Third trimester iron status and pregnancy outcome in non-anaemic women; pregnancy unfavourably affected by maternal iron excess

T.T. Lao1,3, K.-F. Tam2 and L.Y. Chan1,2

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


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A prospective observational study was performed on 488 women with haemoglobin >=10 g/dl at booking to examine the relationship between serum ferritin concentration quartiles at 28–30 weeks gestation with maternal characteristics, pregnancy complications and infant outcome. While there was no difference in the maternal characteristics or gestational age, the infant size decreased significantly and progressively from the lowest to the highest quartile. Despite a significant difference in the incidence of multiparous women, there was no difference in the incidence of most complications except for prelabour rupture of the membranes and infant admission to the neonatal unit. Compared with the other three quartiles, the highest quartile was associated with increased risk for preterm delivery and neonatal asphyxia, while the lowest quartile was associated with decreased risk of pre-eclampsia, prelabour rupture of the membranes, and infant admission to the neonatal unit. Overall, ferritin quartiles were correlated with other parameters of iron status and red cell indices, and ferritin concentration was inversely correlated with infant birthweight. Our findings suggested that maternal ferritin concentration is primarily a reflection of maternal iron status, and a high level is associated with unfavourable outcome. The rationale of routine iron supplementation in non-anaemic women needs to be re-examined.

Key words: ferritin/iron status/pregnancy outcome


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
During pregnancy, the needs of the growing fetus and placenta, as well as the increasing maternal blood volume and red cell mass, impose such a demand on maternal iron stores that iron supplementation at daily doses between 18 and 100 mg from 16 weeks gestation onwards could not completely prevent the depletion of maternal iron stores at term (Thomsen et al., 1993Go; Milman et al., 1994Go). The development of iron deficiency anaemia is associated with increased risk of preterm births and low birthweight infants (Ulmer and Goepel, 1988Go; Bhargava et al., 1991Go; Scholl et al., 1992Go; Hirve and Ganatra, 1994Go; Scholl and Hediger, 1994Go; Spinillo et al., 1994Go; Swain et al., 1994Go; Singla et al., 1997Go). Furthermore, mothers given iron supplementation had decreased risk of preterm delivery compared with mothers without supplements (Scholl et al., 1997Go). Thus the relationship between maternal iron deficiency and preterm birth and fetal growth restriction seems to be well established.

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, 1973Go). 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., 1974Go; Worwood, 1977Go; Puolakka et al., 1980Go; Kaneshige, 1981Go; Romslo et al., 1983Go). In pregnancy, serum ferritin concentration is maximum at 12–16 weeks gestation, then falls with advancing gestation to reach a nadir at the third trimester (Puolakka et al., 1980Go; Kaneshige, 1981Go; Milman, 1994). Prenatal mineral and vitamin supplement given from the first trimester would maintain serum ferritin at a higher concentration (Puolakka et al., 1980Go; Milman et al., 1994Go; Scholl et al., 1997Go).

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., 1996Go), at the highest quartile (Goldenberg et al., 1996Go), or above the 90th percentile (Scholl, 1998Go). 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., 1996Go; Tamura et al., 1996Go; Scholl 1998Go). 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., 1998Go).

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, 1996Go). 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.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Our regional hospital caters for public patients only, with ~5000 deliveries per annum. At the first antenatal visit, blood is taken to determine the Hb concentration, mean corpuscular volume (MCV) and blood group. The MCV screening is performed to identify mothers at risk of carrying the thalassaemia traits, and those with a MCV of <80 fl will have further investigations including the father's MCV. Prenatal diagnosis will be performed if the couple's MCV results are both <80 fl. Patients having a Hb concentration <10 g/l at any time during pregnancy are diagnosed to have anaemia. They are further investigated to determine the cause of anaemia and then treated accordingly. A multivitamin preparation containing 29 mg of elemental iron is prescribed to all patients from 20 weeks gestation. At 28–30 weeks, the Hb concentration is determined again, and iron therapy given where necessary.

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 28–30 weeks gestation, to study their serum ferritin concentration after informed consent was obtained. The gestation of 28–30 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., 1991Go), and high serum ferritin concentration at 28 weeks gestation was shown to be associated with increased risk of preterm delivery (Scholl, 1998Go). 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 13–180 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 {chi}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 ({rho}) 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).


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Of the 511 patients recruited, 488 were eventually delivered in our hospital. The distribution of the serum ferritin concentration was positively skewed; the 25th, 50th and 75th quartile values were 18, 26 and 44 pmol/l respectively. The numbers of patients from the lowest to the highest quartile were 144, 116, 111 and 117 respectively. There was no difference in the maternal age, height, weight or body mass index (BMI) among the four groups (Table IGo). Although there was no difference in the gestational age, there was significant decrease in the birthweight, the birthweight ratio (birthweight divided by the mean value for gestation), the crown–heel length, as well as the placental weight, from the lowest to the highest quartile. However, there was no difference in the mean infant BMI, the placental weight to birthweight ratio (placental ratio), or the Apgar scores at the first and fifth minute.


