JBRA Assist. Reprod. 2020;00(0):00-00
1State University of Bahia (UNEB) - Life Sciences Department. Salvador - Bahia - BrazilCONFLICT OF INTEREST
Objective: To evaluate the efficacy and safety of using low molecular weight heparin (LMWH) in women with a history of recurrent abortion without an identified cause.
Methods: To develop a systematic review to select the studies. Total found 437 papers. Seven studies were completed or requested. The following variables were analyzed: clinical pregnancy, implantation rate, live births, abortion, premature birth, pregnancy, continuous pregnancy, beyond the 20th gestational week, congenital abnormality, hemorrhage, preeclampsia, placental premature detachment.
Results: The LMWH group had a higher incidence of continuous pregnancy after the 20th week of gestation and there was no significant difference between the LMWH group and the expectant management group in the analysis of other variables.
Conclusions: There was no data showing risk and/or less use of LMWH compared to expectant management; on the contrary, LMWH use increased the incidence of evolutionary pregnancy after the 20th gestational week. LMWH has some influence on prophylactic treatment of repeat abortion for unknown cause.
Keywords: Recurrent abortion, Low molecular weight heparin, Expectant conduct, Live births
Repeat abortion, also called habitual gestational loss, was defined, according to Stirrat (1990), as the successive spontaneous cessation of three or more pregnancies with 20-22 gestational weeks or less (Montenegro & Rezende Filho, 2008). However, according to the Practice Committee of the American Society for Reproductive Medicine (2008), habitual abortion is considered when there is two or more consecutive gestational losses.
Habitual gestational loss is a common obstetric complication that affects about 5% of pregnant women (Practice Medicine, 2012; Rai & Regan, 2006). There are Several factors that may be involved in the etiology of recurrent miscarriages, including genetic, anatomical (arcuate, bicornuate, septate, T-shaped and unicornuate uterus), endocrine abnormalities (luteal phase insufficiency), hyperprolactinemia, thyroid disease, polycystic ovary syndrome, immunological, infectious, metabolic, thrombophilia and maternal age (Burlá et al., 2015). However, around 50% of cases have no identified cause (Practice Committee of the American Society for Reproductive Medicine, 2012).
Considering that episodes of thrombosis in the uteroplacental circulation occur independently of the presence of thrombophilia (Badawy et al., 2008; Nelson & Greer, 2008), some authors began to institute empirical prophylactic treatment with low molecular weight heparin (LMWH) and/or small doses of aspirin in women with habitual miscarriage of unexplained cause (Badawy et al., 2008; Pasquier et al., 2015). Although there are already studies indicating the benefit of thromboprophylaxis (Badawy et al., 2008; Fawzy et al., 2008; Shaaban et al., 2017; Urman et al., 2009), there are also studies showing that there are no significant differences in the outcome of pregnancies of women undergoing LMWH. Therefore, this strategy should not be instituted as routine practice until there are studies that prove the exact mechanism of action and the benefit of this therapy in repetitive abortions (Pasquier et al., 2015; Schleussner et al., 2015; Di Nisio et al., 2005; Kaandorp et al., 2010; Clark et al., 2010; de Jong et al., 2014; Visser et al., 2011).
Failure to implant in couples undergoing assisted reproduction is also a relatively common phenomenon that affects their feelings of frustration and despair. Implantation failure, as well as habitual abortion, has been attributed to a number of factors; however, most have no particular cause. Knowledge about the contribution of coagulation disorders in the implantation failure process underlies the use of anticoagulants during assisted reproduction therapy (Urman et al., 2009). The success of this therapy can be assessed by the implantation rate, which is defined as the number of observed gestational sacs divided by the number of embryos transferred (Zegers-Hochschild et al., 2009).
Thus, considering the existence of still inconclusive studies and, knowing the emotional repercussions of spontaneous abortion that involves feelings of loss and blame for the impossibility of completing the pregnancy, this requires adequate, safe and humanized technical attention. This study aims to evaluate the efficacy and safety of LMWH use in women with a history of recurrent miscarriage without an identified cause.
