Iron Stores in Early Pregnancy and Risk of Lower Birthweight
Iron Stores in Early Pregnancy and Risk of Lower Birthweight
The present longitudinal study assessed, in non-anaemic pregnant women at gestational Weeks 8–12, the relation between maternal iron stores (depleted or non-depleted) in the first trimester and birthweight of children, when antenatal daily iron supplementation, at moderate doses, was taken during pregnancy.
All the women in the study were healthy (with no obstetric pathology), Caucasian, of similar socioeconomic status and smoking habits to the rest of our society (Carrillo et al., 2010; Río et al., 2010; Pueyo et al., 2011).
As far as we are aware, there are no studies in humans on the effect of early gestational depleted iron stores without anaemia on premature birth and low birthweight. In contrast, there are several important studies correlating the presence of iron-deficiency anaemia early in pregnancy with premature delivery (Scanlon et al., 2000; Scholl, 2005). Also, there are studies that indicate the benefit of gestational iron supplementation when iron-deficiency anaemia is detected early in pregnancy (Madhavan Nair et al., 2004; Bánhidy et al., 2011). Again, as far as we are aware, the impact of moderate iron antenatal supplementation on iron depleted stores without anaemia in early pregnancy has not been explored, and controversy surrounds the impact of moderate iron supplementation in the absence of gestational anaemia (Casanueva et al., 2006; Prescrire Int, 2009 [editorial]). Current literature even suggests that high supplemental iron may have negative consequences on pregnancy outcomes (Pena-Rosas and Viteri, 2009). The women in the study received moderate dose iron supplements (mean: 48.3 mg/d, 95% CI: 45.2–54.4) and adherence to the supplementation regimen was carefully monitored by an investigator who was independent from the health-care provision personnel in the hospital. The participants were not aware of their iron status, which assured the validity of adherence, which was 92% ± 18 and was similar for both groups.
SF at gestational Weeks 8–12 was used to classify the women because it is considered to be the best biochemical parameter for monitoring a deficient iron status in pregnancy (Walsh et al., 2011). The SF measure identifies a deficient iron status earlier than other biomarkers, such as TS and Hb, identifying without error the subjects without iron stores as it does not have false negatives. However, a known limitation of SF is that it increases not only with the iron content of the organism but also with acute or chronic inflammation, malignancy or liver disease, even in women with iron deficiency (Zimmermann, 2008). As TS does not increase in the presence of inflammation (Zimmermann, 2008), some authors suggest that TS should also be measured (Rambod et al., 2008; Muñoz et al., 2011) in order to detect inconsistent values (high SF and low TS) that could hide a possible inflammation with iron deficiency. Hence, women with low TS but with elevated SF values at any time of pregnancy were excluded from the statistical analysis (n = 3; 1%) in order to pre-empt false positives of SF affecting the analyses.
In the present study, the group of women with non-depleted iron stores in early pregnancy had higher values for biochemical parameters of iron status than women with depleted stores in early pregnancy. However, both groups reached the end of pregnancy with a high proportion of women with biochemical iron levels below the cut-off points of SF and TS simultaneously, indicative of iron depletion and iron deficiency (Table II). However, even though Hb concentrations also decreased, the mean value remained within normal limits in both groups. The incidence of anaemia, based on current cut-off points (Centers for Disease Control and Prevention, 1998), increased but was only mild (no cases <80 g/l). These changes in biochemical and haematological parameters were similar to those observed in other studies in which supplementation with similar iron doses (Cogswell et al., 2003; Soares et al., 2010) or even five times higher doses (Romslo et al., 1983) did not pre-empt this decline. The initial iron stores positively influence the final effect on the biochemical parameters, even when the iron dose supplementation is the same. In a study in the USA, which included non-anaemic women with good iron stores (SF mean of 40 µg/l), daily iron supplementation (30 mg) for 8 weeks commencing before Week 20 of gestation did not improve biochemical levels, and iron stores became depleted (mean SF of 7.4 µg/l) by late pregnancy (Cogswell et al., 2003). However, Siega-Riz et al. (2006) found that the same level of iron supplementation (30 mg) was sufficient to avoid ending pregnancy with depleted iron stores in a greater number of women when they had had high SF levels (~83 µg/l) in early pregnancy; the mean SF level being around 21 µg/l at the end of gestation. These studies suggest, albeit not conclusively that, in healthy pregnant women, the presence of initial iron stores benefits IBW as well as the mother, provided the gestation period ends with a good iron status. In the current study, even though the initial mean iron stores in the non-depleted group were ~40 µg/l, this was not sufficient to prevent depletion of iron stores in most women later on in pregnancy.
In our population, the 20% of non-anaemic women with depleted iron stores in early pregnancy had a more pronounced risk of becoming iron deficient during pregnancy than their counterparts with higher early iron stores.
