11 prior
                                                                              pregnancies before the diagnosis of thrombophilia. No
                                                                              patient had received dalteparin prior to the diagnosis of
Considering the within-subject covariance, statistical analy-                 thrombophilia. Treatment with ASA was initiated in the
sis was performed using a method of generalized estimating                    first trimester in women taking ASA alone (n=32), but was
equations (GENMOD procedure) for categorical data and                         initiated at between 16 and 24 weeks of gestation in five
a mixed model for repeated measures (MIXED procedure)                         women using combined ASA and dalteparin. Doses of sub-
for continuous data such as birth weight and gestational                      cutaneous dalteparin varied between 3500 U twice daily and
age.18 The effect of prophylaxis on preeclampsia, FGR, pla-                   7500 U twice daily. Dalteparin alone was given in 13 preg-
cental abruption, and stillbirth, as well as the effect on birth              nancies. In 26 cases, dalteparin was combined with
weight and gestational age at delivery, was then calculated.                  low-dose ASA. Most patients began using the medication in
                                                                              the first trimester. A few women initiated ASA prophylaxis
Each complication was introduced in models as a depend-
                                                                              in the periconceptional period, and dalteparin was added
ent variable; the treatment regimens (ASA, dalteparin, or
                                                                              during the first trimester. One patient received 120 mg of
both) were included as independent variables. Gestational                     ASA daily. There were no cases of heparin-induced
age at delivery was also entered as a confounding factor in                   thrombocytopenia, bone fracture, or hematomas associated
mixed models estimating the association between treatment                     with regional anaesthesia.
and birth weight. Thus, in these models, the effect of
dalteparin was adjusted for ASA and the effect of ASA was                     The family history was positive for thrombophlebitis in two
adjusted for dalteparin. We also performed the analysis                       cases, pulmonary embolism in one case and stroke in three
including women who were not treated during pregnancy                         cases. The past medical history was positive for deep vein
compared with those treated with combined ASA and                             thrombosis in one case and stroke in one case. Nine women
dalteparin. In addition, in order to assess the effect of treat-              were identified as smokers.
ment in women at higher risk of adverse pregnancy                             The characteristics of pregnancies according to the type of
outcomes compared with the effect in all women, we per-                       treatment are shown in Table 1. Gestational age at delivery
formed the statistical analyses in women with adverse out-                    was greater in treated than in untreated pregnancies, but this
comes in their first pregnancy. This evaluation was executed                  difference was not statistically significant in MIXED model
with the software SAS/STAT package version 9.0 (SAS                           analysis. However, birth weight increased significantly (by
Institute Inc., Cary NC).                                                     890 g) in women given combined dalteparin and ASA

                                                                                                           OCTOBER JOGC OCTOBRE 2007 l   789

       Table 2. Distribution of the inherited thrombophilias among treated and untreated pregnancies with normal
       and adverse outcomes

                                                          Treated Pregnancies (n = 50)       Untreated Pregnancies (n = 60)

                                  Number of subjects   Normal outcome    Adverse outcome   Normal outcome    Adverse outcome
       Thrombophilic conditions        n = 43           n = 45 (90%)       n = 5 (10%)      n = 15 (25%)       n = 45 (75%)

       Factor V Leiden mutation        16 (37%)              14                  1               6                  18
       Factor II mutation              6 (14%)               6                   2               1                  11
       Protein S deficiency            6 (14%)               7                   1               4                   3
       MTHFR mutation                  7 (16%)               10                  0               0                   4
       Combined defects                8 (19%)               8                   1               4                   9

prophylaxis (MIXED model P < 0.001 adjusted for gesta-               and one on low-dose ASA) and no stillbirths occurred after
tional age).                                                         treatment.

