1 Department of Obstetrics and Gynaecology, The University of Hong Kong, Tsan Yuk Hospital, and 2 Department of Obstetrics and Gynaecology, Princess Margaret Hospital, Kowloon, Hong Kong, People's Republic of China
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Abstract |
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Key words: ferritin/iron status/pregnancy outcome
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Introduction |
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The best parameter of maternal iron status currently available is serum ferritin concentration. Ferritin is a major iron storage protein found not only in the spleen, liver and bone marrow, but also in the mucosal cells of the small intestine, in the placenta, kidneys, testes, skeletal muscles and in the circulating plasma (Crichton, 1973). Ferritin provides iron for the synthesis of iron-containing proteins including haemoglobin (Hb) and myoglobin. Its concentration is highly correlated with bone marrow iron stores, and is decreased before changes in transferrin saturation, serum iron, or Hb concentration, occur, so that its measurement is superior to the measurement of transferrin saturation or serum iron concentration in the diagnosis of iron deficiency (Lipschitz et al., 1974
; Worwood, 1977
; Puolakka et al., 1980
; Kaneshige, 1981
; Romslo et al., 1983
). In pregnancy, serum ferritin concentration is maximum at 1216 weeks gestation, then falls with advancing gestation to reach a nadir at the third trimester (Puolakka et al., 1980
; Kaneshige, 1981
; Milman, 1994). Prenatal mineral and vitamin supplement given from the first trimester would maintain serum ferritin at a higher concentration (Puolakka et al., 1980
; Milman et al., 1994
; Scholl et al., 1997
).
In view of the strong association between iron deficiency anaemia and preterm delivery and low birthweight infants, one would have expected low serum ferritin concentration to be associated with these pregnancy outcomes. However, recent studies have shown that the risk of preterm delivery was increased in women with high second trimester serum ferritin concentration, whether defined as above the median (Tamura et al., 1996), at the highest quartile (Goldenberg et al., 1996
), or above the 90th percentile (Scholl, 1998
). It was proposed that ferritin concentration reflected clinical as well as subclinical genital tract infection which had later led to preterm delivery (Goldenberg et al., 1996
; Tamura et al., 1996
; Scholl 1998
). This opinion was supported by the finding that increased ferritin concentration was associated with neonatal sepsis in women with premature rupture of membranes at <32 weeks gestation (Goldenberg et al., 1998
).
Nevertheless, it is unlikely that all women with elevated ferritin concentration were suffering from a clinical or a subclinical infection, and the possibility of maternal iron excess should also be entertained. While there is abundant literature on maternal iron deficiency and the benefit of iron supplementation, there are practically no data on the possible effect of a high iron concentration or iron excess in pregnancy. With increasing affluence in many societies and the heightened awareness of the importance of adequate nutritional intake in pregnancy, many pregnant women have improved their dietary intake of iron or have taken additional self-purchased iron supplement. These factors probably explain the fall in the incidence of iron deficiency anaemia by more than half in our hospital over the past 3 decades (Lao and Pun, 1996). We believe that in the non-anaemic women, an elevated ferritin concentration is more likely to be a reflection of increased maternal iron store if this is correlated with other parameters such as serum iron concentration and transferrin saturation, or with Hb concentration and red cell indices such as the mean corpuscular volume (MCV). We have therefore performed a prospective observational study in a group of non-anaemic Chinese women to elucidate the relationship between maternal ferritin concentration, other parameters of iron status and pregnancy outcome.
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Materials and methods |
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In a prospective study, mothers who were booked before 20 weeks gestation with a Hb concentration >10 g/dl were recruited over a 4 month period in the antenatal clinic at the time of the repeat Hb estimation at 2830 weeks gestation, to study their serum ferritin concentration after informed consent was obtained. The gestation of 2830 weeks was chosen for the blood sampling because the demand for and the power of absorption of iron is greatest in the third trimester (Whittaker et al., 1991), and high serum ferritin concentration at 28 weeks gestation was shown to be associated with increased risk of preterm delivery (Scholl, 1998
). The study was approved by the hospital ethics committee. None of these subjects was given iron preparations in addition to the routine supplementation, as they were not anaemic. Patients with pre-existing anaemia or other blood disorders and haemoglobinopathies, who might have very high ferritin concentration due to a problem with utilization, were excluded.
