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Table of Contents
ORIGINAL ARTICLE
Year : 2022  |  Volume : 71  |  Issue : 1  |  Page : 34-41

Effects of maternal iron deficiency anemia on placenta and cord blood iron status with specific reference to the iron transport protein ferroportin 1


1 Department of Obstetrics and Gynecology, Gandhi Hospital, Secunderabad, Telangana, India
2 Division of Pathology and Microbiology, National Institute of Nutrition, Hyderabad, Telangana, India
3 Division of Pathology and Microbiology, National Institute of Nutrition (Indian Council of Medical Research), Hyderabad, Telangana, India

Date of Submission17-Aug-2020
Date of Acceptance30-Sep-2021
Date of Web Publication17-Mar-2022

Correspondence Address:
Dr. Mullapudi Venkata Surekha
Division of Pathology and Microbiology, National Institute of Nutrition (Indian Council of Medical Research), Jamai-Osmania, Tarnaka, Hyderabad - 500 007, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jasi.jasi_158_20

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  Abstract 


Introduction: Iron deficiency anemia is the most prevalent nutritional deficiency disorder in pregnant women. During pregnancy, nutrients, including iron, are transferred from the mother to the fetus through the placenta, in which the placental transport protein Ferroportin1 (FPN1) plays a crucial role. It has been frequently observed that developing fetus is immune to anemia despite the presence of anemia in the mother, the mechanisms underlying which have not been identified. We, therefore, planned the present study to explore the effect of maternal iron deficiency anemia on the expression of FPN1 in the placenta. Material and Methods: Two hundred pregnant women recruited were divided into anemic and nonanemic groups based on their predelivery hemoglobin levels (<11 g/dl and ≥11 g/dl, respectively). After delivery, placental expression of FPN1 was studied by immunohistochemistry and mRNA analysis, and neonatal anthropometry was performed. Results: Of the 200 women, 59% were anemic. FPN1 protein immunohistochemical staining in placenta showed a statistically significant increase with increasing severity of anemia. Similarly, placental mRNA expression levels of the FPN1 gene were observed to be higher in anemic mothers when compared with nonanemic mothers. Discussion and Conclusion: Thus, our study for the first time shows that maternal iron deficiency increases placental FPN1 protein and mRNA expression, thereby probably facilitating increased transport of iron from the mother to the fetus.

Keywords: Anaemia, cord blood, ferroportin1, iron deficiency, pregnancy


How to cite this article:
Gadhiraju S, Sujatha T, Putcha UK, Surekha MV. Effects of maternal iron deficiency anemia on placenta and cord blood iron status with specific reference to the iron transport protein ferroportin 1. J Anat Soc India 2022;71:34-41

How to cite this URL:
Gadhiraju S, Sujatha T, Putcha UK, Surekha MV. Effects of maternal iron deficiency anemia on placenta and cord blood iron status with specific reference to the iron transport protein ferroportin 1. J Anat Soc India [serial online] 2022 [cited 2022 May 24];71:34-41. Available from: https://www.jasi.org.in/text.asp?2022/71/1/34/339873




  Introduction Top


Iron deficiency anemia is the most prevalent nutritional deficiency disorder in the world.[1] According to WHO, globally, 38.2% of pregnant women are affected by anemia,[2] leading to low birth weight and increased risk of maternal and perinatal mortality.[3]

During pregnancy, the placenta forms an interface between the mother and the fetus, and the nutrients are transported from the mother to the fetus through specialized nutrient transporters located on the placental villi.[4] Ferroportin (FPN) is a transmembrane protein that transports iron from inside the cell to outside and is the only known iron exporter.[5] In the placental syncytiotrophoblast cells, iron is transferred across the cell and is released into fetal circulation with the help of FPN.

Maternal iron deficiency leads to the development of anemia in the developing fetus; however, it is observed that the degree of deficiency seen in the fetus is of lesser severity than that of the mother, but the mechanisms behind this adaptation have not been identified. Our earlier study showed interesting results in which we observed newborns of anemic mothers had normal blood cell parameters despite the presence of anemia in mothers. Literature search performed by us revealed few to nil studies on FPN1 expression in the placenta in the condition of maternal iron deficiency. Thus, we planned this study to investigate the effect of maternal iron deficiency anemia on the expression levels of FPN1 in the placenta.


