Maternal Iron Deficiency Elicits Changes in Placental Development and Alters Fetal Growth Trajectories

Iron is an essential mineral that participates in oxygen transport, DNA synthesis and repair, and as a cofactor for various cellular processes. Iron deficiency (ID) is the most common nutritional deficiency worldwide and pregnant women are one of the populations most at risk. ID during pregnancy poses major health concerns for the developing baby, including fetal growth restriction and long‐term health complications. Maternal ID may indirectly impair fetal growth through changes in the structure and function of the placenta, however, the effect of ID on the placenta is not well understood. Objective This project aims to establish a model of ID in pregnant rats and investigate the resulting changes in placental development and fetal growth. Methods Pregnant Sprague‐Dawley rats were fed either a low iron (10 mg iron/kg) or iron‐replete (37 iron/kg) diet starting two weeks before pregnancy to induce a state of ID anemia alongside respective controls. Detection of sperm in a vaginal lavage was designated gestational day (GD) 0.5. Conceptuses were dissected at either GD 13.5 or GD 18.5. Dam and fetal hemoglobin (Hb) concentration and body weight were measured. Placentas were weighed, cryosectioned and stained with hematoxylin and eosin to assess the cross‐sectional areas of the labyrinth and junctional zones (anatomical units of the rodent placenta). Placental mRNA expression of iron transporters and other nutrient transporters was measured by Clariom S microarray. Results Compared to controls, ID reduced maternal hemoglobin (Hb) throughout pregnancy, including a 44% (P=0.0006) reduction on GD 18.5. Fetal Hb was also reduced in ID on GD 18.5 by 47% (P<0.0001). ID caused a 14% (P=0.03) reduction in total fetal body weight and reduced fetal liver weight by 18% (P=0.003) compared to controls. There was no change in fetal brain, heart or kidney weight. Interestingly, relative placental size was increased in ID by 33% (P=0.0008), including a 27% (P=0.007) increase in junctional zone area and no change in labyrinth zone area. Conclusion Maternal ID was associated with the development of anemia in both moms and fetuses. ID also decreased fetal weight and increased placental growth, specifically in the junctional zone. Significance and Implications Decreased iron availability and oxygen‐carrying capacity in pregnancy may stimulate placental structural changes as a compensatory response to maintain fetal nutrition and oxygenation. Although such adaptations may provide short‐term benefits to the baby, they may ultimately lead to placental insufficiency and failure to meet fetal demands, resulting in fetal growth restriction. Since the placenta forms the interface between a mother and her baby, these modifications may yield new diagnostic indices of fetal distress in ID pregnancies, such as placental size changes that can be detected by ultrasound or post‐partum analysis of placental nutrient transporters and markers of inflammation. Knowledge of such changes may, therefore, lead to earlier interventions and improved fetal outcomes. Support or Funding Information Canadian Institutes of Health Research