ABSTRACT
Objectives:
To explore whether uniform supplementation causes iron overload among a cohort of South Indian non-anemic pregnant women with diabetes-in-pregnancy (DIP).
Methods:
The study took place between May 2022 and May 2024 and consisted of 120 participants from 2 groups: healthy pregnant women (HP) and pregnant women with DIP. Levels of Hb and the serum indices of iron homeostasis-iron, unsaturated iron-binding capacity, total iron-binding capacity, transferrin saturation, ferritin, hepcidin, soluble transferrin receptor (sTfR), and sTfR index, were estimated. The levels of high-sensitivity C-reactive protein, indices of oxidative stress, malondialdehyde, total antioxidant status (TAS), and oxidative stress index (OSI; ratio of MDA/TAS), and inflammatory markers, interleukin-10 (IL-10) and interleukin-18 (IL-18), were also estimated. The perinatal outcomes between the 2 groups were compared.
Results:
The serum iron and ferritin levels were lower, and HbA1c levels were higher in the DIP than in HP. The indices of iron homeostasis and Hb were comparable between the 2 groups. While the levels of OSI were higher in the DIP, the pro-inflammatory markers were comparable between the 2 groups. The perinatal outcome of DIP was inferior in comparison to HP.
Conclusion:
The current uniform daily oral iron supplementation dose in non-anemic South Indian women with DIP did not show evidence of iron overload in our cohort, contrary to expectations.
Keywords: Anemia in pregnancy, diabetes-in-pregnancy, iron homeostasis, oxidative stress, inflammation, iron overload
As per previous definitions, hyperglycemic pregnancy was considered one category of complications among pregnant women labeled as gestational diabetes mellitus (GDM). According to this categorization, the severe form of hyperglycemia, diabetes mellitus, was not differentiated from the milder categories like impaired glucose tolerance and impaired fasting glycemia. This categorization resulted in the discrimination of pregnant women diagnosed with severe hyperglycemia, that is, diabetes mellitus. Women with severe hyperglycemia, as in diabetes-in-pregnancy (DIP), deserve special attention because of their more significant risk of developing maternal and fetal complications.1 In 2013, WHO defined DIP as a separate new group of complications of pregnancy with pregnant women diagnosed with already existing diabetes or with fasting glucose level ≥126 mg/dL or 2-hr post-glucose load value of oral glucose tolerance test (OGTT) ≥200mg/dL or random blood sugar ≥200mg/dL anytime during pregnancy.1 This definition is equivalent to the 2006 WHO criteria for diagnosing diabetes among the non-pregnant general population.2 Diabetic pregnancy culminates with poor fetal and maternal outcomes. Macrosomia, that is, fetal overgrowth, is the hallmark of DIP. Postnatal metabolic disturbances, preeclampsia, birth injuries, and still birth are some of the complications of macro somic infants. Later in life, they have higher chances to suffer from cardiovascular diseases, diabetes mellitus, and obesity. One of the causes of the above complications is oxidative stress. There are several causes for oxidative stress in the biological system. Pregnancy, as such, is a state of oxidative stress and a state of higher inflammation. However, another cause for oxidative stress could be the uniform prophylactic iron supplementation given to all non-anemic pregnant women, irrespective of any complications. In India, uniform prophylactic iron supplementation of 60-100mg/day is provided to all non-anemic pregnant women from the second trimester onwards until term, irrespective of the complications.3 However, iron supplementation in a state of inflammation, as in DIP, can lead to iron overload. Iron overload can lead to oxidative stress, inflammation, and associated complications such as ferroptosis and pyroptosis.4 The risk for the development of GDM and preeclampsia is much higher when there is iron overload.5
Women with sufficient iron status through their nutritional intake and iron supplementation are more vulnerable to developing iron overload. The changes in iron homeostasis are intimately linked to oxidative stress, inflammation and the differential expression of lipid metabolism genes in the placenta.6 These biochemical derangements can ultimately lead to placental dysfunction, culminating in the adverse perinatal outcome. In DIP, a condition of inflammation, the regular dose of iron supplementation may lead to iron overload, causing further increment in oxidative stress. The iron overload may induce insulin resistance as well as betacell dysfunction. One of the previous studies among non-anemic pregnant women observed that prophylactic supplementation of iron enhanced inflammation and oxidative stress.7 In another study, we observed that iron supplementation in non-anemic early on set preeclampsia patients led to iron overload, causing oxidative stress compared to non-anemic healthy pregnant women.8 However, whether maternal excess iron contributes to adverse pregnancy outcomes is unclear and is an important research question. Iron overload affects insulin signaling through oxidative stress.9 The harmful reactive oxygen species generated by iron overload can cause damage to nucleic acids, lipids, and proteins.10 Therefore, the present study aimed to evaluate whether the supplementation of 60-100 mg/day to Indian diabetic pregnant women causes iron overload and thereby contributes to adverse maternal outcomes. In this study, we assessed the indices of iron homeostasis, inflammatory markers, and oxidative stress in maternal venous blood of women diagnosed with DIP compared to healthy pregnancy women (HP).