After venepuncture, 3 ml of blood was collected into a plain bottle and then sent to the laboratory where the serum was divided into aliquots for the later batched assay of serum ferritin concentration (Microparticle Enzyme Immunoassay, IMx System of Abbott Laboratories, Abbott Park, IL, USA). The intra- and inter-batch coefficients of variation were 3.4 and 3.5% respectively. The normal reference range established by the laboratory for premenopausal women in our local population was 13180 pmol/l. The results of the serum ferritin concentration were blinded to the managing obstetricians.
After delivery, the data on maternal and infant characteristics, and the presence of complications including antepartum haemorrhage, pre-eclampsia, prelabour rupture of membranes (PROM; rupture of membranes for 1 h before the onset of labour) which could be a cause of preterm labour and delivery and which might reflect subclinical genital tract infection, preterm labour (spontaneous labour before 37 completed weeks of gestation), preterm delivery (delivery before 37 weeks gestation with or without preterm labour), and neonatal asphyxia (Apgar score <7 as defined by the paediatricians), were retrieved from the records of those who delivered in our hospital for analysis. We have distinguished between spontaneous preterm labour resulting in preterm delivery (preterm labour) and all pregnancies delivering preterm (preterm delivery) to determine whether a raised ferritin concentration might be associated with only preterm labour, or preterm delivery, or both. The data were analysed according to the serum ferritin concentration quartiles. The relationship between serum ferritin concentration and maternal and infant measurements such as age, weight, and height were also analysed. One-way analysis of variance was used to determine differences in continuous variables in relation to the ferritin quartiles, with Duncan's multiple range test set at the 5% level to identify the groups which were different. The
2 test or the Fisher's exact test was used for categoric variables depending on the number in each cell. Pearson's correlation coefficient (r) was calculated to examine the relationship between the incidence of each complication/outcome and the ferritin quartiles. Spearman's correlation coefficient (
) was used to correlate serum ferritin concentration with maternal and infant parameters, and multiple regression analysis using log-transformed ferritin, iron and transferrin concentrations was used to determine which parameters were significant determinants of infant birthweight outcome. The statistical analysis was performed using a commercial computer package (SPSS/PC).
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Results |
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On the other hand, when the lowest quartile was compared with the other three quartiles combined, significantly lower incidence of pre-eclampsia (0.7 versus 5.2%, P = 0.019, RR 0.127, 95% CI 0.0160.964), PROM (5.6 versus 15.9%, P = 0.002, RR 0.312, 95% CI 0.1440.674), and admission into the neonatal unit (0 versus 4.6%, P = 0.0045) was found. There was no difference in antepartum haemorrhage (4.9 versus 6.1%), preterm labour (2.8 versus 2.9%), preterm delivery (2.8 versus 4.9%), and Apgar score <7 at the first (0.7 versus 3.2%) and the fifth minute (0 versus 0.9%), or LGA infants (18.8 versus 12.2%).
In association with the increasing ferritin quartiles, there was progressive and significant increase in the serum concentrations of iron and transferrin saturation, and decrease in the transferrin concentration (Table III). Although there was no significant difference in the Hb concentration at booking among the four groups, the Hb concentration and the other red cell indices as well as the haematocrit at 2830 weeks showed significant progressive increase from the lowest to the highest quartile. However, no difference in the white cell count was found.
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710 (log transferrin) 231 (log ferritin)
As there was a significant difference in the haematocrit among the four quartiles, it was possible that the effect on birthweight was due to plasma volume changes independent from changes in iron stores. On further analysis, gestational age and birthweight was significantly correlated with haematocrit (P < 0.0001 and P = 0.022 respectively). Regression analysis was used to examine the relationship between gestational age, maternal weight, haematocrit and log-transformed ferritin concentration on birthweight. The significant parameters for birthweight included maternal weight (P < 0.0001), gestational age (P < 0.0001), and log-transformed ferritin concentration (P < 0.0001), but not haematocrit (P = 0.397).
