Iron Deficiency during Pregnancy

Prenatal maternal nutrition is a controllable factor that strongly influences fetal development and subsequent neonatal outcomes. The required intake for many nutrients during pregnancy significantly increase and their deficiencies during pregnancy have proven to have devastating effects relating to their role in fetal development. Iron requirements in particular rise substantially during pregnancy due to the expansion of the maternal erythrocyte mass and its role in the development of the central nervous system (CNS), including; neuronal synapse formation, myelination and the synthesis of certain neurotransmitters. Iron deficiency (ID) is the most common nutritional disorder around the world, affecting both industrialized and non-industrialized countries. Thus when the iron requirements increase during pregnancy, ID becomes the main nutritional concern for pregnant women. The prevalence of ID during pregnancy in developed countries ranges from 18%-40%, while it effects 30%-70% in developing countries [1].

There is great awareness of the widespread, high incidence of ID during pregnancy. The main reason why it is still prevalent today is because unlike other nutrients which involve simple supplementation to rectify the deficiency, the intricacy of iron absorption and homeostasis significantly reduce the effect basic supplementation regimes have of treating/preventing ID during pregnancy. Another factor, the bioavailability of iron is substantially higher in its haem form (obtained when eating red meat). Supplements can only provide iron in its non-haem form. Given that most women have a low iron status before they’re pregnant, majority cannot meet the sudden rise in iron requirements during gestation.
If iron levels are low, haemoglobin synthesis is reduced which means iron status can influence the amount of oxygen that is delivered to the fetus, a major factor in overall fetal development. In addition its role in CNS development means that a low iron status can compromise fetal brain and neuronal development. A recent longitudinal study by Hernandez-Martinez and colleagues [2] was designed to look at the effects of ID at different stages of pregnancy on neonatal behaviour. A total of 299 well-nourished Spanish pregnant women were recruited for the study. Each participant was given 40-60mg/day of iron (mean: 48.9mg/day) from their obstetrician at week 15 of gestation. Blood and clinical history was collected from the participants during each trimester; 1st (10-15 weeks; before supplementation); 2nd (24-27 weeks) 3rd (33-34 weeks). Serum ferritin, transferrin and iron levels were obtained. ID was diagnosed in participants who had transferrin saturation (TS%) <16% and ferritin levels <12µg/L. Neonatal behaviour was assessed by the Neonatal Behaviour Assessment Scale (NBAS). Multiple linear regression models were then applied to determine if iron status at the first, second and third trimester of pregnancy are significant predictors of neonatal behaviour (NBAS scores). Neonatal behaviour itself is an important predictor of temperament and psychological problems in early childhood and later in life.

Iron status, in particular ID, were significant predictors of neonatal behaviour which varied depending on the stage of pregnancy. In the first and second trimester, ID was associated with autonomic stability. In the third trimester, ID and iron status were associated with the motor system, robustness and endurance, and state organization (infant arousal and state liability). This means early ID in the first and second trimesters of pregnancy has a more general effect on brain responses to stressful situations. An altered autonomous response to stimulations is an indication of brain immaturity. ID at the end of pregnancy on the other hand, has more specific effects on motor maturity and self-regulation. Poor motor system NBAS scores have been related to difficult temperament and a higher risk of behavourial and externalizing problems in childhood [3-5]. Poor state organization NBAS scores have also been related to a higher risk of behavioural problems and ADHD [6]. The difference in the effects of ID at different stages of pregnancy can be accounted for the stage of fetal development at that time. In the last trimester, synaptogenesis occurs in the fetal brain, in which iron plays a significant role. If synapse formation and myelination is altered by ID, then neural transmission is compromised and would thus influence motor system development in neonates like what was observed in this study. As synaptogenesis does not occur until late gestation, ID during the first two trimesters may not compromise motor development and state organization if ID can be successfully treated before the third trimester starts. However, ID is still important to rectify in the early stages of pregnancy (or before) as the fetal autonomous nervous system is compromised by insufficient iron levels, most likely caused by its requirements in general fetal brain and neuronal cell development as well as haemoglobin synthesis.

These results demonstrate that sufficient iron levels are required throughout the entire length of pregnancy to avoid poor neurodevelopment and behavioural outcomes in the neonate. The study’s findings also highlighted a continuing issue that current iron supplements are not effective enough. At the start of the study (before supplementation) the incidence of ID in pregnant women participants was 8.3%. After 9-12 weeks of supplementation at 24-27 weeks gestation, the incidence of ID rose to 42.6%. After 18-19 weeks of supplementation at 33-34 weeks gestation, the incidence reached a staggering 62.5%. Given that subjects of the study were from industrialized Spain, were well nourished and were provided with 40-60mg/day of iron, it is interesting to see the incidence of ID is 20% higher than the average for industrialized countries [1]. A great concern is that iron supplementation of 40-60mg/day appears to do very little in reducing the incidence of ID, in which the ramifications of this was identified in the study itself.

So what can be done about the high incidence of ID if iron supplementation is not working? Ascorbic acid (vitamin C) has been added to many supplements because it can increase iron absorption in the intestines. But what appears to provide the greatest of hope is the administration of the iron-binding protein, lactoferrin to pregnant women. Supplementation of 200mg of lactoferrin (8.8mg of iron) was shown to significantly increase serum iron levels as well as haemoglobin levels in pregnant women (n = 107) in just 30 days [7]. This was observed at all trimesters of pregnancy. More importantly, it was able to increase these levels significantly higher than a very large dose of iron (502mg of ferrous sulphate – 156mg of iron) in pregnant women (n = 98). As an additional benefit, no side effects were reported from pregnant women taking lactoferrin, whereas 95% of the women taking the iron supplement reported side effects (mostly gastrointestinal) [7]. The benefits of lactoferrin are thought to lie in the protein’s ability to increase intestinal cell absorption of iron (via lactoferrin receptors in the intestines) and assist in iron transportation (via modulation of other proteins involved) [8-9].

Lactoferrin supplementation may provide effective treatment to the worldwide problem of ID during pregnancy and reduce the subsequent outcome of ID-induced neonatal behavioural problems.

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