Compared to Normal-Weight Pregnant Women, Overweight Pregnant Women Fail to Upregulate Iron Absorption in the Third Trimester Despite Iron Deficiency and Their Infants Are Born with Lower Body Iron Stores

Introduction: Overweight/obesity (OWOB) causes low-grade systemic inflammation which induces hepcidin and a reduces fractional iron absorption (FIA) even when iron stores are low. Pregnancy increases iron needs because of the expansion of maternal blood volume and fetal needs. It is unclear whether and/or to what extent OWOB during pregnancy influences FIA, iron supply of the fetus and risk of iron deficiency in mother and newborn. In this study, we (1) determined the impact of maternal OWOB on FIA in pregnancy and on the transfer of iron to the fetus and newborn iron status; (2) confirmed the relationship between BMI, hepcidin, serum ferritin (SF) and inflammatory markers.

Methods: In this prospective experimental multi-center case-control study (normal-weight (NW) n=40; OWOB n=37) we administered labeled [57Fe]- or [58Fe]-FeSO4 to women during the 2^nd and 3^rd trimester of pregnancy. We measured FIA by determining erythrocyte incorporation of iron stable isotopes 14 days after administration. From pregnancy week (PW) 12 until PW 36, iron-, inflammation and hepcidin were monitored. Iron transfer to the fetus was determined isotopically as the concentration of circulating iron in the infant aged three days. We assessed iron status in infants born to NW (n=29) and OWOB (n=31) at age three days, three months and six months.

Results: Subject characteristics in PW 12 for the NW/OWOB were: mean (±SD) age: 29±6/ 30±6 years, median (IQR) pre-pregnancy BMI: 21.6 (20.3-23.7)/ 31.6 (28.4-35.9) kg/m² (p<0.001), mean (±SD) hemoglobin: 12.3±1.1/ 12.4±0.9 g/dL, median (IQR) SF: 27.7 (17.3-48.2)/ 30.6 (16.6-64.4) µg/L and median (IQR) interleukin-6: 1.41 (1.03-1.95)/ 2.37 (1.91-3.85) pg/ml (p<0.001). Independent sample t-test showed no difference in FIA between NW and OWOB in the 2^nd trimester with median FIA (IQR) 12.3 (7.2-20.6) and 10.1 (6.9-17.2) % (p=0.788). Despite the OWOB had ≈30% lower body iron stores (BIS) and comparable hepcidin concentrations to the NW in the 3^rd trimester, FIA was significantly higher in the NW compared to the OWOB with median FIA (IQR) 22.3 (10.6-33.8) and 12.7 (10.4-18.1) % (p=0.042). In the NW, FIA was upregulated by 80% in the 3^rd trimester compared to the 2^nd trimester, whereas in the OWOB FIA, it was only upregulated by 25%. Linear mixed effect model analysis (LMM) showed a significant group-effects on weight, IL-6 and CRP throughout pregnancy (all p<0.05), but surprisingly no group-effect on hepcidin. In multiple regression analysis, the main predictor of hepcidin throughout pregnancy was BIS, not inflammation. Iron transfer to the newborn was non-significantly higher in the NW compared to the OWOB with mean (±SD) circulating iron in the newborn at age three days 136.6 ± 42.7 and 126.3 ± 32.4 mg. LMM on infant BIS and on infant serum transferrin receptor (sTfR) over the first six months showed significant group (p=0.024, p=0.046) and time-effects (both p<0.001) with lower BIS and higher sTfR in infants born to OWOB. Median (IQR) BIS at age six months were 7.7 (6.3-8.8) and 6.6 (4.6-9.2) mg/kg bodyweight in infants born to NW and OWOB.

Conclusion: In normal pregnancy, FIA increases over time to support increased iron needs of mother and fetus. Our data show a dramatically reduced increase in FIA in OWOB pregnant women in the 3^rd trimester, despite low BIS and low hepcidin, and this results in less iron transfer to the fetus. Future molecular studies are needed to clarify the mechanism of reduced FIA and fetal iron transfer in OWOB. To our knowledge, this is the first study assessing the impact of maternal OWOB on infant iron status at multiple time points over the first six months. Our findings strongly argue for careful monitoring of iron status in OWOB pregnancy and for defining a more effective iron supplementation regimen for this population group. Prevalence of anemia in pregnancy and infancy is high, especially in low and middle income countries and is often associated with severe health consequences. If iron status of OWOB pregnant women and their infants could be improved by optimizing iron supplementation guidelines for OWOB, this could have major benefits.