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Technical Briefs |
1
Department of Clinical Pathology, College of Medicine, Inha University Hospital, 7-206, 3-ga, Shinheung-dong, Jung-gu, Inchon 400-103, Korea
2
Deparment of Obstetrics, College of Medicine, Inha University Hospital, 7-206, 3-ga, Shinheung-dong, Jung-gu, Inchon 400-103, Korea
a author for correspondence: fax 82-32-890-2529, e-mail jwchoi{at}inha.ac.kr
Among the physiologic changes during pregnancy, the disproportionate increases in plasma volume and red cell mass produce a decrease in hemoglobin concentration. Pathologic anemia of pregnancy is mostly attributable to iron deficiency associated with increased requirements and inadequate intake (1), but physiologic changes also occur in iron markers. Iron plays an essential role in a spectrum of metabolic processes. Cellular iron uptake is facilitated by transferrin receptor (TfR)-mediated endocytosis (2). Serum TfR (sTfR) is a sensitive indicator of iron deficiency in inflammatory states and in the anemia of chronic diseases because its concentration is not influenced by the acute phase response (3). The sTfR concentration is closely related to erythroid TfR turnover; therefore, sTfR may be a useful marker to monitor erythropoiesis in various clinical situations (4).
Erythropoiesis is a highly dynamic process and can be monitored by quantitative reticulocyte counting. Flow cytometric analysis of reticulocytes provides a quantitative reticulocyte measurement with high sensitivity and precision (5). The fluorescence intensity of reticulocytes is directly proportional to erythrocyte RNA content, and reticulocytes can be divided into three subpopulations by fluorescence intensity: low fluorescence reticulocytes, middle fluorescence reticulocytes, and high fluorescence reticulocytes (5)(6). The reticulocyte maturity index (RMI) is calculated from the proportion of reticulocyte subpopulations and can be used as the earliest and most sensitive predictor of bone marrow erythropoiesis (6).
The sTfR concentration and the RMI during normal pregnancy have not been studied extensively, and the reported values for sTfR show a wide range of discrepancies. Therefore, in the present study, we investigated the sequential changes in sTfR concentrations according to gestational age in healthy pregnant women without anemia and iron deficiency. We also evaluated the relationship between the sTfR concentrations and the RMI during normal pregnancy.
We measured sTfR, hematologic and iron markers, and reticulocyte
subpopulations in 355 apparently healthy pregnant, postpartum, or
nonpregnant subjects (Table 1
). We excluded subjects with evidence of
anemia or iron deficiency, or with complications during pregnancy.
Gestational age was determined by sonographic examination and the date
of the last menstrual period. Second trimester was defined as
12.1–24.0 weeks of gestation. The study was approved by the Committee
of Ethics at the Inha University Hospital, and informed consent was
obtained from all subjects. Maternal blood (9 mL) was drawn into
iron-free evacuated tubes before the introduction of iron
supplementation when the subjects visited the outpatient Department of
Obstetrics. After blood samples were collected, all pregnant women were
supplemented with one 256-mg tablet of ferrous sulfate (80 mg of
elemental iron) per day; however, vitamin B12 and
folate were not supplemented. The compliance rate for the iron
supplementation was checked by personal interviews throughout the
pregnancy. Complete blood cell counts and reticulocyte
subpopulations were measured with EDTA-anticoagulated blood within
3 h after collection. Sera for the measurement of sTfR were stored
in 500-µL aliquots at -70 °C until analysis.
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Anemia was defined as a hemoglobin <110 g/L in pregnant women by WHO
criteria (7). Nonanemic women who had a serum ferritin
concentration <12 µg/L were classified as having iron deficiency.
Routine complete blood cell counts and red cell indices were determined
with the electronic counter SE 9000 (Sysmex). Reticulocytes and their
subpopulations were analyzed automatically by the R-3000 flow cytometry
(Sysmex). RMI was calculated from the equation, RMI = [(middle
fluorescence reticulocytes + high fluorescence reticulocytes) x
100]/low fluorescence reticulocytes, and was expressed as the
percentage (8). The corrected reticulocyte count was
calculated, based on a normal hematocrit of 45%, from the following
formula: corrected reticulocyte count (%) = (subject’s
hematocrit/45) x reticulocyte count (%). Serum iron and total
iron-binding capacity were assayed with the Hitachi 747
automatic chemical analyzer (Hitachi), and ferritin was measured by the
ACS:180 chemiluminescence assay (Chiron). The sTfR was measured
immunoenzymetrically using IDeATM sTfR kits
(Orion Diagnostica). The intraassay CVs (n = 20) for three samples
(mean sTfR, 1.3–6.5 mg/L) were 3.2–5.4%; the interassay CVs
calculated from duplicate results in 10 subsequent assays were
3.5–6.1%. Data analysis was conducted using SAS 6.12 for Windows (SAS
Institute). The Mann–Whitney test was used to compare the difference
of values. Correlation coefficients were calculated by the Spearman
method for ranked values. P 
0.01 was considered
statistically significant.
