van Hoorn 2016.

Study characteristics
Methods	RCT: ISRCTN87325378
Participants	32 women were randomised. Setting: 13 hospital centres in (5 university and 6 non‐university/teaching hospitals in the Netherlands, 2 hospitals in Australia, and 1 hospital in Sweden. Study dates: December 2000 to December 2009. Inclusion criteria: < 12 weeks' gestation, aged ≥ 18 years, history of uteroplacental insufficiency and birth < 34 weeks' gestation (hypertensive disorders of pregnancy (including pre‐eclampsia, HELLP syndrome, eclampsia) and/or SGA infant), and antiphospholipid antibodies (anticardiolipin antibodies present and/or lupus anticoagulant present) [women without antiphospholipid antibodies were included in de Vries 2012) Exclusion criteria: women with 1 or more antithrombin deficiency, homozygosity for factor V Leiden and prothrombin G20210A mutations, diabetes mellitus, known malignancy, known peptic ulceration, severe renal or hepatic insufficiency, history of VTE, haemorrhagic diathesis, idiopathic thrombocytopenia, earlier participation in the FRUIT trial, or LMWH use in earlier pregnancy.
Interventions	Group 1 (n = 16): LMWH and aspirin: once‐daily dalteparin (5000 IU, by subcutaneous self‐administration), starting at 6‐12 weeks' gestation until the onset of labour or prior to the caesarean section, plus once‐daily aspirin (80 mg, oral), stating at < 12 weeks and continued to 36 weeks' gestation. The daily dose of dalteparin was adjusted for body weight: women < 50 kg received dalteparin 2500 IU, those > 80 kg 7500 IU. Dalteparin injections started at 6 to 12 weeks' gestation, and stopped at the onset of labour or prior to caesarean section. Aspirin was commenced at < 12 weeks' gestation and stopped at 36 weeks' gestation (women in Australia were treated with aspirin 100 mg daily as the standard dose). In women who developed local skin reactions, treatment with dalteparin was altered to enoxaparin and, if the reaction was persistent, to nadroparin. Group 2 (n = 16): aspirin alone: daily aspirin (80 mg, orally), commencing at < 12 weeks' gestation, until 36 weeks' gestation (women in Australia were treated with aspirin 100 mg daily as the standard dose). All women: educated on self‐injection, and after birth weight‐adjusted dalteparin (for 6 weeks) was prescribed.
Outcomes	Review outcomes reported: symptomatic thromboembolic events; symptomatic PE; symptomatic DVT; bleeding episodes (reports placental abruption); adverse effects not sufficient to stop treatment (reports skin reactions, pain, itching, swelling, allergy; reports need for an alternate LMWH; reports haematoma); fetal loss (reports spontaneous miscarriage < 16 weeks; reports fetal death > 16 weeks (miscarriage excluded)); thrombocytopenia. Other outcomes reported: hypertensive disorders of pregnancy (pre‐eclampsia and/or eclampsia and/or HELLP syndrome) onset before 34 weeks' gestation and irrespective of gestational age; SGA; miscarriage; preterm birth; length of maternal and neonatal admission; pre‐eclampsia; eclampsia; HELLP syndrome; termination of pregnancy; gestational age at miscarriage; gestational age at birth; birthweight.
Notes	Funding sources: Quote: "The study was supported by a single 2‐year investigator grant period 2000–2001 by Pfizer, formerly Pharmacia, grant number 524E‐CVD‐9101‐0001, annual Dutch investigators meetings, a single grant to support a midwife to recruit Australian women, and support for a local meeting in Sweden in 2004. Pharmacia was not the sponsor of the study. A follow‐up study of the trial received a 1‐year investigator grant period in 2014 by Pfizer." Declarations of interest: Quote: "All authors have declared that they have no conflicts of interest." "After the completion of recruitment to the inheritable thrombophilia group of the trial, and given the slow inclusion rate of women with acquired thrombophilia, an interim analysis was performed after delivery of 29 women. The Data Monitoring committee advised cessation of recruitment since accrual was slow and the incidence… of early onset HD (3.4%) was far lower than expected (60%), and the decision was taken by the trial management group to halt the study."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "using a computer to select random permuted blocks of four, with stratification for hospital and presence/absence of chronic hypertension."
Allocation concealment (selection bias)	Low risk	Quote: "Randomisation was carried out by an independent centre."
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: "Neither study personnel nor participants were blinded to treatment assignment, as placebo injections during pregnancy were at that time not considered to be ethically acceptable."
Blinding of outcome assessment (detection bias) All outcomes	High risk	Quote: "The adjudication of the study endpoints was not blinded, but was performed by the chief researcher (JdeV) using absolute values of blood pressure, proteinuria and appropriate laboratory tests in the adjudication, after an initial local assessment at each centre."
Incomplete outcome data (attrition bias) All outcomes	Low risk	No losses to follow‐up or exclusions.
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.