SCRIPT: Sickle Cell Risk in Pregnancy Tool

Overview

Sickle Cell Disease (SCD), common in persons of Black ancestry, affects the shape of hemoglobin, the oxygen-carrying part of red blood cells (RBC). It is characterized by many complications, the most dreaded of which are related to pregnancy - affecting both the mother and unborn child. Compared to those without SCD, people with SCD have more adverse pregnancy outcomes (APO): 6x maternal mortality, 2x preeclampsia \& preterm birth, 4x risk of having a baby not growing well in the womb \& stillbirth. There is also greater need for access to care (7x higher hospitalization often multiple times lasting days to months). Yet up to 30% of SCD pregnancies are uncomplicated. Treatments in pregnancy are limited and carry risks. A method to distinguish pregnancies at high-risk of APO that may benefit from these potentially risky treatments, from those likely to be uncomplicated, is urgently needed. To meet this need, the investigators developed a calculator to estimate pregnancy complication risk, using single-centre data. Its accuracy and precision will now be evaluated with international information from several centers by testing the calculator, and adjusting it as needed, using already available pregnancy-data from study centres in several countries. Those age \>16 years, who have a confirmed SCD genotype, pregnancy with one baby, and pregnancy care and birth at a participating study centre will be included. Pregnancy care for the participants will be up to their doctors, with no changes based on the study. SCRIPT - the new tool - will guide future care by predicting who may benefit from specific treatments, reducing harm to low-risk individuals \& will allow selection of high-risk patients for a future trials to determine whether currently available and novel treatments in well-selected patients can improve APO sufficiently to balance treatment-related harms.

Sickle Cell Disease (SCD) is the most common haemoglobinopathy; predominantly affecting persons of African descent(1). In comparison to those without SCD, pregnant persons with SCD have a six-fold higher risk of mortality, twice the risk of preeclampsia and preterm birth, and nearly a four-fold risk of having a small for gestational age infant or experiencing stillbirth(2,3). Furthermore, there is a higher rate of resource utilization in this group, with nearly 50% of pregnancies complicated by at least one antenatal admission and an overall seven-fold higher hospitalization risk compared to pregnancies without SCD(4,5). These admissions are most commonly secondary to vaso-occlusive events or anemia, can occur on multiple occasions, and can last days to months(4,5). During pregnancy, red blood cell (RBC) transfusion remains the only recommended intervention(6), with some evidence suggesting that prophylactic transfusion may modify adverse pregnancy outcomes (APOs)(7,8), with a possible positive effect on hospitalization rates through decreased complications, though this requires further study. However, transfusion is not without risk. Beyond its typically-feared infectious complications(9), transfusion in SCD is associated with alloimmunization rates of over 30%(10-12), can induce life-threatening hyperhemolysis(13), and will eventually lead to iron overload(14). At the same time, up to 30% of pregnancies in individuals with SCD remain uncomplicated(2,3,15,16). A tool is thus urgently needed to separate high-risk individuals who would benefit from transfusion from low-risk individuals who would accrue transfusion risks with minimal, if any benefit. Using a single-centre cohort, the investigators developed maternal and fetal risk prediction models, as the first step in permitting the selection of patients most likely to benefit from transfusion(16). Ultimately, a multi-center international randomized controlled trial (RCT) is required to determine the benefits of prophylactic transfusion in this setting; yet, before such an RCT is conceived, the model(s) must be refined and validated with a larger sample to allow for appropriate participant selection. The investigators proposed a multicenter international cohort study to enhance the predictive capacity and validate the current model(s) within the participating centers. The academic centers (located in Canada, USA, and France), have multi-disciplinary experts dedicated to managing pregnant persons with SCD, and the combination of MFM and Haematology site co-leads provides essential interdisciplinary expertise with synergistic medical and obstetric perspectives. Once completed, the Sickle Cell Risk In Pregnancy Tool (SCRIPT) will inform medical decisions regarding transfusion and will set the stage for appropriate selection of high-risk individuals for inclusion in an RCT aimed to definitively determine whether prophylactic transfusion in well-selected pregnant individuals with SCD does indeed improve APOs to the degree that would balance its potential associated harms.