The distribution of thrombophilic abnormalities among                DISCUSSION
treated and untreated pregnancies with normal and adverse
outcomes is shown in Table 2. Factor V Leiden mutation               This is an exploratory study comparing the efficacy of treat-
was the most frequent defect, affecting 16 of 43 women               ment with ASA, dalteparin, or a combination of the two in
(37%) in the cohort. Other mutations were equally                    preventing complications of pregnancy such as severe early
distributed in our cohort. Of pregnancies completed with             onset preeclampsia, FGR, placental abruption, or late fetal
prophylaxis, 90% (45/50) had a normal outcome, but in                death. The results in our population of women with inher-
pregnancies without prophylaxis, complications occurred in           ited thrombophilias suggest that combined prophylactic
75% (45/60) of cases. The various obstetric complications            therapy with dalteparin and ASA is associated with a greater
associated with thrombophilia are shown in Table 3. When             gestational age at delivery, a heavier birth weight, a 20%
all obstetrical complications are taken into account, factor V       reduction in the risk of preeclampsia, and a 30% reduction
Leiden mutation was found in 52% (10/19) of pregnancies              in FGR. The use of dalteparin or ASA alone offers similar
with early onset preeclampsia or HELLP syndrome, in 39%              efficacy, but the combination of the two appears to have
(11/28) of cases with FGR, and in 43% (6/14) of cases with           superior effects. These effects are strengthened when the
placental abruption. Factor II mutation was present in 25%           analysis focuses specifically on the subgroup of women
(7/28) of cases of FGR, 21% (3/14) of cases of intrauterine          whose first pregnancy had an adverse outcome.
fetal demise, and 46% (6/13) of cases of placental                   We defined a study population that was as homogeneous as
abruption. Women with protein S deficiency or MTHFR                  possible, with the following chosen criteria: severe early
mutation experienced varied complications. The rate of first         onset preeclampsia at under 34 weeks’ gestation, FGR at or
trimester miscarriage was 28% (43/150). Five women had               below the third percentile, and fetal loss in the second or
at least three miscarriages, five women had four, and one            third trimester. In this study, women with antiphospholipid
had five consecutive miscarriages.                                   antibody syndrome were excluded from the analysis, as
                                                                     were women with only recurrent pregnancy loss in the first
The probability of developing an obstetric complication
                                                                     trimester, because the underlying etiology may be quite dif-
despite prophylactic therapy in all participating women is
                                                                     ferent from one case to another. Despite this, the miscar-
shown in Table 4. Combined prophylactic therapy was the
                                                                     riage rate remained much higher in our study group than
most effective for preventing preeclampsia and FGR; ASA
                                                                     that observed in a standard population. As previously
and dalteparin as monotherapies were equally effective in
                                                                     reported,19,20 we observed a higher risk of recurrence of an
preventing preeclampsia and FGR. In women with compli-
                                                                     adverse pregnancy outcome in our cohort, and the type of
cations in their first pregnancy, the beneficial effect of com-
                                                                     complication changed from one pregnancy to the next.
bined prophylaxis is more apparent (Table 5) and the use of
dalteparin or ASA as monotherapy is less effective. We were          Including the outcomes of several singleton pregnancies
not able to estimate the probability of developing placental         from the same woman in the analysis offers advantages in
abruption or stillbirth because only two women developed             regard to selection bias and to statistical power. More pre-
placental abruption (one in the combined therapy group               cisely, the comparison of several pregnancies from the same

                    Dalteparin and Low-Dose Aspirin in the Prevention of Adverse Obstetric Outcomes in Women With Inherited Thrombophilia

           Table 3. Pregnancies with thrombophilia and different obstetric complications

                                                                               Thrombophilic conditions

                                                       Factor V Leiden     Factor II   Protein S     MTHFR          Mutations
           Pregnancy complications                        mutation         mutation    deficiency    mutation   2      3      4

           HELLP syndrome                                    1

           HELLP syndrome + Placental abruption                               2

           HELLP syndrome + FGR                              3                             1

           Preeclampsia                                      2

           Preeclampsia + FGR                                3                             1            1       2

           Preeclampsia + FGR + IUFD                                          1

           Preeclampsia + placental abruption                1

           Preeclampsia + placental abruption + IUFD                                                    1

           Placental abruption                               1                             1                    2

           Placental abruption + IUFD                        4                                                  1

