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Journal of the American College of Nutrition, Vol. 18, No. 3, 261-267 (1999)
Published by the American College of Nutrition

Original Paper

Zinc and IGF-I Concentrations in Pregnant Women with Anemia before and after Supplementation with Iron and/or Zinc

Soroku Nishiyama, MD, FACN, Kohji Kiwaki, MD, Yoshinobu Miyazaki, MD and Taiji Hasuda, MD

Department of Pediatrics, Kumamoto University, School of Medicine (S.N., K.K.), Kumamoto, JAPAN
Department of Obstetrics and Gynecology, Jikei Hospital (Y.M., T.H.), Kumamoto, JAPAN

Address reprint requests to: Soroku Nishiyama, MD, Department of Pediatrics, Kumamoto University, School of Medicine, Honjo 1-1-1, Kumamoto 860-8556, JAPAN.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Objective: The objective of our study was to investigate zinc (Zn) status and effects of Zn supplementation in relation to insulin-like growth factor-I (IGF-I) and iron deficiency anemia in pregnant women. The role of Zn and IGF-I in hematologic abnormalities has remained unclear.

Methods: Thirty-eight Japanese women, when examined at the second trimester of pregnancy, had hemoglobin concentrations below 11.0 g/dL and 32 of 38 had normocytic erythrocytes. These 38 women were divided into three groups, and we compared the hematological status and serum IGF-I levels before and after iron (Group A) or Zn (Group B) or iron plus Zn (Group C) supplementation.

Results: The concentrations of hemoglobin (Hb) did not change in groups A and B. In group C, Hb levels were significantly increased from 10.3±0.3 to 11.0±0.6 g/dL. Furthermore, numbers of RBC and reticulocytes also increased significantly. Concentrations of iron, IGF-I and total iron binding capacity (TIBC) were increased, and concentrations of erythropoietin were decreased, but not statistically. There were significant positive correlations between increases in IGF-I and increases in Hb and RBC in the Zn administered groups.

Conclusion: Zn status to some extent can account for hematological abnormalities in pregnant women. Zn derived IGF-I has a role in the regulation of hematopoiesis in pregnant women.

Key words: pregnant women, anemia, zinc deficiency, iron deficiency, insulin-like growth factor I

Abbreviations: Zn=zinc • IGF-I=insulin-like growth factor I • RBC=red blood cells • Hb=hemoglobin • TIBC=total iron binding capacity • MCV=mean corpuscular volume • MCH=mean corpuscular hemoglobin


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Anemia is the most common hematologic problem in pregnant women. What is referred to as the "physiologic anemia of pregnancy" is a dilutional process secondary to an increase in plasma volume [1]. However, nutritional deficiencies, hemolysis and other disorders can cause a significant anemia that can affect both mother and fetus.

A mild deficiency of zinc in pregnant women may be associated with abnormal taste acuity, prolonged gestation, slowed labor, atonic bleeding and increased risk to the fetus [2]. Zn supplementation reduced the frequency of the above complications. Zn deficiency also was seen to be related to a factor responsible for intrauterine growth retardation and poor uterine contractility [3,4]. There is little documentation concerning anemia and Zn deficiency in pregnant women [5].

We have reported Zn deficiency in relation to anemia in female endurance runners, based on total body Zn clearance [6]. We also reported that Zn supplementation aids in overcoming anemia in these endurance runners, in disabled patients and in premature infants [6,7]. This hematological picture simulates iron deficiency anemia. However, a low number of red blood cells (RBC) and low levels of total iron binding capacity (TIBC) did not differ from findings in subjects with a typical iron deficiency anemia, and most had normocytic normochromic anemia.

In addition to erythropoietin, insulin-like growth factor I (IGF-I) was found to stimulate hematopoiesis in both laboratory animals and humans [8–10]. Zn deficiency markedly decreases expression of the IGF-I and growth hormone receptor genes [11,12]. Zn deficiency associated with iron deficiency anemia was apparently first recorded by Prasad et al. in 1961 [13]. Such patients had a specific Zn deficiency consisting of dwarfism, hypogonadism, visceromegaly and hematologic abnormalities that simulated iron deficiency anemia.

