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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Alabama.
Address reprint requests to: Jinrong Hou, MD Department of Obstetrics and Gynecology University of Alabama at Birmingham Civitan International Research Center Building 1719 Sixth Avenue South, Room 329 Birmingham, AL 35294 E-mail: jhou{at}civmail.circ.uab.edu
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Abstract |
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Methods: Serum ferritin concentrations were measured at approximately 25 and 36 weeks’ gestation in 480 multiparas with singleton fetuses who participated in a study of risk factors for repeated FGR. Asymmetric FGR was defined by low birth weight for gestational age criteria and a ponderal index less than 2.32, and symmetric FGR was defined by the same birth weight for gestational age criteria and a ponderal index of at least 2.32.
Results: Among 480 infants, 370 were appropriate for gestational age (AGA), 58 had asymmetric FGR, and 52 had symmetric FGR. Higher ferritin concentrations were associated with black race, maternal age 25 years or older, and smoking. Mothers of asymmetric-FGR infants had higher mean ferritin levels than mothers of AGA infants at 25 weeks’ (38.0 versus 20.2 µg/L, P < .01) and 36 weeks’ gestation (21.0 versus 13.3 µg/L, P < .01), whereas mothers of symmetric-FGR infants had significantly lower ferritin levels at 36 weeks (8.3 µg/L). For mothers with serum ferritin levels of at least 26 µg/L (highest quartile at 25 weeks), the adjusted odds ratio (OR) for asymmetric-FGR infants was 3.4, 95% confidence interval (CI) 1.6, 7.2. There was a similar association between the highest quartile of serum ferritin at 36 weeks (at least 20 µg/L) and asymmetric FGR (adjusted OR 2.7, 95% CI 1.3, 5.8). Women with serum ferritin levels less than 3 µg/L (lowest quartile at 36 weeks) had an adjusted OR for symmetric-FGR infants of 2.2, 95% CI 1.01, 4.6.
Conclusion: High maternal serum ferritin levels are associated with asymmetric FGR, whereas low serum ferritin levels are associated with symmetric FGR.
Fetal growth restriction (FGR) affects approximately 10% of live infants and increases risk of perinatal mortality and morbidity.1,2 Causes of FGR are heterogeneous, and caring for FGR infants poses diagnostic and therapeutic challenges.1,3 Prenatal identification of FGR is crucial because proper evaluation and management are generally associated with favorable outcomes. The division is controversial, but infants with FGR are often divided into symmetric (generally small in all dimensions) and asymmetric (appropriate length but thin) categories on the basis of ponderal index at birth and various prenatal ultrasound measurements. Detecting growth restriction and differentiating between asymmetric and symmetric categories has become a major task of prenatal care.2,4 Morbidity and mortality risks for the two types of FGR appear to differ, so it might be important to define etiologies and evaluate management strategies for reducing risks of various types of FGR.
Concentration of serum ferritin is considered a reliable indicator of total body iron stores, with low levels indicating deficiency.5,6 High levels have been associated with many conditions, including acute and chronic infections, and ferritin is an acute-phase reactant.7,8 Several investigators associated altered serum ferritin or placental isoferritin concentrations with various pregnancy complications such as preeclampsia, early preterm delivery, and low birth weight (LBW).9–13 However, none have reported changes of ferritin levels during pregnancy relating to different patterns of fetal growth. The objective of this study was to evaluate the association between serum ferritin levels and types of FGR.
