Aspirin or heparin or both for improving pregnancy outcomes in women with persistent antiphospholipid antibodies and recurrent pregnancy loss
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effects of aspirin or heparin (including low‐molecular‐weight heparins), or both for improving pregnancy outcome in women with persistent (on two occasions not less than 12 weeks apart) APLA, either LAC, aCL or aβ2 antibodies or a combination and recurrent pregnancy loss (miscarriage or fetal loss).
Background
Description of the condition
Antiphospholipid antibodies (APLA) are directed against phospholipids and include lupus anticoagulant (LAC), immunoglobulin G (IgG) or immunoglobulin M (IgM) anticardiolipin (aCL) and IgG or IgM anti‐β2‐glycoprotein‐I (aβ2) antibodies. The presence of APLA is associated with a hypercoagulable state (Harris 1983), which is an increased (pathological) tendency of clotting in the blood. The APLA are mostly known for their role in antiphospholipid syndrome (APS), also known as antiphospholipid antibody syndrome or Hughes syndrome. This is an autoimmune disorder characterized by the occurrence of a clinical event (recurrent pregnancy loss and/or thrombosis) and the presence of APLA. Currently, the diagnosis of APS is made according to the Sydney criteria established in 2006 (also known as the revised Sapporo criteria) and is based on both clinical and biochemical findings (Miyakis 2006). The clinical criteria include venous and/or arterial thrombosis and well‐defined pregnancy complications such as (recurrent) pregnancy loss (miscarriage or fetal loss) and pre‐eclampsia, whereas the biochemical criteria include persistent (after a 12‐week window) presence of APLA. The diagnosis of APS is made if a woman meets at least one of the clinical criteria and at least one of the biochemical criteria.
Antiphospholipid antibodies are reported to be present in 1% to 5.6% of healthy individuals with prevalence increasing with age (Petri 2000). In women with recurrent first trimester pregnancy losses the presence of these antibodies was detected in 15% (Rai 1995). Presence of antibodies without clinical events does not indicate treatment, as only a minority of individuals with APLA will develop APS (Ruiz‐Irastorza 2010). The prevalence of APS is estimated to range from 40‐50 per 100.000 individuals (Gómez‐Puerta 2014), and is especially increased in women with autoimmune and rheumatic diseases such as systemic lupus erythematosus (SLE) (Love 1990).
Knowledge on the mechanisms and triggers inducing the development and persistence of APLA and the different clinical manifestations are poorly understood. It is thought that beside presence of the antibodies, a trigger such as pregnancy, hormonal therapy, malignancy, smoking or infection plays a key role in disease initiation (Jacobs 2000).
Recently it has been suggested that women with different disease manifestations may represent different subgroups with subsequently, a different course of disease in terms of recurrence risk and type of events. For example, women presenting with thrombotic events may represent a different subgroup from women presenting with pregnancy complications, or women presenting with venous events might be a different subgroup again from women presenting with arterial events (Meroni 2012; Lockshin 2013). Moreover, it was suggested that the risk of (recurrent) pregnancy complications may differ between groups of women. For example, the risk of pregnancy complications (and type of complication) may differ in women with previous complications compared with women with no previous complication, or between women with high and low APLA titres, or be different in women with positive LAC antibodies versus negative LAC antibodies (Erkan 2002; Ioannou 2010; Lockshin 2012).
Description of the intervention
Aspirin and heparins (either unfractionated or low‐molecular‐weight heparin) are antithrombotic drugs, often prescribed with the intention to prevent excessive clotting of the blood. Aspirin, also known as acetylsalicylic acid, prevents the formation of thromboxane A2, and inhibits platelet aggregation (Vane 1971; Vane 2003). Heparins inhibit thrombus formation by binding to the natural anticoagulant antithrombin, which results in a potent activation of this enzyme (Chaung 2001).
How the intervention might work
Antithrombotic therapy has been found to reduce the risk of recurrent (either venous or arterial) thrombosis in APS (Branch 2012). Traditionally it is hypothesized that pregnancy complications in APS are also the result of a hypercoagulable state, partially by thrombosis of the placental vasculature. Recent hypotheses describe a more intertwined pathophysiological mechanism in which both the coagulation system, as well as inflammation are involved (Redecha 2008; Samarkos 2012). Aspirin and heparin may both have a beneficial effect on coagulation and inflammation (Vane 2003; Vignoli 2006; Kozlowski 2011), and are thought to reduce the risk of pregnancy loss in APS.