  Material and Methods Top


This was a cross-sectional study in which 200 pregnant women in their third trimester of pregnancy, attending the Obstetrics and Gynecology Department of Gandhi hospital, Hyderabad, for their delivery, were enrolled. The institutional ethical committee report of both the National Institute of Nutrition (NIN) and Gandhi hospital was obtained before the start of the study.

The subjects, found to be anemic on admission, were asked to participate in the study after signing an informed consent form. Information on sociodemographic factors, dietary intake and clinical status was collected. The weight, height, and body mass index (BMI) were also noted.

Study groups

Anemic group

Pregnant women with Hb <11 g/dL as defined by the World Health Organization.

Nonanemic group

Healthy pregnant women with Hb ≥11 g/dL.

Inclusion criteria

18–45 years age, 36–42 weeks of gestation, and single pregnancy (primiparous or multiparous).

Exclusion criteria

Hemolytic anemia, hypertension, diabetes mellitus, thyroid disease and HIV, hepatitis C virus, and hepatitis B surface antigen positive women.

Sociodemographic and anthropometric information

Using a well-designed questionnaire, information on age, family history, socioeconomic status, and clinical history of the subjects were obtained. Weight and height of the mothers were recorded for calculating BMI. After birth, anthropometric measurements of newborns were noted.

Sample collection and processing

  1. About 10 ml of blood was drawn before delivery from the mothers and collected in ethylenediaminetetraacetic acid and plain vacutainers (Beckton Dickinson). After delivery, 10 ml of cord blood was collected in similar types of vacutainers, and both maternal and cord blood samples, after collection, were immediately transported in ice to Pathology lab of NIN
  2. Collection of placentas


  3. The placentas were collected within 30 min of delivery. For m-RNA analysis, fresh samples were collected from the maternal side, within 5 cm of the radius of the umbilical cord insertion, omitting the membranous layer, about 1 cm deep below the surface and kept in vials containing 5 ml of RNA later solution and stored at −80°C until further analysis.

  4. Histopathology of placentas


  5. After collection of samples for m-RNA analysis, the remaining whole placentas were stored at room temperature, in containers filled with 10% neutral buffered formalin.

  6. Parameters studied in maternal and cord blood Hb, red cell indices, and ferritin.
  7. Parameters studied in the placenta


    1. Weight, size, gross anomalies, histomorphology (ii) FTN-1 expression by immunohistochemistry and m-RNA analysis (iv) cord length, morphology.


  8. Parameters studied in the Newborns


  9. Weight, crown-rump length, head, mid-arm circumference, and skinfold thickness.

  10. Hemoglobin estimation and complete blood count (CBP) was performed within 06 h of sample collection, in an automated Coulter counter (ADVIA 120, Seimens).Hb, differential count, total leukocyte count (TLC), red blood cell count (RBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), MCH concentration (MCHC), red cell distribution width (RDW), and hemoglobin distribution width (HDW) were analyzed. The serum was separated and stored at −80°C until further analysis for ferritin.
  11. Estimation of serum ferritin by ELISA method


  12. Serum ferritin was estimated using ferritin SA ELISA kit of Calbiotech, Inc., which uses solid phase sandwich assay method, based on the streptavidin-biotin principle.

  13. Histopathology


The placentas were weighed after removal of cords and membranes, their size, shape, and gross findings were noted. After overnight fixation in 10% neutral buffered formalin, four sections were taken, about 5 cm from within the radius of insertion of the cord, away from the margins, and close to the maternal surface. The tissues were processed in an automatic tissue processor (Shandon), embedded in paraffin, and their 5 μ thick sections taken.

The immunohistochemical expression for FPN-1proteinwas studied in formalin-fixed and paraffin-embedded placental tissues. The primary antibody used was polyclonal rabbit SLC40A1from Biorbyt, and the secondary antibody was Dako Real Flex Mini Envision Detection with Peroxidase/Wash buffer/Antigen retrieval buffer/DAB+, Rb/Mo One-Step Method. The stained sections were studied under a light microscope (Nikon Eclipse E800) by two histopathologists, and relevant images were captured in a digital camera attached to the microscope.