Methods
In this cross-sectional analytical study, participants were recruited from pregnant women attending the antenatal clinics/wards of our Institute’s Department of Obstetrics and Gynecology. The study consisted of 120 participants divided into 2 groups.
Group I. Healthy pregnant women (HP) who did not have a present or past history of any pregnancy complications.
Group II. Pregnant women diagnosed with DIP with fasting blood glucose level ≥126mg/dL or 2-hr post-glucose load value of OGTT ≥200mg/dL or random glucose ≥200mg/dL at any time during pregnancy as per the WHO criteria.1 Non-anemic pregnant women (Hb ≥11g/dL) by WHO criteria11 throughout pregnancy in the age group of 18-40 years with prophylactic iron supplementation of 60-100mg/day were selected for the study. Pregnant women with a body mass index (BMI) of 22±3Kg/m2 at ≤12 weeks of gestation were recruited for the study. Pregnant women diagnosed with already existing diabetes, GDM, renal diseases, major vascular complications, severe preeclampsia, known infections in the current pregnancy, autoimmune disorders, in vitro fertilization (IVF), and twin/multiple pregnancies were excluded from the study. Pregnant women of the gestational age group ≥34 weeks were screened, and after evaluating the inclusion and exclusion criteria, the participants were enrolled in the study. Since only limited information is available in the literature regarding DIP, the sample size was calculated based on GDM as a reference. The sample size was calculated with the assumption of mean difference and standard deviation for one of the reported parameters, malondialdehyde (MDA), the end product of lipid peroxidation, with a statistical power of 90% and a confidence interval of 95%.12
The Institutional Ethics Committee approved the study protocol (JIP/IEC/2022/29), and informed consent was taken from the study participants. The recruitment of the study participants took place for 2 years, from May 2022 to May 2024.
The indices of iron homeostasis, oxidative stress, inflammatory markers, and hemoglobin A1c (HbA1c) were estimated in the maternal blood. Six millilitres of fasting maternal blood were collected once from each of the participants before delivery (anytime between 34 weeks and delivery) in clot activator vials (4ml) and EDTA vials (2ml). The clot activator tubes, after the collection of blood samples, were centrifuged at 4000RPM for 5 minutes, and routine biochemical analytes were estimated immediately with the sera. The remaining sera were stored at -80ºC for further use. The routine analytes were estimated in a clinical chemistry analyzer (Beckman Colter AU5811). Ferritin and sTfR were estimated using a chemiluminescence-linked immunoassay (CLIA, Beckman Colter DxI). Commercial ELISA kits were used for the estimation of serum hsCRP (Calbiotech, CR375C), IL-10, IL-18 (R&D systems, DL1000 Band DL180respectively), and Hepcidin (Elabsciences, E-EL-H6202) using a microplate spectrophotometer from Molecular Devices Spectramax Plus 384, USA. Malondialdehyde was estimated using the method of Yagi et al.13 Total antioxidant status (TAS) was by the method of Benzie et al.14 Oxidative stress index (OSI) is the ratio of MDA to TAS. The samples collected in EDTA vials were used to estimate HbA1 causing high-performance liquid chromatography (HPLC).
Statistical analyses
The normal distribution of parameters was assessed by the Kolmogorov-Smirnov test. All parametric data are expressed in mean±SD. A comparison between groups was carried out using an unpaired T-test for parametric tests. All non-parametric data was expressed in median (Interquartile Range). Comparison between the groups were carried out by Mann-Whitney U Test. McNamar’s Chi-square test checked changes in the proportion of unpaired data. Confidence interval of non-parametric data was carried out manually using the formula by Campbell and Gardner.15 A p-value less than 0.05 was considered statistically significant. All statistical analyses were performed using Statistical analysis was performed by the IBM SPSS Statistics for Windows version 22.0 (IBMCorp, Armonk, NY, USA).