MATERIAL AND METHODS
To describe the results of this meta-analysis, we used the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) (Moher et al., 2009). This systematic review is registered in the PROSPERO database under registration number: CRD42017082373.
To establish the focus of the systematic review, we used the following clinical issues: the population studied, the intervention and comparisons, study design and study results from which we extracted the data. Thus, the goal of this systematic review was “to detect the efficacy of LMWH in the prophylactic treatment of women with recurrent abortion compared with the expectant management”. We used only randomized and quasi-randomized studies, and we structured the meta-analysis following the “PICOS” format (Population, Intervention, Comparison, Results, Type of study) (Howick, 2009) (Table 1).
• P: Women with repeat abortion history.
• I: Low molecular weight heparin treatment
• C: Expectant conduct
• O: Effectiveness
• S: Randomized and quasi-randomized studies
The selected studies had to include women with recurrent abortion with two or more consecutive gestational losses; to compare the efficacy of LMWH versus the expectant management in prophylactic treatment of habitual abortion, and to be a randomized or quasi-randomized trial. The studies were not included if they were published in summary format, letter to the editor, comments, meta-analysis, review article, or studies that included any drug other than LMWH in the study population that included women with repeat abortion of known cause.
Study strategy (Appendix 1)
We carried out an electronic search in MEDLINE and PubMed in October 2017. There was no language restriction for the papers. We based the study on the following combined Medical Subject Headings of the National Library of Medicine (MeSH) terms: "habitual abortion", "anticoagulants", "watchful waiting", "gestational age", "fetal death", "live births", "premature birth", "prolonged pregnancies", "perinatal death", "intrauterine growth retardation", "congenital abnormality", "obstetric complications", "pregnancy associated hypertension", "pre-eclampsia", "placenta previa", "placental abruption", "uterine hemorrhage", "postpartum hemorrhage".
Two researchers (ATBD and SAO) selected the publications independently. Initially, we assessed the titles and abstracts of all the studies found by the research strategy. Any divergence in study selection and/or data extraction was cleared by consensus between the two researchers. We read the papers that had insufficient information in the title and abstract in their entirety. Only studies that had the inclusion criteria and did not meet the non-inclusion criteria were selected for the meta-analysis. We generated a list of potential studies for inclusion in the systematic review. We checked references from reviews and meta-analyzes to find papers that could possibly meet the inclusion criteria.
Data collection process
Two researchers (ATBD and SAO) independently extracted data using a standardized form and, again, disagreements were solved by consensus. We extracted and combined the data from all included items reporting intervention and patient outcomes. These authors evaluated the eligibility and quality of the studies and, subsequently, extracted data from the papers. The standardized form included information such as authors, journal, year of publication, design, duration and place of study, demographics of participants, inclusion and exclusion criteria, type of interventions, and outcomes.
Data and results
We combined the studies in groups, according to the interventions performed and the outcomes found. We combined the data, to run the following analyzes:
• Is LMWH efficient for prophylactic treatment of recurrent abortion?
• What is the best conduct for prophylactic treatment of habitual abortion?
• Which approach causes fewer adverse effects as congenital abnormality, bleeding, preeclampsia and placental premature detachment?
• Which conduct best prolongs pregnancy beyond 20 gestational weeks?
• What is the best conduct to increase implantation rate?
• Which conduct generates the most premature births?
• Which conduct contributes to the higher number of multiple pregnancies?
Partiality assessment risk
We followed the guidelines suggested by the Cochrane Collaboration group to assess the risk of partiality studies (Higgins & Green, 2011). Sequence generation, allocation concealment, blinding, and incomplete outcome data were evaluated for each trial included in the review. A low risk of bias was considered when a "yes" judgment for all domains was obtained, while a high risk of bias was considered when a "no" judgment for one or more domains was obtained. Table 2 depicts the quality assessment of the included trials.