Immunohistochemical analysis

Immunoreactivity was classified by estimating the percentage (P) of placental trophoblast cells showing the characteristic staining (from an undetectable level or 0%, to homogeneous staining or 100%) and by estimating the intensity (I) of staining (1 – weak staining, 2 – moderate staining, and 3 – intense staining). Results were scored by multiplying the percentage of positive cells by the intensity, i.e., by the so-called quick score (Q) (Q = P × I; maximum = 300).[6]

9. Real-time polymerase chain reaction (RT-PCR) analysis of FPN1 gene.

The mRNA expression of FPN1 gene was analyzed using the manual Trizol method. About 20 mg of placental tissue was treated with 1 ml of the TRI reagent in a 1.5 ml microcentrifuge tube. The isolated RNA's quantity and purity were measured spectrophotometrically by measuring the OD at absorbance ratios of 260/280 and 260/230, respectively, using Nanodrop 2000c spectrophotometer (Thermoscientific). The RNA isolated (1 ug) per target was treated with DNase1, according to the manufacturer's instructions. The total RNA (200 ng) was reverse-transcribed into cDNA by using the transcriptor cDNA synthesis kit (Bio-Rad). Reverse transcription reaction was carried out using a thermocycler (Applied Biosystems), under the following conditions; 25°C for 5 min, 46°C for 20 min, 95°C for 1 min with a hold at 4°C. RT-PCR reactions were carried out using light cycler CFX 96 (Bio-Rad), and each reaction contained 0.5 μl of the primer (Bioartis), 10 μl 2x SYBR Green PCR Mastermix (Thermoscientific), 8 μl of nuclease-free water, and 1 μl of 15 ng/μl of cDNA in a 15 μl reaction. The PCR reactions were set at 95°C for 3 min, 95°C for 15 s, and finally 57°C for 30 s (40 repeats). The results were obtained as cycle threshold, and single melt curves were obtained for all samples, indicating that a single PCR product was generated. β-actin was used as an endogenous control gene with relative expression of a gene expressed as 2-△CT. Each sample was pipetted into 96-well plates were run in duplicate. Negative control of PCR-grade H2O and positive control (human placental tissues) were used. The primer was designed using National Center for Biotechnology Information sequence ID and purchased from Bio-Artis: Ferroportin: Forward: 5'-TTACCAGAAAACCCCAGCTC-3', reverse 5'-CAGGGGTTTTGGCTCAGT AT-3' and β-actin: Forward: 5′-CCAACCGCGAGAAGA TGA-3′, reverse: 5′-CCA GAG GCG TAC AGG GAT AG-3′.Plate-to-plate variation was controlled by normalizing gene expression to β-actin and control by using the △△CT method.[7]

Statistical analysis

Assuming a 95% confidence interval, a prevalence of 15% anemia in newborns and the margin of error being 5%, the required sample size calculated was 196.

Data processing and statistical analyses were performed using SPSS version 19.0 (SPSS Inc., Chicago, IL, USA). Continuous data were summarized as means ± standard deviation (SD) and categorical data as numbers (%). Descriptive statistics such as mean, SD, and prevalence were calculated for all variables. Mean values for all variables were compared by unpaired t-test across both healthy and anemia groups. Correlation coefficients calculated relationships between Hb, MCV, MCH, MCHC, RBC, RDW, HDW, serum ferritin. and Chi-square test was performed for associations. A nonparametric test was done wherever required. Pearson's correlation analysis was carried out to evaluate the correlation between different variables. The level of significance was considered as 0.05.


  Results Top


Nearly 59% of the pregnant mothers recruited were anaemic among with 60% having moderate anaemia, 28% mild anaemia and 12% severe anaemia.

[Table 1] shows that 72% of the women were in the age group of 18–23 years, among whom 38% are anemic. A BMI >23 was observed in 75% of the women. Nineteen women (9.6%) were college educated, whereas 89 (45.2%) each were illiterate and school educated. 53 (59.6%) of these illiterate women were anemic. Among the 171 (86.8%) unemployed women, 60.2% were anemic. The monthly family income of 68.7% was between Rs. 5000 and 10,000. Maternal red cell parameters are displayed in [Table 2], in which Hb, RBC count, PCV, MCV, MCH, and MCHC including serum ferritin are significantly lower in anemic mothers, while RDW and HDW values are significantly higher. [Table 3] shows that Hb, PCV, RBC, MCV, and MCH are higher while serum ferritin levels are significantly lower in cord blood of anemic mothers. [Table 4] shows that all neonatal anthropometric parameters are lower in newborns of anemic mothers. Pearson's correlations in [Table 5] highlight the negative correlation of maternal Hb with cord blood Hb, but significant positive correlation with cord blood ferritin. Cord blood Hb shows a negative correlation with maternal ferritin.
Table 1: Sociodemographic and economic characteristics of pregnant women

