- Email: [email protected]
Comparison of tests for diagnosis of iron depletion in pregnancy
Comparison of tests for diagnosis of iron depletion 1n pregnancy Warren G. Thompson, MD New York, New York The serum ferritin level was used to diagnose iron depletion in 137 pregnant patients who came to an inner-city hospital outpatient clinic. Seventy-three patients (53.3%) had ferritin levels <20 µg/L, indicating iron depletion. The prevalence of iron depletion was 29% in the first trimester, 64% in the second trimester, and 71 % in the third trimester (p < 0.001 ). The sensitivities of serum iron (2.8%), transferrin saturation (12.5%), mean corpuscular volume (6.8%), and red cell distribution width (16.4%) were too low for screening or diagnosing iron depletion and deficiency. Serum ferritin level should be used to screen for and diagnose iron depletion and deficiency in pregnancy. (AM J OssTET GYNECOL 1988;159:1132-4.)
Key words: Iron deficiency anemia, ferritin, transferrin saturation, red cell distribution width There is a high incidence of iron deficiency in pregnancy' because iron is transferred from mother to fetus regardless of maternal iron stores. 2 Serum ferritin was obtained to determine the incidence of iron depletion and deficiency in a group of outpatients in an inner-city, municipal hospital. The usefulness of the red cell distribution width, the mean corpuscular volume, serum iron, and transferrin saturation for screening and diagnosing iron deficiency was also determined.
Material and methods Patients coming to the Obstetrics Clinic at Bellevue Hospital for the first prenatal visit were eligible for the study. After the purpose of the study was explained, patients provided written informed consent. Information obtained from the patients and the medical record included age, number of previous pregnancies, expected date of delivery, whether the patient took iron tablets, and whether the patient had any long-term diseases (chronic liver disease, chronic renal disease, rheumatoid arthritis, neoplasms, and other inflammatory disorders). Blood was drawn to obtain a complete blood count, transferrin saturation, and serum ferritin. Complete blood counts were performed on a Coulter counter (Model S-Plus IV). Serum iron and transferrin levels were measured according to the method of Goodwin et al. 3 Serum ferritin was measured by a one-stage,
From the Division of Primary Care Internal Medicine, Department of Medicine, New York University School of Medicine. Supported in part by a grant from the Sergei Zlinkoff Foundation. Received for publication January 28, 1988; revised May 17, 1988; accepted June 12, 1988. Reprint requests: Warren Thompson, MD, Bellevue Hospital 1N-49, First Avenue and 27th Street, New York, NY 10016.
1132
Table I. Iron depletion in pregnancy (ferritin < 20 µg/L)
Pregnancy trimester l 2 3 Parity 0 1-2 3 or more Age 18-23 23-30 30-44 Iron tablets Yes No Total
Iron depleted n (%)
Not depleted n
Total n
14 (29) 39 (64) 20 (71)
34 22 8
48 61 28
11 (39) 32 (55) 30 (59)
17 26 21
28 58 51
36 (59) 24 (51) 13 (45)
25 23 16
61 47 29
20 (48) 53 (56) 73 (53)
22 42 64
42 95 137
two-site immunoradiometric assay (RAMCO Laboratories, Inc., Houston). This assay is diagnostic of iron depletion.
Statistical analysis To determine whether iron deficiency was more or common with advancing age, increasing parity, and increasing trimester of pregnancy, logistic regression was performed using the BMDP statistical package1 for the microcomputer. Jes~
Results Patients ranged in age from 18 to 44 years, with an average age of 26 years. Two thirds of the patients were of Hispanic origin, one sixth were black, and one sixth were white. Twenty percent of the women were pregnant for the first time, 43% had been pregnant once
Volume 159 Number 5
Tests of iron depletion in pregnancy
1133
Table II. Prediction of iron depletion* Test
% saturation< 16 Iron< 40 µg/dl ( < 7 µmol/L) MCV < 80 fL RDW> 15% Hemoglobin< 12 gm/di (<120 gm/L)
Iron depleted (n = 73)
Not depleted (n = 64)
9 (12.5%) 2 (2.8%) 5 (6.8%) 12 (16.4%) 39 (53.4%)
Total (n = 137)
I (!.6%) 0 (0%)
10
2 (3.1%)
7 12 68
0 (0%)
29 (45.3%)
2
MCV, Mean corpuscular volume; RDW, red cell distribution width.
