The transformative “Global Plan Toward the Elimination of New HIV Infections Among Children by 2015 and Keeping Their Mothers Alive”1 has been instrumental in reducing mother-to-child transmission of the human immunodeficiency virus (HIV). However, children continue to be infected with HIV. The 2017 report from the Joint United Nations Programme on HIV/AIDS (UNAIDS) states that globally 160 000 (100 000-220 000) children younger than 15 years were newly infected with HIV in 2016, and 2.1 million (1.7 million-2.6 million) children younger than 15 years were estimated to be living with HIV in 2016.2 These numbers indicate that health programs managing children infected with HIV are still necessary and potentially valuable.
HIV is defined as a neurotropic virus that has the propensity to infect cells in the central nervous system.3 , 4 This may result in neurocognitive impairment in children infected with HIV.5 , 6 Neurological manifestations of the virus were described early on in the epidemic in both children and adults.7–9
Child neurodevelopment is influenced both positively and negatively by innumerable environmental, social, parental, and individual factors.10 , 11 Childhood HIV infection can have a direct negative effect on neurocognitive development. A 2009 systematic review of 54 studies showed that 81% of the studies reviewed reported HIV infection as having a detrimental effect on neurodevelopment in affected children.12 An updated 2014 systematic review by the same lead author concluded that children infected with HIV were still at risk of cognitive delays in some domains and may make up a group with special educational needs.13 Developmental delays have been described in cognitive development,14 , 15 receptive and expressive language abilities,16 and fine and gross motor skills.17 Long-term behavioral and emotional difficulties18 and psychiatric disorders19 have been described in children and adolescents living with HIV.
Eastern Africa and Southern Africa have the greatest number of children younger than 15 years infected with HIV—estimated at 1 million (930 000-1.2 million).2 This region comprises low-income and low-middle-income countries that have well-documented barriers to basic education for children20 and poorly developed organizations and programs to deal with the increased developmental and educational needs of large numbers of children with developmental delay due to HIV infection. Inability to benefit from education and long-term lower productivity are consequences of a poor start in life.21
It has been reported that in utero exposure to maternal HIV infection can have a detrimental outcome on the neurodevelopment of HIV-exposed uninfected (HEU) children.22 Conflicting data exist concerning whether neurodevelopmental outcomes in HEU infants are adversely affected by exposure to maternal antiretrovirals (ARVs)—either through in utero exposure or by postnatal exposure through ingested breast milk. However, 2 recently published large cohort studies have confirmed previously available evidence finding no early neurodevelopmental differences between HEU (both when exposed to maternal triple antiretroviral treatment [ART] and maternal monotherapy-only) and HIV-unexposed uninfected (HUU) infants.23 , 24 This is reassuring considering the expanding population of HEU infants.
Pediatric ART has shown remarkable benefits in the prevention and reversal of the negative developmental consequences of HIV infection. Infants initiated on ART at an early age, that is, less than 3 months of age, performed as well as HIV-uninfected infants in all domains except locomotion, whereas infants who deferred ART initiation had lower scores on all domains tested.25 HIV-related neurodevelopmental shortfalls have been shown to improve in children taking ART, with a longer duration of ART resulting in decreased impairment.26–28 Access to ART for children living in regions with the greatest HIV burden, that is, Eastern and Southern Africa, is however not universal and was reported to be 63% (56%-71%) in 2015.29
However, not all negative neurodevelopmental consequences related to HIV infection can be ameliorated by ART. A 2014 systematic review by Sherr et al30 reported on interventions aimed specifically at reducing cognitive delay in HIV-infected and HEU children. Four published studies were included in the review and effective interventions included a coping skills intervention, home-based stimulation program, Computerized Cognitive Rehabilitation Therapy, and a Mediational Intervention for Sensitizing Caregivers (MISC). The authors concluded that special educational interventions need to be incorporated into programs and policy as a matter of urgency. The necessity for expanding existing maternal and child health services to include interventions aimed at improving neurodevelopmental outcomes is echoed in publications by UNICEF in collaboration with the South African Department of Health, as well as the World Health Organization (WHO).31 , 32
We conducted a scoping review to map existing literature describing interventions that have been employed with the aim of mitigating, improving, or preventing childhood neurodevelopmental delays resulting from exposure to and infection with HIV in young children.
