Beta thalassemia major and pregnancy outcomes: Evidence of severe transfusion burden and iron overload complications in a national cohort Free

Introduction: Beta thalassemia major (Cooley's anemia) results from a severe reduction or absence of beta-globin chain synthesis, leading to ineffective erythropoiesis, chronic hemolytic anemia, and iron overload from increased intestinal absorption and chronic transfusions. Pregnancy poses unique challenges including increased metabolic demands, potential cardiac decompensation from pre-existing iron cardiomyopathy, and risks of alloimmunization complicating transfusion management. Fetal risks include growth restriction from chronic maternal hypoxia. Previous studies are limited to small case series from thalassemia-endemic regions. We evaluated pregnancy outcomes in women with beta thalassemia major using contemporary US national data, hypothesizing increased maternal morbidity, transfusion requirements, and evidence of iron overload complications compared to matched controls.

Methods: The National Inpatient Sample (2017-2022) was systematically queried for delivery hospitalizations in women aged 15-50 years using validated algorithms. Beta thalassemia major was identified using ICD-10 code D56.1, excluding minor/trait forms (D56.3) and sickle-cell thalassemia (D57.4). Our stringent case definition focused on clinically significant beta thalassemia. We performed 1:4 nearest neighbor matching with replacement, using 0.1 standard deviation calipers on the logit of propensity scores incorporating demographics, socioeconomic factors, hospital characteristics, and baseline comorbidities. Covariate balance was assessed using standardized differences. Primary outcomes encompassed severe maternal morbidity, transfusion requirements, and iron overload complications. Secondary outcomes included obstetric complications and resource utilization. Statistical analyses employed survey-weighted regression models accounting for the complex sampling design. For outcomes with zero events in one group, we calculated exact confidence intervals. Rare events utilized Fisher's exact tests. Continuous outcomes were analyzed using gamma regression with a log link.

Results: Of 4,184,870 deliveries, 1,359 (0.03%) had beta thalassemia major. We successfully matched 1,356 cases to 5,419 controls, achieving excellent covariate balance (all standardized differences <0.01). Beta thalassemia pregnancies demonstrated a severe hematologic burden: anemia prevalence was 93.4% vs 59.6% (OR=9.62, 95%CI 7.66-12.08, p<0.001). Transfusion requirements were markedly elevated at 6.0% vs 1.4% (OR=4.47, 95%CI 3.25-6.15, p<0.001), representing a 4.5-fold increase in risk. Critically, iron overload was documented exclusively in the beta thalassemia cohort (3 cases vs 0; Fisher’s exact p=0.008). Severe maternal morbidity occurred in 18.8% vs 19.7% of pregnancies, a difference that was not statistically significant (OR=0.95, 95%CI 0.81-1.11, p=0.483). Intrauterine growth restriction remained significantly elevated (13.0% vs 9.8%; OR=1.37, 95%CI 1.14-1.64, p=0.001). Healthcare utilization showed 7% longer hospitalizations (2.9 vs 2.7 days; rate ratio=1.07, 95%CI 1.01-1.14, p=0.017) and 8% higher costs ($26,565 vs $24,594; rate ratio=1.08, 95%CI 1.02-1.14, p=0.008).

Conclusions: This comprehensive analysis reveals that beta thalassemia major in pregnancy carries a substantial transfusion burden, with rates 4.5-fold higher than matched controls. The exclusive occurrence of documented iron overload complications in beta thalassemia highlights a unique pathophysiology requiring specialized management. Fetal growth restriction in 13% of cases suggests chronic placental insufficiency. These findings mandate preconception care including cardiac and hepatic iron assessment, optimization of chelation therapy, establishment of extensive blood product availability, and multidisciplinary coordination between hematology, maternal-fetal medicine, and transfusion medicine. Serial growth assessment and antenatal testing are essential given the high rates of growth restriction. Future research should evaluate optimal transfusion triggers in pregnancy and the safety profiles of modern iron chelators.