*The percentages in the iron-depleted column are sensitivities; whereas the percentages in the not depleted column are falsepositive rates
or twice previously, and 37% had been pregnant three or more times. Thirty-one percent of women reported taking iron tablets (most took one multivitamin with iron). Women who took iron before their first visit to the Prenatal Clinic had been referred from the Gynecology Clinic where pregnancy had been diagnosed. Thirty-five percent of women were in the first trimester of pregnancy, whereas 45% and 20% were in the second and third trimesters, respectively. The incidence of iron deficiency in this pregnant population is high. Seventy-three of 137 (53.3%) patients had serum ferritin levels <20 ng/ml (20 µg/L) and were classified as iron depleted or deficient (Table I). Patients more advanced in their pregnancies were more likely to be iron depleted (p < 0.001). Women in the first trimester had an incidence of iron depletion of 29%, whereas women in the third trimester had an incidence of 71 % (Table I). Nulliparous women and older women had a lower incidence of iron depletion than did multiparous women and younger women, respectively. However, logistic regression with iron depletion as the dependent variable and age, parity, and week of pregnancy as the independent variables revealed that only the week of pregnancy predicted iron depletion. The proportion of patients who were iron depleted was not significantly different for patients who took iron at the time they came to the clinic (p > 0.05, x2). · Table II lists the sensitivities and false-positive rates of the transferrin saturation, serum iron, mean corpuscular volume, and red cell distribution width. None of these tests detected even one fifth of the irondepleted patients. A hemoglobin level < 12 gm I di ( 120 gm/L) was seen in 53% of the iron-depleted patients; however, 45% of the patients without iron depletion also had a hemoglobin value <12 gm/di (120 gm/L). The average platelet count did not vary between irondepleted patients and patients not iron depleted (p > 0.05, t test). If the red cell distribution width, mean corpuscular volume, or transferrin saturation are abnormal, the likelihood of iron deficiency is very high
because the specificities of these tests are excellent (they have low false-positive rates). The one patient who had a transferrin saturation value < 16% who was classified as not iron deficient had a ferritin level of <30 ng/ml (30 µg/L) and actually may have been iron deficient (in which case the specificity of the transferrin saturation would have been 100%). Comment
Iron deficiency is common in pregnant women for three reasons: (I) Many women of childbearing age are in precarious iron balance (33% to 50% of women between the ages of23 and 30 years have no bone marrow iron), (2) the erythrocyte volume increase in pregnancy requires iron, and (3) fetal iron requirements are satisfied before maternal iron needs. 2 Absent bone marrow iron is an extremely common finding in pregnancy. 1· 5 A low ferritin level in pregnancy correlates with absent bone marrow iron stores, 6 indicating that a low ferritin level represents true iron deficiency. Approximately half the patients in the present study had a hemoglobin value > 12 gm/ di ( 120 gm/L), so iron depletion 7 may be a more appropriate term than iron deficiency for these patients. The clinical significance of iron depletion is unclear, but there is reason to believe that it may b,, harmful. 8 Although there is some disagreement, 9 most studie~ have found that women with iron deficiency deliver babies with lower cord ferritin levels. 10-12 The difference in infant iron stores can persist for at least as long as 6 months. 12 · 13 Women who are not treated with iron postpartum continue to have persistently lower ferritin levels. 13-15 These studies have also demonstrated that lower cord, infant, and postpartum maternal ferritin levels can be prevented by adequate iron supplementation during pregnancy. 13· 15 The red cell distribution width and the mean corpuscular volume have been proposed as useful screening tests for iron ' deficiency. 16 The red cell distribution width measures variability of red cell size (anisocytosis).16 The red cell distribution width and mean cor-
