Details for the studies included are in the Characteristics of included studies.
We included nine studies (1228 women for the primary outcome live birth) (Badawy 2008; Clark 2010; Dolitzky 2006; Fawzy 2008; Giancotti 2012 Kaandorp 2010; Martinelli 2012; Tulppala 1997; Visser 2011) in this review. In the studies Badawy 2008 and Dolitzky 2006, full study populations were included. For the studies Clark 2010; Fawzy 2008; Giancotti 2012; Kaandorp 2010; Martinelli 2012; Tulppala 1997; and Visser 2011, we could not include full study populations, but had to extract data on the women fulfilling the inclusion criteria of the review. Reasons for including only part of the original study population are explained for each study.
Badawy 2008 evaluated the effect of LMWH (enoxaparin 20 mg/day) in women with three or more consecutive first trimester miscarriages. Women were included if no risk factors for RM could be identified (women with inherited thrombophilia were excluded) and randomised to either treatment or no-treatment (no placebo). Therapy was commenced once fetal viability was detected on ultrasound and continued until 34 weeks' gestation. The primary outcome was pregnancy loss and pregnancy complications, but live births could be calculated from the report and were confirmed by the study author. Of 350 women enrolled, 10 women (four (2.3%) and six (3.4%) in both arms) were lost to follow-up, leaving 170 women in each study arm for analysis. Side effects of treatment were only reported for women randomised to treatment, not in those randomised to no-treatment.
Clark 2010 studied the effect of LMWH (enoxaparin 40 mg/day) and aspirin (75 mg/day) from before seven weeks' gestation until 36 weeks' gestation on live birth in 296 women with RM, defined as a minimum of two consecutive early pregnancy losses (at or before 24 weeks' gestation). Intervention with LMWH and aspirin combined with intense pregnancy surveillance was compared with intense pregnancy surveillance without pharmacological intervention. Women were included upon a positive pregnancy test (before seven weeks' gestation). Investigations for uterine or chromosomal abnormalities and antiphospholipid syndrome were conducted only for women with three or more previous miscarriages. Women who were included because of two previous miscarriages were excluded from our analysis, because it could not be confirmed that previous miscarriages were 'unexplained'. The primary outcome measure in the study was live birth. Adverse events of intervention were reported, though could not be extracted for the women with three or more previous miscarriages. One-hundred and twenty-two women were included in the review (64 randomised to LMWH and aspirin versus 58 randomised to surveillance).
Dolitzky 2006 evaluated the effect of LMWH compared with aspirin in 104 women with unexplained RM. RM was defined as three or more consecutive first trimester miscarriages or at least two consecutive second trimester miscarriages. The objective was to compare the effect of enoxaparin and aspirin on live birth rate. Women were only included if there was no apparent risk factors for the miscarriages and women with inherited thrombophilia were excluded. The treatment with enoxaparin (40 mg/day) or aspirin (100 mg/day) was started from the time of detection of a fetal heart beat at six to 12 weeks' gestation and continued until a gestational age of 37 weeks. Of the 107 included women, 54 received enoxaparin, 50 aspirin and three were lost to follow-up. Besides the primary outcome measure of live birth, secondary outcomes like preterm delivery, intrauterine growth restriction, and pre-eclampsia were reported.
Fawzy 2008 assessed the effect of LMWH (enoxaparin 20 mg/day) compared with combination treatment (oral prednisone and progesterone from the onset of pregnancy until 12 weeks of gestation and aspirin from the onset of pregnancy until 32 weeks of gestation) compared with placebo (for oral intervention) in women with three or more consecutive unexplained miscarriages (before 24 weeks' gestation) with the same partner. Women with inherited thrombophilia were excluded. From this study, we extracted data for the 107 women receiving enoxaparin or placebo. Of these women, 57 were assigned to enoxaparin and 50 to placebo. Treatment was started when a fetal pole was detected and continued until term. The primary outcome was live birth, but secondary outcomes such as obstetric complications and neonatal outcomes were also reported.
Giancotti 2012 evaluated the effect of LMWH or aspirin or a combination of these in 167 women with a history of two or more unexplained miscarriages before 12 weeks' gestation. Women with uterine or chromosomal abnormalities were excluded, but women with inherited thrombophilia or antiphospholipid syndrome were eligible. Women were randomised to LMWH (enoxaparin 40 mg/day from diagnosis of intrauterine pregnancy until delivery) or aspirin (100 mg/day from diagnosis of pregnancy until 32 weeks' gestation) or first aspirin (100 mg/day from diagnosis of pregnancy), which was replaced by LMWH at 32 weeks' gestation (enoxaparin 40 mg/day continued until delivery). For this analysis, we included only data from women without antiphospholipid antibodies randomised to either LMWH (n = 40) or aspirin (n = 46). The primary outcome of the study was live birth, and no secondary outcome measures were reported.
