University of Virginia Health System

Determining Point Prevalence and Etiology of Iron Deficiency Anemia in
School Age Children of Limpopo Provence, South Africa

Introduction:

In 1993 anemia was ranked the 8^th leading causes of disease among women and girls in developing countries by the World Bank.[i] Since then, numerous studies have emerged demonstrating the harmful affects anemia has in the setting of poverty. In a study termed "broadly representative of Southern Africa hospital practice," Lewis et al found that a primary diagnosis of anemia accounted for 10% of deaths in all hospital admissions. The same study showed that 2/3 of febrile patients were anemic (Hemoglobin < 11g/dL) while 18% suffered severe anemia (Hb< 7g/dL). [ii] Children have shown to be at risk as well, with anemia rates of 46%-66% reported, and over half of them suffering from iron deficiency.[iii]^,[iv],[v] It is this iron deficiency in the setting of anemia that places children at risk of increased disease burden and developmental delays.

The literature is full of examples of the long term effects of iron deficiency anemia (IDA) on infant and child development. A review of 10 studies comparing the subsequent lives of infants treated for IDA, to those never affected showed long term negative effects on IQ, increased rate of grade repetition, elevated levels of anxiety and depression, social problems, and a "widening gap in cognitive scores to 19 years old," among anemic individuals.ⁱⁱⁱ  A longitudinal study following children born in 1991-1992 linked low hemoglobin levels at 8 months of age (≤9.5 g/dL) with a substantial decrease in locomotor functioning 10 months later.[vi] More specifically, the presence of IDA in children has been shown to increase Auditory Brainstem Response (ABR) latencies, a sign of impaired mylenation during infant brain development (an iron requiring process).[vii] The latencies continue well after the IDA has been resolved, as was observed in a group of healthy but previously affected 4 y.o. children. Again, impaired myelination in the early months of life was proposed as a likely mechanism.[viii] Another study using data from the National Health and Nutrition Examination Survey II demonstrated that children with IDA were twice as likely to score below average on math tests, than unaffected children.[ix]

The best evidence the effects of IDA extend well into adolescence comes from Lozoff et al. In 1987 a group of 191 Costa Rican infants were tested for IDA and then underwent motor and mental functioning evaluations. The anemic infants scored significantly lower in both categories. All affected infants were then treated for IDA and deemed "non-anemic" by the evaluators. Improvement in motor and mental scores was observed in 36% of treated children. The 64% that remained impaired were later found to have had more severe initial IDA than their peers.[x] The investigators returned 10 years later to conduct a follow up study and were able to evaluate 87% of the original patients. The same subjects who had initial presentations of severe IDA also reported significantly reduced scores on tests of mathematics, writing, motor functioning, and spatial memory. The investigators concluded that avoiding severe IDA in infancy is crucial to normal cognitive and motor development.[xi]

In addition to developmental delays, Anemia also places infants and children at a greater risk of contracting infectious disease. Numerous studies name anemia as an independent risk factor in the etiology of diarrheal disease and childhood respiratory infections.[xii]^,[xiii] Others implicate malnutrition, a condition generally indicated by anemia, as causative in the development of disease.[xiv]^, [xv] In light of such studies one could argue that childhood infectious disease and childhood anemia are a package  and one cannot be addressed without acknowledging the role of the other.

There are several known causes of IDA. In affluent countries occult blood loss is almost always at the root of the anemia, usually as a result of GI bleeds in men and excessive bleeding during menstruation and/or childbirth in women.[xvi] Among children of developing countries IDA is most likely due to infectious and/or nutritional factors. In tropical countries, hookworm infections by Ancylostoma duodenale and/or Necator americanus are generally to blame.[xvii]^{,[xviii],[xix]} Recently, active Helicobacter pylori infection has begun to emerge as a possible cause of IDA as well. Cardenas et al. show H. Pylori to be associated with a 40% increase in ID among 7462 children age 3 or older.[xx] Using a different approach, Kurekci et al administered antibiotic therapy to pediatric patients suffering from H. Pylori as well as IDA/ID. Following H. pylori eradication, they observed a significant increase in hemoglobin and mean corpuscular volume in patients with concurrent IDA as well as significantly increased ferritin levels in ID patients, all without iron supplementation.[xxi] Finally, the role of nutrition in the etiology of IDA cannot be ignored.⁶

As of July 2004, 4.1 million of Limpopo's residents (representing 77% of the population) were living below the poverty line.[xxii] Within these households, access to clean drinking water and poor sanitation are of major concern, and also happen to be major factors contributing to hookworm and H pylori infections.^18,[xxiii] In two separate studies, Potgieter et al, and Obi et al demonstrated significantly elevated levels of fecal coliforms in tap, stored spring, and surface domestic water.[xxiv]^,[xxv] The presence of such risk factors makes the Venda region an ideal setting in which to investigate the prevalence of anemia and its etiology.