1134 Thompson
puscular volume are routinely reported as part of a complete blood count by most laboratory instruments. The red cell distribution width is superior to the mean corpuscular volume, but neither is sufficiently sensitive to screen for iron depletion and deficiency. Previous studies have also found that the mean corpuscular volume and transferrin saturation are poor markers for iron deficiency in pregnancy. 10• 11 • 1'· 15 No previous studies have reported the actual sensitivities of the mean corpuscular volume or transferrin saturation in pregnancy, and the sensitivity of the red cell distribution width has not been reported in a pregnant population. In this population the ip.cidence of falsely low mean corpuscular volume and falsely high red cell distribution width was quite low. However, in populations with a high incidence of a-thalassemia or J3-thalassemia minor (which would lower the mean corpuscular volume), hemoglobinopathies, liver disease, B 12 deficiency, or folate deficiency (all of which would raise the red cell distribution width), the specificity of the mean corpuscular volume and red cell distribution width would be lower. If the red cell distribution width is elevated or the mean corpuscular volume is low, this study suggests that iron deficiency is extremely likely in the absence of these conditions. Iron depletion as defined by a low serum ferritin level is extremely common in pregnancy in an inner-city hospital clinic population. Studies using serum ferritin levels should be performed to determine the incidence of iron depletion in other populations. Other tests, such as the red cell distribution width, mean corpuscular volume, and transferrin saturation, are not sufficiently sensitive to diagnose iron depletion and deficiency. Serum ferritin level is required to adequately document iron depletion and deficiency during pregnancy. We acknowledge Nancy Goldberg, Frank Hernandez, Kenneth Lampert, MD, Mack Lipkin, Jr., MD, Humra Mahmood, MD, Kanshin Partee, and Kay Williams. REFERENCES 1. deLeeuw NKM, Lowenstein L, Hsieh YS. Iron deficiency and hydremia in normal pregnancy. Medicine 1966; 45:291-315.
November 1988 Am J Obstet Gynecol
2. Pritchard JK, MacDonald JS, Grant NL. William's obstetrics. New York: Appleton-Centry-Crofts, 1985: 192-3, 563-5. 3. Goodwin JF, Murphy B, Guillemette M. Direct measurement of serum iron and binding capacity. Clin Chem 1966;12:47-57. 4. Dixon WJ, Brown MB, Engelman L, et al., eds. BMDP statistical software manual. Berkeley: University of California Press, 1985: 156. 5. Fleming AF, Martin JD, Hahne) R, Westlake AJ. Effects of iron and folic acid antenatal supplements on maternal hematology and fetal well-being. Med J Aust I 974;2:42936. 6. PuolakkaJ,Janne 0, Pakarinen, Vihko R. Serum ferritin in the diagnosis of anemia during pregnancy. Acta Obstet Gynecol Scand Suppl 1980;95:57-63. 7. Cook JD, Lipschitz DA, Miles LEM, Finch CA. Serum ferritin as a measure of iron stores in normal subjects. Am] Clin Nutr 1974;27:681-7. 8. Dallman PR, Beutler E, Finch CA. Effects of iron deficiency exclusive of anemia. Br J Haematol 1978;40: 17984. 9. Ishikawa K, Narita 0, Saito H. Gestational anemia and serum ferritin. Kaku Igaku 1984;21:305-10. 10. Fenton V, Cavill I, Fisher J. Iron stores in pregnancy. Br J Haematol 1977;37:145-9. 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. 12. PuolakkaJ,Janne 0, Vihko R. Evaluation by serum ferritin assay of the influence of maternal iron stores on the iron status of newborns and infants. Acta Obstet Gynecol Scand Suppl I 980;95:53-6. 13. Blot I, Tchernia G, Chenayer M, et al. Iron deficiency in the pregnant woman: its repercussion on the newborn and the influence of systematic iron treatment. J Gynecol Obstet Biol Reprod (Paris) 1980;9:489-95. 14. Taft LI, Halliday JW, Russo AM, Francis BH. Serum ferritin in pregnancy: the effect of iron supplementation. Aust NZ J Obstet Gynecol 1978; 18:226-9. 15. PuolakkaJ,Janne 0, Pakarinen, Vihko R. Serum ferritin as a measure of iron stores during and after normal pregnancy with and without iron supplements. Acta Obstet Gynecol Scand Suppl 1980;95:43-51. 16. BessmanJD, Gilmer PRJr, Gardner FH. Improved classification of anemias by MCV and RDW. Am] Clin Pathol I 983;80:322-6.
