Increased risk of venous thromboembolism and hypertensive disorders during pregnancy in sickle cell disease patients: A meta-analysis focused on actionable outcomes

Abstract There is a paucity of evidence-based interventions to improve outcomes in pregnancy in sickle cell disease (SCD) patients despite an increasing number of studies worldwide reporting pregnancy outcomes during the past decade. The heterogeneity in the definition of outcomes among studies has been recognized (Ashwal et al. 2023) and is a potential barrier to prioritize endpoints for clinical research. There is near-universal exclusion of pregnant women from clinical trials for novel medications for SCD, which limits investigation to medications known to be safe in pregnancy. The purpose of this meta-analysis was to assess the current evidence of the association of SCD in pregnancy with actionable and well-defined outcomes, for which there are interventions used in pregnant healthy patients that can be explored in prospective studies in SCD; for example, aspirin and heparin are used to reduce the risk of preeclampsia or venous thromboembolism (VTE). Given the importance of having precisely defined outcomes for future studies, we analyzed data on individual subtypes of hypertensive disorders, such as pregnancy induced hypertension (PIH) or gestational hypertension (GH), preeclampsia, and eclampsia, and subtypes of VTE complications, divided into deep vein thrombosis (DVT) and pulmonary embolism (PE) rather than studying them only as composite outcomes. A systematic review was conducted using Embase, PubMed, Web of Science, Global Health, CINAHL, Global Index Medicus, and SciELO. We included cohort and case control studies from 16 countries within the years 1973-2023 that compared outcomes between women with SCD and women without SCD. Log response ratio was used to quantify differences in pregnancy outcome risks, incorporating outcome type as a moderator and accounting for non-independence within studies. We found 45 studies fulfilled inclusion criteria, of which 21 were additional studies to the last comprehensive meta-analysis published in 2022, nearly doubling the sample size analyzed. We included 38,386 pregnancies in women with SCD and 19,259,391 pregnancies in women without SCD. There was a significant increase in the risk of aggregated hypertensive disorders (risk ratio [RR]: 1.75, 95% confidence interval [95%CI]1.69-1.80, p<0.001) in pregnant women with SCD. We included under “hypertensive disorders” results from studies that did not stratify among causes of hypertension in pregnancy. From studies that stratified that, we found progressively higher RR for PIH/GH (1.10, 95%CI 1.03-1.17, p=0.0054), preeclampsia (2.01, 95%CI 1.93- 2.09, p<0.001), and eclampsia (2.62, 95%CI 2.35-2.92, p<0.001). There was a notably higher risk of VTE events (10.79, 95%CI 9.52-12.22, p<0.001), with about equally high RR for DVT (9.44, 95%CI 7.96-11.19, p<0.001) or pulmonary embolism (10.00, 95%CI 8.16-12.25, p<0.001) in pregnant women with SCD. Low birth weight was also significantly more common in infants born to women with SCD (1.85, 95%CI 1.75-1.96, p<0.001). To our knowledge, this meta-analysis included the largest number of pregnancies in SCD patients with data collected along with control patients. It provides the most current data and confirms that SCD is associated with a higher risk of VTE and hypertensive disorders in pregnancy. The analysis of subtypes of hypertensive disorders revealed more nuanced risk patterns, with higher risk ratios found in the more severe presentations (eclampsia > preeclampsia > PIH/GH). It also showed that RR for DVT and pulmonary embolism were similar, which may suggest that DVT in this patient population carries a higher risk of embolism. Our findings highlight the importance of ongoing clinical trials investigating aspirin to prevent adverse outcomes in pregnancy in SCD patients, such as the LEARNER (NCT06417411) and PIPSICKLE (NCT05253781) studies. With very high risk ratios, there is great need and opportunity for international collaboration to investigate strategies to prevent DVT and pulmonary embolism in this population leading to practice-changing evidence applicable worldwide.