Kaandorp 2010 evaluated the effect of open label LMWH (nadroparin 2850 IU/day) combined with aspirin (80 mg/day) or aspirin only (80 mg/day) compared with placebo in 364 women with unexplained RM with or without inherited thrombophilia. Previous miscarriage was defined as pregnancy loss at a gestational age of 20 weeks or less. Women were included in the study if they were attempting to conceive or were less than six weeks pregnant. From this study, we extracted data of the 299 women who became pregnant (97 were assigned to aspirin plus nadroparin, 99 were assigned to aspirin only and 103 were assigned to placebo). LMWH was initiated when a viable intrauterine pregnancy was confirmed on ultrasonography at six weeks' gestation until the start of labour. Aspirin or placebo was started at randomisation and continued until a gestational age of 36 weeks. The primary outcome was live birth, and secondary outcomes were adverse pregnancy outcomes and maternal adverse events. Secondary outcomes such as obstetric complications and neonatal events were evaluated for 200 women with ongoing pregnancy beyond 12 weeks of gestation.
Martinelli 2012 evaluated the effect of open label LMWH (nadroparin 3800 IU/day), compared with no treatment in 135 women with previous placenta-mediated pregnancy complications. Women with antiphospholipid syndrome, uterine anomalies or abnormal karyotype were excluded from the study. Inherited thrombophilia was not an exclusion criterion. LMWH was compared with medical surveillance only and treatment was initiated upon randomisation and continued until delivery. Randomisation was performed around the 12th week of gestation, after pregnancy was confirmed on ultrasonography. The primary outcome of the study was a composite outcome of several pregnancy complications. For this review we included data of six women, who had a history of two or more unexplained miscarriages up to 24 weeks' gestation.
Tulppala 1997 evaluated the effect of aspirin (50 mg/day) on live birth rate in 66 pregnant women with preceding RM with or without detectable anticardiolipin antibodies and no other apparent risk factors for their previous miscarriages. RM was defined as three or more consecutive miscarriages (occurring before 22 weeks of gestational age). Aspirin was compared with placebo, and medication was started as soon as a home urinary pregnancy test became positive and continued until delivery. From this study, we extracted data for 54 women who were negative for anticardiolipin antibodies. Of these, 27 were assigned to aspirin and 27 to placebo. Secondary outcomes, such as preterm delivery, obstetric complications, and bleeding rate could not be extracted separately for the group of women with negative anticardiolipin antibodies.
Visser 2011 evaluated the effect of LMWH (enoxaparin 40 mg/day) plus oral placebo (n = 68) compared with LMWH (enoxaparin 40 mg/day) plus aspirin (100 mg/day) (n = 63), compared with aspirin only (100 mg/day) (n = 76) in women with unexplained RM with or without inherited thrombophilia. RM was defined as three or more consecutive first trimester miscarriages, two or more second trimester miscarriages or one third trimester fetal loss combined with at least one first trimester miscarriage. Treatment was initiated upon randomisation (before seven weeks' gestation); aspirin and placebo were discontinued at 36 weeks' gestation whereas enoxaparin was continued until the first signs of labour. The primary outcome was live birth and secondary outcomes were adverse pregnancy outcomes and bleeding. Premature delivery, obstetrical complications and congenital malformations were reported only for women who had live birth. Study authors stated that only one woman was included in the study because of RM based on one fetal loss before, and two fetal losses after 24 weeks' gestation; her data were excluded from this review. Furthermore, data of 10 women (allocated to enoxaparin plus placebo (n = 3, one live birth), enoxaparin plus aspirin (n = 2, one live birth), aspirin only (n = 5, four live births)) were excluded because of the presence of Beta-2 glycoprotein antibodies. One-hundred and ninety-six women were included in this trial.
As can be noted, no study compared the same treatment regimen. Studies compared different doses of LMWH and aspirin or combinations of these, and treatment was started at various gestational ages. As described in the Methods section, we pooled data based on type of intervention, but irrespective of the dose of LMWH or aspirin. Only studies in which the investigational treatment was started at a maximum of 12 weeks' gestation and continued beyond 32 weeks' gestation were included.