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Materials and Methods |
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Subjects were selected according to availability of maternal serum samples during pregnancy and participation of their children in a subsequent study to evaluate neurodevelopment at age five, in relation to various social and medical factors of the mothers during pregnancy and for 5 years thereafter. Four hundred eighty singleton infant-mother pairs who delivered at 36 weeks or later were selected. Among those women, 404 and 390 serum samples were measured for ferritin concentrations at mean gestational ages of 25.3 ± 2.3 standard deviation (SD) weeks and 36.2 ± 0.9 weeks, respectively. Of those samples, 314 women had ferritin concentrations measured twice during pregnancy. Serum ferritin concentrations were measured with the use of the MAGIC Ferritin [125/I] radioimmunoassay kit (Ciba-Corning Diagnostic, Irvine, CA). The coefficient of variation was approximately 5.8% by repeated measures of control samples that were supplied by the manufacturer. Ferritin in serum is fairly stable when frozen at -70C, and our values were comparable to those reported.6
Dietary records (24-hour recall) were taken from each subject by trained personnel at 18 and 30 weeks’ gestation. Birth weight was measured in grams within 1 hour of birth. Gestational age was defined as completed weeks from onset of last menstrual period (LMP) confirmed within 2 weeks by ultrasound before 20 weeks’ gestation. If a woman was unsure of her LMP, or if there was more than a 2-week discrepancy between ultrasound-generated and LMP-generated gestational ages, ultrasound age was used to calculate gestational age at delivery. For this study, FGR was defined as birth weight less than the 15th percentile for gestational age based on Alabama standards for race, sex, and parity.14 The 15th percentile birth weight at each gestational age corresponded roughly to 10th percentile birth weights defined by Williams et al,15 and were less than those of Miller and Merritt.16 Using those standards, we had an overall rate of 13.2% of FGR. Asymmetric FGR was defined in this study as a ponderal index less than 2.32. Maternal body mass index (BMI) was calculated as weight (kg)/height (m)2. Maternal smoking was defined as use of cigarettes at the first prenatal visit. Previous LBW was defined as a previous infant that weighed less than 2750 g. Hypertension was defined as acute, chronic, or unknown hypertension, systolic pressure exceeding 140 mmHg, or diastolic pressure exceeding 90 mmHg two or more times during pregnancy.
Maternal serum ferritin concentrations were analyzed by mean and quartiles among three groups of infants categorized as appropriate for gestational age (AGA), having asymmetric FGR, and having symmetric FGR. Data analyses were done with SAS statistical software (SAS Institute, Cary, NC). Analytical techniques included 
2 test, Student t test, analysis of variance with Tukey multiple-range test, and multiple logistic regression. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed for asymmetric-FGR and symmetric-FGR groups, compared with the AGA group. Statistical significance was P < .05.
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Results |
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), and there were no significant differences in maternal race, age, and education. However, there were significantly more mothers of FGR infants than mothers of AGA infants who had BMIs less than 22, smoked, and had histories of LBW infants. Maternal hypertension during pregnancy was more common in mothers of asymmetric-FGR infants than mothers of AGA infants.
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). Mothers who smoked during pregnancy had significantly higher mean ferritin levels than nonsmoking mothers at 25 weeks’ (28.8 versus 16.6 µg/L) and 36 weeks’ gestation (16.1 versus 12.0 µg/L). We found similar results in women 25 years or older compared with women less than 25 years old. There was not a statistically significant difference in mean ferritin levels between blacks and whites at 25 weeks, but mean ferritin levels at 36 weeks’ gestation were higher in blacks than whites (15.7 versus 9.1 µg/L, P < .01). Serum ferritin levels were not significantly different between hypertensive women and those without hypertension during pregnancy at 25 and 36 weeks’ gestation. Serum ferritin levels were not associated with maternal BMI or history of LBW infants.
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shows the comparison of mean maternal serum ferritin levels and hematocrit values among groups. Mothers of asymmetric-FGR infants had significantly higher mean serum ferritin levels than mothers of AGA infants at 25 (38.0 versus 20.2 µg/L) and 36 weeks’ gestation (21.0 versus 13.3 µg/L). Mothers of symmetric-FGR infants had lower mean serum ferritin levels at 36 weeks (8.3 µg/L). Similar results were observed in nonhypertensive mothers (n = 445). Mean maternal hematocrit values changed only slightly between 25 and 36 weeks’ gestation, and there were no significant differences in the values among the three groups at 25 and 36 weeks. The percentage of mothers who had hematocrit below 32, a level that was the 10th percentile for this population, was not statistically significantly different among the three groups. There also were no differences in iron intakes, including the 65 mg of iron supplement offered to each subject, among the mothers of AGA, asymmetric-FGR, and symmetric-FGR infants at 18 weeks (80, 81, and 82 mg/day, respectively) and 30 weeks (102, 102, and 98 mg/day, respectively).