In conducting this scoping review, we followed the methodological framework set out by Arksey and O'Malley33 in their definitive 2005 publication. Updated methodological guidance was obtained from the Preferred Reporting Items for Systematic Reviews and Meta-Analysis: extension for Scoping Reviews (PRISMA-ScR)34 as well as from other methodological publications.35–37 The framework described by Arksey—namely, identifying a research question, identifying relevant studies, undertaking study selection, charting the data, and collating and reporting the results—is followed in this scoping review.
Identifying the Research Question
In keeping with the objective of a scoping review, to collate data from across a broad field of knowledge, the following Population-Intervention-Comparison-Outcome (PICO) question was formulated to guide our search, “What interventions other than ART have been employed to mitigate, improve, or prevent adverse neurodevelopmental outcomes in HEU and HIV-infected preschool children?” Consistent with the PICO question of this scoping review, we did not aim to examine the outcomes of the interventions described in the various studies, as our intent was not to perform a systematic review or a meta-analysis of effectiveness.38
Search terms were clearly defined during the initial stages of planning the scoping review to guide the search strategy of the 2 independent reviewers. The period of early childhood is defined by the Convention on the Rights of the Child as the period of survival, growth, and development in children younger than 8 years.39 For the purpose of this scoping review, we chose to limit the upper age of inclusion to 6 years so as to only include children who had not yet started formal schooling. The minimum age was any time during the antenatal period if the intervention had been provided to the mother during pregnancy. A child infected with HIV was defined as having a reactive direct (DNA and/or RNA polymerase chain reaction) or indirect (HIV antibody) test for HIV any time after birth. A child who was exposed to but uninfected with HIV was defined as having been exposed to maternal HIV infection while in utero and during the breastfeeding period but who tested HIV uninfected during postnatal follow-up.
APTA describes an intervention as a purposeful skilled interaction of a physical therapist or other health care provider with the child to enable the child to reach goals and outcomes that are consistent with his or her diagnosis and prognosis.40 We searched for clinical trials that made use of interventions aimed at modifying developmental outcomes.
Studies that used recognized and standardized child assessment tools and reported outcomes related to neurodevelopmental functioning, namely, cognition, receptive and expressive communication, fine and gross motor performance and behavior, were included in this scoping review.
Identifying Relevant Studies
In May 2018, we searched the NCBI PubMed, PsycINFO, CINAHL Plus, Google Scholar, and the Cochrane Library databases to identify relevant literature. Our search included existing systematic reviews and scoping reviews, reference lists of identified articles publications for which full-text articles were available, and gray literature. We excluded case reports of fewer than 10 subjects, unpublished theses, and unpublished conference material. We limited our search to English articles. To include as much evidence as possible, we did not search a specific time span; rather, the time frame searched was limited by the specific database.
Search terms included the following: HIV, HEU, child, preschooler, caregiver, intervention, stimulation, neurodevelopment, and language, cognitive, and motor development. The search terms used are listed in Table 1. Terms were adapted for the different databases.
The following inclusion criteria were applied during the search and selection process: studies were to (1) include at least one of the defined study populations, that is, HIV-infected and/or HEU children, (2) only include children younger than 6 years, (3) include studies in which a clearly described intervention was aimed at the child and/or the caregiver with the aim of the intervention to improve the neurodevelopmental outcomes of the child, (4) standardized neurodevelopmental assessment tools were used to assess neurodevelopment and at least 1 neurodevelopmental domain—namely, cognition, language, or motor function—was reported on, and (5) HIV-infected children were ART-naive or had been started on ART. The authors held an initial meeting to define the inclusion and exclusion criteria. Two reviewers (R.S. and T.v.A.) independently reviewed abstracts and full-text articles, and if there was uncertainty about whether an article should be included, a discussion was held with all authors (R.S., T.v.A., and J.P.) and a final decision made. Regular discussions were held throughout the process to define and redefine search terms and strategies.
Searching the aforementioned databases identified 531 articles (Figure 1). The greatest number was retrieved from PubMed—880 hits when the search terms were applied to the entire text, and 435 after the list was reviewed and collated with search terms applied only to the title and the abstract. In searching PsycINFO, we retrieved 96 hits. And when duplicates were excluded, no new titles were found in CINAHL Plus, Google Scholar, and the Cochrane Library database. Articles were selected and added to a database, and 35 duplicates were removed. The titles and abstracts of the remaining 496 were reviewed independently by 2 reviewers (R.S. and T.v.A.) from which 27 were identified for full-text review. From the reference lists of these 27 articles, a further 10 titles were chosen for review. Applying the inclusion and exclusion criteria to 37 full-text articles resulted in 27 being excluded; reasons for exclusion included study population older than 6 years, n = 7; content not applicable to our search, n = 15; and the study not having an intervention, n = 5 (Figure 1). The Appendix details the search terms and strategies used for the PsycINFO database (see Supplemental Digital Content 1, available at: http://links.lww.com/REHABONC/A9).