Results
The study recruited 120 pregnant women at over or equal to 34 weeks of gestation. Among them, 60 were recruited in the HP group and 60 in the DIP group. Table 1 describes the general characteristics of the study participants. The height of the participants did not differ significantly between the 2 groups. The maternal age, weight ≤12 weeks, weight at the time of recruitment, maternal weight gain, BMI at ≤12weeks, fasting blood glucose, and HbA1c were higher in DIP than in HP.
Table 1.
- General characteristics of study participants.
| Variables | HP (n=60) | DIP (n=60) | CI (95%) | P-value |
|---|---|---|---|---|
| Maternal age (years) | 26±4 | 29±5 | (-5.2 to -1.5) | <0.001 |
| Weight ≤12 weeks (Kg) | 54±6 | 58±6 | (-7.1 to -1.0) | 0.001 |
| Weight at the time of recruitment (Kg) | 65±7 | 73±9 | (-12.5 to -4.5) | <0.001 |
| Maternal weight gain (Kg) | 10±4 | 14±6 | (-6.9 to -2.0) | <0.001 |
| Height (cm) | 155±6 | 156±7 | (-4.1 to 1.6) | 0.272 |
| BMI ≤ 12 weeks (Kg/m2) | 23 (21, 24) | 24 (23, 24) | (23.1 to 24.0) | <0.001 |
| Fasting blood glucose (mg/dL) | 86 (80,89) | 128 (119,133) | (89 to 115) | <0.001 |
| HbA1c (%) | 5.3±0.5 | 6.4±1.2 | (-1.7 to -0.8) | <0.001 |
HP: healthy pregnancy, DIP: diabetes in pregnancy, BMI: body mass index, HbA1c: hemoglobin A1c
Table 2 compares the 2 groups’ Hb and bio chemical indices of iron homeostasis. The Hb and Hepcidin, levels of soluble transferrin receptor (sTfR), sTfR index, transferrin saturation (TSAT), unsaturated iron binding capacity (UIBC), and total iron binding capacity (TIBC) were comparable between the 2 study groups. The serum iron and ferritin were significantly lower among the DIP group than among the HP group.
Table 2.
- Comparison of Hb and the indices of iron homeostasis between healthy pregnancy (HP) and diabetes-in-pregnancy (DIP).
| Variables | HP (n=60) | DIP (n=60) | CI (95%) | P-value |
|---|---|---|---|---|
| Hb (g/dL) | 11.90±0.7 | 11.90±0.8 | (-0.5 to 0.2) | 0.941 |
| Hepcidin (ng/ml) | 5.15±3.38 | 5.12±2.97 | (-1.3 to 1.4) | 0.963 |
| sTfR (nmol/L) | 19 (16, 21) | 20 (16, 24) | (18.6 to 20.4) | 0.383 |
| sTfR index | 12 (9, 15) | 14 (11, 18) | (11.5 to 14.3) | 0.056 |
| TSAT | 24±13 | 21±12 | (-4.8 to 5.6) | 0.300 |
| UIBC (ug/dL) | 338±100 | 362±95 | (-55 to 32.5) | 0.604 |
| TIBC (ug/dL) | 438±90 | 455±81 | (-55 to 24) | 0.278 |
| Iron (ug/dL) | 100±53 | 95±53 | (-26 to 17) | 0.001 |
| Ferritin (ug/L) | 47±35 | 36±23 | (-0.4 to 26.8) | 0.041 |
sTfR: solubletransferrinreceptor, TSAT: transferrinsaturation, UIBC: Unsaturatedironbindingcapacity, TIBC: total iron binding capacity
A comparison of the markers of inflammation and oxidative stress between the 2 groups is presented in Table 3. Although there was a trend for an increase in hs-CRP levels in the DIP group compared to HP, it did not reach statistical significance. The levels of IL-18 were comparable between the 2 groups. Total antioxidant status (TAS) levels were significantly lower, and the OSI was higher in DIP than in HP. The levels of IL-10 were markedly higher in DIP.
Table 3.