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Table 2: Blood cell parameters in anaemic and nonanaemic pregnant women

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Table 3: Comparison of blood cell parameters between cord blood of newborns of anaemic and nonanaemic mothers

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Table 4: Anthropometric data of newborns of anemic and nonanemic mothers

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Table 5: Pearson's correlations between maternal and cord blood parameters

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[Graph 1] shows that serum ferritin values were significantly lower in anemic mothers. [Graph 2] shows that, among the different grades of anaemia, serum ferritin is lowest in severe anaemia. [Graph 3] shows higher levels of serum ferritin in cord blood when compared to the mother's blood. [Graph 4] shows a statistically significant increase in immunohistochemical staining for FPN1 in placental cells with increasing severity of anemia. [Graph 5] demonstrates that mRNA expression of FPN1 gene is higher in anemic women in comparison to nonanemic women.



[Figure 1], [Figure 2], [Figure 3], [Figure 4] show the immunohistochemical staining in trophoblasts, which was observed to be weak in mild anemia and strongly positive in severe anemia.
Figure 1: Microphotograph is of negative control, in which the trophoblastic cells show no immunostain as the only secondary antibody is added (×40)

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Figure 2: Microphotograph shows immunostaining for ferroportin in placentas from mothers with mild anemia. A mild degree of immunostaining is observed in the cytoplasm of the trophoblastic cells. Ferroportin immunostain; (×40)

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Figure 3: Microphotograph shows immunostaining for ferroportin in placentas from mothers with moderate anemia. A moderate degree of immunostaining is observed in the cytoplasm of the trophoblastic cells. Ferroportin immunostain; (×40)

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Figure 4: Microphotograph shows immunostaining for ferroportin in placentas from mothers with severe anemia. Intense staining is observed in the cytoplasm of the trophoblastic cells. Ferroportin immunostain; (×40)

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  Discussion Top


The placenta is an essential organ for the development of a fetus and forms an interface for nutrient transfer between the mother and the fetus. Iron transfer from mother to fetus takes place across the placenta with the help of iron transport proteins.[8] Surprisingly, the fetus seldom seems to develop anemia, despite the presence of maternal anaemia.

The WHO considers anemia in pregnant women as a serious public health problem when the prevalence is higher than 40%. We enrolled 200 pregnant women in the present study, 59% of whom were anemic. The prevalence of anemia observed in our study was higher than the National prevalence of 50.3% and 49.8% state prevalence.[9] However, other studies have reported a lower prevalence of anemia.[10],[11] The high prevalence of anemia is an important finding in our study indicating that maternal anemia is still a rampant problem in our part of the country, which needs to be tackled at the community level at the earliest. The majority (60%) of women presented with moderate anemia, followed by 28% with mild anemia and the least (12%) with severe anemia. Contrary to the present study, other studies, however, reported mild anemia being the most common.[9],[12],[13],[14] The reason for the higher incidence of moderate anemia (60%), in our study, could be either poor compliance of the women in taking iron and folic acid tablets supplied by the government or associated Vitamin B12 and folate deficiency. Moreover, it is also a disturbing finding which calls for more in-depth analysis of the cause and also measures to tackle it, as maternal anemia has numerous long-term adverse effects on the fetus.

The majority of the women (75%) had an association between anemia and a high BMI >23, which is similar to other studies.[15],[16] Although obesity and iron deficiency usually represent opposite ends of the spectrum of malnutrition, the association between high BMI and anemia in our study proves to be a significant finding and thus needs to be addressed as a measure of nutritional and health status.

We observed that most of the anemic women were illiterate and unemployed in our study. Kefiyalew et al.[16] had similarly reported a significant number of women with anemia being illiterate and unemployed. These findings highlight the fact that illiteracy, low family income and lower levels of education are risk factors for the development of anemia either due to inaccessibility of the women to food or due to a lack of their knowledge on the intake of iron-rich food which thus leads to the development of anemia.