           IUFD                                                               2                         1              1

           IUFD + FGR                                        1                1            1            1

           FGR                                               4                6                                 3            1

woman assures ideal matching for the effects of maternal                 thrombophilia. Likewise, homozygosity for the C677T
and genetic factors, age, and obstetric history. A longitudi-            MTHFR mutation was found in 16% of the women with
nal study design with baseline and repeated follow-up mea-               obstetrical complications, compared to a rate in historical
sures increase the statistical power of such studies.21                  controls of 7.5% of women with normal pregnancies.17
                                                                         Based upon our results, there is no convincing evidence
The different thrombophilias observed in our population                  linking the MTHFR mutation to an adverse pregnancy
parallel the results of previous studies. Dekker et al.                  outcome. Free access to vitamin supplementation might
screened women with severe preeclampsia at least 10 weeks                explain our findings.
post partum for the presence of inherited or acquired
thrombophilias. A high rate of protein S deficiency, acti-               There are few published studies reporting the use of
vated protein C resistance, hyperhomocysteinemia, and                    LMWH, ASA, or a combination of the two for the preven-
anticardiolipin IgG or IgM was found, but no cases of                    tion of adverse obstetric outcomes.22–30 Some of the avail-
antithrombin deficiency or protein C deficiency were iden-               able studies reported the effects of LMWH as a single pro-
tified.4 Kupferminc et al. reported a higher prevalence of               phylactic agent.22–25 Others used both ASA and
thrombophilias (65%) in women with obstetrical complica-                 LMWH.25–30 In all of these studies, the results tended to
tions than in controls (18%).5 The prevalence of                         show a benefit from use of both or either of LMWH and
thrombophilias in a control group of women who delivered                 ASA. However, many of them included in their cohort both
at the same hospital as the current study has been previously            hereditary and acquired thrombophilias and first and late
published.17 When those control group observations are                   third trimester fetal losses. None included a placebo group.
compared to our current results, the prevalence of Factor V              Paidas et al.22 reported results from a cohort study of use of
Leiden mutation, Factor II mutation, and MTHFR C677T                     LMWH or unfractionated heparin in women with prior
mutation are much higher in the present study cohort. The                adverse pregnancy outcomes. These authors used a study
risk of thrombophilia may have been overestimated                        design similar to our study. The outcomes of pregnancies
because of selection bias, because charts were selected on               treated with prenatal heparin administration in the index
the basis of an indexed pregnancy and the identification of              pregnancy were compared to the outcomes of previous
prophylactic therapy. Furthermore, data from this retro-                 untreated pregnancies in these 41 women. Women who
spective study do not indicate the prevalence of adverse                 received prenatal heparin therapy had a nearly 80% reduction
outcomes in an obstetrical population of women without                   in the risk of overall adverse pregnancy outcome compared

                                                                                                    OCTOBER JOGC OCTOBRE 2007 l      791

      Table 4. Probability of developing preeclampsia or fetal growth restriction in relation to a specific
      prophylactic therapy in all women

      Complication                        Treatments                        OR                         95% CI                P

      Preeclampsia                         Dalteparin                      0.92*                      0.78–1.1              0.26
                                              ASA                          0.87†                      0.76–1.0              0.06
                                       Dalteparin + ASA                    0.80‡                      0.70–0.91             0.001
      Fetal growth restriction             Dalteparin                      0.81*                      0.70–0.94             0.005
                                              ASA                          0.88†                      0.77–1.0              0.06
                                       Dalteparin + ASA                    0.70‡                      0.60–0.82           < 0.001
      *Adjusted for ASA.
      †Adjusted for dalteparin.
      ‡For combined therapy versus no therapy groups (pregnancies with only ASA or only dalteparin. use were excluded)

      Table 5. Probability of developing preeclampsia or fetal growth restriction in relation to a specific prophylactic
      therapy in women having at least one complication in first pregnancy (31 subjects, total of 82 pregnancies)

      Complications                       Treatments                        OR                          95% CI               P

      Preeclampsia                         Dalteparin                      0.88*                       0.73–1.1             0.17
                                              ASA                          0.85†                       0.70–1.0             0.12
                                       Dalteparin + ASA                    0.75‡                       0.62–0.90            0.002
      Fetal growth restriction             Dalteparin                      0.75*                       0.62–0.91            0.003
                                              ASA                          0.87†                       0.74–1.1             0.18
                                       Dalteparin + ASA                    0.65‡                       0.54–0.80           < 0.001
      *Adjusted for ASA.
      †Adjusted for Dalteparin.
      ‡For combined therapy versus no therapy groups (pregnancies with only ASA or only dalteparin use were excluded).