- Comparison of Parameters of oxidative stress and inflammatory markers between the study participants.
| Variables | HP (n=60) | DIP (n=60) | CI (95%) | P-value |
|---|---|---|---|---|
| hsCRP (mg/L) | 8.9 (4.3, 16) | 12 (8.2, 16.2) | (8.6 to 12.8) | 0.081 |
| MDA (umol/L) | 2.5±0.5 | 2.7±0.6 | (-0.3 to 0.1) | 0.077 |
| TAS (umol/L) | 909±159 | 817±160 | (61.3 to 202.7) | 0.002 |
| OSI | 28.7±7.4 X 10-4 | 34.4±9.8 X 10-4 | (-9.1 X 10-4to -2.0 X 10-4) | 0.001 |
| IL-10 (pg/ml) | 3.1 (1.5, 6.7) | 17 (4.7, 33) | (3.3 to 7.4) | 0.001 |
| IL-18 (pg/ml) | 260 (190, 321) | 280 (290, 372) | (234.7 to 282.8) | 0.399 |
MDA: malondialdehyde, TAS: total antioxidant status, OSI: oxidative stress index (ratio of MDA/TAS), HP, healthy pregnancy DIP: diabetes-in-pregnancy
A comparison of perinatal outcomes between the groups is shown in Table 4. APGAR score at 1 minute and placental efficiency (baby weight(g)/placental weight(g) were comparable between the 2 groups. Gestational age at delivery was lower in the DIP group than in the HP group. Baby weight, baby length, placental weight, and ponderal index were higher in the DIP group than in HP. The APGAR score at 5 minutes was lower in the DIP group than in the HP group.
Table 4.
- Comparison of the perinatal outcome between the study groups.
| Variables | HP (n=60) | DIP (n=60) | CI (95%) | P value |
|---|---|---|---|---|
| Gestational age at the time of delivery (days) | 277 (274,281) | 265 (262,270) | (270 to 274) | <0.001 |
| APGAR 1’ | 8 (8,8) | 8 (8,8) | (8 to 8) | 0.104 |
| APGAR 5’ | 9 (9,9) | 9 (9,9) | (9 to 9) | 0.004 |
| Baby weight (g) | 2819 ± 406 | 3738 ± 218 | (-1056.3 to -764.7) | <0.001 |
| Baby length (cm) | 48 (47,49) | 49 (48,50) | (48 to 49) | <0.001 |
| Placental weight (g) | 445 ± 80 | 560 ± 68 | (-152.7 to -92.5) | <0.001 |
| Placental efficiency | 6.5 ± 1.40 | 6.8 ± 0.95 | (-0.7 to -0.3) | 0.226 |
| Ponderal index (g/cm3) | 2.6 ± 0.44 | 3.1 ± 0.40 | (-0.7 to -0.3) | <0.001 |
APGAR: appearance, pulse, grimace, activity, respiration, HP, healthy pregnancy DIP: diabetes-in-pregnancy
Discussion
Regular supplementation of iron in pregnancy complications with impaired glucose tolerance may enhance free radical generation and lead to iron overload. Studies have reported iron overload, namely, an increase in iron homeostasis indices in GDM.16 Since there were no reports on the status of iron homeostasis in DIP, our hypothesis was to find even higher levels of iron overload in a condition with severe hyperglycemia. However, our study yielded a different result. There was no systemic iron overload among South Indian pregnant diabetic patients. The index of iron overload, ferritin, was found to be lower in the diabetic group, along with a significant reduction in serum iron, with the remaining iron homeostasis parameters being comparable between the groups. Two factors could explain this observation.
Effective clinical management of patients during short-term impaired glucose tolerance would have prevented the onset of iron overload. The mean percentage of HbA1c of 6.4% among the DIP group towards the end of the pregnancy illustrates a well-controlled state of impaired glucose tolerance. This effective clinical management of the patients of the present study is further evident from the relatively comparable levels of Hepcidin, hsCRP, the pro-inflammatory marker IL-18, and MDA, the end product of lipid peroxidation, between the 2 groups of the study. Earlier studies have reported significantly higher oxidative stress and inflammation in gestational diabetes mellitus.17 Hepcidin is an important index of iron homeostasis, especially in inflammation. Since hepcidin levels in the DIP of our study were comparable with HP, it rules out the possibility of systemic iron overload among them. The risk for GDM was higher among women with elevated serum ferritin and C-reactive Protein (CRP).18 In the present study, TAS and the oxidative stress index were significantly higher in DIP than in HP. Increased levels of anti-inflammatory cytokine IL-10 in DIP compared to HP may be a beneficial effect of the effective treatment rendered to the DIP women. IL-10 prevents excessive inflammation and immune-mediated damage.