Maternal red cell parameters such as Hb, RBC count, PCV, MCV, MCH, and MCHC, including serum ferritin, were significantly low in anemic mothers, which is consistent with other studies.[14] Another parameter useful for the diagnosis of iron deficiency is RDW, which is a quantitative measure of anisocytosis. Increased RDW levels indicate a heterogeneous population of erythrocytes, formed by cells of various sizes. In iron deficiency, RDW levels are always found to be increased. In our study, too, RDW of anemic pregnant women was observed to be higher when compared to nonanaemic ones, thus corroborating the literature.[17]

Many studies have been carried out in maternal and cord blood. While some have reported a negative impact of maternal iron deficiency anemia on the iron stores of the newborns,[18] others could not find any relationship.[19] However, Jaime-Pérez et al. and other investigators[11],[14],[20] had reported normal to above normal Hb levels in the cord blood, thus corroborating with our mean Hb value of 15.75 ± 2.15 g/dl, which is above the average cord blood Hb value of 13 g/dl. This finding shows that the fetus can maintain normal Hb levels irrespective of maternal Hb levels.

A negative correlation was found between cord blood Hb and mother's Hb, RBC, PCV, MCV, and MCH. This finding thus indicates that cord blood Hb values are independent of the mother's values, unlike Timilsina et al., who found a positive correlation.[21]

Placental weight, the weight of newborns, crown-rump length, mid-arm, and head circumference, all were observed to be lower in the newborns of anemic mothers when compared to the nonanemic women, consistent with other studies.[22],[23] This highlights the crucial role played by iron as an essential nutrient for the development and growth of the fetus.

FPN is one of the iron transporter proteins located on the basolateral side of syncytiotrophoblasts and is a crucial protein required for the efflux of the iron out of the trophoblasts of the placenta into the fetal circulation. Few animal studies show that, in the presence of a low supply of micronutrients in the maternal diet, signals from the fetus can upregulate the expression of micronutrient transporters in the placenta for its nutrition.[24],[25]

These findings are in line with cell culture studies by Li et al.,[26] in which the BeWo placental cell line was treated with the iron chelator desferrioxamine when FPN mRNA levels were found to be increased. However, there are very few to none studies on the behavior of FPN1 in human subjects, especially in the context of anemia in pregnancy. The only one of such studies in pregnant mothers,[27] however, showed no significant effect of maternal anemia on the placental FPN1 expression. A previous study conducted by us revealed an interesting finding of increased Hb and hematological values in the cord blood, despite the presence of anemia in the mothers. This finding prompted us to undertake the present study in which we hypothesized that maternal iron deficiency increases placental FPN1expression by upregulating the FPN1 gene in order to facilitate increased transport of iron across the placenta. We found immunohistochemical staining for the FPN1 protein was localized to the cytoplasm of the trophoblastic cells. We also studied FPN1 immunoexpression in different grades of anemia and observed a statistically significant increase in the immunoexpression with increasing severity of anemia. In mild anemia, the trophoblastic cells showed a weak staining intensity, while in severe anemia, the cells showed intense positive staining.

In order to further strengthen our findings and test our hypothesis, we also studied the expression of FPN1at the genetic level by performing the mRNA analysis of the FPN1 gene in the placental tissue. Consistent with the protein expression, we observed that m-RNA expression too was higher in anemic women when compared to the nonanemic women. However, our results are not in agreement with Li et al.,[27] who found no significant change in either protein or mRNA expression of FPN1 in the maternal anemia groups. The reason for this discrepancy could be due to their small sample size (40 cases). Thus, our study, with greater sample size, for the first time showed that, in maternal iron deficiency anemia, there is upregulation of FPN1 gene, leading to increased expression of FPN1 protein and mRNA in the placenta, thus confirming our hypothesis.


  Conclusion Top


Our study thus shows that, apart from a high prevalence of moderate anemia in pregnant women of our city, there is increased expression of the placental iron transport protein FPN1 in the placenta at both protein and mRNA level which probably explains the immunity of fetus to the development of anemia despite the presence of maternal anemia by facilitating increased transport of iron to the fetus.

Acknowledgement

All the authors acknowledge Indian Council of Medical Research and National Institute of Nutrition for funding this study and also want to thank all the participants of this study. The manuscript has been read and approved by all the authors, and the requirements for authorship as stated earlier in this document have been met, and each author believes that the manuscript represents honest work.

Financial support and sponsorship

This study was financially supported by Indian Council of Medical Research and National Institute of Nutrition for funding this study (Fund number: 16 PT-03).

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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