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Hemoglobin and Red Cell Indices Correlated With Serum Ferritin Concentration in Late Pregnancy

From the Department of Obstetrics and Gynaecology, The University of Hong Kong, Tsan Yuk Hospital, Hong Kong, People’s Republic of China.

Address reprint requests to: Dr. K. F. Tam, Department of Obstetrics and Gynecology, Tsan Yuk Hospital, Hospital Road, Hong Kong, People’s Republic of China

	Abstract

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Objective: To study the correlation between third-trimester serum ferritin concentration and hemoglobin and red cell indices to select the best hematologic characteristic to identify women who need iron therapy.

Methods: In a prospective study, blood was drawn from pregnant women with hemoglobin above 10 g/dL, and thalassemia trait excluded at booking, at 28–30 weeks’ gestation to study the correlation (Spearman value) between serum ferritin concentration and hemoglobin level, mean corpuscular volume, mean cell hemoglobin, mean cell hemoglobin concentration, and hematocrit. The best relationship was identified using receiver operating characteristic (ROC) curves.

Results: Serum ferritin concentration correlated significantly with hemoglobin ( = .211), mean corpuscular volume ( = .332), mean cell hemoglobin ( = .304), and hematocrit ( = .199). The area under the ROC curve was largest for hemoglobin.

Conclusion: Serum ferritin concentration at the early third trimester correlated best with hemoglobin level. If a hemoglobin level of 11 g/dL or below (25% of all patients) was used as the cutoff, 64% of women who needed iron therapy were identified.

Anemia during pregnancy usually reflects maternal iron deficiency, which has been associated with low birth weight, prematurity, and perinatal mortality.¹ Iron deficiency can also cause impaired psychomotor development in infants, impaired cognitive performance in children, and decreased work capacity and less efficient response to exercise in adults.¹ However, the criterion for diagnosing anemia is controversial, due to variation in normal cutoff value from 11.0 g/dL proposed by the World Health Organization in 1979,² to 10.5 g/dL, to 10.0 g/dL as adopted in our hospital.³ Some advocate iron prophylaxis given to every pregnant woman,⁴ regardless of hemoglobin level, especially because it has been reported that anemia is a late sign of iron deficiency.⁵

On the other hand, a longitudinal study⁶ found that infants of mothers receiving either routine or selective iron prophylaxis during pregnancy did equally well on an average of 6.5 years of follow-up in time and number of hospitalizations. When prescribing iron supplements, we must consider compliance of patients⁷ and possible adverse effects of iron supplements. Some iron preparations have bad smells, causing nausea and vomiting, and constipation is a frequent complaint.⁸ Iron intake also can interfere with the absorption of other essential elements such as zinc, which might become deficient after long-term iron intake.⁹ It is therapeutically important to identify iron deficient women for iron therapy before they develop anemia.¹⁰

Serum iron and transferrin saturation and serum ferritin concentration have been used to assess iron status.^11,12 The low sensitivity of transferrin saturation and the day-to-day, and even hour-to-hour, fluctuations of serum iron levels made them less efficient than ferritin for diagnosing iron deficiency,¹¹ which is the only condition associated with decreased serum ferritin concentration.¹² Thus, iron replacement in deficient mothers, detected by low serum ferritin concentration, seems most appropriate. Because the demand for iron is not distributed evenly over time, but increases through pregnancy, with the power of iron absorption increasing from the first to the third trimester,¹³ assay of standardized serum ferritin concentration at the beginning of the third trimester was the best time to assess maternal iron status, but it is expensive to measure serum ferritin concentration in every patient.

With these considerations, a prospective study was done to determine the correlation between serum ferritin concentration and different red cell indices to see whether hemoglobin level or indices such as the mean corpuscular volume¹⁴ provide the best indication of serum ferritin concentration.

	Materials and Methods

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Ours is a regional hospital with about 5000 annual deliveries that provides obstetric training to medical students. Patients are predominantly Chinese (88%) of lower socioeconomic class. Filipino is the second most common ethnic group using the hospital. A multivitamin preparation, Obimin (United Laboratories/Westmont Pharmaceuticals, Manila, Phillippines, containing 29 mg elemental iron, calcium, copper, iodine, and multiple vitamins), is prescribed to all patients from 20 weeks’ gestation.

