Cardiovascular outcomes in maternal iron deficiency anemia with pre-existing hypertension

Introduction: Iron deficiency (ID) is the most common nutritional deficiency worldwide with pregnant mothers most at risk. If left untreated, ID alone has been shown to be associated with a number of pregnancy complications. Additionally, anemia is identified as a modifiable risk factor of hypertensive disorder in pregnancy (HDP) with recognizable decreases in hemoglobin (Hb) levels observed. Often times pregnancy is the first-time hypertension is identified in mothers by obstetricians, and therefore, the likelihood of these two morbidities co-existing within the pregnant population is high and underreported. During pregnancy, the pregnant mother undergoes anatomical and physiological changes, including expansion of blood volume and a decrease in total peripheral vascular resistance (TPVR) to maintain the growing conceptus. However, these changes are blunted in HDP which can impair oxygen delivery to the fetus. Interestingly, anemia has been shown to cause systemic vasorelaxation which is accompanied by an increase in cardiac output. Experiments using rat models of essential hypertensive have shown that dietary ID anemia reduces blood pressure and confers cardiovascular protection. However, to our knowledge, no studies have examined the effects of maternal ID anemia superimposed with hypertension during pregnancy. Whereas ID anemia has classically been seen as a pregnancy complication, here we hypothesized that dietary ID anemia would confer protection during pregnancy in spontaneously hypertensive rats (SHR). Methods: Female SHR are fed either an iron-replete (37mg/kg) or an iron-restricted (3mg/kg) diet prior to and during pregnancy. Blood pressure measurements were performed using tail-cuff plethysmography at gestational day (GD) 0, 7, 14 and 21; uterine blood flow assessments and echocardiography were also performed at these times. Pregnant SHRs were then euthanized at GD21 and tissues were collected, and flash frozen for gene expression patterns assessed by RT-qPCR. Results: Perinatal ID caused a decrease in maternal Hb levels compared to control. Despite this, no changes in maternal growth parameters including relative heart and kidney weight were evident between ID and control SHRs. Maternal ID reduced diastolic, systolic and mean arterial pressure throughout gestation compared to untreated SHR dams. Fetal hemoglobin decreased in both ID male and female pups; however, female fetal body weight was unaffected while male counterparts showed decreases. Interestingly, fetal placental weights were not affected by ID. RT-qPCR in the heart showed no increases in p53, albeit Bax and BAD were increased, as well as Bcl-2 and Caspase 3 gene expression. This was accompanied by an upregulation of antioxidant genes SOD1 and Catalase within the heart. These increases point to the possible elevation of intrinsic apoptosis pathways and oxidative stress in ID hearts. No such changes were apparent within the kidney of ID SHRs. Summary: These preliminary results suggest that while ID may positively impact pregnancies with pre-existing hypertension, there are also deleterious outcomes. Although additional experiments are needed, the results could advance how clinicians treat ID and anemia in persons with HDP.