The second factor that explains the absence of iron overload could be the higher incidence of anemia among Indian pregnant women.19 A higher prevalence of anemia in Indian pregnant women (63%) indicates that anemia continues to be a significant public health problem in rural areas of the country.20 Although we recruited non-anemic women, mean Hb levels in both groups were 11.9 g/dL, almost at the lowest levels of the normal range.
Iron overload is associated with chronic inflammation. Diagnosing iron overload in a state of anemia of chronic inflammation is a dilemma and a clinical challenge. The indices of iron homeostasis are helpful in the identification of iron overload. The recent systematic review and meta-analysis by Kaili et al16 reported higher Hb and elevated serum levels of Hepcidin, transferring saturation, ferritin, and iron, as well as lower total iron binding ability among GDM patients. They also reported that the GDM risk is linked with higher Hb and serum ferritin levels. Higher serum iron levels among GDM women were also reported by Khambalia et al21 in their systematic review. Increased total iron intake, including iron supplementation during pregnancy, was found to be a risk factor for GDM in a study conducted in Finland.22 Increased risk for subsequent type 2 diabetes was observed among non-anemic women who had GDM and undertook long-term intake of iron supplements after their pregnancy.23
In GDM patients, serum Ferritin concentration was reported to be higher compared to a healthy pregnancy.16 Serum Ferritin is an acute phase reactant and a marker of iron reserves throughout the body. Women with both high serum Ferritin and C reactive Protein (CRP) are reported to be at a higher risk of developing GDM.24 Among pregnant women at 24- 28 weeks of gestation with Hb levels in the highest quartile (>13 g/dL), the prevalence of GDM was found to be significantly increased in a prospective observational study.25 However, in the present study, the Hb levels of the DIP group were comparable with the HP.
Among the pregnant women with GDM, serum levels of TSAT were reported to be higher and TIBC lower.16 The TIBC represents the amount and the ability of Transferrin to combine with iron. When the body experiences iron overload, blood Transferrin levels decrease, leading to a decrease in the TIBC level. These are indicators of iron overload in a state of inflammation. In our observation, there were no differences in both TSAT and TIBC between the two groups of the study.
The perinatal outcome differed significantly between the two study groups. The DIP group were more prone to deliver the baby earlier compared to HP. Baby weight, baby length, placental weight and ponderal index were significantly elevated in the DIP group compared to HP. However, the placental efficiency was similar in both groups.
This study was initiated to reconsider whether women with DIP need routine preventive or selective iron supplementation during pregnancy because of the potential iron overload in a state of inflammation and oxidative stress. The clinical management of pregnant women with diabetes appears to be effective in curtailing the expected changes in the indices of iron homeostasis. Among Indian pregnant women, the prevalence of anemia has been found to be high. Therefore, the present practice in India of uniform prophylactic iron supplementation of 60- 100 mg/day to all non-anemic pregnant women from the second trimester onwards till term, irrespective of the complications, is recommended.
In conclusion, based on our observations, it may be concluded that the current daily oral iron supplementation dose in non-anemic South Indian women with Diabetes-in-pregnancy does not cause maternal systemic iron overload contrary to expectations.
Limitations of the study
The present study establishes absence of systemic iron overload in a South Indian cohort of DIP. Further investigations are required to find out the iron homeostasis at the tissue levels and during the long term follow up of the patients after pregnancy. The observations of the present study may be validated in other populations with lower and higher prevalences of anemia. Another observation is the role of effective clinical management of diabetic pregnancy. Our study was carried out in a tertiary health care centre where management of the impaired glucose tolerance of pregnant women was expected to be better. The same observations may not be extrapolated to the country’s primary and secondary healthcare centres, where the clinical management of patients may be inferior. This warrants further studies to test the generalizability of our observations. Yet another limitation of the study is that diabetic pregnant women were already on treatment with insulin and oral hypoglycaemic agents since diagnosis.
Acknowledgment
We gratefully acknowledge the financial support from our Institute through intramural funds and the Council of Scientific and Industrial Research, Government of India, for providing financial support to the first author. Also, we would like to thank Grammarly (https://app.grammarly.com) for editing the English language.
Footnotes
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