To accomplish the meta-analysis, we used the Cochrane Collaboration's Review Manager Software (RevMan 5.3; <http://tech.cochrane.org/revman>). The metanalytic measure of interest is the odds ratio, which we obtained using the Mantel-Haenszel method. In cases where the number of events in one of the groups was zero, we used the Peto's method. In addition to the odds ratios, the respective 95% confidence intervals (CI) as well as the forest plot were presented. We assessed the heterogeneity between the studies by the Higgins and Thompson I2 statistics and the Cochran Q test. We applied the random effect model when the I2 statistic was higher than 50%, or when the null hypothesis of the Cochran Q test was rejected. The statistical tests applied were bilateral and the adopted significance level was 5%. We conducted a systematic literature search to identify randomized and quasi-randomized trials comparing LMWH use and expectant conduct in the prophylactic treatment of repeat abortion. In total, we found 437 papers as we can see in Figure 1. At the end of the review process, 7 papers met the inclusion criteria and were described and evaluated (Badawy et al., 2008; Pasquier et al., 2015; Shaaban et al., 2017; Urman et al., 2009; Schleussner et al., 2015; Berker et al., 2011; Noci et al., 2011) (Fig. 1). There were six randomized studies and one quasi-randomized study. We excluded 433 studies, because they either did not meet the inclusion criteria or did not provide sufficient data for inclusion in the meta-analysis, or were literature review studies. From these studies, 280 evaluated women with a determined cause of miscarriage as thrombophilia, 80 included aspirin with or without LMWH in the intervention group or had women on aspirin as a control group. We added three studies identified in the meta-analyses’ references that met the inclusion criteria. We also included studies evaluating the efficacy of LMWH in the prophylactic treatment of repeat abortion in pregnant women by in vitro fertilization. Table 2 shows the quality assessment of the included studies.
Description of included studies (Appendix 2)
The included studies represented 1,855 patients (936 undergoing LMWH and 919 in the expectant management group). Appendix 1 shows the summary characteristics of the studies included in this review. Four studies (Badawy et al., 2008; Pasquier et al., 2015; Shaaban et al., 2017; Schleussner et al., 2015) evaluated the use of LMWH prevention of indeterminate recurrent miscarriage and the other three studies (Urman et al., 2009; Berker et al., 2011; Noci et al., 2011) evaluated the effect of LMWH on implantation rates in women with recurrent implantation failure (RIF), but without coagulation disorders.
We assessed the number of women who reached clinical pregnancy after treatment. We analyzed this in only three articles (Berker et al., 2011; Noci et al., 2011; Urman et al., 2009). When comparing LMWH versus expectant management, there was no statistically significant difference between the groups (RR=1.20; 95% CI: 0.83, 1.75; I2=0%; p=0.33) (Fig. 2).
Three studies (Berker et al., 2011; Noci et al., 2011; Urman et al., 2009) evaluated the implantation rate after treatment. When comparing the two interventions there was no statistically significant difference (RR=1.21; 95% CI: 0.88, 1.65; I2=0%; p=0.24) (Fig. 3).
There were five studies (Berker et al., 2011; Noci et al., 2011; Pasquier et al., 2015; Schleussner et al., 2015; Urman et al., 2009) that evaluated the incidence of live births after treatment. When comparing the five studies, we found no significant static difference between the groups (RR=1.02; 95% CI: 0.77, 1.34; I2=0%; p=0.91) (Fig. 4).
We assessed the presence of spontaneous abortion with the institution of treatment. Four papers evaluated this outcome (Badawy et al., 2008; Noci et al., 2011; Pasquier et al., 2015; Shaaban et al., 2017). When comparing the two interventions, there was no statistically significant difference between the groups (RR=0.69; 95% CI: 0.31, 1.50; I2=83%; p=0.35) (Fig. 5).
We evaluated the number of premature births that occurred after treatment. It was possible to analyze it in only two studies (Badawy et al., 2008; Urman et al., 2009). When comparing LMWH versus expectant management, there was no statistically significant difference between the groups (RR=0.96; 95% CI: 0.56, 1.66; I2=5%; p=0.89) (Fig. 6).