Regarding the outcomes of pregnancy, the IBW distributions were within the normal range (World Health Organization, 1993), with similar percentages of low birthweight (7%; <2500 g) and macrosomia (2%; >4000 g) as that reported in other studies conducted in healthy pregnant women in Spain (Valero De Bernabé et al., 2004; Agudelo-Suárez et al., 2009).
Our results also showed that non-anaemic women who commenced pregnancy with depleted iron stores delivered babies weighing ~148 g (95% CI: −296, −1) less than women with non-depleted iron stores in early pregnancy. This difference in the birthweight was reaffirmed and even increased to 192 g (95% CI: −364, −21) when adjusting for other parameters of iron status in pregnant women (initial Hb and TS < 16%) as well as for the other confounding variables, such as age of the mother, BMI at the first visit, parity, length of pregnancy, gender of the baby, smoking habits, socioeconomic status of the family and iron supplementation.
IBW is negatively influenced by the smoking habit during pregnancy, as highlighted by Guzikowski and Pirogowicz (2008) and IBW is positively influenced by a higher maternal BMI in early pregnancy, as reported by Brynhildsen et al. (2009) and by a longer gestation period (Kramer, 1987).
Our study, however, cannot eliminate the influence of some non-included variables, such as stress, strenuous work, genetics of the mother or some other factors related to birthweight which, if distributed non-homogeneously in the study sample, might influence the IBW.
Several studies have shown an association between anaemia during pregnancy and a lower IBW (Scholl et al., 1992; Steer, 2000) but the current study is the first to show that iron depletion among non-anaemic women early in gestation (and receiving moderate supplemental iron) results in babies with a significantly lower birthweight.
Our conclusions, based on the results of the present study, are that non-anaemic pregnant women with depleted iron stores in early pregnancy have children who are smaller than those from women who begin pregnancy with non-depleted iron stores, even when both groups of women receive a moderate daily iron supplementation.
These findings reaffirm the importance of health promotion to insure that women of reproductive age, especially those who may become pregnant, have adequate iron stores.
The results from this study also contribute to the ongoing discussion in the literature on the effects of daily antenatal ingestion of various doses of iron supplements on the outcomes of pregnancy. In our study, optimal birthweight occurs when women who are non-smokers enter pregnancy with BMI between 22 and 26 kg/m, in a non-anaemic condition, with iron stores ideally >300 mg (reflected by SF >30 µg/l) and who receive antenatal supplements that provide moderate iron in the pregnancy, so as to maintain Hb levels between 95 and 125 g/l.
Discussion
The present longitudinal study assessed, in non-anaemic pregnant women at gestational Weeks 8–12, the relation between maternal iron stores (depleted or non-depleted) in the first trimester and birthweight of children, when antenatal daily iron supplementation, at moderate doses, was taken during pregnancy.
All the women in the study were healthy (with no obstetric pathology), Caucasian, of similar socioeconomic status and smoking habits to the rest of our society (Carrillo et al., 2010; Río et al., 2010; Pueyo et al., 2011).
As far as we are aware, there are no studies in humans on the effect of early gestational depleted iron stores without anaemia on premature birth and low birthweight. In contrast, there are several important studies correlating the presence of iron-deficiency anaemia early in pregnancy with premature delivery (Scanlon et al., 2000; Scholl, 2005). Also, there are studies that indicate the benefit of gestational iron supplementation when iron-deficiency anaemia is detected early in pregnancy (Madhavan Nair et al., 2004; Bánhidy et al., 2011). Again, as far as we are aware, the impact of moderate iron antenatal supplementation on iron depleted stores without anaemia in early pregnancy has not been explored, and controversy surrounds the impact of moderate iron supplementation in the absence of gestational anaemia (Casanueva et al., 2006; Prescrire Int, 2009 [editorial]). Current literature even suggests that high supplemental iron may have negative consequences on pregnancy outcomes (Pena-Rosas and Viteri, 2009). The women in the study received moderate dose iron supplements (mean: 48.3 mg/d, 95% CI: 45.2–54.4) and adherence to the supplementation regimen was carefully monitored by an investigator who was independent from the health-care provision personnel in the hospital. The participants were not aware of their iron status, which assured the validity of adherence, which was 92% ± 18 and was similar for both groups.
SF at gestational Weeks 8–12 was used to classify the women because it is considered to be the best biochemical parameter for monitoring a deficient iron status in pregnancy (Walsh et al., 2011). The SF measure identifies a deficient iron status earlier than other biomarkers, such as TS and Hb, identifying without error the subjects without iron stores as it does not have false negatives. However, a known limitation of SF is that it increases not only with the iron content of the organism but also with acute or chronic inflammation, malignancy or liver disease, even in women with iron deficiency (Zimmermann, 2008). As TS does not increase in the presence of inflammation (Zimmermann, 2008), some authors suggest that TS should also be measured (Rambod et al., 2008; Muñoz et al., 2011) in order to detect inconsistent values (high SF and low TS) that could hide a possible inflammation with iron deficiency. Hence, women with low TS but with elevated SF values at any time of pregnancy were excluded from the statistical analysis (n = 3; 1%) in order to pre-empt false positives of SF affecting the analyses.
