Severe malaria in children is associated with long-term neurocognitive impairment, but it is unclear whether it is associated with long-term behavioral problems.
Children <5 years old with cerebral malaria (CM) or severe malarial anemia (SMA) treated at Mulago Hospital, Kampala, Uganda were assessed for behavioral outcomes at 0, 6, 12, and 24 months using the Child Behavior Checklist. Sample sizes at 0, 12, and 24 months were 122, 100, and 80 in the CM group, 130, 98, and 81 in the SMA group, and 149, 123, and 90 in healthy community control (CC) children, respectively. Age adjusted z-scores for behavioral outcomes were computed using scores for the CC group. Study groups were compared using regression models adjusted for age, nutritional status, preschool education, and socioeconomic status.
At 12 months, children with SMA had higher z-scores than CC children for internalizing (mean difference, 0.49; SE, 0.14; P = .001), externalizing (mean difference, 0.49; SE, 0.15; P = .001), and total problems (mean difference, 0.51; SE, 0.15; P < .001). Children with CM had higher adjusted z-scores than CC children for externalizing problems (mean difference, 0.39; SE, 0.15; P = .009) but not internalizing or total problems. At 24 months, children with CM or SMA both had increased internalizing and externalizing behavioral problems compared with CC children (P ≤ .05 for all).
CM and SMA are associated with long-term internalizing and externalizing behavioral problems in children. They may contribute substantially to mental health morbidity in children <5 years old in malaria endemic areas.
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RE:Children’s Research Often Goes Unpublished LETTER TO THE EDITOR
Drs. Florence Bourgeois and Natalia Pica – paediatricians at Harvard Medical School and Boston Children’s Hospital – recently published a manuscript in Pediatrics (Pediatrics 2016; 138: 1-9) investigating interventional clinical trials in children conducted between 2008 and 2010. Their paper revealed two “troubling” findings. First, that 104 of the 559 trials started (19%) were discontinued before they were completed. Second, of the 455 completed trials, 136 (30%) were not published. This is clearly a problem; as Bourgeois and Pita note, there is an ethical imperative to ensure that the results of clinical trials are reported and that the risks taken by the children who participated in the research result in benefits shared by other children.
The determinants for discontinuation and publication are complex. When the funding source was explored, the authors found that discontinuation was less common among industry funded (as opposed to investigator-initiated) and that failure to publish was more common when a trial was funded by industry. However, they also found that a number of unpublished studies were funded by classical academic sources and conducted in highly regarded academic centers. Clearly other factors are at play.
A recent commentary on NPR Health News reviewing this study suggested that this occurs because investigators “don’t take the effort to publish and share their results.” In our opinion this opinion is an unfair assessment. There are several practical issues that negatively impact the publication of clinical trials involving children. Publication of research findings is a difficult journey, especially for child health researchers.
First, trials involving children are more likely to be published in pediatric journals, of which there are many fewer than adult journals. Pediatric studies can certainly make their way into main-stream medical journals – but usually only when they involve very common problems or have very dramatic findings. An important factor – one that applies equally to adult and child researchers – is the hard reality that editors tend to be much more likely to publish positive than negative findings despite initiatives to reduce this pressure.
One inescapable factor that makes the publication of pediatric clinical research less desirable for publication is their relative size. Pediatric clinical trials are often much smaller than those in adults, and editors are often reluctant to devote journal space to these small studies as compared to pivotal clinical trials of drugs in adults which often times contain hundreds and in some cases, thousands of adult participants. Informed parental consent constitutes another challenge. Parents have frequently adopted the belief that they should protect their children from research rather than through research, ignoring the fact that current therapy is often an uncontrolled investigation. As investigators, we have often approached 10-20 families before obtaining permission to enroll one child in a study. The difficulty associated with conducting many pediatric clinical trials is compounded when a regulatory requirement to study a drug in a pediatric population (in order for it to receive approve product labeling for infants and/or children) often entails asking a parent to consent to a clinical trial of a medication that may already be commonly used “off label” in children. Parents often assume that when a medicine is used to treat their child, it has been adequately evaluated in the context of a rigorous, controlled clinical trial. When faced with the evidence that this may not be the case, a conundrum ensues, both for the parent, the practitioner and the investigator working to conduct a clinical trial.
For clinical trials that have one or more sites in the U.S. and are regulated by the U.S. Food and Drug Administration (FDA), registration is required for trials that meet the FDAAA 801 definition of an "applicable clinical trial" and were either initiated after September 27, 2007, or initiated on or before that date and were still ongoing as of December 26, 2007. Additionally clinical trials supported by funding from the National Institutes of Health in the U.S. carry with them an institutional requirement that the trial be entered into ClinicalTrials.gov. In contrast to biomedical journals with low impact factors, which may agree to publish clinical trial results from studies that have negative findings and/or were conducted with less than vigorous scientific rigor and in the process, “bury” the results, ClinicalTrials.gov makes the information completely accessible for professionals and the general public alike. Thus, when an investigator deposits his/her work with this site, they are meeting their ethical imperative to make the information from a trial freely available.
The path to publication is long and difficult, and the authors of this commentary have considerable experience, including completing studies that have taken a long journey to publication. Child health researchers are by and large hard working, ethical and highly motivated professionals who are committed to improving the health and welfare of children through the process of discovery, which includes conducting and publishing research to the highest standard. The implication that the publication gap is due to lack of effort is, in our view, neither accurate nor fair.