We could analyze only two papers (Berker et al., 2011; Urman et al., 2009). When comparing the two treatments, there was no statistically significant difference between the groups (RR=1.02; 95% CI: 0.63, 1.63; I2=0%; p=0.94) (Fig. 7).
Continuous pregnancy beyond the 20th gestational week
Three studies (Schleussner et al., 2015; Shaaban et al., 2017; Urman et al., 2009) evaluated the incidence of continuous pregnancy beyond the 20th gestational week with the institution of treatment. When comparing the two treatments, there was a statistically significant difference between the groups (RR=2.55; 95% CI: 1.79, 3.63; I2=4%; p=0.00001). Treatment with low molecular weight heparin resulted in a higher incidence of continuous pregnancy beyond the 20th gestational week (Fig. 8).
Two studies (Badawy et al., 2008; Pasquier et al., 2015) evaluated the incidence of congenital abnormality after treatment. When comparing the two interventions, there was no statistically significant difference (RR=2.46; 95% CI: 0.78, 7.79; I2=0%; p=0.13) (Fig. 9).
Two studies (Badawy et al., 2008; Pasquier et al., 2015) evaluated the incidence of hemorrhage after treatment. When comparing the two studies, there was no statistically significant difference between the groups (RR=1.54; 95% CI: 0.92, 2.57; I2=0%; p=0.10) (Fig. 10).
We could analyze only two studies regarding the incidence of preeclampsia (Badawy et al., 2008; Shaaban et al., 2017). When comparing LMWH versus expectant management there was no statistically significant difference between the groups (RR=2.83; 95% CI: 0.13, 61.35; I2=91%; p=0.51) (Fig. 11).
Placental premature detachment
We evaluated the presence of placental premature detachment as a side effect during treatment. Only two papers evaluated this outcome (Badawy et al., 2008; Schleussner et al., 2015). When comparing the two interventions, there was no statistically significant difference between the groups (RR=0.55; 95% CI: 0.12, 2.60; I2=0%; p=0.45) (Fig. 12).
In this study, we demonstrated evidence of LMWH not being inferior to the expectant management. The LMWH group had a higher incidence of evolutionary pregnancy beyond the 20th gestational week without including unfavorable factors during pregnancy, since there was no increase in variants such as hemorrhage, preeclampsia, placental premature detachment and preeclampsia in this group. However, it is important to highlight that this outcome was evaluated in only three studies (Shaaban et al., 2017; Urman et al., 2009; Schleussner et al., 2015), which demonstrates the need for a larger number of studies evaluating pregnancies that continue beyond the 20th gestational week.
The rate of spontaneous abortion is a variable of great interest when assessing prophylactic treatments for recurrent miscarriage, and in this study this variable showed no statistically significant difference (RR=0.69; 95% CI: 0.31, 1.50 (83%; p=0.35). However, there is a tendency towards favoring LMWH, but the four studies analyzed (Badawy et al., 2008; Pasquier et al., 2015; Shaaban et al., 2017; Noci et al., 2011) have a high heterogeneity rate (I2=83%), thus requiring more studies for the conclusion to become more reliable.
The use of LMWH showed no statistically significant difference in the implantation rate analysis, when compared to the expectant management (RR=1.21; 95% CI: 0.88, 1.65; I2=0%; p=0.24). However, only three studies (Urman et al., 2009; Berker et al., 2011; Noci et al., 2011) were evaluated by the meta-analysis, indicating that there is also a need for further studies to reach a more reliable conclusion about the action and safety of using LMWH to treat implantation failures.
The preeclampsia variable showed a high heterogeneity between studies (I2=91%). For this variable, two studies were evaluated (Badawy et al., 2008; Shaaban et al., 2017). In the first, the control group had a higher incidence of preeclampsia compared to the intervention group, unlike the second study in which the highest incidence of preeclampsia occurred in the intervention group. The presence of high heterogeneity of this variable makes it questionable the combination of the results of these studies for this outcome.
