Abstract
Background
Pregnant women with a history of venous thromboembolism (VTE), antithrombin deficiency, or other risk factors for VTE, need heparin (unfractionated heparin (UFH) or low‐molecular weight heparin (LMWH)) prophylaxis, mainly through administering subcutaneously. Several methods of administering heparin (UFH or LMWH) subcutaneously have been introduced to prevent adverse pregnant outcomes. The effectiveness and safety of different methods administering subcutaneous heparin (UFH or LMWH) during pregnancy have not been systematically evaluated.
Objectives
To compare the effectiveness and safety of different methods of administering subcutaneous heparin (UFH or LMWH) to pregnant women.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2013) and reference lists of retrieved studies.
Selection criteria
All randomised controlled trials (individual and cluster) comparing the effectiveness and safety of different methods of administering subcutaneous heparin (UFH or LMWH) during pregnancy. Studies reported only as abstracts were eligible for inclusion and would have been placed in studies awaiting assessment, pending the full publication of their results. Quasi‐randomised studies and cross‐over trials were not eligible for inclusion..
Methods of administering subcutaneous heparin include intermittent injections versus indwelling catheters or programmable (auto) external infusion pumps, or any other devices to facilitate the subcutaneous administration of heparin (UFH or LMWH) during pregnancy.
Data collection and analysis
If eligible trials had been identified, trial quality would have been assessed and data extracted, unblinded by review authors independently.
Main results
No trials met the inclusion criteria for the review.
Authors' conclusions
There is no evidence from randomised controlled trials to evaluate the effectiveness and safety of different methods of administering subcutaneous heparin (UFH or LMWH) to pregnant women.
Keywords: Female; Humans; Pregnancy; Anticoagulants; Anticoagulants/administration & dosage; Heparin; Heparin/administration & dosage; Heparin, Low‐Molecular‐Weight; Heparin, Low‐Molecular‐Weight/administration & dosage; Injections, Subcutaneous; Injections, Subcutaneous/methods; Pregnancy Complications, Hematologic; Pregnancy Complications, Hematologic/drug therapy; Venous Thromboembolism; Venous Thromboembolism/drug therapy
Plain language summary
Methods for administering subcutaneous heparin during pregnancy
There is no evidence from randomised controlled trials to evaluate the best method of administering subcutaneous heparin to pregnant women.
Pregnant women have an increased risk of venous thromboembolism (VTE) when compared with non‐pregnant women because of changes in blood clotting. VTE includes deep vein thrombosis (DVT) and pulmonary embolism (PE). DVT is a clot in the deep veins of the leg blocking blood flow; parts of the clot may break away and be carried in the blood to the lungs, to form a PE. DVT is potentially, and PE is definitely, life‐threatening for both mother and baby. Pregnant women with a history of VTE, antithrombin deficiency, or other risk factors for VTE are at an even greater risk and need heparin for prevention of VTE (prophylaxis). Although receiving subcutaneous heparin (either unfractionated heparin (UFH) or low molecular weight heparin (LMWH)) is the main option in the prevention of VTE during pregnancy, the management of thromboprophylaxis in pregnant women has mostly relied on the evidence from non‐pregnant participants. Methods of receiving heparin subcutaneously include giving an injection at regular intervals, or using an indwelling catheter and an infusion pump. Women's satisfaction with receiving subcutaneous heparin is highly important as thromboprophylaxis in pregnancy involves a cost burden, inconvenience, and side effects as a result of a longer duration. Some women may not self‐administer heparin and must rely on others to give them their injections otherwise they stop using the heparin, thus exposing themselves to an increased risk of VTE. However, this review found no randomised controlled trials to show which methods of receiving subcutaneous heparin are effective and safe for pregnant women.
Background
Description of the condition
Pregnancy is associated with physiologic and anatomic changes that increase the risk of venous thromboembolism ((VTE) from the first trimester (James 2011). The true incidence of VTE associated with pregnancy is unknown, yet there is a strong clinical indication of an increased risk when compared with non‐pregnant women (Bates 2004). The estimated incidence varies from 0.76 to 1.72 per 1000 pregnancies, which is four times greater than among the non‐pregnant population (Marik 2008).