Gray literature sources included, CDC Stacks (https://stacks.cdc.gov), Centre for Reviews and Dissemination (https://www.york.ac.uk/crd), GreyLit (http://www.greylit.org), National Information Center on Health Services Research and Health Care Technology (https://hsrr.nlm.nih.gov), Open Grey (http://www.opengrey.eu), and NICE Guidance, Public Health topics (https://www.nice.org.uk/search). The gray literature search yielded no results for our defined PICO question and stipulated inclusion and exclusion criteria.
Charting the Data
Data from the identified studies were extracted and entered directly into an electronic database created for this purpose. Variables collected included author; year of publication; country in which study was conducted; study design; cohort size; number of caregivers, children with HIV, and HEU children; age of child cohort; size of the intervention and control group and details of the comparison; numbers of caregivers and children with HIV taking ART; neurodevelopmental assessments used and details of the developmental domains the specific tests are assessing; specifics of the intervention; results; and conclusions and study limitations.
Collating, Summarizing, and Reporting the Results
We conducted a descriptive, numerical summary analysis using data from identified studies that examined the countries where the research was conducted, age of children in the cohorts, sample size, and duration of the intervention.
A qualitative, thematic analysis was completed describing the types of interventions used, whether the intervention was aimed at the caregiver or the child or both, whether the intervention was used in a cohort of HIV-infected or HEU children, and whether maternal or child ART was used in conjunction with the intervention. Trends in the utilization of various neurodevelopmental assessment instruments were also examined.
Ten studies were identified describing interventions aimed at improving neurodevelopmental outcomes in HIV-infected and HEU preschool children (Table 2). All identified studies were conducted as randomized controlled trials. Eight of the studies took place in African countries, namely, Uganda (n = 4), South Africa (n = 2), and Tanzania (n = 2). One study was conducted in the Dominican Republic, and 1 study did not report study location.
Our inclusion criteria were set to include studies in which the cohort was younger than 6 years. Ages in the 10 selected studies ranged from a gestational age between 12 and 27 weeks through 5 years of age. We included one study by Hernandez-Reif et al that included children up to 8 years old, as in this study the analysis grouped the cohort into children aged 1.5 to 5 years and 6 to 8 years due to the age limitation set by the developmental assessment scale used.
The study by Scafidi and Field41 had the smallest sample size (n = 28) as well as the shortest duration of the intervention and follow-up (10 days), but the participants received the interventional massage therapy 3 times a day. Study populations in the other trials ranged from 52 to 327 children, and the duration of the intervention ranged from 12 weeks to 15 months. The longest follow-up period was 12 months after the final time point at which the intervention had been provided to the child. Interventions varied in intensity as to how often they were provided to the child or caregiver. Caregivers in the 4 Ugandan studies were seen biweekly for 12 months and were taught skills that were performed daily by the caregivers during everyday child-caregiver interactions in the home.42–45 Similarly, in the study by Potterton et al,46 the caregivers were equipped with skills to improve daily play interactions with the children in the home environment. The 2 studies using massage therapy differed in the intensity of the intervention—the children in the study by Hernandez-Reif et al47 received biweekly massage therapy, and in the study by Perez et al48 the caregivers were equipped with the skills to conduct the massage in the home environment on a daily basis.
Interventions were aimed at either the mother/primary caregiver or the child. One study included an intervention aimed solely at the mother, namely, maternal antenatal and postnatal oral vitamin supplementation, although the infants were also exposed to the multivitamins in utero and postnatally through breastfeeding. In all 4 Ugandan studies, the intervention was aimed at the mother/primary caregiver, and children were impacted through caregiver training and development of parenting skills. Nutritional support packages were provided to the mother-child dyad in 3 studies in addition to the study-specific intervention. The interventions in 6 studies focused on caregiver training and relied on the caregiver to continue to provide the intervention, as taught, in the home environment for the study duration. One study relied on the caregiver providing a daily multivitamin supplement to the child. In 2 studies, the children received the intervention directly from the study team for the duration of the study.
We included studies with interventions aimed at both HIV-infected and HEU children. Interventions aimed at children who had been diagnosed with HIV were identified in 4 studies. In these study populations, not all the children were taking ART. The percentage of children in whom ART had been started ranged from 0% to 86%. ART initiation would have been influenced by availability and country-specific pediatric ART initiation guidelines in place at the time the study was conducted. Four studies included HEU children, and 1 reported HIV seroconversion of a child during the follow-up period. Two studies included children exposed to maternal HIV infection, but children's HIV diagnosis was not specifically reported.