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). Compared with mothers of AGA infants, mothers of asymmetric-FGR infants generally had higher serum ferritin levels, and mothers of symmetric-FGR infants had lower serum ferritin levels throughout pregnancy, regardless of maternal smoking status. Among mothers who smoked during pregnancy, mothers of asymmetric-FGR infants had significantly higher serum ferritin levels at 25 weeks than mothers of AGA infants (45.4 versus 26.0 µg/L), whereas mothers of symmetric FGR infants had lower ferritin levels at 36 weeks (8.3 µg/L). The same pattern held true for nonsmoking mothers, but was not as pronounced (Table 4)
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. Forty-eight percent of mothers of asymmetric-FGR infants had ferritin levels of at least 26 µg/L, which was the cutoff of the highest quartile of serum ferritin level at 25 weeks’ gestation in the study population, compared with 23% of mothers of AGA infants and 24% of mothers of symmetric-FGR infants (P < .01). A similar trend also was found for the highest quartile of ferritin at 36 weeks’ gestation: 44% of mothers of asymmetric-FGR infants had ferritin levels of at least 20 µg/L compared with 24% of mothers of AGA infants and 15% of mothers of symmetrically FGR infants (P < .01). A higher proportion of mothers with ferritin levels less than 3 µg/L, the cutoff of the lowest quartile of serum ferritin level at 36 weeks’ gestation, was noted in mothers of symmetric-FGR infants compared with mothers of AGA and asymmetric-FGR infants (39%, 25%, 11%, respectively; P < .05).
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). The highest quartile of serum ferritin levels at 25 weeks was associated with an increased risk of asymmetric FGR compared with those in the lower quartiles (adjusted OR 3.4; 95% CI 1.6, 7.2). A similar, somewhat weaker association was found between the highest quartile of serum ferritin levels at 36 weeks and asymmetric FGR (adjusted OR 2.7; 95% CI 1.3, 5.8). However, no such associations were found for symmetric FGR at 25 weeks’ or 36 weeks’ gestation. The lowest quartile of serum ferritin levels at 36 weeks’ gestation was significantly associated with a two-fold increase in risk of symmetric FGR compared with those in the higher quartiles (adjusted OR 2.2; 95% CI 1.01, 4.6) (not shown in table). |
Discussion |
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In previous studies, maternal hypertension, especially preeclampsia, has been significantly associated with asymmetric FGR.19,20 In this study, maternal hypertension was associated with a two-fold increase in frequency of asymmetric FGR. In this data set, we were not able to distinguish preeclampsia from pregnancy-induced hypertension and chronic hypertension. Entman et al9 showed that women with preeclampsia had elevated levels of serum ferritin. The women with hypertension in our study did not have elevated ferritin levels, probably because of our inability to distinguish among the various types of hypertension. Maternal hypertension of any kind did not account for the association between elevated ferritin and asymmetric FGR. Limiting our analyses to nonhypertensive women did not alter our association between high serum ferritin levels and asymmetric FGR. The fact that asymmetric FGR is common in preeclamptic women20 and in nonpreeclamptic women with high ferritin levels, as in this study, suggests that asymmetric FGR might come at the end of a sequence that involves high ferritin levels. Further research is needed to find out why ferritin is elevated in women who ultimately have asymmetric-FGR infants.
Maternal smoking was associated with higher serum ferritin concentrations in various populations.13,21 Consistent with those findings, serum ferritin concentrations were significantly higher in smokers than non-smokers at 25 and 36 weeks’ gestation, although the difference became smaller with advancing gestation. That indicates that the decline of ferritin levels over time in nonsmoking mothers was not as great as in smoking mothers. The relationship between maternal smoking during pregnancy and FGR was evident in our data and has been well documented in previous studies,3,22 so we were concerned that increased risk of asymmetric FGR in women with high ferritin levels was caused by maternal smoking. However, differences in maternal serum ferritin levels between mothers of asymmetric-FGR and AGA infants were in smokers and nonsmokers. Therefore, the relationship between higher maternal serum ferritin levels and asymmetric FGR was not due solely to the effect of maternal smoking on fetal growth.
One possible explanation for high ferritin levels in mothers of asymmetric-FGR infants was that they were relatively hypovolemic. We did not measure plasma volume in this study, but the fact that hematocrit levels were similar in asymmetric-FGR and AGA mothers suggested that hypovolemia does not explain the differences in the ferritin values among the groups. In general, women have a decrease in serum ferritin during the third trimester of pregnancy, as their stores of iron are depleted by fetoplacental demand and the expansion of maternal red cell mass.6 The declining levels of ferritin during the second and third trimesters of pregnancy in our study were comparable to those in previous reports.6,12 A relationship between lower ferritin values as a measure of maternal iron deficiency anemia and FGR was seen in some previous reports.23,24 Therefore, the fact that mothers of symmetric-FGR infants had lower serum ferritin levels in the third trimester than mothers of normal infants in this study likely indicated poor nutrition.
