The morbid effects of gestational iron deficiency on both maternal and fetal outcomes remains a global health problem affecting 10–90% of pregnant women (1) as iron is a detrimental supplement. According to the World Health Organization, daily oral iron supplementation (30-60 mg of elemental iron daily intake) should be a part of routine antenatal care with a purpose of avoiding poor maternal-fetal outcomes including intrauterine growth restriction, premature delivery, and neonatal and perinatal death (1) (2). However, when pregnant women sunk in excessive amounts of iron, it is prone to cause potential damage to newborns and mothers since emerging researches suggested that exposures to high iron during hematopoiesis in early life might induce anemia with profound developmental effects and probably worse erythropoietin sensitivity to limit erythropoiesis (3) (4) (5).

Serum ferritin is a major iron storage protein, a widely used marker for total body Fe stores, with a Nano-sized core of hydrated iron oxide and a cage-shaped protein shell, containing 20% iron. Recently increasing studies have discovered the phenomenon that higher serum ferritin concentrations are also related with metabolic disorders of pregnancy such as gestational diabetes (GDM), serum dyslipidemia, insulin resistance (IR) calculated by indexes such as homeostasis model assessment-insulin resistance (HOMA-IR), homeostasis model assessment-insulin secretion (HOMA-IS), and homeostasis model assessment- β cell function (HOMA-β) (6) (7) (8) (9). On the contrary, there are still other conflicting researches pronounced that iron supplementation does not increase the risk of GDM but benefit a lot for mothers and fetus in terms of pregnancy outcomes (10) (11).

Considering the paucity of researches but with conflicting findings, evaluating the relationship between serum ferritin and metabolic disorders in the Chinese pregnant population, we utilized epidemiological data of pregnant women from Shanghai General Hospital, China to explore the association between serum ferritin levels and the prevalence of metabolic disorders including GDM, serum dyslipidemia, and IR.

We investigated the relationship between sFer levels in early pregnancy and metabolic disorders including GDM, insulin resistance, hypertriglyceridemia in early and middle pregnancy, and SCH in early and middle pregnancy. The results of our study revealed that elevated serum ferritin levels are positively independently associated with GDM. Furthermore, an increased β-cell function associated with higher ferritin level was observed in pregnancy period. Nevertheless, no obvious correlation between ferritin levels and hypertriglyceridemia in early and middle pregnancy was found.

Our findings correspond well with the previous study by Cheng et al. (13). Cheng et al. conducted a prospective observational study of 851 Chinese pregnant women, and they concluded that increased serum ferritin concentrations of first trimester are involved with an elevated risk of GDM. A longitudinal study of iron status during pregnancy and the risk of GDM from a prospective multiracial cohort (14) suggested that higher iron stores may be related with the development of GDM from early pregnancy, a >2-fold increased odds of GDM with highest quintiles of ferritin compared with lowest ones, which are also in line with our result. The majority of other previous studies are retrospective researches (15) and they also demonstrated that elevated sFer concentrations is positively related with incidence of GDM. Furthermore, our findings are also in accordance with results from previously published prospective studies in non-pregnant individuals on iron store and type 2 diabetes (16) (17) (18). However, 1 large randomized controlled trial conducted in Hong Kong found no association between iron supplementation and GDM (19). The divergence was potentially owing to various body iron stores, and different dosage and time length of iron supplementation in multitudinous pregnant populations.

In terms of insulin resistance, the findings of our research partially concurs with previous work (20) (21). These studies stated that higher content of ferritin and transferrin at baseline were correlated with HOMA-IR, and low HOMA-%, hyperinsulinemia and the metabolic syndrome anomalies (20).

Based on our current study and previous researches, though WHO suggests daily oral iron supplementation (30-60 mg of elemental iron daily intake) should become a part of routine antenatal care, women with lower serum ferritin levels might benefit from iron supplementation but it is likely to contribute some side effects to those with normal plasma ferritin concentrations. Our research suggests that routine iron supplementation for pregnant women may not that suitable considering risk of GDM. Thus, it is necessary for clinicians to assess iron status of pregnant women in early pregnancy to offer individualized iron supplementation recommendations to reduce the incidence of GDM.

Biologically speaking, the observed positive correlation between sFer and glucose homoeostasis is plausible. The underline mechanism by which elevated fasting SF levels pronounce diabetes, damage beta-cell function and decrease insulin sensitivity have not been fully illuminated. However, it has been noted that heme iron shoulder the responsibility of increasing the body’s iron store and thus leading to oxidative injury to pancreatic cells. Furthermore, growing insulin resistance and elevated insulin secretion from the pancreas could cause pancreatic beta-cell exhaustion (22). Some other researches have revealed that high plasma ferritin mirrors increased iron stores of the body and might be taken as an acute phase inflammatory reactant (23) (24). Besides, increased plasma ferritin levels motivate the inflammatory process inducing elevated insulin resistance,decreased insulin secretion by the pancreas, and hepatic dysfunction (25) Ultimately it follows reduced glucose uptake by muscles and mounting gluconeogenesis, hence spelling the development of GDM (26).

In the year of 2017, Li et al. found that growing serum ferritin levels are significantly related to higher risk of of dyslipidemia, independent of other confounding factors such as age and BMI etc. (8) Nevertheless, our findings did not come in accordance with theirs, since our data showed no statistical significance.

The present study has several advantages. Firstly, we evaluated the relationship between serum ferritin and metabolic disorders in Chinese pregnant population as there is a paucity of studies among Chinese pregnant women. Secondly, we analyzed serum ferritin concentrations in early pregnancy, prior to the diagnosis of GDM, which indicates that plasma ferritin would less be influenced by progress of

GDM. Thirdly, the current study suggests that routine iron supplementation for pregnant women may not that suitable considering risk of GDM, which is innovative. Nevertheless, some limitations are also needed to be noticed:Firstly, this study was conducted in a retrospective cohort with a relatively small sample. Secondly, the information on iron supplement use was not provided, so further investigations on the relation of iron supplement with fetal iron status and GDM are needed. Thirdly, we did not assess concentrations of biomarkers of inflammation, but previous studies indicated that plasma ferritin levels can be slightly influenced by inflammation.

In summary, findings from our present study suggest that increased concentrations of plasma ferritin in early pregnancy are significantly and positively associated with insulin resistance and incidence of GDM but not gestational dyslipidemia. Similar studies, especially well-designed cohort studies or randomized trials, should be performed in different types of populations, since plasma ferritin concentrations may play an important role for predication and prevention of GDM, IR and their complications. Further clinical studies are warranted to determine whether it is necessary to encourage pregnant women to take iron supplement as a part of antenatal care. In addition, further researches are warranted to clarify the underlying mechanisms. Anyway, in order to prevent excessive iron intake, a lower-dose or intermittent iron supplements instead of regular daily supplementation of iron possibly is more suitable for women without iron deficiency.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by Shanghai general hospital. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

All the authors participated in designing this study. ZZ and XL collected data. XZ and XG undertook the statistical analyses and interpreted the data. ZZ and YZ wrote the first draft of the manuscript, which was reviewed by all the other authors, especially HW and XX, who also offered further contributions as well as advice.