Why it is important to do this review
This is a new review which will supersede the previous, out‐of‐date review by Empson and colleagues (Empson 2005), which included all potential therapies for preventing recurrent pregnancy loss in women with APLA. This new review focusses on a narrower scope than Empson 2005, as currently in clinical practice only aspirin or heparins, or both are used in women with APLA in an attempt to reduce pregnancy complications. However, it is uncertain whether these antithrombotic therapies reduce the risk of pregnancy complications in women with persistent (on two occasions not less than 12 weeks apart) APLA.
Objectives
To assess the effects of aspirin or heparin (including low‐molecular‐weight heparins), or both for improving pregnancy outcome in women with persistent (on two occasions not less than 12 weeks apart) APLA, either LAC, aCL or aβ2 antibodies or a combination and recurrent pregnancy loss (miscarriage or fetal loss).
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled trials, cluster‐randomized trials and quasi‐randomized controlled trials that assessed the effect of aspirin or heparin (including low‐molecular‐weight heparin), or both, on pregnancy outcomes in women with persistent APLA and recurrent pregnancy loss. We planned to exclude cross‐over trials due to the nature of outcomes we are considering. Studies only published as abstract will be included if sufficient data are available to determine study eligibility. If necessary we will contact the authors of the abstract for further information.
Types of participants
Pregnant women with persistent (on two occasions not less than 12 weeks apart) APLA, either LAC, aCL or aβ2 antibodies or a combination and recurrent (two or more, which do not have to be consecutive) pregnancy loss (which entails any miscarriage or fetal loss, however defined by the trial authors).
Types of interventions
Interventions: aspirin, heparin (including low‐molecular‐weight heparin) or a combination of aspirin and heparin. We will consider any treatment regimen and dose.
Comparison: one of these treatments compared with another or with no treatment or with placebo, for example, aspirin or heparin, or both, versus no treatment or placebo and heparin with or without aspirin versus aspirin.
Types of outcome measures
Primary outcomes
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Pregnancy loss (total, early loss < 24 weeks, late loss ≥ 24 weeks)
Secondary outcomes
For the mother
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Pre‐eclampsia (definition according to original study)
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Adverse events in the mother (definitions according to original study: (A) bleeding, (B) heparin‐induced thrombocytopenia, (C) allergic reactions)
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Venous thromboembolism
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Arterial thromboembolism
For the child
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Preterm delivery of a live infant (before 37 weeks, 24 to 28 weeks, 28 to 32 weeks and 32 to 37 weeks)
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Intrauterine growth restriction (definition according to original study)
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Adverse events in the child (definitions according to original study: (A) congenital malformations, (B) neonatal bleeding)
Search methods for identification of studies
The following methods section of this protocol is based on a standard template used by Cochrane Pregnancy and Childbirth.
Electronic searches
We will search Cochrane Pregnancy and Childbirth’s Trials Register by contacting the Information Specialist.
The Register is a database containing over 20,000 reports of controlled trials in the field of pregnancy and childbirth. For full search methods used to populate Cochrane Pregnancy and Childbirth's Trials Register including the detailed search strategies for CENTRAL, MEDLINE, Embase and CINAHL; the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service, please follow this link to the editorial information about the Cochrane Pregnancy and Childbirth Group in the Cochrane Library and select the ‘Specialized Register ’ section from the options on the left side of the screen.
Briefly, Cochrane Pregnancy and Childbirth’s Trials Register is maintained by the Information Specialist and contains trials identified from:
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monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
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weekly searches of MEDLINE (Ovid);
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weekly searches of Embase (Ovid);
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monthly searches of CINAHL (EBSCO);
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handsearches of 30 journals and the proceedings of major conferences;
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weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.
Search results are screened by two people and the full text of all relevant trial reports identified through the searching activities described above is reviewed. Based on the intervention described, each trial report is assigned a number that corresponds to a specific Pregnancy and Childbirth Group review topic (or topics), and is then added to the Register. The Information Specialist searches the Register for each review using this topic number rather than keywords. This results in a more specific search set that will be fully accounted for in the relevant review sections (Included, Excluded, Awaiting Classification or Ongoing).
In addition, we will search ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) for unpublished, planned and ongoing trial reports. The terms we plan to use are given in Appendix 1.
Searching other resources
We will search the reference lists of retrieved studies.