We investigated hematological events in relation to status of the IGF-I levels when iron and/or Zn was prescribed for pregnant women with relatively low levels of TIBC, but with normocytic anemia.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Materials
Subjects studied were those included in a examination during the second trimester of pregnancy (gestation weeks: 20.9±1.4 weeks). Among 120 Japanese pregnant women aged 20 to 38 years, 38 (31.7%) had a hemoglobin concentration under 11.0 g/dL and 18 of these women (47.3%) had serum TIBC concentrations under 410 µg/dL. One woman had microcythemia (MCV under 79 fL), 32 normocytemia (MCV 80 to 100 fL), and five macrocythemia (MCV over 101 fL). With regard to hemoglobin, five had hypochromic anemia (MCH under 27 pg) and 33 normochromic anemia (MCH 28 to 34 pg). Thirty-five subjects had an RBC under 390x104/mm3, and only three an RBC over 391x104/mm3. Age, body weight and height were 30.2±4.1 years, 52.3±2.9 kg and 158.2±3.1 cm, respectively. The 38 women had no evidence of chronic disease such as hepatitis, collagen and hematological disorders. No woman studied used tobacco, consumed alcohol or used recreational drugs.

The 38 women, divided into three groups at their choice, were prescribed iron citrate 100 mg/day in group A (n=10), ß-alanyl-L-histidinate zinc [14,15] (porapre zinc) 34 mg/day in group B (n=11) and iron citrate 100 mg plus porapre zinc 34 mg in group C (n=17) for eight weeks, respectively. Two five-day dietary surveys were made by a registered dietitian prior to this treatment and during supplements of iron and/or zinc. Their daily diets contained fairly adequate kilo calories (2130±123 kcal), protein (85±12 g), fat (61±12 g), carbohydrate (310±24 g) and copper (1.3±0.56 mg), but not calcium (680±286 mg), iron (9.8±1.2 mg) and Zn (10.9±1.6 mg). Fifty-six age-matched healthy non-anemic pregnant women served in a control group.

Methods
Serum concentrations were measured for total protein, albumin, phosphorous (Pi), iron, ferritin, TIBC, Zn, folic acid, free triiodothyronine (free T3), IGF-I and erythropoietin. The ethical committee of Kumamoto University gave permission for the study and informed consent was obtained from each subject.

Zn levels were measured by atomic absorption spectrophotometry (Perkin-Elmer model 403) [16], ferritin levels were measured using enzyme immunoassay kits and erythropoietin levels were measured using radioimmunoassay kits (Chugai Institute, Tokyo, Japan). Intra- and interassay coefficiency of variations were 4.9% and 6.8%, respectively. Free T3 levels were measured by radioimmunoassay, using Amerlex-MAB free T3 kits (Ortho Clinical Diagnostics, Amersham, UK). Intra- and interassay coefficiency of variations were 5.7% and 5.5%, respectively. IGF-I levels were measured by radioimmunoassay using Somatomedin C II Chiron kits (Chiron, Tokyo, Japan). Intra- and interassay coefficiency of variations were 4.8% and 7.8%, respectively. Folic acid levels were measured using competitive protein binding assay. Total protein, albumin, phosphorous, TIBC and iron concentrations were measured using an autoanalyzer (Technicon Co, New York).

Statistics
Unpaired t-test and paired t-test were used for statistical assessments with StatView 4.5 to evaluate mean levels of treated groups and controls, and to determine values of pretreatment and after treatment in each group. Values are expressed as mean±SD. All p values are two-tailed.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
RBC, Hb and hematocrit (Hct) in members of the control group were significantly higher than in members of the treated groups. Serum IGF-I, iron and Zn levels in control-group members were higher, and serum folic acid, TIBC and erythropoietin levels were lower than in members of the treated groups, but not statistically (Tables 1 and 2). The subjects with microcytic or hypochromic anemia had lower serum iron and ferritin levels than other subjects tested (data not shown). Before treatment, no differences were obtained in Hb, RBC, Hct, MCV, MCH and other biochemical and trace elements among the three treated groups, as shown in Tables 1 and 2. Among control-group members, as well as treated-group members (n=94), significant relationships were found between concentrations of Hb and iron (r=0.388, p<0.01), Zn (r=0.376, p<0.01) and erythropoietin (r=-0.446, p<0.01). There were significant relationships between the numbers of RBC and concentrations of Zn (r=0.349, p<0.01), but not serum iron and erythropoietin (Fig. 1). After treatment, concentrations of Hb and the numbers of RBC did not change in groups A and B (Fig. 2). In group C (Zn plus iron therapy), Hb levels and reticulocytes increased from 10.3±0.3 to 11.0±0.6 g/dL (p<0.01, Fig. 2) and from 14.7±4.7 to 18.6±6.9% (p<0.05), respectively. The numbers of RBC also increased from 354±26 to 373±31x104/mm3 (p<0.05).