In their meta-analysis, Di Nisio et al. (2005) compared aspirin, unfractionated heparin and LMWH use compared with one another, or a placebo to prevent birth loss in pregnant women or women who were trying to become pregnant and who had a history of at least two consecutive abortions with no apparent causes. One of the included studies (Gris et al., 2004) resulted in increased live birth rates compared to low aspirin doses. Four patients had preeclampsia in the enoxaparin intervention group, and three participants in the aspirin group had it. There was one case of premature birth in the aspirin intervention group. However, since the studies included in the meta-analysis had a small sample size and methodological limitations, they concluded that thromboprophylaxis should not be prescribed until convincing data exists.
There was a meta-analysis in 2009 (Kaandorp et al., 2009), evaluating the efficacy and safety of aspirin, LMWH and fractional heparin compared with one another or with placebo in women with a history of at least two miscarriages of spontaneous causes. The rate of live births was similar between the enoxaparin group (82%) and the aspirin group (84%) (RR 0.97; 95% CI: 0.81 to 1.16). Three women had preeclampsia in the aspirin group and no women had preeclampsia in the enoxaparin group. In each group, there was one birth with congenital abnormalities. None of the studies showed greater efficacy of one treatment over the other, so the meta-analysis concluded that the use of anticoagulants should not be recommended.
In 2014, nine studies included in a meta-analysis (de Jong et al., 2014) reviewed the effects of LMWH, fractional heparin or aspirin, or a combination of both compared with one another or to placebo in the prophylactic treatment of pregnant women with a history of at least two miscarriages. There were three studies assessing the LMWH effects (Badawy et al., 2008; Fawzy et al., 2008; Martinelli et al., 2012). There were no differences between treatment groups among individual studies for gestational complications, bleeding or thromboembolic events. Based on these results, the review showed that the use of anticoagulants in women with recurrent miscarriage was not effective.
Although these meta-analyses do not specifically compare LMWH and expectant management, they are important because they show in their results that patients who received prophylactic LMWH treatment had statistically insignificant results when compared to other treatments, which differs from our study, that already presents statistically significant differences favoring the LMWH group when analyzing the continuous pregnancy beyond the 20th gestational week variable.
We believe this study contributes to the still unresolved debate about the use of LMWH in the prophylactic treatment of recurrent miscarriage. When comparing this intervention with expectant management, there was no data to show risk and/or lower efficacy of LMWH. On the contrary, LMWH was more effective in increasing the incidence of evolutionary pregnancy beyond the 20th gestational week; thus indicating that LMWH has some influence on the prophylactic treatment of recurrent miscarriage of unknown cause.
Therefore, we need further studies with standardized methods to evaluate the comparison of LMWH and expectant management.