We will not apply any language or date restrictions.
Data collection and analysis
The following methods section of this protocol is based on a standard template used by Cochrane Pregnancy and Childbirth.
Selection of studies
We will screen all titles and abstracts identified by the search strategy. Two authors will independently screen for eligible studies based on title and abstract. We will resolve conflicts through discussion and if necessary by involving a third review author, who has the final vote. All studies without an abstract will be reviewed in full text.
Secondly, two review authors will independently review the full text of all studies that were included on the basis of title and abstract for eligibility. We will resolve all conflicts through discussion and if necessary by involving a third author, who has the final vote.
We will create a study flow diagram to map out the number of records identified, included and excluded (Moher 2009).
Data extraction and management
We will extract data by means of a data extraction form designed by the review authors. Sources of trial funding and trialist declarations of interest will also be included in the data extraction form. For every eligible study, the data will be extracted by two authors independently of one another. When uncertainties about the study data are encountered, we will contact the authors of the specific study and request additional information. We will resolve all disagreements through discussion and if necessary by involving a third review author, who has the final vote. We will enter the extracted data into the Review Manager 5 (RevMan 5) software (RevMan 2014).
Assessment of risk of bias in included studies
Two review authors will independently assess risk of bias for each study 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 a third 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:
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low risk of bias (any truly random process, e.g. random number table; computer random‐number generator);
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high risk of bias (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number);
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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:
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low risk of bias (e.g. telephone or central randomization; consecutively‐numbered, sealed, opaque envelopes);
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high risk of bias (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth);
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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:
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low, high or unclear risk of bias for participants;
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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:
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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 randomized 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 that we undertake.
We will assess methods as:
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low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);
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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 randomization);
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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:
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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);
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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 have been reported incompletely and so cannot be used; study failed to include results of a key outcome that would have been expected to have been reported);
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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:
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low risk of other bias;
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high risk of other bias;
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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 Cochrane Handbook for Systematic Reviews of Interventions (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.
Assessment of the quality of the evidence using the GRADE approach
We will use the GRADE approach to assess the quality of the evidence, as outlined in the GRADE handbook in order to assess the quality of the body of evidence relating to the following outcomes for the main comparisons 1) heparin or aspirin, or both, versus no treatment or placebo and 2) heparin with or without aspirin versus aspirin.
Primary outcomes
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Pregnancy loss (total, early loss less than 24 weeks, late loss 24 weeks or more)
Secondary outcomes
For the mother
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Pre‐eclampsia (definition according to original study)
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Adverse events in the mother (definitions according to original study: (A) bleeding, (B) heparin‐induced thrombocytopenia, (C) allergic reactions)
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Venous thromboembolism
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Arterial thromboembolism
For the child
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Preterm delivery of a live infant (before 37 weeks, 24 to 28 weeks, 28 to 32 weeks and 32 to 37 weeks).
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Intrauterine growth restriction (definition according to original study).
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Adverse events in the child (definitions according to original study: (A) congenital malformations, (B) neonatal bleeding).
We will use the GRADEpro Guideline Development Tool to import data from RevMan 5 (RevMan 2014) in order to create 'Summary of findings' tables. We will use the GRADE approach to produce a summary of the intervention effect and a measure of quality for each of the above outcomes. The GRADE approach uses five considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of the body of evidence for each outcome. The evidence can be downgraded from 'high quality' by one level for serious (or by two levels for very serious) limitations, depending on assessments for risk of bias, indirectness of evidence, serious inconsistency, imprecision of effect estimates or potential publication bias.
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 standardized mean difference to combine trials that measure the same outcome, but use different methods.
Unit of analysis issues
Cluster‐randomized trials
If encountered, we will include cluster‐randomized trials in the analyses together with the individually randomized trials. We will adjust for sample sizes, guided by the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011). If possible, we will use the estimate of the intra‐cluster correlation coefficient (ICC) derived from the study, from a similar study or from a study with a similar population. When we use ICCs from external sources, we will mention it explicitly in the review, and we will conduct appropriate sensitivity analyses. When both cluster‐randomized trials and individually randomized trials are encountered, we will use relevant data for the review. We will combine results from both cluster‐randomized trials and individually randomized trials if little heterogeneity is observed between study designs, provided that the interaction between the effect of intervention and choice of randomization unit is considered to be unlikely. Heterogeneity will be recognized in the randomization unit and we will conduct a sensitivity analysis to explore the effects of this randomization unit.