Rationale:

I've witnessed more sides of humanity in the last six months than I have in my entire life. I've seen everything from soul stirring acts of kindness to unbelievable crimes of apathy and a lot in between. I spent a summer in India and accompanied a doctor on a 5 hour hike in the Himalayas to bring a patient his blood pressure medication. The next day I watched a child of no more than 10 hold a half dead infant in one hand and beg for change with the other. The whole time city-life marched on around her as if she were a statue. I returned to the states and went to Wise, VA with the RAM clinic where patients drove 5-10 hours and slept on line in a parking lot to see a doctor the next morning. When it was their turn, each patient was welcomed with open arms and selfless care...unless it was the fourth morning...by then we were gone and they were alone. I've had incredible conversations about the inherent goodness of man with my classmates until three in the morning, and then had another tell me my morals would get in the way of my paycheck someday. For the past several months I've spent a large deal of my time exploring the ins and outs of this global contradiction between motives and morals, and while a resolution may forever escape me, I have found a purpose: to learn as much as I can about the plight of the world's poor and to work to improve it. I believe the Pfizer scholarship provides me with an ideal opportunity to begin doing just that.

Hypothesis:

Iron deficiency anemia (IDA) in school aged children in Limpopo Provence, South Africa is associated with manageable conditions (hookworm infection, H pylori, poor nutrition).

Methodology:

I plan to determine the point prevalence for anemia and two infectious causes of anemia in a population of school-aged children in the Venda region, Limpopo Provence, South Africa. The eventual success of this project will stem, in part, from logistical support provided by the South Africa-Virginia Networks and Associations (SAVANA) research consortium. SAVANA was created in an effort to foster research collaborations between the University of Virginia and South African centers of higher learning, and will provide a unique foundation from which to launch my study. First and foremost, I will have access to state of the art laboratory facilities at The University of Venda for Science and Technology. This will allow me to conduct the required bench work in a controlled, supervised environment. Secondly, I'll be able to utilize existing lines of communication between UNIVEN and the surrounding communities to gain the approval of the necessary provisional authorities and to eventually enroll study participants. Finally I'll be adding to the collective knowledge base that has resulted from the SAVANA consortium, as well as open doors for future UNIVEN-UVa collaborations. Specific methodology follows below.

Hemoglobin Status:

To determine hemoglobin status I plan to use the HemoCue 201+ as it is able to generate reliable results in 10-20 seconds without an external power source. In addition to convenience, the HemoCue system only requires a 10μl sample from a finger stick, minimizing both patient trauma and blood loss, important considerations given the vulnerability of my selected study population.[xxvi] Following the recommendations of Stoltzfus et al, children will be considered to have IDA if their total hemoglobin <9g/dL.ⁱ

Presence of Infections:

Stool samples will be collected to test for the hookworm and H pylori infections. I will conduct microscopic analysis of the samples to determine worm load. H pylori stool antigen testing[xxvii] will be performed as well to determine presence of active infection. All laboratory work will be carried out under the supervision/direction of Samie Amidou.

Nutritional Status:

Each patient agreeing to participate will fill out a questionnaire evaluating household nutritional status and socio-economic factors.

Human Subject Protection and Benefits

I have recently spoken with UVA-IRB Compliance Coordinator Blaise Spinelli, and he believes this project shows promise for expedited review. Ethical oversight in South Africa will be provided by UNIVEN under the auspices of a preexisting study.

All parties involved in the development of this project have agreed that we should offer some form of treatment to study patients who prove to be anemic and/or carry active infections. Recommended treatment of IDA in infants is a "4 week course of ferrous sulfate (3-4 mg/kg of elemental iron, in divided doses, between meals with juice)."[xxviii] Recommended treatment of hookworm infection in infants and children is either Mebendazole (100mg, twice daily for 3 days) or Pyrantel Pamoate (11mg/kg/day for 3 days with a maximum 1g/day).[xxix] H pylori treatment has been discussed, but is questionable ethically given its questionable risk/benefit profile in pediatric patients.

Expected Outcomes:

My primary objective is to determine the prevalence of iron deficiency anemia among a group of school-aged children in the Venda Region of Limpopo Provence South Africa. I'm also interested in what associations, if any, exist between anemia, hookworm infection and/or H pylori, and how nutritional variables factor into the etiology. With good fortune, this study will represent the first step in a long-term effort to monitor and, if need be, control anemia among the children of Venda.