Key words: Iron deficiency anemia, ferritin, transferrin saturation, red cell distribution width There is a high incidence of iron deficiency in pregnancy' because iron is transferred from mother to fetus regardless of maternal iron stores. 2 Serum ferritin was obtained to determine the incidence of iron depletion and deficiency in a group of outpatients in an inner-city, municipal hospital. The usefulness of the red cell distribution width, the mean corpuscular volume, serum iron, and transferrin saturation for screening and diagnosing iron deficiency was also determined.
Material and methods Patients coming to the Obstetrics Clinic at Bellevue Hospital for the first prenatal visit were eligible for the study. After the purpose of the study was explained, patients provided written informed consent. Information obtained from the patients and the medical record included age, number of previous pregnancies, expected date of delivery, whether the patient took iron tablets, and whether the patient had any long-term diseases (chronic liver disease, chronic renal disease, rheumatoid arthritis, neoplasms, and other inflammatory disorders). Blood was drawn to obtain a complete blood count, transferrin saturation, and serum ferritin. Complete blood counts were performed on a Coulter counter (Model S-Plus IV). Serum iron and transferrin levels were measured according to the method of Goodwin et al. 3 Serum ferritin was measured by a one-stage,
From the Division of Primary Care Internal Medicine, Department of Medicine, New York University School of Medicine. Supported in part by a grant from the Sergei Zlinkoff Foundation. Received for publication January 28, 1988; revised May 17, 1988; accepted June 12, 1988. Reprint requests: Warren Thompson, MD, Bellevue Hospital 1N-49, First Avenue and 27th Street, New York, NY 10016.
1132
Table I. Iron depletion in pregnancy (ferritin < 20 µg/L)
Pregnancy trimester l 2 3 Parity 0 1-2 3 or more Age 18-23 23-30 30-44 Iron tablets Yes No Total
Iron depleted n (%)
Not depleted n
Total n
14 (29) 39 (64) 20 (71)
34 22 8
48 61 28
11 (39) 32 (55) 30 (59)
17 26 21
28 58 51
36 (59) 24 (51) 13 (45)
25 23 16
61 47 29
20 (48) 53 (56) 73 (53)
22 42 64
42 95 137
two-site immunoradiometric assay (RAMCO Laboratories, Inc., Houston). This assay is diagnostic of iron depletion.
Statistical analysis To determine whether iron deficiency was more or common with advancing age, increasing parity, and increasing trimester of pregnancy, logistic regression was performed using the BMDP statistical package1 for the microcomputer. Jes~
Results Patients ranged in age from 18 to 44 years, with an average age of 26 years. Two thirds of the patients were of Hispanic origin, one sixth were black, and one sixth were white. Twenty percent of the women were pregnant for the first time, 43% had been pregnant once
Volume 159 Number 5
Tests of iron depletion in pregnancy
1133
Table II. Prediction of iron depletion* Test
% saturation< 16 Iron< 40 µg/dl ( < 7 µmol/L) MCV < 80 fL RDW> 15% Hemoglobin< 12 gm/di (<120 gm/L)
Iron depleted (n = 73)
Not depleted (n = 64)
9 (12.5%) 2 (2.8%) 5 (6.8%) 12 (16.4%) 39 (53.4%)
Total (n = 137)
I (!.6%) 0 (0%)
10
2 (3.1%)
7 12 68
0 (0%)
29 (45.3%)
2
MCV, Mean corpuscular volume; RDW, red cell distribution width.
