Association Between Periconceptional Iron Supplementation And Risk Of Pregnancy Outcomes

Objective:Fe is an essential microelement for human body,whereas,excess iron intake also has underlying toxic effects to cells.Generally,anemia in pregnancy may increase the risks of preterm birth(PTB)and low birth weight(LBW).Previous studies have reported that excess iron intake or high hemoglobin(Hb)increase the risks of gestational diabetes mellitus(GDM)and adverse birth outcomes.The underlying mechanism is that excess iron intake or high iron store may lead to high oxdative stress.This study aims to analyze the association between periconceptional iron supplementation,Hb concentration and GDM risk and other abnormal pregnancy outcomes in Wuhan.Methods:Participants were all from Tongji Maternal and Child Health Cohort,(TMCHC),who were enrolled less than 16 gestational weeks between 2013 and 2016and received routine prenatal cares or delivered at one of the three research hospitals of TMCHC in Wuhan,China.Covariate information on social-demographic status(age,work status and so on),body weight before pregnancy,reproductive factors,illnesses,family history of diseases,lifestyle factors(smoking and alcohol consumption)was obtained from a structured questionnaire at enrollment.All the participants were instructed to report whether they used any supplements from pre-pregnancy at enrollment.Information on supplementation after that was collected during follow-up in middle pregnancy again.Hb values were determined in early pregnancy(at 8-20gestational weeks)and late pregnancy(more than 28 gestational weeks)respectively by collecting the fasting venous blood using colorimetry in the hospitals.Hb values less than 110 g/L was defined as anemia and Hb values more than 130 g/L was defined as hemoconcentration.A 75-g,2-h OGTT was conducted by collecting the venous blood at24-28 weeks of gestation.GDM was diagnosed according to the criteria of the International Association of Diabetes and Pregnancy Study Groups(IADPSG)when any point of plasma glucose values equalled or exceeded the cut off values,≥5.1mmol/L at fasting,≥10.0 mmol/L at 1 h,≥8.5 mmol/L at 2 hBased on dose and duration of iron supplementation,we divided participants into four categories:no iron users(Nonuser),low-dose iron(≤30 mg/d)for any duration(Iron≤30),high-dose iron(>30 mg/d)for short-term(≤3 mo)(Iron>30-S)or long-term(>3 mo)(Iron>30-L).PTB and LBW were calculated based on gestational age at delivery and birth weight.SGA was calculated based on gestational age at delivery,birth weight and newborn sex.Poisson regression models were used to analyze the relative risks(RRs)with 95%confidence intervals(CIs)for the risks of GDM,anemia,hemoconcentraiton,PTB,LBW and SGA with Nonuser as the reference adjusting potential confounding variables.Multivariate linear regression was also used to analyzeβwith 95%(CIs)for plasma glucose values at fasting,at 1 h and at 2 h of OGTT,gestational age at delivery,birth weight and length with Nonuser as the reference adjusting potential confounding variables.Results:1.Among the 5101 pregnant women,97.5%were Han ethinicity.The average age was 28.2±3.5 years old.83.4%were primiparity.The average prepregnancy BMI was20.8±2.7 kg/m~2.The prevalence of family history of diabetes was 8.0%.58.1%had a degree of university and above.The average Hb concentration was 119.4±8.2 g/L in early pregnancy.GDM prevalence was 10.5%.Percentages for four groups were as following:Nonuser(60.8%),Iron≤30(13.7%),Iron>30-S(9.0%)and Iron>30-L(16.5%);GDM prevalences for the four above groups were 8.9%,11.0%,11.6%and15.2%.In the crude model,GDM risk was increased by periconceptional iron supplementation of Iron>30-L(RR,1.70;95%CI,1.40 to 2.07)compared to Nonuser while not in Iron≤30(RR,1.23;95%CI,0.97 to1.56)and Iron>30-S(RR,1.29;95%CI,0.98 to 1.71).After adjusting potential confounding variables including:maternal age,prepregnancy BMI,family history of diabetes,education level,mean household income,employed,smoking,alcohol consumption,parity,gestational weight gain at OGTT,GDM risk was increased by Iron>30-L(adjusted RR,1.55;95%CI,1.27 to 1.88).After futher adjusting early Hb concentration(g/L)and gestational age at early Hb measurement,GDM risk was increased by Iron>30-L(adjusted RR,1.53;95%CI,1.21to 1.93).Stratification analyses(maternal age≤28 years and>28 years,prepregnancy BMI<24.0 kg/m~2 and≥24.0 kg/m~2,with and without family history of diabetes,primiparity and multiparity,weight gain at OGTT≤7.8 kg and>7.8 kg,neonatal sex)and interaction tests were conducted and the results were consistant.Sensitivity analyses were also conducted to assess and ensure the robustness of our results and the results were very well repeated.Whereas,women using high-dose iron had a higher risk of hemoconcentration with a reduced risk of anemia.2.The average gestational age at delivery was 39.4±1.5 weeks.The average birth weight was 3330.8±441.3 g.The average birth length was 50.1±1.5 cm.53.8%was male.Overall PTB was 3.9%,LBW was 2.5%and SGA was 7.1%.Analyses about the associations between periconceptional iron supplementation and birth outcomes were performed according the above mentioned iron user groups and Hb stratifications(anemic and non-anemia).Adjusting potential confounding variables including:maternal age,prepregnancy BMI,education level,mean household income,employed,smoking,alcohol consumption,parity,GDM,weight gain at delivery,cesarean delivery,there was only a slightly association between periconceptional iron supplementation and PTB(Adjusted RR,1.20;95%CI,0.85 to 1.71),especially in non-anemic women(Adjusted RR,1.38;95%CI,0.91 to 2.08),but the association was not significantly different.After restricting analysis to participants aged 20-35 years,with pre-pregnancy BMI of 18.5-28 kg/m~2,without gestational diabetes mellitus,nulliparity and early Hb concentration ranging 110-130 g/L in turn,the results were very well repeated.Besides,no significant differences were observed for SGA and LBW compared to Nonuser.Conclusion:Periconceptional iron supplementation of high dose and long term(>30 mg/d for>3 mo)increased the risk of GDM.Iron supplementation increased the risk of hemoconcentration though reduced the risk of anemia during late pregnancy without any beneficial effect for birth outcomes.Thus,periconceptional iron supplementation of high dose and long term is not recommended.