Hemoglobin Concentration in Early Pregnancy and Severe Neonatal Morbidity and Mortality : Population-Based Cohort Study

Ieta Shams; Grace H Tang; Xuesong Wang; Mark Walker; Nancy N Baxter; Tara Gomes; Joel G Ray; Michelle Sholzberg

doi:10.7326/ANNALS-25-02586

Hemoglobin Concentration in Early Pregnancy and Severe Neonatal Morbidity and Mortality : Population-Based Cohort Study

Ann Intern Med. 2026 Feb 3. doi: 10.7326/ANNALS-25-02586. Online ahead of print.

Authors

Ieta Shams¹, Grace H Tang², Xuesong Wang³, Mark Walker⁴, Nancy N Baxter⁵, Tara Gomes⁶, Joel G Ray⁷, Michelle Sholzberg⁸

Affiliations

¹ Department of Hematology, University of Toronto, Toronto, Ontario, Canada (I.S.).
² Hematology-Oncology Clinical Research Group, St. Michael's Hospital, Toronto, Ontario, Canada (G.H.T.).
³ ICES, Toronto, Ontario, Canada (X.W.).
⁴ Department of Obstetrics and Gynecology, University of Ottawa; Department of Obstetrics, Gynecology and Newborn Care, The Ottawa Hospital; Ottawa Hospital Research Institute; BORN; and Obstetrics and Gynecology, Champlain Maternal Newborn Regional Program, Ottawa, Ontario, Canada (M.W.).
⁵ ICES and Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada; and Faculty of Medicine and Health, University of Sydney, Sydney, Australia (N.N.B.).
⁶ ICES and Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada (T.G.).
⁷ ICES; Li Ka Shing Knowledge Institute and Department of Obstetrics and Gynecology, St. Michael's Hospital; and Department of Medicine, University of Toronto, Toronto, Ontario, Canada (J.G.R.).
⁸ Department of Hematology, University of Toronto; Hematology-Oncology Clinical Research Group, Li Ka Shing Knowledge Institute, and Coagulation Laboratory, Department of Laboratory Medicine and Pathobiology, St. Michael's Hospital, Toronto, Ontario, Canada (M.S.).

PMID: 41628471
DOI: 10.7326/ANNALS-25-02586

Abstract

Background: Anemia affects up to 50% of pregnancies. The relation between early pregnancy maternal hemoglobin concentration and important perinatal outcomes in high-income countries is largely unknown.

Objective: To assess early pregnancy hemoglobin concentration and associated severe neonatal morbidity and mortality (SNM-M) in a high-income setting.

Design: Population-based, retrospective cohort study.

Setting: Ontario, Canada, where health care is publicly funded.

Participants: Women aged 18 to 50 years with a singleton birth between 2007 and 2023 and hemoglobin measurement at 2 to 12 weeks' gestation.

Measurements: The nonlinear relation between early pregnancy hemoglobin concentration and SNM-M was analyzed in 1-g/L increments using restricted cubic splines, with 125 g/L as the referent. The primary outcome was a validated composite measure of SNM-M (major neonatal conditions and critical interventions) up to 27 days after birth. Relative risks (RRs) were adjusted (aRR) for maternal demographic characteristics and chronic conditions.

Results: A total of 1 100 341 births were included. A U-shaped relation was observed between early pregnancy hemoglobin concentration and SNM-M. For example, relative to a hemoglobin value of 125 g/L and a corresponding SNM-M rate of 6.7%, the aRR for SNM-M was 1.08 (95% CI, 1.04 to 1.11) at a hemoglobin concentration of 105 g/L and 1.17 (CI, 1.10 to 1.25) at 90 g/L. The aRR for SNM-M was 1.05 (CI, 1.03 to 1.07) at a hemoglobin concentration of 135 g/L and 1.20 (CI, 1.16 to 1.24) at 150 g/L.

Limitation: Iron replacement status before and during pregnancy was unknown, and residual confounding may influence observed associations.

Conclusion: Maternal anemia and relative erythrocytosis were each associated with neonatal morbidity and mortality in a high-income setting. Randomized clinical trials should evaluate the effect of iron therapy on maternal and perinatal outcomes by degree of hemoglobin correction.

Primary funding source: University of Toronto Alexandra Yeo Hematology Grant.