The changes in sTfR concentrations and iron markers during normal
pregnancy are summarized in Table 1
. The sTfR concentration of pregnant women in the first
trimester did not differ significantly from that of nonpregnant women
(P = 0.215). However, the sTfR concentration in the
second trimester was significantly higher than that in the first
trimester (P <0.01). The mean sTfR value increased
gradually from the second trimester of pregnancy and reached maximal
concentration in the third trimester. The sTfR concentration decreased
abruptly within 1–4 weeks after delivery. No significant difference in
sTfR concentration was observed between the women 12–16 weeks
after delivery and nonpregnant women. Therefore, on the basis of our
results, we believe that the sTfR concentrations increase with
gestational age during pregnancy and return to nonpregnancy
values 12 weeks after delivery.
Our data for the sTfR concentration during pregnancy are in accord with another study showing that the value of sTfR increases from early to late pregnancy (9). However, contradictory results for the sTfR concentration during pregnancy also have been reported. Carriaga et al. (10) reported that the mean sTfR concentration of pregnant women in the third trimester did not differ from the concentration in nonpregnant individuals and that sTfR concentrations were not influenced by pregnancy per se. They reported that the sTfR concentration for healthy male and female volunteers was 5.63 mg/L, which differs substantially from our result for nonpregnant women. In our study, we selected nonpregnant women in the same age group as the pregnant women, who had no iron deficiency, iron deficiency anemia, or history of pregnancy. In our previous study (11), the mean sTfR concentration in healthy adults was 2.13 mg/L, which was similar to the value for the nonpregnant women in the present study. The differences between our studies and the study by Carriaga et al. (10) seem to be derived from the use of different methods for the sTfR assay and the different ages in the control group.
It has been suggested that the low sTfR concentration in early
pregnancy is caused by reduced erythropoiesis, whereas the increase
sTfR concentration in late pregnancy reflects increased erythropoiesis
(9). However, there are few reports on the direct
relationship between the sTfR concentration and RMI in healthy pregnant
women. In this study, we evaluated the changes in reticulocyte
subpopulations and RMI during pregnancy. In our results, the corrected
reticulocyte counts were twofold higher in the third trimester than in
the first trimester. The RMI was threefold higher in the third
trimester than in the first trimester. On the other hand, there were no
significant differences in corrected reticulocyte counts and RMI
between the pregnant women in the first trimester and the nonpregnant
women. As shown in Fig. 1
, the sTfR concentrations increased similarly to the changes in
corrected reticulocyte counts and RMI during pregnancy. The sTfR
concentrations correlated significantly with the corrected reticulocyte
counts (r = 0.61; P <0.01) and the RMI
(r = 0.65; P <0.01). In our study, the sTfR
concentrations, the corrected reticulocyte counts, and the RMI
were two- or three-fold higher in the third trimester than in the first
trimester, even when no significant differences were noted in the iron
markers between the two groups. Therefore, we believe the increased
sTfR concentration during pregnancy reflects increased erythropoietic
activity in this period.
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In conclusion, we found that sTfR concentrations do exhibit gestational age-related changes during pregnancy: the value of sTfR increased with gestational age during pregnancy and returned to nonpregnancy values 12 weeks after delivery. Increases in sTfR concentrations during pregnancy seem to be influenced more by increased erythropoietic activity than by iron depletion in this period.
References
The following articles in journals at HighWire Press have cited this article:
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  C. Thomas and L. Thomas Biochemical Markers and Hematologic Indices in the Diagnosis of Functional Iron Deficiency Clin. Chem., July 1, 2002; 48(7): 1066 - 1076. [Abstract] [Full Text] [PDF]
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 A. Akesson, P. Bjellerup, M. Berglund, K. Bremme, and M. Vahter Soluble Transferrin Receptor: Longitudinal Assessment From Pregnancy to Postlactation Obstet. Gynecol., February 1, 2002; 99(2): 260 - 266. [Abstract] [Full Text] [PDF]
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 S. Muslimatun Weekly Supplementation with Iron and Vitamin A during Pregnancy Increases Hemoglobin Concentration but Decreases Serum Ferritin Concentration in Indonesian Pregnant Women J. Nutr., January 1, 2001; 131(1): 85 - 90. [Abstract] [Full Text]
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) increased with the RMI (•) and corrected
reticulocyte count (
), and peaked in the third trimester. The sTfR
concentrations correlated significantly with the RMI
(r = 0.65; P <0.01) and the
corrected reticulocyte count (r = 0.61;
P <0.01).