Multiple‐arm studies
If studies with more than two intervention arms (multiple‐arm studies) are encountered, we will combine groups to create a single pair‐wise comparison if possible.
We will declare in the 'Characteristics of included studies', table if a trial has an intervention arm that is not applicable or relevant to our review question. We will only include the intervention and control groups that meet the eligibility criteria in the analyses.
Cross‐over trials
We consider cross‐over trials an inappropriate design for this intervention.
Dealing with missing data
For every individual included study, we will determine the level of attrition. We will evaluate the impact on the overall assessment of the intervention of including studies with high proportions of missing data by conducting a sensitivity analysis without these studies.
We prefer to analyse all outcomes on an intention‐to‐treat basis. In other words, if possible, we will include all randomized participants in the analyses, and we will analyse these participants according to their allocated treatment assignment, regardless of whether the allocated intervention was received. For each outcome in every trial, the denominator will be the number of randomized participants minus the participants whose outcomes are missing. In studies with more than 5% loss to follow‐up, we will perform a best case scenario analysis (losses to follow‐up assumed to have a positive outcome, e.g. primary outcome) and a worst case scenario analysis (losses to follow‐up assumed to have a negative outcome, e.g. no primary outcome).
Assessment of heterogeneity
In all meta‐analyses we will assess statistical heterogeneity using the Tau², I² (Higgins 2003) and Chi² statistics (Deeks 2011). We will regard heterogeneity as substantial if Tau² is greater than zero and either I² statistic is greater than 30%, or when the Chi² test for heterogeneity yields a P value equal to or less than 0.10.
Assessment of reporting biases
If the meta‐analyses concern 10 or more studies, we will explore potential reporting bias (mainly publication bias). We will draw funnel plots and visually assess them for asymmetry. If visual assessment leads us to suspect asymmetry, we will conduct additional analyses to explore these potential biases.
Data synthesis
We will carry out statistical analysis using RevMan 5 software (RevMan 2014). We will use fixed‐effect meta‐analysis for combining data where it is reasonable to assume that studies are estimating the same underlying treatment effect: that is, where trials are examining the same intervention, and the trials’ populations and methods are judged sufficiently similar. If there is clinical heterogeneity sufficient to expect that the underlying treatment effects differ between trials, or if we detect substantial statistical heterogeneity, we will use random‐effects meta‐analysis to produce an overall summary, if an average treatment effect across trials is considered clinically meaningful. We will treat the random‐effects summary as the average of the range of possible treatment effects and we will discuss the clinical implications of treatment effects differing between trials. If the average treatment effect is not clinically meaningful we will not combine trials.
If we use random‐effects analyses, we will present the results as the average treatment effect with 95% confidence intervals, and the estimates of Tau² and I² statistic.
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.
The risk of (recurrent) pregnancy complications may differ between different subgroups of women, such as previous placenta‐mediated complications, number of pregnancy losses, high‐ or low‐titre antibodies and positive or negative LAC antibodies. For this reason we plan to carry out the following subgroup analyses.
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Previous placenta‐mediated complication (pre‐eclampsia; intrauterine growth restriction or placental abruption, or both) versus no previous placenta‐mediated complication
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Two versus three or more pregnancy losses (which do not have to be consecutive)
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High‐titre antibodies versus low‐titre antibodies
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Positive lupus anticoagulant (LAC) antibodies versus negative LAC antibodies
We will use the following outcomes in subgroup analyses.
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Primary outcome: pregnancy loss (total, early loss less than 24 weeks, late loss 24 weeks or more)
We will assess subgroup differences by interaction tests available within RevMan 5 (RevMan 2014). We will report the results of subgroup analyses quoting the Chi2 statistic and P value, and the interaction test I² statistic value.
Sensitivity analysis
We will carry out sensitivity analyses to explore the effect of use of the full Sapporo criteria for APS, with studies not using the full criteria excluded from the analyses; and trial quality (including quasi‐randomized trials), assessed by random sequence generation and concealment of allocation, with studies assessed as high risk of bias on these domains being excluded from the analyses. Where cluster‐randomized trials are included, we will carry out sensitivity analyses to explore the effects of variation in ICC values and in the randomization unit (i.e. individual versus cluster trials). Sensitivity analyses will be limited to the primary outcome. If deemed appropriate during the course of the review process, we will perform more sensitivity analyses and present the results in a summary table.