The main reason for the increased risk of VTE in pregnancy is the hypercoagulability that occurs and which protects women from haemorrhaging at the time of miscarriage or childbirth (James 2009). The most important risk factors for VTE in pregnancy are personal history of thrombosis and thrombophilia (a hereditary or acquired predisposition to thrombosis) (James 2006; RCOG 2009). Other risk factors include medical comorbidities (e.g. heart or lung disease, cancer), over 35 years of age, obesity, hypertension, smoking and having a delivery by caesarean section (Bauersachs 2007; RCOG 2009).
VTE includes deep vein thrombosis (DVT) and pulmonary embolism (PE). DVT is the result of an occlusive clot formation in the deep veins of the leg, from which parts of the clot frequently embolise to the lungs resulting in PE (Fauci 2008). From 75% to 80% of pregnancy‐associated VTE comes in the form of DVT, while 20% to 25% is PE (James 2006). Because DVT is potentially, and PE is definitely, life‐threatening for both mother and fetus, those pregnant women with a high risk of VTE require anticoagulation medications in order to prevent the incidence or recurrence of thrombosis.
Caution is advised in the use of anticoagulation therapy in pregnancy with especial regard to the health of both mother and fetus. Hepain compounds are the preferred anticoagulants in pregnancy (James 2011). Administering heparin carries the risk of bleeding, osteoporosis and heparin‐induced thrombocytopenia (HIT) (Bates 2004). However, James 2009 reported that the rate of recurrent VTE in women who did not receive anticoagulation with heparin varies from 2.4% to 12.2%, while the rate of recurrent VTE in women who did receive anticoagulation ranges from 0% to 2.4%. This shows that receiving heparin as an anticoagulant significantly reduced the risk of recurrent VTE during pregnancy.
The signs and symptoms of DVT, such as swelling, pain, redness, superficial venous dilatation, and Homan's sign (a pain in the calf or behind the knee on dorsiflexion of the ankle), are non‐specific (Fauci 2008). This is because some of the symptoms of DVT are similar to common symptoms that manifest themselves during pregnancy (Barbour 2001). Clinical suspicions are confirmed in 10% of pregnant women, compared with 25% of non‐pregnant participants (Ginsberg 1998).
As regards DVT, compression ultrasonography carries no risk and is the preferred initial test in pregnant women with suspected VTE (Marik 2008). When the results are negative or equivocal and iliac venous thrombosis is suspected, additional confirmatory testing with magnetic resonance imaging (MRI) is recommended (Nijkeuter 2006); MRI does not involve radiation exposure and is not harmful to the fetus (Fraser 2002; Rodger 2006). The use of D‐dimer testing in pregnancy is potentially limited by the level of D‐dimer which increases with the progression of a normal pregnancy, thus, a combination of the D‐dimer level test with other tests is recommended (Nijkeuter 2006).
The signs and symptoms of PE, such as dyspnoea, pleuritic chest pain, cough, and haemoptysis, are also non‐specific. Ventilation‐perfusion scanning is a reasonable first choice for diagnosing PE in pregnancy that gives less radiation exposure to maternal breast tissue and fetus (Chunilal 2009). Computed tomographic (CT) scanning is also the test of choice with relatively low radiation exposure for the fetus, yet concerns about maternal breast radiation exposure remain (James 2011). Women with suspected PE should be informed that these tests carry the risk of potential radiation exposure.
Although maternal mortality from PE can be reduced by conducting a clinical investigation among symptomatic women and by anticoagulation regimens in women with an increased risk of DVT, PE, or both, it is controversial because a clinical evaluation (e.g. a lung scan) exposes the fetus to radiation, and long‐term anticoagulation medications may be inconvenient and painful for women.
Description of the intervention
The anticoagulant, unfractionated heparin (UFH) is administered subcutaneously or intravenously and low molecular weight heparin (LMWH) is usually administered subcutaneously. These are the anticoagulants of choice during pregnancy, due to their established efficacy (Bates 2004) that has been demonstrated in pregnant women with DVT (Fauci 2008). Unlike other anticoagulants such as vitamin K antagonists (e.g. warfarin), both UFH and LMWH have no placental transfer (Bates 2008).