Hemoglobin level, mean corpuscular volume, and blood group are measured routinely at the first antenatal visit. The mean corpuscular volume screening is done to identify mothers at risk of having thalassemia traits, suggesting further investigations, including the father’s mean corpuscular volume, hemoglobin electrophoresis, blood smear, and prenatal diagnosis. Any patient with hemoglobin level below 10 g/dL is diagnosed as anemic and is investigated further for gastrointestinal bleeding, worm infestation, or simple iron deficiency. At 28 to 30 weeks, the hemoglobin level is repeated to identify mothers with anemia. In all cases, serum ferritin concentration is measured to determine if the anemia is due to iron deficiency. In our population, the incidence of anemia was 2%, with half the cases due to thalassemia trait and the rest due to iron deficiency.

In a prospective study, low-risk mothers booked before 20 weeks’ gestation were recruited over a 3-month period in the antenatal clinic at repeat hemoglobin estimation, between 28 and 30 weeks’ gestation, irrespective of race, diet, iron supplementation, or other variables, to study their serum ferritin concentrations and red cell indices, including hemoglobin level, mean corpuscular volume, mean cell hemoglobin, mean cell hemoglobin concentration, and hematocrit after informed consent. Patients with preexisting anemia or other blood disorders, and hemoglobinopathies, were excluded.

Three milliliters of blood were drawn and the serum separated for the later batched assay of serum ferritin concentration (Microparticle Enzyme Immunoassay; IMx System of Abbott Laboratories, Abbott Park, IL). Another 2 mL of blood were drawn and the red cell indices were determined by an automated counter (Coulter Maxm, Beckman Coulter, Santa Clara, CA). The results of the serum ferritin concentration were not available to the managing obstetricians.

Results from the laboratory were collected. Calculations and correlations (Spearman rank correlation coefficient ) were done by a commercial computer package (SPSS for Windows, Standard Version 1989–1995, SPSS Inc., Chicago, IL). Comparison between indices was performed with ROC curves¹⁵ using the PCSTAT2 (a noncommercialized database program designed by professor P. C. Ho and Dr. T. C. Pun of our department).

	Results

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Four hundred thirty-seven mothers were recruited into the study. The results of serum ferritin concentrations were missing in three subjects. Another four did not have complete blood results, and they were repeated at the following visit. Those seven subjects were excluded from the study. The final study group consisted of 430 mothers. The maternal age (mean ± standard deviation [SD]) was 29.3 ± 5.0 years. There were 222 (51.6%) nulliparas, 158 (36.7%) para 1s, and 50 (11.6%) para 2s. The majority of the mothers were Chinese (n = 382, 88.8%). The five red cell indices, hemoglobin level, mean corpuscular volume, mean cell hemoglobin, mean cell hemoglobin concentration, and hematocrit, had normally distributed values. Their mean value, standard deviation, and correlation with serum ferritin concentration are shown in Table 1.

Because hemoglobin level, mean corpuscular volume, mean cell hemoglobin, and hematocrit correlated significantly with serum ferritin concentration, ROC curves (Figures 1–4) were constructed to compare the usefulness of different indices in showing the iron status of the pregnant women. The largest area under the ROC curve (AUC) was found with hemoglobin (AUC = 0.78), followed by mean corpuscular volume (AUC = 0.76), and finally by mean cell hemoglobin (AUC = 0.72) and hematocrit (AUC = 0.72).

View larger version (13K): [in this window] [in a new window]   Figure 1. Receiver operating characteristic curve for hemoglobin. AUC = area under the curve.

View larger version (13K): [in this window] [in a new window]   Figure 4. Receiver operating characteristic curve for hematocrit. AUC = area under the curve.

	Discussion

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A high degree of correlation was shown between serum ferritin concentration and bone marrow iron stores. In the stage of latent iron deficiency (absence of storage iron), as assessed by marrow iron content, serum ferritin concentration decreased, but the transferrin saturation, serum iron, and hemoglobin levels were all unchanged.¹⁷

During pregnancy, the total increase in plasma volume is about 42%, whereas the total red cell volume is less than one-third of the increase in plasma volume.¹⁸ This leads to hemodilution, and it was suggested that estimation of hemoglobin alone might not be a good indicator of iron status. On the other hand, Letsky¹⁴ has claimed that mean corpuscular volume is a more sensitive indicator of iron deficiency. These observations suggest that the complete blood picture, including red cell indices, is required to provide evidence of iron deficiency if serum ferritin concentration is not assayed.