We thank Vinícius Fernando Calsavara who helped us with the statistical analysis
Appendix 1. Research Strategy
2 Abortions, Habitual) OR (Habitual Abortion) OR (Habitual Abortions) OR (Miscarriage, Recurrent) OR (Miscarriages, Recurrent) OR (Recurrent Miscarriage) OR (Recurrent Miscarriages) OR (Abortion, Recurrent) OR (Abortions, Recurrent) OR (Recurrent Abortion) OR (Recurrent Abortions)
5 (Anticoagulation Agents) OR (Agents, Anticoagulation) OR (Anticoagulant Agents) OR (Agents, Anticoagulant) OR (Anticoagulant Drugs) OR (Drugs, Anticoagulant) OR (Anticoagulant) OR (Indirect Thrombin Inhibitors) OR (Inhibitors, Indirect Thrombin) OR (Thrombin Inhibitors, Indirect)
7(Waiting, Watchful) OR (Watchful Waiting) OR (Watchful Waiting) 10 (Age, Gestational) OR (Ages, Gestational) OR (Gestational Ages) OR (Maturity, Chronologic Fetal) OR (Chronologic Fetal Maturity) OR (Fetal Maturity, Chronologic) OR (Fetal Age) OR (Age, Fetal) OR (Ages, Fetal) OR (Fetal Ages)
13 (Fetal Death) OR (Deaths, Fetal) OR (Fetal Deaths) OR (Fetal Demise) OR (Demise, Fetal) OR (Fetal Mummification) OR (Mummification, Fetal)
15 (Live Births)
17 (Birth, Premature) OR (Births, Premature) OR (Premature Births) OR (Preterm Birth) OR (Birth, Preterm) OR (Births, Preterm) OR (Preterm Births)
19 (Pregnancies, Prolonged) OR (Prolonged Pregnancies) OR (Prolonged Pregnancy)
21 (Death, Perinatal) OR (Deaths, Perinatal) OR (Perinatal Deaths) OR (Neonatal Death) OR (Death, Neonatal) OR (Deaths, Neonatal) OR (Neonatal Deaths)
24 (Growth Retardation, Fetal) OR (Retardation, Fetal Growth) OR (Intrauterine Growth Retardation) OR (IUGR) OR (Growth Retardation, Intrauterine) OR (Retardation, Intrauterine Growth)
27 (Abnormality, Congenital) OR (Congenital Abnormality) OR (Deformities) OR (Deformity) OR (Congenital Defects) OR (Congenital Defect) OR (Defect, Congenital) OR (Defects, Congenital) OR (Abnormalities, Congenital) OR (Birth Defects) OR (Birth Defect) OR (Defect, Birth) OR (Defects, Birth)
29 (Complication, Obstetric Labor) OR (Complications, Obstetric Labor) OR (Labor Complication, Obstetric) OR (Labor Complications, Obstetric) OR (Obstetric Labor Complication) OR (Labor Complications) OR (Complication, Labor) OR (Labor Complication) OR (Complications, Labor)
31 (Hypertension, Pregnancy Induced) OR (Pregnancy-Induced Hypertension) OR (Pregnancy Induced Hypertension) OR (Hypertensions, Pregnancy Induced) OR (Induced Hypertension, Pregnancy) OR (Induced Hypertensions, Pregnancy) OR (Gestational Hypertension) OR (Hypertension, Gestational) OR (Transient Hypertension, Pregnancy) OR (Hypertension, Pregnancy Transient) OR (Pregnancy Transient Hypertension)
33 (Pre-Eclampsia) OR (Preeclampsia) OR (Pregnancy Toxemias) OR (Pregnancy Toxemia) OR (Toxemia, Pregnancy) OR (Edema-Proteinuria-Hypertension Gestosis) OR (Edema Proteinuria Hypertension Gestosis) OR (Gestosis, Edema-Proteinuria-Hypertension) OR (Hypertension-Edema-Proteinuria Gestosis) OR (Gestosis, Hypertension-Edema-Proteinuria) OR (Hypertension Edema Proteinuria Gestosis) OR (Toxemia Of Pregnancy) OR (Of Pregnancies, Toxemia) OR (Of Pregnancy, Toxemia) OR (Pregnancies, Toxemia Of) OR (Pregnancy, Toxemia Of) OR (Toxemia Of Pregnancies) OR (EPH Complex) OR (EPH Toxemias) OR (EPH Toxemia) OR (Toxemia, EPH) OR (Toxemias, EPH) OR (EPH Gestosis) OR (Gestosis, EPH) OR (Toxemias, Pregnancy) OR (Preeclampsia Eclampsia 1) OR (1, Preeclampsia Eclampsia) OR (1s, Preeclampsia Eclampsia) OR (Eclampsia 1, Preeclampsia) OR (Eclampsia 1s, Preeclampsia) OR (Preeclampsia Eclampsia 1s) OR (Proteinuria-Edema-Hypertension Gestosis) OR (Gestosis, Proteinuria-Edema-Hypertension) OR (Proteinuria Edema Hypertension Gestosis)