The potential risks of administering heparin ‐ bleeding, osteoporosis and HIT ‐ differ between UFH and LMWH. In one study (Ginsberg 1989), the rate of major bleeding in pregnant women receiving UFH was 2%, which is consistent with the reported rates of bleeding associated with administering heparin in non‐pregnant women (Hull 1982a) and with warfarin therapy (Hull 1982b) when used for the treatment of DVT. In contrast, complications resulting from bleeding in pregnant women receiving LMWH are uncommon. Moreover, there was no statistically significant difference in bone loss between those who received LMWH and those who were untreated, suggesting that bone loss associated with prophylactic LMWH therapy is no different from the normal physiologic losses that occur during pregnancy (Carlin 2004). However, bone density was significantly lower in those receiving UFH compared with both those who were not treated and those who received the LMWH dalteparin (Monreal 1994). The risk of HIT with heparins is also low and may be lower with LMWH than with UFH, although as yet the actual risk is still unclear (Bates 2008). LMWHs are now commonly used for prophylaxis of maternal thromboembolism (Bates 2012) because they are at least as effective as and safer than UFH (RCOG 2009).
Methods of administering heparin subcutaneously include giving an intermittent injection, or using an indwelling catheter and an infusion pump. For prophylaxis with intermittent subcutaneous injections, UFH is usually given in fixed doses of 5000 U two or three times per day in non‐pregnant participants. With these low doses, it is unnecessary to monitor coagulation, but monitoring is required when it is given for treatment (Fauci 2008). However, there is concern that this low dose may be insufficient in high‐risk groups, including pregnant women with prior VTE, because it does not reliably produce detectable heparin (UFH) levels (Bates 2008).
The duration and doses of subcutaneous LMWH during pregnancy vary depending on guidelines and studies. For prophylaxis, several dose regimens of LMWHs have been used, including administering subcutaneous enoxaparin 40 mg per 24 hours (Gates 2004), dalteparin 5000 U per 24 hours (Pettila 1999; Rey 2000), and an adjusted dose of LMWH to achieve a peak anti‐Xa level of 0.2 to 0.4 U/mL (Blomback 1998; Dulitzki 1996).
Rey 2000 reported that dalteparin 5000 U per 24 hours was suitable for most pregnant women and did not need to be modified in the third trimester because anti‐Xa activity levels did not vary significantly throughout pregnancy. In contrast, with the same regimen, where 5000 U of dalteparin was administered once daily, the mean anti‐Xa level at 12, 24, and 36 week's gestation was significantly reduced at two hours post‐injection when compared with postpartum (Sephton 2003). This suggests that there are inter‐ and intra‐individual handling differences as pregnancy progresses.
The Duke protocol (James 2005) reflects the increasing requirements for both UFH and LMWH as pregnancy progresses: UFH 5000 U subcutaneously per 12 hours before eight weeks, 7500 U subcutaneously per 12 hours from eight to 28 weeks, then 10,000 U subcutaneously per 12 hours after 28 weeks; or enoxaparin (LMWH) 30 mg twice‐daily before 28 weeks, then 40 mg twice daily after 28 weeks. Although higher dosages ranging from UFH 13,000 to 40,000 per 24 hours (mean 19,100 U per 24 hours) with 25 weeks of the average duration of prevention have been given, a 2.7% (five out of 184) recurrence of thrombotic events was recorded in spite of the high‐dose prophylaxis (Dahlman 1993). Barbour 1995 also concluded that the adjusted high dose of UFH 7500 U to 10,000 per 12 hours may be reasonable in the second and third trimester as long as the activated partial thromboplastin time (aPTT) is not significantly elevated, while prophylaxis with low‐dose anticoagulation is recommended for pregnant women with a history of thrombosis (Bates 2004).
One study (Anderson 1993) has investigated the comparative effectiveness and safety of using an indwelling Teflon catheter and a subcutaneous injection. Teflon catheters were inserted over an introducer steel needle at a 30o angle into the subcutaneous tissues of the abdomen by means of a sterile technique. After removal of the needle, the catheter was fixed in place with an adhesive foam pad. UFH was injected slowly, twice daily, through an external port at the proximal end of the indwelling Teflon catheter by means of an insulin syringe and a 25‐gauge needle. The entire catheter was 3.5 cm in length with the Teflon portion that was inserted subcutaneously being 2 cm in length. Catheters were changed weekly to reduce the risk of infection. There were no differences in the mean heparin dose or aPTT between the two methods of heparin administration. The study also used a questionnaire to obtain information from women about their preferred route of heparin administration. Of the 12 women interviewed, 11 reported that the catheter caused less pain and bruising than the subcutaneous injections given twice daily, although five women developed urticarial reactions at the sites of the injections and these reactions tended to be more severe when the catheter was used.
