Abstract
Background
Thrombophilias, which are associated with a predisposition to thrombotic events, have been implicated in adverse obstetrical outcomes such as intrauterine growth restriction, stillbirth, severe early onset pre‐eclampsia, and placental abruption. Heparin administration in pregnancy may reduce the risk of these events.
Objectives
The objective of this review was to assess the effects of heparin on pregnancy outcomes for women with a thrombophilia.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (July 2002), MEDLINE, EMBASE, CINAHL, Scidex (via OVID Technologies ‐ July 2002) and reference lists and personal files. We updated the search of the Cochrane Pregnancy and Childbirth Group's Trials Register on 3 August 2012 and added the results to the awaiting classification section.
Selection criteria
Randomized controlled trials comparing heparin with placebo or no treatment, or randomized controlled trials comparing any two treatments. Quasi randomized studies would be included.
Data collection and analysis
Data would be abstracted from identified studies and recorded on a paper form by two reviewers.
Main results
No studies were included.
Authors' conclusions
There are no completed trials to determine the effects of heparin on pregnancy outcomes for women with a thrombophilia.
[Note: The 23 citations in the awaiting classification section of the review may alter the conclusions of the review once assessed.]
Keywords: Female; Humans; Pregnancy; Anticoagulants; Anticoagulants/therapeutic use; Heparin; Heparin/therapeutic use; Pregnancy Complications, Hematologic; Pregnancy Complications, Hematologic/drug therapy; Thrombophilia; Thrombophilia/drug therapy
Plain language summary
Heparin for pregnant women with acquired or inherited thrombophilias
No evidence from trials on the effects of heparin on pregnancy outcomes for women with a thrombophilia.
Thrombophilias are a group of disorders where the person's blood is prone to thrombosis (clotting). These blood clots can cause life‐threatening complications such as DVT (deep vein thrombosis). Thrombophilia can cause a number of serious complications in pregnancy, such as growth restriction, stillbirth and severe pre‐eclampsia. Heparin is an anti‐clotting drug which thins the blood. It does not seem to have adverse effects on the baby during pregnancy, and few adverse effects on the pregnant woman. However, the review found no trials on the effects of heparin on pregnancy outcomes for women with a thrombophilia.
Background
Thrombophilias are a diverse group of coagulation disorders associated with a predisposition to thrombotic (clotting) events. These hypercoagulable states can be either inherited or acquired. Inherited thrombophilias include the prothrombin gene mutation (resulting in increased concentration of prothrombin in plasma) and activated protein C resistance (APCR ‐ almost always secondary to factor V Leiden mutation, which results in failure of inactivation of activated factor V). Other inherited thrombophilias are deficiency of physiological anticoagulants protein C, protein S and antithrombin. Acquired thrombophilias include those associated with antiphospholipid antibodies, generally anticardiolipin antibodies and lupus anticoagulant. Hyperhomocysteinemia (elevated fasting plasma homocysteine) can be inherited or acquired. These disorders have been strongly associated with venous thromboembolism such as deep vein thrombosis and potentially fatal pulmonary embolism. However, a number of recent publications have implicated these disorders in adverse obstetrical events such as intrauterine growth restriction, stillbirth, severe early onset pre‐eclampsia, and placental abruption.
Pre‐eclampsia
Pre‐eclampsia, defined as proteinuric hypertension in pregnancy, is a disorder that results from impaired placental development and function. The presence of thrombophilias has been found to significantly increase the risk of developing pre‐eclampsia. The prevalence of factor V Leiden mutation, hyperhomocysteinemia and protein S deficiency are increased in women who have a history of pre‐eclampsia compared with women with a history of normal obstetric outcome. Published data come from case series (Dekker 1995; Rotmensch 1997; Kahn 1998; Leeda 1998; Nagy 1998) and case control studies of varying size and quality (Dizon‐Townson 1996; Lindoff 1997; Rajkovic 1997; Krauss 1998; Kupferminc 1999).
The incidence of APCR in women with a history of pre‐eclampsia ranges from 16% to 33% (Dizon‐Townson 1996; Lindoff 1997; Krauss 1998). The factor V Leiden mutation was found in approximately 60% to 100% of those with APCR, the vast majority being heterozygous for the mutation (Lindoff 1997; Krauss 1998). Furthermore, a case control study has reported an 8.9% incidence of APCR in women with pre‐eclampsia compared with 4.2% in normal pregnancy controls (Dizon‐Townson 1996). In two other case control studies, the calculated odds ratios and 95% confidence interval for the development of severe pre‐eclampsia were 5.3 (1.8 to 15.6) (Kupferminc 1999) and 4.3 (1.2 to 15.7) (Nagy 1998).