*The percentages in the iron-depleted column are sensitivities; whereas the percentages in the not depleted column are falsepositive rates
or twice previously, and 37% had been pregnant three or more times. Thirty-one percent of women reported taking iron tablets (most took one multivitamin with iron). Women who took iron before their first visit to the Prenatal Clinic had been referred from the Gynecology Clinic where pregnancy had been diagnosed. Thirty-five percent of women were in the first trimester of pregnancy, whereas 45% and 20% were in the second and third trimesters, respectively. The incidence of iron deficiency in this pregnant population is high. Seventy-three of 137 (53.3%) patients had serum ferritin levels <20 ng/ml (20 µg/L) and were classified as iron depleted or deficient (Table I). Patients more advanced in their pregnancies were more likely to be iron depleted (p < 0.001). Women in the first trimester had an incidence of iron depletion of 29%, whereas women in the third trimester had an incidence of 71 % (Table I). Nulliparous women and older women had a lower incidence of iron depletion than did multiparous women and younger women, respectively. However, logistic regression with iron depletion as the dependent variable and age, parity, and week of pregnancy as the independent variables revealed that only the week of pregnancy predicted iron depletion. The proportion of patients who were iron depleted was not significantly different for patients who took iron at the time they came to the clinic (p > 0.05, x2). · Table II lists the sensitivities and false-positive rates of the transferrin saturation, serum iron, mean corpuscular volume, and red cell distribution width. None of these tests detected even one fifth of the irondepleted patients. A hemoglobin level < 12 gm I di ( 120 gm/L) was seen in 53% of the iron-depleted patients; however, 45% of the patients without iron depletion also had a hemoglobin value <12 gm/di (120 gm/L). The average platelet count did not vary between irondepleted patients and patients not iron depleted (p > 0.05, t test). If the red cell distribution width, mean corpuscular volume, or transferrin saturation are abnormal, the likelihood of iron deficiency is very high
because the specificities of these tests are excellent (they have low false-positive rates). The one patient who had a transferrin saturation value < 16% who was classified as not iron deficient had a ferritin level of <30 ng/ml (30 µg/L) and actually may have been iron deficient (in which case the specificity of the transferrin saturation would have been 100%). Comment
Iron deficiency is common in pregnant women for three reasons: (I) Many women of childbearing age are in precarious iron balance (33% to 50% of women between the ages of23 and 30 years have no bone marrow iron), (2) the erythrocyte volume increase in pregnancy requires iron, and (3) fetal iron requirements are satisfied before maternal iron needs. 2 Absent bone marrow iron is an extremely common finding in pregnancy. 1· 5 A low ferritin level in pregnancy correlates with absent bone marrow iron stores, 6 indicating that a low ferritin level represents true iron deficiency. Approximately half the patients in the present study had a hemoglobin value > 12 gm/ di ( 120 gm/L), so iron depletion 7 may be a more appropriate term than iron deficiency for these patients. The clinical significance of iron depletion is unclear, but there is reason to believe that it may b,, harmful. 8 Although there is some disagreement, 9 most studie~ have found that women with iron deficiency deliver babies with lower cord ferritin levels. 10-12 The difference in infant iron stores can persist for at least as long as 6 months. 12 · 13 Women who are not treated with iron postpartum continue to have persistently lower ferritin levels. 13-15 These studies have also demonstrated that lower cord, infant, and postpartum maternal ferritin levels can be prevented by adequate iron supplementation during pregnancy. 13· 15 The red cell distribution width and the mean corpuscular volume have been proposed as useful screening tests for iron ' deficiency. 16 The red cell distribution width measures variability of red cell size (anisocytosis).16 The red cell distribution width and mean cor-