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  		Table 1. Hematological Findings, IGF-I and Free T3 Levels before and after Treatment

 

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  		Table 2. Changes in Biochemical and Trace Elements before and after Treatment

 


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  		Fig. 1. Relationship between serum zinc levels and hemoglobin levels (left panel r=0.376, p<0.01) and numbers of RBC (right panel r=0.349, p<0.01) before treatment (therapy groups plus control group n=96).

 


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  		Fig. 2. Change in hemoglobin concentrations in pregnant women prescribed iron, zinc and iron plus zinc during eight weeks. Concentrations of hemoglobin significantly increased in pregnant women given iron plus zinc (p<0.01). + indicates mean±SD.

 
Significant relationships were obtained between increased values of Hb levels and increased values of IGF-I (r=0.563, p<0.05), and between increased numbers of RBC and increased values of IGF-I (r=0.747, p<0.01) in the Zn-treated group (n=11, Fig. 3). Significant relationships were also found between increased values of Hb levels and increased values of IGF-I (r=0.431, p<0.01), and between increased numbers of RBC and increased values of IGF-I (r=0.451, p<0.01) in the Zn-treated groups (B plus C n=28, Fig. 4). When findings in responders (n=7) and non-responders (n=4) in group B (Zn-only therapy) were compared, concentrations of ferritin in responders were significantly higher than in the non-responders (50.6±25.2 vs. 22.7±4.5 ng/mL), whereas serum iron levels were similar (102±49 vs. 102±59 µg/dL). Zn supplementation to responders with sufficient ferritin levels increased erythropoiesis, whereas supplementation to non-responders with poor ferritin levels led to iron deficiency anemia. In the responders a tendency was found toward Zn deficiency and a decrease in Zn derived protein and enzymes, as compared to findings in non-responders (Zn: 61.7±12.6 vs. 68.4±4.0 µg/dL, TIBC: 384±16 vs. 416±42 µg/dL, ALPase: 79.1±7.2 vs. 94.7±3.7 mIU/mL, total protein: 6.5±0.4 vs. 6.8±0.3 g/dL).



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  		Fig. 3. Relationship between increase in IGF-I and hemoglobin concentrations (left panel r=0.563, p<0.05) and increase in numbers of RBC (right panel r=0.747, p<0.01) in pregnant women given zinc only (group B, n=11).

 


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  		Fig. 4. Relationship between increase in IGF-I and hemoglobin concentrations (left panel r=0.431, p<0.01) and increase in numbers of RBC (right panel r=0.451, p<0.01) in pregnant women given zinc (group B plus C, n=28).

 
Serum IGF-I levels were increased in groups B and C, albeit not statistically. In group A, serum Zn levels were significantly decreased, and serum ferritin, TIBC and erythropoietin were increased, but not statistically. In group B, serum iron was significantly decreased, accompanied by elevation of serum TIBC and Zn. Thus, Zn supplementation may lead to the utilization of iron. In group C, serum TIBC levels were significantly increased. Serum iron and Zn were increased, and serum erythropoietin was decreased, but not statistically.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We found that the combination of iron and Zn therapy significantly increased hemoglobin levels in pregnant women. Either iron or Zn alone might explain the deficiency of iron and Zn in pregnant women. Serum ferritin levels correlate well with bone marrow iron stores in pregnant women [17] and are more specific and sensitive than serum transferrin saturation or erythrocyte protoporphyrin determination for diagnosing iron deficiency anemia in pregnancy [18]. Low serum ferritin concentrations suggested the possibility of low Zn intake [19]. A serum ferritin level of less than 35 µg/L is always associatedwith absence of iron in the bone marrow [17], suggesting the possibility of a Zn deficit [19]. If serum ferritin is well above 35 µg/L, other causes of anemia should be considered [17]. Similarly, our pregnant patients had concomitant Zn and iron deficiencies. The microcytosis often associated with iron deficiency may not be evident since the MCV usually rises slightly during a pregnancy [20]. Thus, iron deficiency should be considered even when the MCV is normal.

