Risk factors for thrombo-embolism in neonates: A systematic review of the literature and call to action

Abstract BACKGROUND: While venous thrombo-embolism (VTE) is increasingly recognized in neonates and prothrombotic risk factors are increasing being identified, no risk prediction model currently exists to enable early identification of neonates at high risk of VTE. A thorough understanding of existing evidence is necessary to inform the development of a risk-assessment model. We aimed to describe maternal, obstetrical, and neonatal risk factors associated with VTE in neonates METHODS: Literature search was performed for peer-reviewed randomized and non-randomized trials, retrospective and prospective cohort studies, case-control studies and case series of ≥10 patients (1990-2024). Studies were eligible if ≥90% of participants were neonates, defined as infants up to 28 days and with corrected gestational age ≤44 weeks at time of VTE diagnosis, and if studies reported VTE risk factors, including symptomatic and/or clinically unsuspected events. The review was registered on PROSPERO (CRD42024518801). Catheter-related risk factors are reported separately. Study screening and data extraction were performed independently by two investigators; risk of bias was assessed using the Risk of Bias in Non-randomised Studies of Interventions (ROBINS-I) tool. Risk factors described in ≥3 studies were considered. Random effect meta-analysis was performed in the absence of substantial methodological or clinical heterogeneity; results are expressed using mean difference (MD) or odds ratio (OR) with 95% confidence intervals (CI). Heterogeneity was estimated using restricted maximum-likelihood model and expressed using I2. RESULTS: The search yielded 10,579 references, with 283 full-text articles retrieved. Of these, 58 studies (3,450,114 neonates) reporting on the predictive impact of maternal, obstetrical, and neonatal risk factors for VTE were included. Most studies were retrospective (n=25, 43%) or case-control (n=15, 26%) studies; 20 (34%) studies were published within the last 5 years. While VTE definition often did not differentiate symptomatic and clinically unsuspected VTE, 28 (50%) of studies performed at least one surveillance imaging for VTE screening. Most studies (n=48, 86%) had serious risk of bias in at least one domain, typically risk of confounding. Maternal/obstetrical risk factors: Pre-eclampsia and maternal diabetes were predictive of neonatal thrombosis in 2 of 4 (3,102,008 neonates) and 2 of 3 studies (3,106,857 neonates), respectively, while cesarean section was not predictive of thrombosis in 4 studies (40,925 neonates). Demographic variables: Among neonates hospitalised to the NICU, low birthweight was associated with VTE (OR: 2.05, 95% CI: 1.41-3.00, p<0.001, I2=0%, 4 studies). Conversely, gestational age (MD: -0.45, 95%CI: -1.71-0.82, p=0.49, I2=76%, 5 studies) and sex were not significantly associated with VTE (male vs. female, OR: 1.17, 95% CI: 0.94-1.45, p=0.15, I2=24%, 17 studies). Neonatal risk factors: Cardiac disease (OR: 5.90, 95% CI: 1.16-30.03, p=0.03, I2=62%, 3 studies) and infection (OR: 3.16, 95% CI: 1.87-5.33, p<0.001, I2=90%, 7 studies) were significantly associated with VTE. Asphyxia (OR: 5.88, 95% CI: 0.85-40.72, p=0.07, I2=94%, 4 studies), mechanical ventilation (OR: 2.00, 95% CI: 0.52-7.60, p=0.31, I2=99%, 4 studies), and surgery (OR: 3.05, 95% CI: 0.88-10.51, p=0.08, I2=95%, 4 studies) were more frequent in neonates with VTE, albeit not reaching statistical significance. The effect of respiratory distress syndrome, necrotizing enterocolitis, and cholestasis on VTE development was reported in fewer than three studies and was not analyzed. Medication and blood products: Overall, eight studies (202,480 neonates) investigated the impact of postnatal medication (total parental nutrition, steroids, recombinant factor VIIa) or blood product administration in neonates (any, fresh frozen plasma, activated 4-factor prothrombin complex concentrates, antithrombin concentrates) on the risk of VTE; with no intervention examined in more than one study. CONCLUSION: Several risk factors for VTE have been reported in the literature, including pre-eclampsia, maternal diabetes, low birthweight, infection, and cardiac disease. However, important discrepancies between studies and limited data regarding the impact of common conditions and medications persist. Comprehensive prospective research is urgently needed to enable accurate risk prediction and improve VTE prevention in neonates.