This study indicated that, despite adequate iron therapy in infancy, 4-y-old children who had IDA in infancy showed altered sleep organization throughout the night. The pattern of REM sleep episode duration in controls showed the expected lengthening with advancing thirds of the night. In contrast, former IDA children did not. Instead, compared with controls, the duration of their REM sleep episodes was longer in the first third and shorter in the last third of the night. The timing of REM sleep episodes also differed between groups. Former IDA children showed a higher number of REM sleep episodes, significant in the first third and a suggestive tendency in the third, whereas they showed fewer REM sleep episodes in the second third. In addition, the first sleep cycle in former IDA children differed markedly relative to controls: the latency to the first REM sleep episode was shorter, the episode tended to be longer, and the episodes of NREM2 and SWS were shorter.
One possible explanation for the differences could be the higher proportion of males in the former IDA group. At age 4–6 y, boys have been observed to sleep longer and spend more time in NREM2 than girls (17
). Since we used gender as a covariate in all statistical comparisons, this factor is unlikely to explain the differences in sleep characteristics between former IDA and control children. Another factor might be daytime sleep, which exerts a strong inhibitory effect on the expression of SWS in the subsequent night (18
). The longer duration of the prior waking episode in the former IDA group would usually be associated with increased SWS amount at the onset of the sleep episode, instead of the decreased SWS we observed. This appears to make it unlikely that differences in daytime sleep and waking account for the findings. However, the REM sleep rebound effect is a slower mechanism than the increased SWS after sleep deprivation. Therefore, the longer duration of the prior daytime waking episode in the IDA children could contribute to an increased REM sleep pressure and, hence, more REM sleep in the first part of the night.
An additional explanation could be differing amounts of sleep alterations. In particular, restless legs syndrome and periodic limb movements during sleep have been associated with conditions characterized by compromised iron status (20
). Even though this aspect was outside the scope of the current study, our results do not seem to point in this direction. Sleep alterations related to such leg movement disorders are characterized by disturbed sleep onset and/or maintenance (20
), whereas the groups in our study showed similar sleep latency and WASO was smaller in the former IDA group.
Some characteristics of REM sleep organization in formerly IDA children might be an expression of a slower developmental profile of this state. The pattern and distribution of REM sleep change and its recurrence time throughout the night typically lengthens as children get older (25
). Regarding the altered REM features in former IDA children, the results might also be relevant to the increase in symptoms of anxiety and depression reported in young adolescents who had chronic, severe iron deficiency in infancy (28
). Our findings of shorter latency and prolonged duration of the first episode and absence of progressive lengthening of episodes duration with advancing sleep period are reminiscent of REM sleep patterns often observed in depressive patients (29
The mechanisms by which IDA in infancy could result in long-lasting changes in sleep state organization are unknown. However, it is possible that they relate to brain processes in which iron plays an important role. Long-lasting effects of iron deficiency on the developing dopamine (DA) system are a promising example (2
). Neuromodulation by the DA system plays an important role in sleep regulation (30
), including the modulation of REM sleep quality, quantity, and timing (31
). Furthermore, IDA alters DA neurotransmission in specific areas of the brain, among which are those critically involved in sleep regulation (33
). For instance, the basal ganglia become high in iron concentration and are more highly interconnected with REM-regulatory structures in the mesopontine tegmentum than with any other brain region (35
). Some changes induced by early iron deficiency in the basal ganglia are not corrected with iron supplementation (2
The dynamic balance between neurotransmitter systems is another important consideration. The ultradian alternation of NREM sleep/REM sleep appears to be controlled by a permanent interacting balance between brainstem aminergic and cholinergic neuronal discharges (33
). Relevant to this issue are findings in recent iron deficiency studies in rodent models showing alterations not only in the DA system but also central serotonin and noradrenergic transporters and levels (8
). Since only some of the changes were reversible by iron supplementation at weaning (8
), the resulting IDA-induced neurotransmission imbalance could affect the fine-graded neural mechanisms involved in the regulation of sleep states patterning.
In addition, a recently described model involves reciprocal inhibitory interactions between brainstem gamma-aminobutyric acid (GABA)-ergic REM-off and REM-on populations as main components of the REM switch (38
). Since iron deficiency may also affect GABA-ergic transmission systems (39
), the ongoing balance between the GABA-ergic populations may be altered as well, contributing to the altered transitions into and out of REM sleep observed in former IDA children.
Early alterations in DA pathways exert persistent effects on context-dependent affective responses and cognitive functioning (40
). Altered responses to novel stimuli and settings have been observed in the IDA rodent model and are suggested in human infants by increased wariness/hesitance (reviewed in ref. 2
) and differences between laboratory and home environments in motor activity (6
). However, if former IDA children were particularly affected by the novel environment and procedures, their sleep patterns would probably be different from those we observed, since the so-called first night effect is mainly characterized by longer REM latency, less total sleep time, and less REM sleep, with more intermittent awake time, and lower sleep efficiency (41
Another consideration is iron’s role in normal myelination. Disruptions in iron processing, storage, or availability affect myelin quantity, quality, composition, and compaction (43
), with alterations that persist even if the iron content of the myelin achieves normal levels after iron supplementation (45
). As suggested previously in the same sample (4
), the slower transmission in both auditory and visual systems likely arises from iron’s role in myelination. It is reasonable to postulate that the effects of iron deficiency on myelination might decrease the efficiency of neural signalling not only in sensory systems but also in those involved in the circuitry of sleep regulation.
This study was limited in several ways: a) A single night recording in the laboratory may alter sleep organization in some children more than others, and additional nights would be needed to evaluate this issue. b) Bedtime and sleep onset were determined following the individual child’s routines. Although this may seem more open to uncontrolled factors, we considered it important to increase the children’s comfort by respecting the usual timing of sleep. However, the approach introduced more variability in the time of going to bed and falling asleep. c) Since we did not assess REM sleep in its tonic and phasic stages (46
), we could not estimate the contribution of each REM sleep stage to differences between the groups. Future studies of these relations might help clarify our results. d) We did not assess daytime sleepiness and thus cannot determine whether disrupted nighttime sleep adversely affected waking tone. e) Underlying mechanisms could not be determined in a study like this. Further research, most probably in animal models, is clearly required to elucidate them.
In conclusion, altered temporal organization of sleep patterns in otherwise healthy former IDA children indicate that iron plays a role in the normal progression and establishment of sleep patterning. Our results also suggest that early IDA is associated with lasting alterations in key components of functional integration and brain development that derail the temporal modulation of sleep organization. Sustained alteration in sleep organization for whatever reason may have negative consequences for development. Thus, altered sleep features may represent a fundamental process that interferes with optimal functioning during sleep and wakefulness in former IDA children.