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Table I. Maternal and infant characteristics in relation to serum ferritin quartiles
 
The incidence of multiparous women was different among the four groups, with the highest incidence for the lowest and second highest quartiles, followed by the highest quartile, and then the second lowest quartile (Table IIGo). Yet there was no significant difference in the incidence of antepartum haemorrhage, pre-eclampsia, preterm labour, preterm delivery, or Caesarean section. There was increased incidence of PROM, however, for the three higher quartiles compared with the lowest quartile, and there was a weak but significant linear correlation between the incidence of PROM with increasing quartiles (r = 0.089, P = 0.041). The lowest quartile and the highest quartile had the lowest incidence of small-for-gestational-age (SGA, birthweight <=10th percentile for the local population) infants. The incidence of large-for-gestational-age (LGA, birthweight >90th percentile) infants was highest in the lowest and second highest quartiles, and lowest in the highest quartile, and a significant inverse correlation with increasing quartiles was present (r = –0.110, P = 0.015). There was no significant difference for Apgar score <7 at the fifth minute. The incidence of admission into the neonatal unit was significantly (P = 0.029) different with the highest incidence in the second lowest quartile and zero incidence in the lowest quartile.


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Table II. Pregnancy complications and outcome in relation to serum ferritin quartiles
 
Since the highest quartile group appeared to have the highest incidence of preterm labour and preterm delivery, this group was compared with the other quartiles individually. No significant difference was found in the incidence of antepartum haemorrhage, preterm labour, preterm delivery, or pre-eclampsia hypertension, but the incidence of PROM [P = 0.009, relative risk (RR) 3.06, 95% confidence interval (CI) 1.28–7.32] and asphyxia (P = 0.048, RR 7.73, 95% CI 0.92–65.14) was increased compared with the lowest quartile. However, when compared with the three lower quartiles combined, the highest quartile had increased incidence of preterm delivery (7.7 versus 3.2%, P = 0.038, RR 2.50, 95% CI 1.03–6.09), and asphyxia (5.1 versus 1.6%, P = 0.032, RR 3.30, 95% CI 1.04–10.43), but there was no significant difference for antepartum haemorrhage (6.8 versus 5.4%), preterm labour (4.2 versus 2.4%), PROM (15.3 versus 12.0%) or pre-eclampsia (4.2 versus 3.9%).

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 0.016–0.964), PROM (5.6 versus 15.9%, P = 0.002, RR 0.312, 95% CI 0.144–0.674), 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 IIIGo). 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 28–30 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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Table III. Iron parameters and red cell indices in relation to serum ferritin quartiles
 
Overall, the serum ferritin concentration was positively correlated with maternal age and weight, and inversely with infant gestational age, birthweight, birthweight ratio, placental weight and crown–heel length (Table IVGo). Stepwise multiple regression analysis was performed on the following parameters: maternal weight and BMI, parity, and log-transformed values of serum ferritin, iron and transferrin concentration, as well as the transferrin saturation, to determine which of these parameters were significantly correlated with birthweight after adjusting for gestational age. The significant parameters were maternal weight (P < 0.0001), log-transformed ferritin concentration (P = 0.0009), and log-transformed transferrin concentration (P = 0.0344), and the following regression equation was obtained:


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Table IV. Correlation between serum ferritin concentration and maternal and infant characteristics
 
Birthweight = 1163 + 20 (maternal weight) +

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).


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The incidence of low birthweight infants follows a U-shaped distribution in relation to maternal Hb concentration, being increased with low as well as high Hb concentrations (Murphy et al., 1986Go; Steer et al., 1995Go). The effect of anaemia on pregnancy outcome is also related to the gestation at diagnosis, for low birthweight and preterm births were increased with anaemia diagnosed in early pregnancy but not during or after the second trimester, when the effect becomes reversed (Bhargava et al., 1991Go; Gaspar et al., 1993Go; Rasmussen and Øian, 1993Go; Scholl and Hediger, 1994Go). The association between low birthweight infants and other adverse pregnancy outcomes with a high Hb concentration in the second half of pregnancy is probably related to a failure of the expansion of plasma volume that normally occurs at this time, and the high Hb actually reflected haemoconcentration (Dunlop et al., 1978Go; Koller et al., 1979Go, 1980Go; Sagen et al., 1984Go; Huisman and Aarnoudse, 1986Go; Lu et al., 1991Go; Rasmussen and Øian, 1993Go; Steer et al., 1995Go). Indeed, one study has shown that the incidence of intrauterine growth retardation and preterm delivery was not significantly different between the haematocrit at the highest and lowest quartiles (Forest et al., 1996Go). Thus both Hb and haematocrit not only reflect maternal nutritional status but also act as surrogate for other factors that influence pregnancy outcome.

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., 1966Go). Later studies have shown an association between preterm delivery with low (Ulmer and Goepel, 1988Go; Scholl et al., 1992Go) as well as high ferritin concentrations (Goldenberg et al., 1996Go, 1998Go; Tamura et al., 1996Go; Scholl, 1998Go). In one study (Tamura et al., 1996Go), 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., 1997Go). Nevertheless, a high ferritin concentration is not always equivalent to abundant iron store. Apart from genital tract infection (Goldenberg et al., 1996Go, 1998Go; Tamura et al., 1996Go; Scholl, 1998Go), 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., 1982Go; Raman et al., 1992Go). In cultured hepatic cells, ferritin is secreted in response to iron and the cytokines interleukin-1-ß and tumour necrosis factor-{alpha} (Tran et al., 1997Go). Furthermore, as ferritin can be found in many tissues (Crichton, 1973Go), 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 28–30 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., 1991Go) 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 28–30 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., 1996Go; Tamura et al., 1996Go), 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., 1996Go). 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., 1998Go), 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, 1995Go). 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.


    Notes
 
3 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, Tsan Yuk Hospital, 30 Hospital Road, Hong Kong, People's Republic of China. E-mail: laotth{at}hkucc.hku.hk Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on March 20, 2000; accepted on May 9, 2000.