to untreated controls (OR 0.21; 95% CI 0.11–0.39, P <                            29 331 women: relative risk [RR] 0.85; 95% CI 0.78–0.92)
0.05). This beneficial effect was still present when first                       and a 14% reduction in the risk of fetal or neonatal death
trimester losses were excluded (OR 0.46; 95% CI 0.23–0.94,                       (30 trials with 30 093 women: RR 0.86; 95% CI 0.75–0.99).8
P < 0.05).                                                                       We obtained similar results in our cohort, finding a 13%
                                                                                 and 12% reduction in the respective risks of preeclampsia
A recent randomized trial showed that in women with at                           and FGR with use of low-dose ASA. No data on the use of
least one fetal loss after the tenth week of amenorrhea, pro-                    combined ASA and LMWH in a randomized trial are yet
phylactic administration of LMWH increased the live birth                        available.
rate by a factor of three in women with factor V Leiden
mutation, and by a factor of 11 in women with protein S                          Currently, the clinical management of women with inher-
deficiency when compared with the effects of ASA alone.9                         ited thrombophilias during pregnancy is based upon the
Birth weights were higher and there were fewer                                   results of small studies that are either retrospective cohort
small-for-gestational-age newborns in the LMWH group.                            or case-control studies. This study reports data from a ret-
In our study, we observed similar efficacy of LMWH and                           rospective cohort study; the reliability of the findings is
ASA in the prevention of adverse obstetrical outcomes.                           therefore limited by the study design and must be inter-
From our observations, combined therapy had a superior                           preted with caution. There are no prospective randomized
effect.                                                                          trials including an untreated control group that could con-
                                                                                 firm the benefits of LMWH therapy in this setting. How-
In a systematic review, Duley et al. demonstrated that use of                    ever, the results obtained from this retrospective study
antiplatelet agents, mostly low-dose ASA, is associated with                     merit further investigation. For future study, we will need to
a 15% reduction in the risk of preeclampsia (32 trials with                      consider the timing of the adverse obstetric event and the

                        Dalteparin and Low-Dose Aspirin in the Prevention of Adverse Obstetric Outcomes in Women With Inherited Thrombophilia

type of thrombophilia, and to distinguish between women                             Definitions, evaluation and classification of hypertensive disorders in
                                                                                    pregnancy. CMAJ 1997;157:715–25.
with a history of normal pregnancies and women with both
normal and abnormal pregnancies. Indeed, a placebo-                              13. Arbuckle TE, Wilkins R, Sherman GJ. Birth weight percentiles by
                                                                                     gestational age in Canada. Obstet Gynecol 1993;81:39–48.
controlled trial may not be feasible, since women at higher
                                                                                 14. Odegard OR, Lie M, Abildgaard U. Heparin cofactor activity measured with
risk for a bad outcome would likely be reluctant to be                               an amidolytic method. Thromb Res 1975;6:287–94.
assigned to no treatment. In our study, although results are
                                                                                 15. Wolf M, Boyer-Neumann C, Martinoli JL, Leroy-Matheron C, Amiral J,
limited by the retrospective study design, the small sample                          Meyer D, et al. A new functional assay for human protein S activity using
size, and the use of historical controls (untreated pregnan-                         factor V as substrate. Thromb Haemost 1989;4:1144–5.
cies in the same women), the results suggest that there are                      16. Infante-Rivard C, Rivard GE, Gauthier R, ThéorLt Y. Unexpected
beneficial effects with administration of combined LMWH                              relationship between plasma homocysteine and intrauterine growth
and ASA for the prevention of adverse outcomes in women                              restriction. Clin Chem 2003;49:1476–82.
with hereditary thrombophilias.                                                  17. Infante-Rivard C, Rivard GE, Yotov WV, Génin E, Guiguet M, Weinberg
                                                                                     C, et al. Absence of association of thrombophilia polymorphisms with
CONCLUSION                                                                           intrauterine growth restriction. N Engl J Med 2002;347:19–25.
                                                                                 18. Lipsitz SH, Kim K, Zhao L. Analysis of repeated categorical data using
Combined treatment with LMWH (dalteparin) and                                        generalized estimating equations. Stat Med 1994;13:1149–63.
low-dose ASA decreases the risk of preeclampsia by 20%                           19. Paidas MJ, Ku DH, Arkel YS. Screening and management of inherited
and fetal growth restriction by 30% in women with inher-                             thrombophilias in the setting of adverse pregnancy outcome. Clin Perinatol
ited thrombophilia. These results merit future investigation                         2004;31:783–805.
in a prospective randomized trial.                                               20. Surkan PJ, Stephansson O, Dickman PW, Cnattingius S. Previous preterm
                                                                                     and small for gestational age births and the subsequent risk of stillbirth.
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