36 (Placental Abruption) OR (Abruption, Placental) OR (Abruptions, Placental) OR (Placental Abruptions)
38 (Uterine Hemorrhages) OR (Hemorrhage, Uterine) OR (Uterine Bleeding) OR (Bleeding, Uterine) OR (Uterine Bleedings) OR (Vaginal Bleeding) OR (Bleeding, Vaginal) OR (Bleedings, Vaginal) OR (Vaginal Bleedings)
40 (Hemorrhage, Postpartum) OR (Immediate Postpartum Hemorrhage) OR (Hemorrhage, Immediate Postpartum) OR (Postpartum Hemorrhage, Immediate) OR (Delayed Postpartum Hemorrhage) OR (Hemorrhage, Delayed Postpartum) OR (Postpartum Hemorrhage, Delayed)
41(2 AND 5) AND 10
42(2 AND 5) AND 13
43(2 AND 5) AND 15
44(2 AND 5) AND 17
45(2 AND 5) AND 19
46(2 AND 5) AND 21
47(2 AND 5) AND 24
48(2 AND 5) AND 27
49(2 AND 5) AND 29
50(2 AND 5) AND 31
51(2 AND 5) AND 33
52(2 AND 5) AND 36
53(2 AND 5) AND 38
54(2 AND 5) AND 40
55(2 AND 7) AND 10
56(2 AND 7) AND 13
58(2 AND 7) AND 15
59(2 AND 7) AND 15 Schema: all
60(2 AND 7) AND 17
61(2 AND 7) AND 19
62(2 AND 7) AND 21
63(2 AND 7) AND 21 Schema: all
64(2 AND 7) AND 24
65(2 AND 7) AND 24 Schema: all
66(2 AND 7) AND 27
67(2 AND 7) AND 27 Schema: all
68(2 AND 7) AND 29
69(2 AND 7) AND 31
70(2 AND 7) AND 31 Schema: all
71(2 AND 7) AND 33
72(2 AND 7) AND 33 Schema: all
73(2 AND 7) AND 36
74(2 AND 7) AND 36 Schema: all
75(2 AND 7) AND 38
76(2 AND 7) AND 38 Schema: all
77(2 AND 7) AND 40
78(2 AND 7) AND 40 Schema: all
79((2 AND 5) AND 10)) OR ((2) AND 5) AND 13)) OR ((2) AND 5) AND 15)) OR ((2) AND 5) AND 17)) OR ((2) AND 5) AND 19)) OR ((2) AND 5) AND 21)) OR ((2) AND 5) AND 24)) OR ((2) AND 5) AND 27)) OR ((2) AND 5) AND 29)) OR ((2) AND 5) AND 31)) OR ((2) AND 5) AND 33)) OR ((2) AND 5) AND 36)) OR ((2) AND 5) AND 38)) OR ((2) AND 5) AND 40)) OR ((2) AND 7) AND 10)) OR ((2) AND 7) AND 15)) OR ((2) AND 7) AND 17)) OR ((2) AND 7) AND 19)) OR ((2) AND 7) AND 21)) OR ((2) AND 7) AND 24)) OR ((2) AND 7) AND 27)) OR ((2) AND 7) AND 29)) OR ((2) AND 7) AND 31)) OR ((2) AND 7) AND 33)) OR ((2) AND 7) AND 36)) OR ((2) AND 7) AND 38)) OR ((2) AND 7) AND 40)) OR ((2) AND 7) AND 13)
Appendix 2. Characteristics of included studies
Badawy et al., 2008
Pasquier et al., 2015
Shaaban et al., 2017
Urman et al., 2009
Schleussner et al., 2015
Noci et al., 2011
Berker et al., 2011
Badawy AM, Khiary M, Sherif LS, Hassan M, Ragab A, Abdelall I. Low-molecular weight heparin in patients with recurrent early miscarriages of unknown aetiology. J Obstet Gynaecol. 2008;28:280-4. PMID: 18569468 DOI: 10.1080/01443610802042688
Berker B, Taşkin S, Kahraman K, Taşkin EA,
Atabekoğlu C, Sönmezer M. The role of low-molecular-weight heparin in
recurrent implantation failure: a prospective, quasi-randomized, controlled
study. Fertil Steril. 2011;95:2499-502. PMID: 21244861 DOI:
Clark P, Walker ID, Langhorne P, Crichton L, Thomson A, Greaves M,
Whyte S, Greer IA; Scottish Pregnancy Intervention Study (SPIN) collaborators.
