Pregnancy outcomes in alpha thalassemia major: A population-based analysis using the national inpatient sample 2017-2022

Abstract Introduction: Clinically significant alpha thalassemia, encompassing Hemoglobin H (HbH) disease and alpha thalassemia major, constitutes a spectrum of severe inherited anemias associated with substantial systemic morbidity. Although case series have suggested elevated maternal risk during pregnancy, comprehensive population-based data remain limited. We performed a nationwide cohort study to evaluate maternal complications in pregnancies affected by clinically significant alpha thalassemia compared to matched unaffected controls.Methods: We performed a retrospective cohort study using the National Inpatient Sample (NIS) from 2017-2022. Cases with clinically significant alpha thalassemia were identified using ICD-10-CM code D56.0. A control group was established by stringently excluding all hospitalizations with any ICD-10-CM code for other thalassemias (D56.1-D56.5) or any sickle-cell disorder (D57.0-D57.8). This was done to reduce bias and confounding from other hemoglobinopathies. A control group of pregnancies without any hemoglobinopathy diagnosis was matched up to 4:1 to cases using propensity scores. Covariate balance was confirmed using standardized differences (<0.1). Primary outcomes included severe maternal morbidity (SMM), blood transfusion, and anemia. Secondary outcomes were intrauterine growth restriction (IUGR), length of stay (LOS), and hospital charges. All analyses were performed using StataNow/MP 19.5, incorporating the complex survey design of the NIS.Results: Among 4,184,870 delivery hospitalizations, we identified 1,447 pregnancies with clinically significant alpha thalassemia. Propensity score matching yielded a well-balanced cohort of 1,447 cases and 5,777 controls. Pregnancies with clinically significant alpha thalassemia were associated with dramatically increased rates of anemia (OR 10.85, 95% CI 8.53-13.80, p<0.001) and more than double the requirement for blood transfusion (OR 2.18, 95% CI 1.57-3.04, p<0.001). The risk of IUGR was also significantly elevated (OR 1.32, 95% CI 1.12-1.57, p=0.001). A trend toward increased SMM was observed but did not reach statistical significance (OR 1.13, 95% CI 0.98-1.29, p=0.090). No maternal deaths occurred. Healthcare utilization was significantly higher, with a 9% increase in total hospital charges (RR 1.09, 95% CI 1.04-1.15, p=0.001), while the increase in length of stay was not statistically significant (RR 1.05, p=0.077).Conclusions: This large, nationwide analysis, using a rigorously defined control group, demonstrates that clinically significant alpha thalassemia is associated with significantly elevated rates of anemia and doubled transfusion requirements in pregnancy. It is also associated with an increased risk of IUGR and greater healthcare costs. These findings underscore the need for multidisciplinary care involving maternal-fetal medicine and hematology to manage the significant hematologic risks and optimize maternal and fetal surveillance.