Hyperhomocysteinemia has been found to be associated with the development of pre‐eclampsia (Dekker 1995; Rajkovic 1997; Sohda 1997; Powers 1998; Kupferminc 1999). The hyperhomocysteinemia in pre‐eclamptic pregnancies has been linked to endothelial activation (Powers 1998) suggesting that homocysteine may play a role in promoting the endothelial dysfunction seen in pre‐eclampsia.
There is less information about the association of other inherited thrombophilias with the risk of pre‐eclampsia. In one study, 25% of women with a past history of severe, early‐onset pre‐eclampsia were found to have protein S deficiency (Dekker 1995), several of whom had multiple thrombophilias that included protein S deficiency. The prothrombin gene defect was not significantly associated with pre‐eclampsia (odds ratio: 2.2; 95% confidence interval: 0.4 to 13.9) in another study (Kupferminc 1999). Neither protein C nor antithrombin III deficiencies has been shown to be associated with pre‐eclampsia (Dekker 1995) although the latter defect is rare in the general population (Dekker 1995).
Placental abruption and placental infarction
There is evidence of an association between thrombophilias and placental abruption but the quality of relevant studies is poor. In a series of 21 women whose index pregnancy was complicated by placental abruption, homocysteine levels were significantly higher than in controls (7.9 versus 5.1 umol/L) (Owen 1997). However, this study did not categorize the women into those with and without hyperhomocysteinemia ‐ a distinction that would have been more meaningful clinically. Also, this study did not have a clear definition of placental abruption.
Resistance to activated protein C was studied in 27 women with placental abruption (Wiener‐Megnagi 1998). In the pregnant women with placental abruption, 17 out of 27 had APCR, compared with five out of 29 controls (odds ratio (OR): 8.16; 95% confidence interval (CI): 3.6 to 12.8). This study used a cut‐off of APCR of 2.5 which is much higher than the usual convention. Also, the researchers only performed DNA analysis for factor V Leiden mutation on a small subset of the women.
In a study of 84 women with placental abruption or infarction defined by strict clinical, laboratory and histologic standards, 31% had hyperhomocysteinemia compared with 9% of controls (p 0.05) (Goddijn‐Wessel 1996).
De Vries et al (de Vries 1997) found that in a series of 31 women with placental abruption, 65% tested positive for a thrombophilia. They found 27 coagulation abnormalities in 20 women. The thrombophilias that they identified were low protein S, hyperhomocysteinemia and anticardiolipin antibodies.
Placental infarction and the prevalence of factor V Leiden mutation has been studied in a prospective cohort study of 396 women whose placentas were categorized dichotomously as having greater than or equal to, or less than 10% infarction. There was a 10‐fold increase in factor V Leiden mutation heterozygote status in the infarction group (Dizon‐Townson 1997).
Intrauterine growth restriction and stillbirth
Small‐for‐gestational age babies are typically defined as having birthweights less than the 10th percentile for gestational age, and this group will include babies that are 'growth restricted'. In the large EPCOT (European Prospective Cohort on Thrombophilia) trial, pregnancy outcomes were compared in women with a known thrombophilia (N = 571 women, 1524 pregnancies) and controls (N = 395 women, 1019 pregnancies) (Preston 1996). Significantly more stillbirths occurred in women with a thrombophilia than in the controls. The highest odds for stillbirth were seen in women with combined thrombophilia defects (OR: 14.3; 95% CI: 2.4 to 86.0). Stillbirths were seen only in women with antithrombin III, protein C, and protein S deficiency.
In the previously cited case series by de Vries et al (de Vries 1997), 56% (10/18) of mothers with stillbirths and 85% (11/13) of mothers with a small‐for‐gestational age infant had a thrombophilia. They identified abnormalities in protein S, hyperhomocysteinemia, and high anticardiolipin titers in association with these outcomes. In another case control study of genetic thrombophilia in women with complications of pregnancy, 48% (27/56) of mothers with a history of stillbirth or a small‐for‐gestational age infant with IUGR had a thrombophilia (Kupferminc 1999).
Prevention of adverse obstetrical outcomes in women with thrombophilia
There is very little research on the prevention of adverse obstetrical outcomes in women with thrombophilia. Heparin, through its antithrombotic activity, could potentially improve perinatal outcome in these pregnancies. However, one case series where low molecular weight heparin combined with aspirin was used to treat 26 thrombophilic women with a history of pre‐eclampsia or fetal growth restriction showed heparin did not have a significant effect on birthweight, pre‐eclampsia or fetal growth in the subsequent pregnancy (Riyazi 1998).
Potential adverse effects of heparin
Heparin does not cross the placenta and does not appear to have teratogenic effects in animal studies. Heparin administration may cause pain and slight bruising at injection sites. The risks of heparin administration seem uncommon but include bleeding, heparin‐induced thrombocytopenia (HIT) and heparin‐induced osteopenia with fractures.