Another method of subcutaneous heparin delivery, using a programmable external infusion pump, has been compared with the use of an intermittent subcutaneous injection. In a retrospective study (Floyd 1991), the mean daily dose of UFH when using a subcutaneous infusion pump was higher (29,445 versus 13,822 U), resulting in smoother, more therapeutic heparinisation (mean aPTT, 20.6 versus 10.4 seconds above control) among the subcutaneous infusion pump group when compared with the intermittent subcutaneous injection group. There were two complications (haematoma, site infection) in the intermittent subcutaneous injection group, while none occurred in the subcutaneous infusion pump group. Although the results showed that there was no statistical significance in the smaller number of complications among the subcutaneous infusion pump group, when used in concert with weekly home visits, the subcutaneous infusion pump method nevertheless allowed the administration of the prevention to be more evenly controlled than did the use of intermittent subcutaneous injections.
How the intervention might work
Heparin (UFH and LMWH) acts as an anticoagulant by activating antithrombin and accelerating the rate at which antithrombin inhibits clotting enzymes, particularly thrombin and factor Xa (Fauci 2008). The administration of heparin (UFH and LMWH) protects pregnant women against the risk of producing a thrombosis that can develop into thromboembolism (DVT or PE).
Why it is important to do this review
First, although administering subcutaneous heparin (UFH or LMWH) is the main option in the prevention of VTE during pregnancy, the management of thromboprophylaxis in pregnant women has mostly relied on the evidence from non‐pregnant participants.
Second, thromboprophylaxis in pregnancy involves a cost burden, inconvenience and side effects as a result for a longer duration. Pregnant women who require anticoagulation therapy, especially those with a history of VTE and those on lifelong anticoagulation, will require a switch from the administration of warfarin to heparin‐related compounds (UFH and LMWH) (James 2007; James 2011) when conception has occurred and been detected, because of the effects of warfarin on the fetus. Heparin is more expensive than warfarin (Brill‐Edwards 2000) and LMWH is even more expensive than UFH (James 2011). There is a report that LMWH is at least 10 times the cost of low‐dose heparin in North America (Etchells 1999). It is clear that women who receive insufficient medical cost coverage face financial burdens. Furthermore, women in a region or country where self‐administration is not allowed may need to be hospitalised for the management of administering heparin throughout pregnancy. Others who self‐administer as outpatients require self‐management to inject several times a day depending on agents and dosage used, yet those who do not self‐administer heparin must rely on others to give them their injections otherwise they discontinue the administration, thus exposing themselves to an increased risk of VTE (Anderson 1993). Although bleeding in pregnant women receiving LMWH is uncommon, skin complications (Bank 2003) may occur due to repeated and long‐term injections.
Having considered the disadvantages and adverse effects of administering subcutaneous heparin (UFH or LMWH), women's satisfaction is highly important, since the effectiveness and safety of administering subcutaneous heparin (UFH or LMWH) during pregnancy using different methods is still not clear. This underscores the importance of conducting a systematic review to investigate the effectiveness and safety of different methods of administering subcutaneous heparin (UFH or LMWH) in this high‐risk of VTE group of pregnant women.
Objectives
To compare the effectiveness and safety of different methods of administering subcutaneous heparin (UFH or LMWH) to pregnant women.
Methods
Criteria for considering studies for this review
Types of studies
We planned to include all randomised controlled trials (individual and clustered) investigating methods for administering subcutaneous heparin (UFH or LMWH) during pregnancy. Studies reported only as abstracts were eligible for inclusion and would have been placed in studies awaiting assessment, pending the full publication of their results. Quasi‐randomised studies and cross‐over trials were not eligible for inclusion.
Types of participants
Women requiring heparin (UFH or LMWH) during pregnancy. We excluded pregnant women under intensive care.