In the present study, serum ferritin concentration was used to indicate iron status of pregnant women and was compared with hemoglobin level and other red cell indices to determine which was the best indicator of iron deficiency. In our laboratory, the serum ferritin concentration was determined by a microparticle enzyme immunoassay. The normal range of 13–180 pmol/L was established from 98 normal premenopausal women using nonparametric estimates to calculate the 95% confidence interval (CI). Because this normal range was derived from a small sample of nonpregnant women, it might not apply to our obstetric population. We established the reference range for third trimester of pregnancy. The 95th percentile is 88.5 pmol/L, and the 5th percentile is 11 pmol/L, which was used to define iron deficiency. On the basis of this definition, 25 (5.8%) of 430 pregnant women were diagnosed with iron deficiency, but only four (16%) of the 25 patients had hemoglobin levels below 10 g/dL, suggesting that even nonanemic women might have latent iron deficiency¹⁷ and that a drop in the hemoglobin level is a late sign.

The results of this study indicate that hemoglobin level and red cell indices mean corpuscular volume, mean cell hemoglobin, and hematocrit all showed significant correlation with serum ferritin concentration. However, the area under the ROC curve constructed from hemoglobin level is larger than all the others from mean corpuscular volume, mean cell hemoglobin, and hematocrit, showing that hemoglobin level is superior to the other three red cell indices in predicting the serum ferritin concentration, thus the iron status of the pregnant women, despite the problem of hemodilution. Our findings also disputed the suggestion that the earliest effect of iron deficiency on the erythrocyte is a reduction in cell size and that the mean corpuscular volume is the most sensitive indicator of underlying iron deficiency.¹⁴

From our data, using a hemoglobin level of less than 10 g/dL as the cutoff, only 16% of iron-deficient patients could be identified. With such a low sensitivity, this screening method was not useful for the identification of patients who needed iron supplementation. If we had used a hemoglobin level of 10.5 g/dL or below (11% of all patients) as the cutoff, 36% of iron-deficient patients would have been included. If a hemoglobin level of 11.0 g/dL or below (25% of all patients) had been used, 64% of iron-deficient patients would have been included. Thus, by using the hemoglobin level of 11.0 g/dL, it is possible to identify 64% of iron-deficient women for iron therapy, before they develop anemia.¹⁰

Our findings suggest that in the absence of preexisting anemia and hemoglobinopathies, measurement of the maternal hemoglobin level alone at the beginning of the third trimester is sufficient to determine maternal iron status, despite the contributory effect of hemodilution. Therefore, our practice of routine screening of hemoglobin level at 28–30 weeks could identify the individuals who require iron therapy in the last trimester, when maternal iron demand is greatest.

View larger version (13K): [in this window] [in a new window]   Figure 2. Receiver operating characteristic curve for mean corpuscular volume. AUC = area under the curve.

View larger version (13K): [in this window] [in a new window]   Figure 3. Receiver operating characteristic curve for mean cell hemoglobin. AUC = area under the curve.

	Footnotes

Received May 11, 1998. Received in revised form August 20, 1998. Accepted September 3, 1998.

	References

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4. Horn E. Iron and folate supplements during pregnancy: Supplementing everyone treats those at risk and is cost effective. BMJ 1988;297:1325.

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11. Romslo I, Haram K, Sagen N, Augensen K. Iron requirement in normal pregnancy as assessed by serum ferritin, serum transferrin saturation and erythrocyte protoporphyrin determinations. Br J Obstet Gynaecol 1983;90:101–7.[Medline]

12. Worwood M. The clinical biochemistry of iron. Sem Hematol 1977;14:3–30.[Medline]

13. Whittaker PG, Lind T, Williams JG. Iron absorption during normal pregnancy: A study using stable isotopes. Br J Nutr 1991;65:457–63.[Medline]

14. Letsky E. Blood volume, haematinics, anemia. In: de Swiet M, ed. Medical disorders in obstetric practice. Oxford, UK: Blackwell Scientific Publication, 1984:59.

15. Chard T, Lilford RF. How useful is a test? In: Studd J, ed. Progress in obstetrics and gynaecology. Volume 9. London, UK: Churchill-Livingstone, 1991:3–15.

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