The aim of this review is to provide up to date information on the potential benefits and harms of heparin in thrombophilic pregnant women.
Objectives
The objective of this review was to determine whether or not heparin use in pregnant women with a thrombophilia improved pregnancy outcome. Specifically, the objective was to determine whether or not heparin decreased the incidence of the following perinatal outcomes in women with a thrombophilia:
stillbirth;
intrauterine growth restriction;
placental abruption;
pre‐eclampsia.
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled trials comparing heparin with placebo or no treatment, or randomized controlled trials comparing any two treatments. Quasi randomized studies would be included. Publications in abstract form alone were not considered.
Types of participants
Participants were pregnant women with a diagnosis of a thrombophilic disorder. They did not necessarily have a previously poor obstetrical history. Thrombophilias were either inherited or acquired.
Inherited thrombophilias:
factor V Leiden mutation;
prothrombin gene mutation;
protein S deficiency;
protein C deficiency;
antithrombin III deficiency.
Acquired thrombophilias:
anticardiolipin antibodies;
lupus anticoagulant;
hyperhomocysteinemia.
Types of interventions
The intervention was the subcutaneous injection of heparin. We included both unfractionated and low molecular weight heparin.
Types of outcome measures
Outcome measures were either a composite of perinatal morbidity and mortality or individual outcomes including the following:
Stillbirth.
Small for gestational age (as a surrogate for intrauterine growth restriction (IUGR)) ‐ which was defined as birthweight less than 10th percentile for gestational age.
Placental abruption ‐ significant antepartum hemorrhage in the absence of any other identifiable cause such as placenta previa.
Pre‐eclampsia was defined as proteinuric hypertension in pregnancy, where blood pressure was greater than 140/90 or 30/15 above baseline with proteinuria, either two plus on dip stick or 300 mg in a 24 hour period.
Maternal outcomes included thromboembolic disease and side‐effects of treatment.
Search methods for identification of studies
Electronic searches
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (July 2002). We updated this search on 3 August 2012 and added the results to Studies awaiting classification.
The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co‐ordinator and contains trials identified from:
monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
weekly searches of MEDLINE;
weekly searches of EMBASE;
handsearches of 30 journals and the proceedings of major conferences;
weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.
Details of the search strategies for CENTRAL, MEDLINE and EMBASE, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.
In addition, we searched the following: MEDLINE, EMBASE, CINAHL and Scidex on 1 July 2002 using the search strategy in Appendix 1 via OVID Technologies.
Searching other resources
We also searched reference lists and personal files.
We did not apply any language restrictions.
Data collection and analysis
Data were to be abstracted from identified studies and recorded on a paper form. This would be done by two reviewers. Disagreements would be settled by discussion between the reviewers to reach a consensus. Authors were to be contacted as needed for additional information.
Meta‐analyses were to be performed with the fixed effects model. Heterogeneity between trial results was to be assessed using a standard chi‐squared test. Odds ratios were to be calculated using the 'Peto method'.
Subgroup analysis would, if appropriate, be performed for the following:
therapeutic versus prophylactic doses of heparin;
heparin versus placebo and heparin compared with no treatment.
Studies meeting the inclusion criteria would be assessed for methodological quality using the following attributes:
blinding of randomization;
blinding of intervention;
complete follow up;
blinding of outcome measure;
analysis by intention to treat.
Results
Description of studies
No completed studies were included. See the table of Characteristics of ongoing studies. (Twenty‐three reports from an updated search in August 2012 have been added to Studies awaiting classification.)
Risk of bias in included studies
No completed studies were identified.
Effects of interventions
There were no included trials.
Discussion
No completed randomised trials were identified.
Authors' conclusions
Implications for practice.
There is no information from randomised trials which could influence current practice.
Implications for research.
Further studies are required to evaluate the effect of heparin on pregnancy outcomes for women with a thrombophilia. Two randomised studies are currently ongoing and may provide additional information.
[Note: The 23 citations in the awaiting classification section of the review may alter the conclusions of the review once assessed.]
Feedback
Cundiff, July 2007
Summary
Relevant randomised trials were ongoing at the time of publication of this review. One is now published and compared dalteparin (5,000 units/day until 20 weeks then 5,000 units 12 hourly until 37 weeks or onset of labor) to no treatment [1]. Prophylaxis with dalteparin at doses used in this study did not reduce coagulation activation in high risk thrombophilic women during pregnancy. No clinical data have been reported.
Despite the lack of evidence from randomised trials, opinion‐based treatment guidelines for pregnant women with thrombophilia by the Royal College of Obstetricians and Gynaecologists and the American College of Chest Physicians include giving thromboprophylaxis [2, 3].