Types of interventions
Intermittent injections versus indwelling catheters or programmable (auto) external infusion pumps, or any other devices to facilitate the subcutaneous administration of heparin (UFH or LMWH) during pregnancy.
Types of outcome measures
Primary outcomes
Women's satisfaction
Incidence of VTE
Secondary outcomes
Maternal death
Local and systemic bleeding (haemorrhage)
Pain
Urticarial reaction
Local and systemic infection and bruising
Withdrawal because of adverse events (discontinuation of heparin because of serious and threatened adverse events)
Pregnancy outcomes (e.g. miscarriage, fetal death)
Any adverse events reported by the included trials (e.g. osteoporosis, HIT)
Search methods for identification of studies
Electronic searches
We contacted the Trials Search Co‐ordinator to search the Cochrane Pregnancy and Childbirth Group’s Trials Register (31 January 2013).
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.
Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co‐ordinator searches the register for each review using the topic list rather than keywords.
Searching other resources
We searched the reference lists of relevant studies. We did not apply any language restrictions.
Data collection and analysis
Selection of studies
Two review authors independently assessed the inclusion of the one potential study identified as a result of the search strategy. We resolved any disagreement through discussion.
There are no included studies in this review. Full methods of data collection and analysis to be used in future updates of this review are provided in Appendix 1.
Results
Description of studies
Results of the search
The search of the Cochrane Pregnancy and Childbirth Group's Trials Register retrieved two reports relating to one trial that we subsequently excluded because the study was a randomised, multiple, cross‐over study (Anderson 1993). There are no included studies in this review.
Risk of bias in included studies
There are no included studies in this review.
Effects of interventions
There are no included studies in this review.
Discussion
It is disappointing that no randomised controlled trials are available to assess the effectiveness and safety of different methods of administering subcutaneous heparin (UFH or LMWH) to pregnant women.
The lack of relevant studies identified by the review reflects the ethical concerns that emerge in this population requiring heparin (UFH or LMWH) prophylaxis during pregnancy. Random allocation of women at risk of VTE to one method of administering subcutaneous heparin (UFH or LMWH) or another may not be acceptable to women or their families, and therefore, informed consent of the study would be difficult. Although VTE and thrombophilia are not rare, it may be difficult to complete such a trial, because of the difficulty of recruiting pregnant women with a previous VTE or with thrombophilia.
In a randomised, multiple, cross‐over study that has been excluded in this review, women alternated every two weeks between having heparin administered through the indwelling Teflon catheter and receiving heparin via subcutaneous injections. Ten of the 12 women in this trial preferred to have subcutaneous heparin administered through an indwelling Teflon catheter rather than by twice‐daily injections (P = .04), and 11 women reported that the catheter caused less pain and bruising than twice‐daily injections (P < .01). Although the interpretation of the result is limited by the small number of participants, it does indicate that the bioavailability of heparin is not affected by repeated injections into the same subcutaneous site (Anderson 1993).
The risk of severe adverse pregnancy outcomes is lower under the management of heparin prophylaxis during pregnancy but the potential adverse pregnancy outcomes are serious due to discontinuation of heparin prophylaxis. Therefore, large trials would be required to demonstrate that effectiveness and safety of different methods of administering subcutaneous heparin (UFH or LMWH) during pregnancy is assured.
Authors' conclusions
Implications for practice.
There are no randomised controlled trials that have shown the effectiveness and/or safety of different methods of administering subcutaneous heparin (UFH or LMWH). Although the risk of severe adverse pregnancy outcomes is generally low under the management of heparin prophylaxis during pregnancy, women’s satisfaction seems to be different depending on the methods of administration. Thus, the methods of administering subcutaneous heparin (UFH or LMWH) to pregnant women should be considered, based upon women’s informed preference and the risk of adverse outcomes rather than based upon availability of clinical devices or expertise, avoiding discontinuation due to discomfort, pain and financial burden.
Implications for research.
There is a need for large scale randomised controlled trials with adequate sample sizes to assess the effectiveness and/or safety of different methods of administering subcutaneous heparin (UFH or LMWH) to pregnant women. Future trials should ideally assess effectiveness of any devices to facilitate the subcutaneous administration of heparin (UFH or LMWH) during pregnancy compared with intermittent injections via indwelling catheters or programmable (auto) external infusion pumps.
