Salim 2016.

Study characteristics
Methods	RCT: NCT01068795
Participants	144 women were randomised. Setting: 1 university teaching hospital and 3 specialised community clinics in Israel. Study dates: October 2009 to January 2015. Inclusion criteria: singleton pregnancies at ≤ 14 weeks' gestation, prior placenta‐mediated pregnancy complications or a lower leg thrombotic event (documental calf vein thrombosis), and testing positive for any thrombophilia (homozygous or heterozygous for prothrombin‐20210A or factor V Leiden mutations; homozygous for the mutation of cytosine to thymine at nucleotide 677 in the gene encoding methylenetetrahydrofolate reductase accompanied with homocysteine elevated serum levels; and tested positive for anti‐thrombin III, protein C and S deficiencies, lupus anticoagulant, anti‐cardiolipin IgG and/or IgM and anti‐β2 glycoprotein IgG and/or IgM) (prior placenta‐mediated pregnancy complications included: prior severe pre‐eclampsia; prior birth of SGA infant; with placenta related antepartum signs; prior placental abruption; or prior unexplained pregnancy loss (3 losses < 13 weeks, 2 losses 14‐22 weeks, any loss > 23 weeks)). Women were categorised as having low‐risk thrombophilia (factor V Leiden heterozygous; prothrombin gene mutation heterozygous; protein C deficiency; protein S deficiency; anti‐phospholipid antibody) or high‐risk thrombophilia (antithrombin III deficiency; homozygous for factor V Leiden; homozygous for prothrombin mutation; combined thrombophilias). Exclusion criteria: women who had previous pregnancy complications that could be attributed to multiple gestations; having fetuses with major congenital anomalies or chromosomal abnormalities, fetal infection, or hydrops fetalis; women with pre‐gestational diabetes; or women who required therapeutic dosage of LMWH or had a contraindication to LMWH therapy.
Interventions	Group 1 (n = 74): LMWH adjusted dose: starting around 14 weeks GA, adjusted dose of antepartum enoxaparin according to the results of anti‐FXa levels until birth. The initial dose was 40 mg and increased by fractions of 20 mg, according to anti‐FXa level. The targeted prophylactic level was 0.2 IU/mL or more 3.5 to 4 hours post‐injection. Quote: "All women had levels of anti‐FXa examined approximately every 8–10 weeks… A blood sample was taken from all women 3.5‐4 h after the injection of enoxaparin at the central laboratory. Subsequently, the results were computerised and enoxaparin dose was then adjusted in the next visit among women in the adjusted‐dose group. Women attended follow‐up visits every 3–4 weeks." Group 2 (n = 70): LMWH fixed dose. starting around 14 weeks GA, maintained fixed dose of 40 mg enoxaparin, once daily by subcutaneous self‐injection, until birth regardless of the results of anti‐factor Xa. Women in both groups with antiphospholipid antibodies were given low dose aspirin in addition to enoxaparin. Postpartum, all women were prescribed enoxaparin 40 mg once daily by subcutaneous injection from day 1 until day 42.
Outcomes	Review outcomes reported: symptomatic thromboembolic events; symptomatic PE; symptomatic DVT; bleeding episodes (reports placental abruption; postpartum haemorrhage; and side effects ‐ bleeding); adverse effects sufficient to stop treatment; adverse effects not sufficient to stop treatment (reports skin allergy); fetal loss (reports spontaneous abortion, assumed to be < 23 weeks; and reports intrauterine fetal death > 23 weeks); thrombocytopenia. Other outcomes reported: composite outcome (1 or more of the following events: any pregnancy loss, pre‐eclampsia, SGA, placental abruption, and VTE); components of the composite outcome; gestational age at birth; preterm birth; mode of birth; birthweight; Apgar score < 7 at 5 minutes; cord pH < 7,1; and anti‐FXa levels (and < 0.2 IU/mL); maternal placental vascular lesions; fetal placental vascular lesions.
Notes	Funding sources: not reported. Declarations of interest: "None declared."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomisation was performed using a computer randomisation sequence generation program."
Allocation concealment (selection bias)	Low risk	Quote: "The randomisation sequence results were kept in the delivery ward in a closed study box. The site investigator enrolled participants after confirming eligibility. The sequence was concealed until intervention was assigned (and after obtaining a signed informed consent)."
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: "Women and providers were not masked to the treatment arm."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	For secondary analyses: "Placentas were examined by the same pathologist who was blinded to group allocation."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Of 74 women in intervention group, all included in intention to treat analyses; of 70 women in control group 4 excluded from intention to treat analyses (2 lost to follow‐up, and 2 discontinued intervention – 1 due to side effects, and 1 due to ineligibility).
Selective reporting (reporting bias)	Unclear risk	No trial protocol to confidently assess selective reporting.
Other bias	Low risk	No other obvious risk of bias identified.