Given the risks of heparin, the implications for practice section in the review should say that heparin should not be used for pregnant women with acquired or inherited thrombophilias outside of a randomised trial, with either a placebo or antiplatelet agent for the control group.
1. Abou‐Nassar K, Kovacs MJ, Kahn SR, et al. The effect of dalteparin on coagulation activation during pregnancy in women with thrombophilia. A randomized trial. Thromb Haemost 2007; 98(1):163‐171. 2. Thromboprophylaxis during pregnancy, labour and after vaginal delivery. Royal College of Obstetricians and Gynaecologists: London (UK). 2004 (Guideline; no. 37). Available at: http://www.rcog.org.uk/resources/Public/pdf/Thromboprophylaxis_no037.pdf. 3. Bates SM, Greer IA, Hirsh J, Ginsberg JS. Use of antithrombotic agents during pregnancy: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(3_suppl):627S‐644.
(Summary of comment from David K Cundiff, July 2007)
Reply
We agree with the comment and we will amend the review when we update it.
(Reply from Mark Walker, February 2008)
Contributors
Feedback: David K Cundiff Reply: Mark Walker
What's new
| Date | Event | Description |
|---|---|---|
| 3 August 2012 | Amended | Search updated. Twenty‐three reports added to Studies awaiting classification. |
History
Protocol first published: Issue 2, 2002 Review first published: Issue 2, 2003
| Date | Event | Description |
|---|---|---|
| 19 February 2008 | Amended | Converted to new review format. |
| 19 February 2008 | Feedback has been incorporated | Reply from author to previously published feedback. |
| 13 November 2007 | Feedback has been incorporated | Feedback from DK Cundiff added. |
Notes
This review will be updated by a new review team following the publication of a new protocol.
Acknowledgements
Dr Arne Ohlsson for his teaching and promotion of the Cochrane Collaboration.
Appendices
Appendix 1. search strategy
pregnancy complications/
infant mortality/
1 or 2
exp heparin/
randomized controlled trial.pt.
controlled clinical trial.pt.
exp clinical trials/
5 or 6 or 7
exp thrombophilia/
exp Factor V
Factor V deficiency/
prothrombin/
antiphospholipid syndrome/
exp blood coagulation factor inhibitors/
exp antibodies, antiphospholipid/
exp blood coagulation disorders/
hyperhomocysteinemia/
or/9‐17
3 and 4 and 8 and 18
Characteristics of studies
Characteristics of ongoing studies [ordered by study ID]
de Vries 2000.
| Trial name or title | Low molecular weight heparin (FRagmin) in pregnant women with a history of Uteroplacental Insufficiency and Thrombophilia (The FRUIT study). |
| Methods | |
| Participants | Pregnant women with a previous history of pre‐eclampsia or small for gestational age infants (< 10 percentile) before 34 weeks' gestation and a documented inherited thrombophilia. |
| Interventions | Low molecular weight heparin (Fragmin) and low dose aspirin (100 mg per day) for treatment group and low dose aspirin only for control group. |
| Outcomes | Primary outcome is reduction in recurrence of pre‐eclampsia. Secondary outcome is reduction in the recurrence of small for gestational age infants. Other endpoints include reduction of spontaneous abortion, preterm birth, maternal admission to the hospital and NICU admission. |
| Starting date | |
| Contact information | JIP de Vries, Division of Maternal‐Fetal Medicine, University Hospital, Free University Amsterdam. |
| Notes |
Rodgers 2000.
| Trial name or title | Thrombophilia in Pregnancy Prophylaxis Study (TIPPS). |
| Methods | |
| Participants | Pregnant women with a documented thrombophilia. |
| Interventions | Low molecular weight heparin. |
| Outcomes | Pre‐eclampsia, stillbirth, IUGR, spontaneous abortion, placental abruption, and venous thromboembolism. |
| Starting date | July 2000 |
| Contact information | Mark Rodgers, Ottawa General Hospital, 501 Smyth Road, Ottawa, Ontario Canada K1H 8L6. |
| Notes |
NICU: neonatal intensive care unit IUGR: intrauterine growth restriction
Contributions of authors
1. Mark Walker Developed and wrote first draft of the protocol and review. One of the reviewers who evaluated the studies identified by the search strategy. 2. Victoria Allen Edited second draft of protocol and review. One of the reviewers who evaluated the studies identified by the search strategy. 3. Sarah Ferguson Edited first draft of protocol and co‐wrote second draft of protocol and review. Developed the search strategy to identify appropriate studies for the review.
Sources of support
Internal sources
No sources of support supplied
External sources
Ministry of Health Career Scientist Award, Canada.
Declarations of interest
None known.
Edited (no change to conclusions)
References
References to studies awaiting assessment
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