An additional 375 mg (approximately) of Zn is required by pregnant women in order to meet requirements of fetal growth [21]. The recommended dietary allowance for Zn in adult, nonpregnant females is 12 mg/day, whereas for pregnant and lactating women it is 15 to 19 mg/day [22]. According to most surveys, however, it appears that the Zn intake by women (nonpregnant and pregnant) is around 9.5 mg/day [23]. Physicians should monitor pregnant women for Zn intake and consider Zn supplementation to avoid related deficiencies. Maternal Zn deficiency has been observed as a causal factor in the pathogenesis of congenital malformations and neutral tubular defects [24].

There can be high levels in TIBC in subjects with typical iron deficiency anemia [25]. After Zn therapy (groups B and C), levels of TIBC in the pregnant women increased significantly. Thus, our pregnant patients were considered to have relatively low TIBC levels. High TIBC means that iron deficiency anemia will respond to iron administration, but if the TIBC is low, there will be no response to iron administration inasmuch as low TIBC indicates lack of iron utilization. In pregnancy, it appears that low TIBC and decreased iron utilization may be due to Zn deficiency. An increase in TIBC always indicates that the utilization of iron has been normalized and that iron supplementation should be effective in correcting anemia. The absolute value for TIBC may be helpful in distinguishing between iron deficiency and the anemia seen in the presence of chronic disorders or Zn deficiency [26]. These low levels in TIBC seen in subjects with iron deficiency anemia seemed to concur with the normocytic anemia seen in cases of relatively low TIBC levels in pregnant women which lead to Zn and iron deficiency [26]. Thus, normocytic anemia with low levels in TIBC might serve as a pertinent indicator for diagnosing Zn deficiency. To define Zn deficiency in such cases, it is important to rule out chronic diseases. After treatment with both iron and Zn therapy (group C), hemoglobin levels increased significantly, yet levels were low compared to those found in control groups. This accounted for the lack of a significant response in erythropoietin levels, even though the erythropoietin levels did increase to nearly control levels.

In addition to erythropoietin, IGF-I has been linked to the physiologic elevation of Hb levels in laboratory animals and humans [8–10]. We noted a significantly positive correlation between an increase in IGF-I and an increase in Hb and RBC when Zn was prescribed (groups B and C). Plasma IGF-I levels have been shown to increase after Zn supplementation in malnourished children and in children who are short for their ages [27, 28]. Zn deficiency is associated with a decrease in expression of hepatic IGF-I and growth hormone receptor genes in rats [11,12]. In our study, Zn-derived IGF-I may have stimulated hematopoiesis, which resulted in increases in serum Hb and RBC levels. Furthermore, IGF-I and IGF-binding proteins reflect the growth and developmental stages of fetuses and may influence fetal development [29]. Intake of Zn alone may lead to adverse effects, because chronic Zn intake can lead to iron deficiency anemia [30].

Zn is clearly involved in several aspects of normal hematopoiesis by virtue of its role in various enzyme systems linked to DNA synthesis (including thymidine kinase and DNA polymerases) [31,32] which are key structural components of a large number of proteins. The binding of Zn stabilizes the folded conformations of domains so that interactions between proteins and other macromolecules such as DNA may be facilitated [33]. Furthermore, Zn is a zinc-finger transcription factor, GATA-1, required for erythropoiesis [34,35]. Thus, the administration of Zn along with iron presumably increases the production of proteins and globin related to hematopoiesis in the bone marrow, and anemia is overcome. Zn supplementation in our study only for eight weeks may have been too short a time, since the serum Zn level, at the end of eight weeks, remained on the low side. Further, long-period studies of Zn supplementation to pregnant women will be required. Finally, supplementation of iron and Zn separately will be required, since administration of iron and Zn simultaneously may have reduced the optimal effects on hemoglobin level.


   ACKNOWLEDGMENTS
 
We thank M. Ohara for critical comments.

Received August 1, 1998. Accepted March 1, 1999.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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