Acknowledgements
The authors would like to acknowledge the help received from the Cochrane Pregnancy and Childbirth Group.
As part of the pre‐publication editorial process, this review has been commented on by three peers (an editor and two referees who are external to the editorial team) and the Group's Statistical Adviser.
Appendices
Appendix 1. Methods of the review
Data collection and analysis
Selection of studies
Two review authors will independently assess the inclusion of all the potential studies we identify as a result of the search strategy. We will resolve any disagreement through discussion or, if required, we will consult the third review author.
Data extraction and management
We will design a form to extract data. For eligible studies, two review authors will extract the data using the agreed form. We will resolve discrepancies through discussion or, if required, we will consult an additional review author. We will enter data into the Review Manager software (RevMan 2011) and check for accuracy. When information regarding any of the above is unclear, we will attempt to contact authors of the original reports to provide further details.
Assessment of risk of bias in included studies
Two review authors will independently assess the risk of bias for each study, as well as for cluster‐randomised trials separately using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreement by discussion or by involving an additional assessor.
(1) Random sequence generation (checking for possible selection bias)
We will describe for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.
We will assess the method as:
low risk of bias (any truly random process, e.g. random number table; computer random number generator);
high risk of bias (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number);
unclear risk of bias.
(2) Allocation concealment (checking for possible selection bias)
We will describe for each included study the method used to conceal allocation to interventions prior to assignment and will assess whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.
We will assess the methods as:
low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
high risk of bias (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth);
unclear risk of bias.
(3.1) Blinding of participants and personnel (checking for possible performance bias)
We will describe for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We will consider that studies are at low risk of bias if they were blinded, or if we judge that the lack of blinding would be unlikely to affect results. We will assess blinding separately for different outcomes or classes of outcomes.
We will assess the methods as:
low, high or unclear risk of bias for participants;
low, high or unclear risk of bias for personnel.
(3.2) Blinding of outcome assessment (checking for possible detection bias)
We will describe for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We will assess blinding separately for different outcomes or classes of outcomes.
We will assess methods used to blind outcome assessment as:
low, high or unclear risk of bias.
(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)
We will describe for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We will state whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information is reported, or can be supplied by the trial authors, we will re‐include missing data in the analyses which we undertake.
We will assess methods as:
low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);
high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomisation);
unclear risk of bias.
(5) Selective reporting (checking for reporting bias)
We will describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found.
We will assess the methods as:
low risk of bias (where it is clear that all of the study’s pre‐specified outcomes and all expected outcomes of interest to the review have been reported);
high risk of bias (where not all the study’s pre‐specified outcomes have been reported; one or more reported primary outcomes were not pre‐specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);
unclear risk of bias.
(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)
We will describe for each included study any important concerns we have about other possible sources of bias.
We will assess whether each study was free of other problems that could put it at risk of bias:
low risk of other bias;
high risk of other bias;
unclear whether there is risk of other bias.
(7) Overall risk of bias
We will make explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Handbook (Higgins 2011). With reference to (1) to (6) above, we will assess the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings. We will explore the impact of the level of bias through undertaking sensitivity analyses ‐ see 'Sensitivity analysis'.
Measures of treatment effect
Dichotomous data
For dichotomous data, we will present results as summary risk ratio with 95% confidence intervals.
Continuous data
For continuous data, we will use the mean difference if outcomes are measured in the same way between trials. We will use the standardised mean difference to combine trials that measure the same outcome, but use different methods.
Unit of analysis issues
Cluster‐randomised trials
We will include cluster‐randomised trials in the analyses, along with individually‐randomised trials. We will adjust their sample sizes using the methods described in the Handbook (Higgins 2011), using an estimate of the intracluster correlation co‐efficient (ICC) derived from the trial (if possible), or from another source. If ICCs from other sources are used, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster‐randomised trials and individually‐randomised trials, we plan to synthesise the relevant information. We will consider it reasonable to combine the results from both, if there is little heterogeneity between the study designs and an interaction between the effect of the intervention and the choice of the randomisation unit is considered to be unlikely. We will also acknowledge heterogeneity in the randomisation unit and perform a separate meta‐analysis.