SPIN (Scottish Pregnancy Intervention) study: a multicenter, randomized
controlled trial of low-molecular-weight heparin and low-dose aspirin in women
with recurrent miscarriage. Blood. 2010;115:4162-7. PMID: 20237316 DOI:
de Jong PG, Kaandorp S, Di Nisio M, Goddijn M, Middeldorp S. Aspirin
and/or heparin for women with unexplained recurrent miscarriage with or without
inherited thrombophilia. Cochrane Database Syst Rev. 2014;7:CD004734. PMID:
24995856 DOI: 10.1002/14651858.CD004734.pub4
Di Nisio M, Peters L, Middeldorp S. Aspirin or anticoagulants for
the treatment of recurrent miscarriage in women without antiphospholipid
syndrome. Cochrane Database Syst Rev. 2005;2:CD004734. PMID: 15846729 DOI:
Fawzy M, Shokeir T, El-Tatongy M, Warda O, El-Refaiey AA, Mosbah A.
Treatment options and pregnancy outcome in women with idiopathic recurrent
miscarriage: a randomized placebo-controlled study. Arch Gynecol Obstet.
2008;278:33-8. PMID: 18071727 DOI: 10.1007/s00404-007-0527-x
Gris JC, Mercier E, Quéré I, Lavigne-Lissalde G, Cochery-Nouvellon
E, Hoffet M, Ripart-Neveu S, Tailland ML, Dauzat M, Marès P.
Low-molecular-weight heparin versus low-dose aspirin in women with one fetal
loss and a constitutional thrombophilic disorder. Blood. 2004;103:3695-9. PMID:
14739212 DOI: 10.1182/blood-2003-12-4250
Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventions, version 5.1.0. The Cochrane Collaboration; 2011. Available from: https://training.cochrane.org/handbook/archive/v5.1/.
Kaandorp S, Di Nisio M, Goddijn M, Middeldorp S. Aspirin or
anticoagulants for treating recurrent miscarriage in women without
antiphospholipid syndrome. Cochrane Database Syst Rev. 2009;1:CD004734. PMID:
19160241 DOI: 10.1002/14651858.CD004734.pub3
Kaandorp SP, Goddijn M, van der Post JA, Hutten BA, Verhoeve HR,
Hamulyák K, Mol BW, Folkeringa N, Nahuis M, Papatsonis DN, Büller HR, van der
Veen F, Middeldorp S. Aspirin plus heparin or aspirin alone in women with
recurrent miscarriage. N Engl J Med. 2010;362:1586-96. PMID: 20335572 DOI:
Martinelli I, Ruggenenti P, Cetin I, Pardi G, Perna A, Vergani P,
Acaia B, Facchinetti F, La Sala GB, Bozzo M, Rampello S, Marozio L, Diadei O,
Gherardi G, Carminati S, Remuzzi G, Mannucci PM; HAPPY Study Group. Heparin in
pregnant women with previous placenta-mediated pregnancy complications: a
prospective, randomized, multicenter, controlled clinical trial. Blood.
2012;119:3269-75. PMID: 22289887 DOI:
Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred
reporting items for systematic reviews and meta-analyses: the PRISMA statement.
BMJ. 2009;339:b2535. PMID: 19622551 DOI: 10.1136/bmj.b2535
Noci I, Milanini MN, Ruggiero M, Papini F, Fuzzi B, Artini PG.
Effect of dalteparin sodium administration on IVF outcome in non-thrombophilic
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