Iron Treatment of Sleep Disorders in Children With Autism Spectrum Disorder

Autism Spectrum Disorders (ASD) are characterized by difficulties in language, social
communication, and repetitive and restricted behaviors. ASD affects as many as 1 in 90-150
children. Sleep issues/insomnia is very common in children with ASD (50-80%). Insomnia has a
negative impact on both the developmental and behavioral function of the child and the
quality of life for the family. Causes of insomnia in children with ASD are multifactorial
and can be difficult to treat effectively. Low iron stores, as manifest by low serum
ferritin levels, is also common in children with ASD. Both insomnia and low iron stores are
associated with Restless Legs Syndrome (RLS) and Periodic Limb Movement of Sleep (PLMS).
Children with ASD often have difficulty communicating symptoms or tolerating Polysomnography
(Sleep Study). This makes establishing a diagnosis of RLS or PLMS very difficult in children
with ASD. Because polysomnography is not well tolerated in children with ASD and cannot
measure sleep over time in a natural environment, improvements in sleep with treatment with
iron will be measured by standard actigraphy (a watch that measures movements during sleep)
and sleep diaries. The investigators also propose to evaluate periodic limb movement index
(PLMI) as a predictor of response to iron treatment for insomnia in children with ASD, as
measured by the PAM-RL, an actigraph designed to measure PLMS. The investigators will
collect secondary data regarding attention and behavior over the course of the study to
monitor improvement in daytime functioning in both groups. Many clinicians will empirically
treat children with ASD, insomnia and low ferritin levels (< 50ng/ml) with iron. This is
based on data from a previous open label trial demonstrating subjective improvement in
restless sleep in children with ASD with low/low normal ferritin levels who were treated
with iron. In order to evaluate the efficacy of such treatment, The investigators propose a
randomized placebo-controlled trial of oral elemental iron for treatment of insomnia in
children with ASD and ferritin levels that are low but above the laboratory cut off for
deficiency. This study will evaluate the effectiveness of treatment of insomnia with oral
ferrous sulfate (iron) at a dose of 3mg/kg divided twice per day for 3 months compared to
placebo.

Inclusion Criteria:

- Child has a clinical diagnosis of autism spectrum disorder, meeting Diagnostic and
Statistical Manual of Mental Disorders (DSM-IV-TR) criteria, confirmed by the Autism
Diagnostic Observation Schedule.

- Age 2 years to 10 years 11 months.

- Child has sleep onset latency of greater than 40 minutes on 3 or more nights per
week, an average greater than 30 minutes per night, or night waking at least 3 times
per week requiring parental intervention or lasting >20 minutes per night.

- A mean sleep latency of 30 minutes or more, or night waking will be need to be
confirmed by 7 days of scorable actigraphy data prior to randomization.

- Ferritin between 17ng/ml and 49 ng/ml, confirmed at a central lab.

- The child has been screened for medical conditions that affect sleep by their
clinician and referred for subspecialty evaluation, as needed, for coexisting
disorders (e.g., Gastrointestinal reflux disease, epilepsy).

- We will include children with coexisting medical, psychiatric, and neurological
disorders as long as they have been evaluated by a physician and a treatment plan has
been implemented, with the child on a stable dose of medication for one month

- Parents and their child are willing and able to provide informed consent (and assent,
depending on child's age and cognitive function) and to cooperate with study
procedures. Children with coexisting intellectual disability who can cooperate with
study procedures are eligible.

- A child with known genetic syndromes comorbid with autism spectrum disorder (ASD),
including Fragile X, down syndrome, neurofibromatosis, or tuberous sclerosis will be
included as long as they meet other eligibility criteria.

Exclusion Criteria:

- Family history of hemochromatosis

- Elevated C-reactive protein (CRP) (may be repeated and enrolled once inflammation has
resolved)

- Anemia - low hemoglobin (<11.0 g/dL for children <5 and <12.0 g/dL for children 6-11)
(unless cause of anemia is known, is not due to iron deficiency, and there would be
no contraindication to treatment with iron.)

- Fever in past week or active infection.

- Current treatment with iron in any amount other than that in a multivitamin

- Severe constipation/GI issues that are not adequately managed

- Treatable sleep and medical condition such as obstructive sleep apnea or severe
eczema that are not adequately managed.

- A child who is currently participating in other interventional research studies.

- Child with a seizure in the previous 2 years.

- A child taking medications that significantly influence RLS symptoms such as
antinausea drugs (prochlorperazine, promethazine, triethylpyrazine or
metoclopramide), antipsychotic drugs (haloperidol or phenothiazine derivatives such
as chlorpromazine, promazine, triflupromazine, methotrimeprazine, fluphenazine,
mesoridazine, perphenazine, thioridazine, and trifluoperazine), antidepressants that
increase serotonin only if the onset of sleep issues was associated with starting the
medication, and some cold and allergy medications-that contain sedating
antihistamines(methdilazine, promethazine, trimeprazine).

- A child taking a medication that has a significant drug interaction with iron that
cannot be addressed by the timing of administration such as Cholestyramine and
Colestipol, Tagamet, Zantac, Pepcid, Axid, ACE inhibitors (captopril, enalapril, and
lisinopril), carbidopa, levodopa, levothyroxine, tetracyclines, and quinolones.

- Girls who have started menstruating.

- Inability or unwillingness of subject or legal guardian/representative to give
written informed consent.

- Allergic to turmeric (natural dye used in placebo).

- Allergy to prilocaine/lidocaine, if the participant requires it for procedures

- The onset of sleep symptoms was related to the onset of puberty.