The use of maternal/caregiver ART was not widely reported, but this is important as caregiver well-being has been shown to impact the well-being of the child.49 Seven studies did not report on the use of caregiver ART, and 1 study specifically reported that antenatal maternal ART had been unavailable at the time the study was conducted. One study only reported on the maternal prevention of mother-to-child-transmission (PMTCT) regimen used, and another reported the maternal PMTCT regimen as well as the use of antenatal ART.
A wide variety of child neurodevelopmental assessment instruments were used to asses development, with some studies using more than 1 tool. As per our inclusion criteria, studies were required to employ validated neurodevelopmental assessment tools measuring at least one of the following: cognitive ability, receptive and/or expressive language ability (communication), and fine and/or gross motor performance. The following assessment tools were used: Bayley Scales of Infant Development II and III (BSID II/BSID III), Behavior Rating Inventory of Executive Function–Preschool version (BRIEF), Brazelton Neonatal Behavior Assessment, Child Behavior Checklist (CBCL), Color Object Test (COAT), Developmental Profile II (DP-II), Early Child Vigilance Test (ECVT), Griffiths Scales of Mental Development (GSMD), and the Mullen Scales of Early Learning (MSEL).
Interventions identified in the studies have been grouped into 3 subgroups according to the recipient of the intervention/interventional training, that is, (1) interventions aimed at training the child's primary caregiver, (2) interventions provided directly to the child, and (3) intervention provided directly to the child's mother.
Interventions Aimed at Training the Child's Primary Caregiver. All the 4 studies carried out in Uganda used a similar intervention42–45 whereby the caregivers randomized to the intervention group received training on the MISC model. The MISC training program provides strategies for caregivers to enhance day-to-day caregiver-child interactions and thereby aim to advance the cognitive development of the child. The MISC model does not rely on toys, equipment, or educational resources. The caregivers were trained during hour-long biweekly sessions alternating between the child's home and the research office. The training was conducted over a 12-month period. The caregivers in the comparison control groups of the 4 Ugandan studies received training on a nutrition and hygiene information program designed by the Uganda Community Based Association for Women and Child Welfare (UCOBAC). The UCOBAC program is reported to meet the minimum standard of care for Ugandan families affected by HIV infection. The UCOBAC training was provided to the caregivers in the control arms during hour-long biweekly sessions alternating between the child's home and the research office over a 12-month period. In 2 of the studies, one with HIV-infected and the other with HEU children, the caregivers in both the intervention and control groups were provided with biweekly nutritional support packages in addition to the caregiver training.42 , 45
The South African study46 provided the caregivers of young HIV-infected children with a developmental stimulation program structured around activities of daily living with developmentally appropriate play incorporated into activities such as bathing and feeding. Home programs were also individually structured according to the needs of each child as indicated by the child's performance on the BSID II. Caregivers were provided with children's books and were encouraged to read and talk with their children in the home. The home program was updated every 3 months over the period of 1 year.
The second South African study in which the intervention was aimed at the child and taught to the caregiver was a study in which mothers were trained to massage their HEU infants for 15 minutes per day from study enrollment at 6 weeks of age through to when the child reached 9 months of age.48 Study participants were seen at 2-weekly intervals at the study clinic, and nutritional support packages were provided to mothers.
Although the Tanzanian study did not require parental training as such, the intervention was caregiver dependent as caregivers were requested to provide their HEU children with a daily multivitamin supplement starting during the second month of life.50
Interventions Provided Directly to the Child. Two studies provided an intervention directed at the child without requiring caregiver training or involvement. Both of these interventions provided massage therapy to the children. In a very early study published in 1996, researchers massaged HIV-exposed neonates for three 15-minute periods during 3 consecutive hours daily for 10 days while the neonates were in the hospital ward after birth.41 The second study enrolled older children infected with HIV onto a study lasting 12 weeks in which children were massaged for 20 minutes twice weekly by trained researchers.47
Intervention Provided Directly to the Child's Mother. One study reported child neurodevelopmental outcomes based on a maternal intervention in which mothers were provided with antenatal and postnatal vitamin supplements.51 Infants were indirectly exposed to the vitamin supplement in utero and while breastfeeding and received no further intervention.
