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BACKGROUND: Pregnancy alters hematologic state as measured by complete blood count (CBC), but the longitudinal changes in CBC indices that define healthy pregnancies are not well established. In a large cohort based at an academic health system in the United States, we aimed to define reference intervals and typical longitudinal changes in CBC indices during pregnancy. We then tested for associations between extreme CBC values for gestational age or extreme longitudinal changes in CBC indices and obstetric complications.METHODS AND FINDINGS: We studied nine CBC indices in individuals with singleton pregnancies who delivered after 30 weeks' gestation and presented for prenatal care prior to 20 weeks. The electronic health record (EHR)-based Maternal Health Cohort (Massachusetts General Hospital; 1998-2016) formed our discovery cohort of 45,992 pregnancies, 18% of which had relevant complications. We developed a validation cohort of 48,868, 27% with complications from EHR data in the Mass General Brigham healthcare system from 2016 to 2024. In pregnancies without complications in the discovery cohort, we derived gestational-age-specific reference intervals (2.5th-97.5th percentile) and established typical intra-pregnancy longitudinal changes. In the validation cohort, we then tested CBC values outside of the 26-29 weeks' gestation reference interval and CBC rare changes (uncommon changes in magnitude and direction) between 7-14 and 26-29 weeks' gestation for association with a composite outcome (hypertensive disorders of pregnancy, small for gestational age birthweight, preterm birth) and its individual components using generalized estimating equations. Derived reference intervals differed from those in the literature for mean red cell volume, mean red cell hemoglobin, red cell count, and mean red cell hemoglobin concentration; reference intervals for other indices were similar to those previously published. In validation, hematocrit, hemoglobin, and red cell count values above their gestational-age specific reference intervals were associated with increased risk of the composite obstetric outcome: odds ratios (ORs) of 1.4 (95% CI [1.2, 1.5 p < 0.0001) for hematocrit; 1.6 (95% CI [1.4, 1.8] p < 0.0001) for hemoglobin; and 1.6 (95% CI [1.4,1.7] p < 0.0001) for red cell count. Extreme increases in hemoglobin (>0.67 g/dL) or red cell count (>0.07 106/mm3) between 7-14 weeks' and 26-29 weeks' gestation were associated with increased risk for preterm birth, OR for hemoglobin 1.9 (95% CI [1.5, 2.5] p < 0.0001) and red cell count 2.1 (95% CI [1.7, 2.6] p < 0.0001). Limitations include the retrospective nature of the study and the exclusion of both pregnancies without prenatal care prior to 20 weeks' and pregnancies delivered before 29 weeks' gestation.CONCLUSIONS: Elevated red blood cell-related measurements and unusually large intra-pregnancy increases in those measures are associated with subsequent obstetric complications.