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Discussion |
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The relationship between maternal serum ferritin concentration and pregnancy outcome is less clear. An early study found no association between iron deficiency and spontaneous preterm labour (Paintin et al., 1966). Later studies have shown an association between preterm delivery with low (Ulmer and Goepel, 1988
; Scholl et al., 1992
) as well as high ferritin concentrations (Goldenberg et al., 1996
, 1998
; Tamura et al., 1996
; Scholl, 1998
). In one study (Tamura et al., 1996
), serum ferritin concentration was inversely correlated with gestational age but no similar correlation could be found with other indices of iron deficiency, and the subjects with inadequate iron status had had a lower, though statistically not significant, odds ratio for early preterm delivery. On the other hand, mineral and vitamin supplements increased ferritin concentration at 28 weeks gestation and decreased the risk of preterm delivery (Scholl et al., 1997
). Nevertheless, a high ferritin concentration is not always equivalent to abundant iron store. Apart from genital tract infection (Goldenberg et al., 1996
, 1998
; Tamura et al., 1996
; Scholl, 1998
), serum ferritin concentration is increased in pregnancy-induced hypertension and eclampsia as a result of release of tissue ferritin and change of ferrokinetics (Entman et al., 1982
; Raman et al., 1992
). In cultured hepatic cells, ferritin is secreted in response to iron and the cytokines interleukin-1-ß and tumour necrosis factor-
(Tran et al., 1997
). Furthermore, as ferritin can be found in many tissues (Crichton, 1973
), damage or injury to any of these tissues can theoretically raise the serum ferritin concentration. It is therefore likely that maternal serum ferritin concentration also acts as a surrogate for other factors that impact on pregnancy outcome.
We examined the relationship between raised ferritin concentration and pregnancy outcome in non-anaemic subjects. We have therefore excluded those with anaemia or thalassaemia trait diagnosed before the third trimester to eliminate the confounding effects of pre-existing iron deficiency anaemia, as well as that of increased iron store despite the presence of anaemia in carriers of thalassaemia trait. We could not demonstrate any correlation between ferritin concentration at 2830 weeks gestation and the maternal nutritional status at the commencement of pregnancy, since there was no significant difference in the weight or BMI, or Hb at booking. In spite of this, the higher quartiles had concomitant increase in other parameters of iron status and red cell indices, in addition to the increased Hb concentration. These associations could not be attributed simply to the presence of complications such as infection or pre-eclampsia, as no consistent correlation could be demonstrated between ferritin quartiles with the incidence of these complications. Furthermore, the difference in the incidence of PROM disappeared when the highest quartile was compared to the other three quartiles combined, and there was no difference in the white cell count. In our subjects, ferritin concentration was therefore most likely to be a reflection of increased iron stores at the time of blood sampling. This could have been consequent to increased dietary intake and/or intestinal absorption. Of interest, we could find no correlation between ferritin quartiles with the placental ratio, in contrast to a previous study (Godfrey et al., 1991) in which the placental ratio was correlated with maternal iron status as indicated by the MCV.
Overall, the pregnancy outcome in the highest quartile was less favourable. Although our subjects had blood sampling at 2830 weeks gestation, which was later than in some of the studies that had demonstrated a relationship between raised ferritin and preterm birth (Goldenberg et al., 1996; Tamura et al., 1996
), we could still find a similar association. In addition, the risk of asphyxia was increased in the highest ferritin quartile, an observation not reported before. Increased maternal iron store also appeared to have a negative impact on birthweight. As the Hb and haematocrit values did not demonstrate an increasing trend with increasing quartiles, increased blood viscosity was unlikely to have been the underlying factor. This would agree with the report that no significant difference in the prevalence of fetal growth restriction and preterm delivery could be found between the highest and lowest haematocrit quartiles (Forest et al., 1996
). It was possible that in addition to the effect on Hb and haematocrit, changes in maternal iron metabolism exerted an independent effect on pregnancy outcome.
Although the clinical utility of ferritin level in predicting neonatal outcome may appear limited (Goldenberg et al., 1998), the results of this and other studies suggested a need to re-examine maternal iron metabolism and pregnancy outcome. 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 (Hemminki and Merilainen, 1995
). Thus if an elevated ferritin concentration reflects maternal iron excess, and is associated with an unfavourable pregnancy outcome, the rationale of routine iron supplementation in non-anaemic mothers should be re-examined.
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Notes |
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References |
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Submitted on March 20, 2000; accepted on May 9, 2000.