Dealing with missing data
For included studies, we will note the levels of attrition. We will explore the impact of including studies with high levels of missing data in the overall assessment of the treatment effect by using sensitivity analysis. For all outcomes, we will carry out analyses, as far as possible, on an intention‐to‐treat basis, i.e. we will attempt to include all participants randomised to each group in the analyses, and all participants will be analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial will be the number randomised minus any participants whose outcomes are known to be missing.
Assessment of heterogeneity
We will assess statistical heterogeneity in each meta‐analysis using the T², I², and Chi² statistics. We will regard heterogeneity as substantial if the I² is greater than 30% and either the T² is greater than zero, or there is a low P value (less than 0.10) in the Chi² test for heterogeneity.
Assessment of reporting biases
If there are 10 or more studies in the meta‐analysis we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually, and use formal tests for funnel plot asymmetry. For continuous outcomes, we will use the test proposed by Egger 1997, and for dichotomous outcomes, we will use the test proposed by Harbord 2006. If asymmetry is detected in any of these tests or is suggested by a visual assessment, we will perform exploratory analyses to investigate it.
Data synthesis
We will carry out a statistical analysis using the Review Manager software (RevMan 2011). We will use a fixed‐effect model for combining data where trials are examining the same intervention, and the trial's populations and methods are judged sufficiently similar. We will weight effect estimates by the inverse of their variance, giving greater weight to larger trials. If we suspect clinical or methodological heterogeneity between treatment effects, we will use a random‐effects model. We will carry out meta‐analysis by study type (randomised trial, cluster‐randomised trial).
If we use random‐effects analyses, we will present the results as the average treatment effect with its 95% confidence interval, and the estimates of T² and I².
Subgroup analysis and investigation of heterogeneity
If we identify substantial heterogeneity, we will investigate it using subgroup analyses and sensitivity analyses. We will consider whether an overall summary is meaningful, and if it is, use random‐effects analysis to produce it.
If possible, we plan to carry out subgroup analyses for the primary outcomes and secondary outcomes as follows.
Type of heparin (UFH versus LMWH)
Previous VTE during pregnancy
A family history of VTE
Thrombophilia
Other risk factors (e.g. age, obesity, antiphospholipid syndrome)
For fixed‐effect inverse variance meta‐analyses, we will assess differences between subgroups by interaction tests. For random‐effects and fixed‐effect meta‐analyses using methods other than inverse variance, we will assess differences between subgroups by inspection of the subgroups' confidence intervals.
Sensitivity analysis
We will perform sensitivity analyses in order to explore the effect of trial quality for important outcomes in the review. If there is a risk of bias associated with a particular aspect of study quality (e.g. allocation concealment), we will explore this by sensitivity analysis. We will use primary and secondary outcomes in the sensitivity analysis.
Characteristics of studies
Characteristics of excluded studies [author‐defined order]
| Study | Reason for exclusion |
|---|---|
| Anderson 1993 | Trial is a randomised, multiple‐crossover study and does not meet inclusion criteria of the review. |
Contributions of authors
This review was drafted by Hatoko Sasaki (HS), which was edited by Naohiro Yonemoto (NY), Nobutsugu Hanada (NH) and Rintaro Mori (RM).
Sources of support
Internal sources
New Source of support, Not specified.
External sources
No sources of support supplied
Declarations of interest
None known.
New
References
References to studies excluded from this review
Anderson 1993 {published data only}
- Anderson DR. The use of an indwelling teflon catheter for subcutaneous heparin administration during pregnancy: a randomized crossover study. JAMA 1993;270:678. [PubMed] [Google Scholar]
- Anderson DR, Ginsberg JS, Brill‐Edwards P, Demers C, Burrows RF, Hirsh J. The use of an indwelling Teflon catheter for subcutaneous heparin administration during pregnancy. A randomized crossover study. Archives of Internal Medicine 1993;153(7):841‐4. [PubMed] [Google Scholar]
Additional references
Bank 2003
Barbour 1995
- Barbour LA, Smith JM, Marlar RA. Heparin levels to guide thromboembolism prophylaxis during pregnancy. American Journal of Obstetrics and Gynecology 1995;173(6):1869‐73. [DOI] [PubMed] [Google Scholar]
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Bates 2004
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