1134 Thompson
puscular volume are routinely reported as part of a complete blood count by most laboratory instruments. The red cell distribution width is superior to the mean corpuscular volume, but neither is sufficiently sensitive to screen for iron depletion and deficiency. Previous studies have also found that the mean corpuscular volume and transferrin saturation are poor markers for iron deficiency in pregnancy. 10• 11 • 1'· 15 No previous studies have reported the actual sensitivities of the mean corpuscular volume or transferrin saturation in pregnancy, and the sensitivity of the red cell distribution width has not been reported in a pregnant population. In this population the ip.cidence of falsely low mean corpuscular volume and falsely high red cell distribution width was quite low. However, in populations with a high incidence of a-thalassemia or J3-thalassemia minor (which would lower the mean corpuscular volume), hemoglobinopathies, liver disease, B 12 deficiency, or folate deficiency (all of which would raise the red cell distribution width), the specificity of the mean corpuscular volume and red cell distribution width would be lower. If the red cell distribution width is elevated or the mean corpuscular volume is low, this study suggests that iron deficiency is extremely likely in the absence of these conditions. Iron depletion as defined by a low serum ferritin level is extremely common in pregnancy in an inner-city hospital clinic population. Studies using serum ferritin levels should be performed to determine the incidence of iron depletion in other populations. Other tests, such as the red cell distribution width, mean corpuscular volume, and transferrin saturation, are not sufficiently sensitive to diagnose iron depletion and deficiency. Serum ferritin level is required to adequately document iron depletion and deficiency during pregnancy. We acknowledge Nancy Goldberg, Frank Hernandez, Kenneth Lampert, MD, Mack Lipkin, Jr., MD, Humra Mahmood, MD, Kanshin Partee, and Kay Williams. REFERENCES 1. deLeeuw NKM, Lowenstein L, Hsieh YS. Iron deficiency and hydremia in normal pregnancy. Medicine 1966; 45:291-315.
November 1988 Am J Obstet Gynecol
2. Pritchard JK, MacDonald JS, Grant NL. William's obstetrics. New York: Appleton-Centry-Crofts, 1985: 192-3, 563-5. 3. Goodwin JF, Murphy B, Guillemette M. Direct measurement of serum iron and binding capacity. Clin Chem 1966;12:47-57. 4. Dixon WJ, Brown MB, Engelman L, et al., eds. BMDP statistical software manual. Berkeley: University of California Press, 1985: 156. 5. Fleming AF, Martin JD, Hahne) R, Westlake AJ. Effects of iron and folic acid antenatal supplements on maternal hematology and fetal well-being. Med J Aust I 974;2:42936. 6. PuolakkaJ,Janne 0, Pakarinen, Vihko R. Serum ferritin in the diagnosis of anemia during pregnancy. Acta Obstet Gynecol Scand Suppl 1980;95:57-63. 7. Cook JD, Lipschitz DA, Miles LEM, Finch CA. Serum ferritin as a measure of iron stores in normal subjects. Am] Clin Nutr 1974;27:681-7. 8. Dallman PR, Beutler E, Finch CA. Effects of iron deficiency exclusive of anemia. Br J Haematol 1978;40: 17984. 9. Ishikawa K, Narita 0, Saito H. Gestational anemia and serum ferritin. Kaku Igaku 1984;21:305-10. 10. Fenton V, Cavill I, Fisher J. Iron stores in pregnancy. Br J Haematol 1977;37:145-9. 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. 12. PuolakkaJ,Janne 0, Vihko R. Evaluation by serum ferritin assay of the influence of maternal iron stores on the iron status of newborns and infants. Acta Obstet Gynecol Scand Suppl I 980;95:53-6. 13. Blot I, Tchernia G, Chenayer M, et al. Iron deficiency in the pregnant woman: its repercussion on the newborn and the influence of systematic iron treatment. J Gynecol Obstet Biol Reprod (Paris) 1980;9:489-95. 14. Taft LI, Halliday JW, Russo AM, Francis BH. Serum ferritin in pregnancy: the effect of iron supplementation. Aust NZ J Obstet Gynecol 1978; 18:226-9. 15. PuolakkaJ,Janne 0, Pakarinen, Vihko R. Serum ferritin as a measure of iron stores during and after normal pregnancy with and without iron supplements. Acta Obstet Gynecol Scand Suppl 1980;95:43-51. 16. BessmanJD, Gilmer PRJr, Gardner FH. Improved classification of anemias by MCV and RDW. Am] Clin Pathol I 983;80:322-6.