Serum ferritin is an acute-phase reactant, known to increase in response to many inflammatory conditions. Chronic inflammation also suppresses erythropoiesis, underutilizing iron and increasing the store of iron. That increase in iron stores is shown by increased serum levels of ferritin.9 Therefore, high maternal levels of ferritin might indicate exposure to infection or a noninfectious inflammatory condition in addition to adequate iron status. We suggest that one possible explanation for the association between high ferritin levels and asymmetric FGR in this study was that high serum ferritin levels might serve as a marker for either noninfectious vascular inflammatory response or infection.
We believe more research is warranted on the relationship of maternal serum ferritin levels to pregnancy outcomes, specifically abnormal patterns of fetal growth. Although the underlying mechanism for altered ferritin metabolism in women with asymmetric FGR has not been elucidated fully, the strong association between high maternal serum ferritin levels and asymmetric FGR, which was independent of maternal smoking and hypertension, suggests that serum ferritin levels might serve as markers to identify women at risk of having asymmetric-FGR infants. Whether that measurement ultimately will be useful clinically for predicting or serving as an adjunct to the diagnosis of asymmetric-FGR fetuses is worth further investigation.
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Footnotes |
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Received June 3, 1999. Received in revised form September 1, 1999. Accepted September 10, 1999.
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References |
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2. Peleg D, Kennedy CM, Hunter SK. Intrauterine growth restriction: Identification and management. Am Fam Physician 1998;58:453–60, 466–7.[Medline]
3. Prada JA, Tsang RC. Biological mechanisms of environmentally induced causes of IUGR. Eur J Clin Nutr 1998;52:S21–7.
4. Goldenberg RL, Cliver SP. Small for gestational age and intrauterine growth restriction: Definitions and standards. Clin Obstet Gynecol 1997;40:704–14.[Medline]
5. Lipschitz DA, Cook JD, Finch CA. A clinical evaluation of serum ferritin as an index of iron stores. N Engl J Med 1974;290:1213–6.
6. Kaneshige E. Serum ferritin as an assessment of iron stores and other hematologic parameters during pregnancy. Obstet Gynecol 1981;57:238–42.
7. Kushner I. The acute phase response: An overview. Methods Enzymol 1988;163:373–83.[Medline]
8. Kuvibidila S, Yu L, Warrier RP, Ode D, Mbele V. Usefulness of serum ferritin levels in the assessment of iron status in non–pregnant Zairean women of childbearing age. J Trop Med Hyg 1994;97:171–9.[Medline]
9. Entman SS, Richardson LD, Killam AP. Elevated serum ferritin in the altered ferrokinetics of toxemia of pregnancy. Am J Obstet Gynecol 1982;144:418–22.[Medline]
10. Maymon R, Bahari C, Moroz C. Placental isoferritin: A new serum marker in toxemia of pregnancy. Am J Obstet Gynecol 1989;160: 681–4.[Medline]
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14. Cliver SP, Goldenberg RL, Cutter GR, Hoffman HJ, Copper RL, Gotlieb SJ, et al. The relationships among psychosocial profile, maternal size, and smoking in predicting fetal growth retardation. Obstet Gynecol 1992;80:262–7.
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17. Rondo PH, Abbott R, Rodrigues LC, Tomkins AM. Vitamin A, folate, and iron concentrations in cord and maternal blood of intra–uterine growth retarded and appropriate birth weight babies. Eur J Clin Nutr 1995;49:391–9.[Medline]
18. Rondo PH, Abbott R, Rodrigues LC, Tomkins AM. The influence of maternal nutritional factors on intrauterine growth retardation in Brazil. Paediatr Perinat Epidemiol 1997;11:152–66.[Medline]
19. Misra DP. The effect of the pregnancy–induced hypertension on fetal growth: A review of the literature. Paeditr Perinat Epidemiol 1996;10:244–63.
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22. Bosley AR, Sibert JR, Newcombe RG. Effects of maternal smoking on fetal growth and nutrition. Arch Dis Child 1981;56:727–9.[Abstract]
23. Rosen AC, Hafner E, Auerbach L, Rosen HR, Schuchter K, Huber K, et al. Placental isoferritin in pregnancies with small–for–gestational age fetuses. Prenat Diagn 1996;16:641–6.[Medline]
24. Singla PN, Tyagi M, Kumar A, Dash D, Shankar R. Fetal growth in maternal anaemia. J Trop Pediatr 1997;43:89–92.
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