In the present study, the group of women with non-depleted iron stores in early pregnancy had higher values for biochemical parameters of iron status than women with depleted stores in early pregnancy. However, both groups reached the end of pregnancy with a high proportion of women with biochemical iron levels below the cut-off points of SF and TS simultaneously, indicative of iron depletion and iron deficiency (Table II). However, even though Hb concentrations also decreased, the mean value remained within normal limits in both groups. The incidence of anaemia, based on current cut-off points (Centers for Disease Control and Prevention, 1998), increased but was only mild (no cases <80 g/l). These changes in biochemical and haematological parameters were similar to those observed in other studies in which supplementation with similar iron doses (Cogswell et al., 2003; Soares et al., 2010) or even five times higher doses (Romslo et al., 1983) did not pre-empt this decline. The initial iron stores positively influence the final effect on the biochemical parameters, even when the iron dose supplementation is the same. In a study in the USA, which included non-anaemic women with good iron stores (SF mean of 40 µg/l), daily iron supplementation (30 mg) for 8 weeks commencing before Week 20 of gestation did not improve biochemical levels, and iron stores became depleted (mean SF of 7.4 µg/l) by late pregnancy (Cogswell et al., 2003). However, Siega-Riz et al. (2006) found that the same level of iron supplementation (30 mg) was sufficient to avoid ending pregnancy with depleted iron stores in a greater number of women when they had had high SF levels (~83 µg/l) in early pregnancy; the mean SF level being around 21 µg/l at the end of gestation. These studies suggest, albeit not conclusively that, in healthy pregnant women, the presence of initial iron stores benefits IBW as well as the mother, provided the gestation period ends with a good iron status. In the current study, even though the initial mean iron stores in the non-depleted group were ~40 µg/l, this was not sufficient to prevent depletion of iron stores in most women later on in pregnancy.
In our population, the 20% of non-anaemic women with depleted iron stores in early pregnancy had a more pronounced risk of becoming iron deficient during pregnancy than their counterparts with higher early iron stores.
Regarding the outcomes of pregnancy, the IBW distributions were within the normal range (World Health Organization, 1993), with similar percentages of low birthweight (7%; <2500 g) and macrosomia (2%; >4000 g) as that reported in other studies conducted in healthy pregnant women in Spain (Valero De Bernabé et al., 2004; Agudelo-Suárez et al., 2009).
Our results also showed that non-anaemic women who commenced pregnancy with depleted iron stores delivered babies weighing ~148 g (95% CI: −296, −1) less than women with non-depleted iron stores in early pregnancy. This difference in the birthweight was reaffirmed and even increased to 192 g (95% CI: −364, −21) when adjusting for other parameters of iron status in pregnant women (initial Hb and TS < 16%) as well as for the other confounding variables, such as age of the mother, BMI at the first visit, parity, length of pregnancy, gender of the baby, smoking habits, socioeconomic status of the family and iron supplementation.
IBW is negatively influenced by the smoking habit during pregnancy, as highlighted by Guzikowski and Pirogowicz (2008) and IBW is positively influenced by a higher maternal BMI in early pregnancy, as reported by Brynhildsen et al. (2009) and by a longer gestation period (Kramer, 1987).
Our study, however, cannot eliminate the influence of some non-included variables, such as stress, strenuous work, genetics of the mother or some other factors related to birthweight which, if distributed non-homogeneously in the study sample, might influence the IBW.
Several studies have shown an association between anaemia during pregnancy and a lower IBW (Scholl et al., 1992; Steer, 2000) but the current study is the first to show that iron depletion among non-anaemic women early in gestation (and receiving moderate supplemental iron) results in babies with a significantly lower birthweight.
Our conclusions, based on the results of the present study, are that non-anaemic pregnant women with depleted iron stores in early pregnancy have children who are smaller than those from women who begin pregnancy with non-depleted iron stores, even when both groups of women receive a moderate daily iron supplementation.
These findings reaffirm the importance of health promotion to insure that women of reproductive age, especially those who may become pregnant, have adequate iron stores.
The results from this study also contribute to the ongoing discussion in the literature on the effects of daily antenatal ingestion of various doses of iron supplements on the outcomes of pregnancy. In our study, optimal birthweight occurs when women who are non-smokers enter pregnancy with BMI between 22 and 26 kg/m, in a non-anaemic condition, with iron stores ideally >300 mg (reflected by SF >30 µg/l) and who receive antenatal supplements that provide moderate iron in the pregnancy, so as to maintain Hb levels between 95 and 125 g/l.
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