Caregiver, family, socioeconomic, and child demographics were reported in all the studies. Maternal factors reported included age, anthropometrical measures, CD4 count, WHO HIV disease stage, level of education, marital status, relationship to the child (biological mother vs caregiver), level of partner support, anxiety, depression, functional impairment, mental pain, and parenting stress levels. The household socioeconomic position was documented by reporting household income, material possessions, number of adults and children living in the house, whether each child had his or her own bed, food security and variety, and amount of money spent. The population of children in each study was well described in terms of sex (in all but one study), gestational age, anthropometry, and absence of serious neurological problems.
Interventions used to enhance child development included caregiver training (4 studies), massage provided to the children (3 studies), vitamin supplementation to mothers or children (2 studies), and a stimulation program (1 study). An ideal intervention addressing early childhood stimulation should target the different aspects of child neurodevelopment. This is especially true in HIV disease, which has been shown to affect different developmental domains to varying degrees.17 , 26 , 52 A literature review detailing existing early childhood stimulation interventions in developing countries concluded that joint mother-child interventions consisting of hands-on, practical activities carried out by the mother on a daily basis in the home environment resulted in the most favorable neurodevelopmental outcomes.53
It has been reported that interventions with a greater frequency and intensity of interactions between the provider and the child, as well as those with a longer duration, showed better outcomes.53 Programs that equip caregivers with child-rearing skills that can be used daily in the home would therefore have the most enduring outcomes and have the advantage of extending the benefits to other children in the home. In the studies that we identified, training the caregivers on the MISC program, massage therapy skills, and a home-based stimulation program would have had more enduring effects than an intervention directed only at the child and provided by a trained provider for a limited period of time.
The timing of the studies we reviewed differed regarding the age of the child at which the intervention was started. Only one intervention—a massage program—started shortly after birth and continued for a 10-day period while the neonates were admitted in the ward. Half of the interventions were initiated after the first year of life. Optimal timing of an intervention depends on the type of intervention and its targeted outcome54 as abilities have differing times at which they develop—the “sensitive period.”55 Earlier may not mean better with respect to all developmental domains.
Children uninfected with HIV but who have been exposed to maternal HIV infection have been reported as having worse neurodevelopmental outcomes than HUU children. A recent meta-analysis reviewing data on the neurodevelopmental performance of HIV-infected, HEU, and HUU children reported both HIV-infected and HEU children as having worse neurodevelopmental outcomes than HUU children.22 Environmental confounders and the complexity of HIV infection in the family need to be considered when comparing developmental outcomes of HEU and HUU children. Child-rearing is impacted by maternal health and well-being, and HIV infection is often associated with poverty and adverse social circumstances,56 which can have a negative effect on early child development. Of the 10 studies we identified, only 4 interventions were aimed at HIV-infected children.
Implications for Future Research
Further research is required to evaluate the content, duration, intensity, and timing of developmental interventions to ensure maximum benefits in terms of improving childhood developmental outcomes. Small-scale interventional studies should be tested for generalizability and usability with the aim to incorporate the interventions into pediatric HIV management programs.31 A systematic review of effectiveness is needed to evaluate interventions aimed at reducing a broad array of neurodevelopmental delays. This would assist in decisions concerning comprehensive pediatric HIV management policy.
The 2012 WHO review on developmental difficulties in early childhood states that there have been few studies conducted to directly examine the effectiveness of interventions to prevent developmental difficulties in young children.32 There is a need for future research to investigate documented interventions and their outcomes.
For the purpose of this scoping review, we limited the age range of the participants included in the studies to less than 6 years, as we wanted to include only preschool children who had not yet benefitted from education received from attending formal schooling. The limited age range would have excluded studies in which the intervention was aimed at a wider age range of children. Our search would also have been limited by the availability of information as set by our review question and it is thus possible that information has been omitted. Our database search was concluded on May 25, 2018, and studies matching our inclusion and exclusion criteria published after this date would not have been included in our search. We did not conduct the optional final step involving key stakeholder and consumer consultation as described in scoping review methodology.36 Further consultations may have added additional insights into developmental interventions.
Globally, many children continue to be affected by or infected with HIV. Despite effective ART, HIV-related neurodevelopmental delays are still evident. We searched for studies with interventions, other than ART, aimed at preventing or improving adverse neurodevelopmental outcomes in these children. Of the studies identified, only one provided a home-based program specifically aimed at stimulating neurodevelopment. In view of the number of children affected by the HIV pandemic and the paucity of data found addressing our research question, further research investigating interventions to improve neurodevelopmental outcomes is warranted.
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