Birth asphyxia, or failure to initiate spontaneous respiration, is the leading specific cause of neonatal mortality in low- and low-middle income countries (L/LMIC) and accounts for about one million the four million neonatal deaths that occur each year worldwide . Birth asphyxia is also the main cause of neonatal encephalopathy [1–3] and long-term morbidity including intellectual disability, cerebral palsy, and other neurodevelopmental disorders [2–4]. Mortality and morbidity from birth asphyxia disproportionately affect more infants in L/LMIC, particularly those from the lowest socioeconomic groups . Therefore, neonatal resuscitation is being implemented through formal training programs in many L/LMIC [6, 7]. Although improving resuscitation in L/LMIC may save lives, this intervention may also increase the number of survivors at risk for neurodevelopmental impairment. This has not been evaluated well in L/LMIC. However, prior empirical findings suggest that low cost, home-based, parent-provided early developmental interventions can reduce this risk and improve developmental outcomes in children .
Sequelae of birth asphyxia
Birth asphyxia can result in hypoxic-ischemic brain injury that selectively affects vulnerable areas of the immature brain. The type of neurodevelopmental sequelae, as determined by the specific area of the brain damaged and by the severity, duration, and timing of the insult, can include cognitive disabilities such as mental retardation, motor disabilities, and visual and hearing impairment [e.g, [4, 9]]. Even in the absence of mental retardation, children surviving birth asphyxia may display general cognitive abilities in the lower range of normal and learning disabilities. Sociocultural factors found in L/LMIC, such as poverty, illiteracy, low status of women, poor hygiene, lack of clean water and sanitation, and inadequate access to health care and social services exacerbate the risk for neurodevelopmental disability following birth asphyxia .
Early developmental intervention
Programs of early developmental intervention (EDI) are capable of preventing or limiting the declines in cognitive development that may occur in the first years of life following brain insult. EDI has been defined as a broad array of activities designed to enhance a young child's development . EDI interventions are intended to affect children directly via structured experiences and indirectly through influencing the care giving environment. These services can be provided in a variety of contexts, including home, center, hospital, and/or clinic, with the intensity of the interventions being based on the child's and family's needs and resources, the cultural milieu, and access to trained professionals. The primary goals for EDI include improving the child's developmental trajectories and assisting the family in addressing the needs of a child with, or at risk for, developmental delays.
The positive effects of EDI on early child development have been demonstrated in numerous controlled trials in the US and other high-income countries [e.g., [12–17]], which have been confirmed through meta-analyses [18, 19] as well as expert reviews [e.g., [16, 20, 21]]. The average effect size across studies evaluating EDI has ranged from 0.50 - 0.75 [21, 22].
Early developmental intervention in L/LMIC
The effects of EDI on early child development in infants with birth asphyxia in L/LMIC have not been evaluated sufficiently to determine if these interventions should become standard practice. We are aware of only one small single-center randomized controlled trial targeting the risk group of infants with birth asphyxia. Conducted in China , the effects of EDI were evaluated in 64 infants with birth asphyxia, who were randomized to EDI (n = 34) or conventional care (n = 30). A group of term infants (n = 38) without birth asphyxia was also provided conventional care for comparison. A relatively low-intensity home-based, parent-provided intervention included home visits to teach the parents how to provide stimulating activities with their infants. Following two visits in the first month, subsequent home-visit were made monthly during the first year and then every two months in the second year, when parents received continued instruction to apply age-appropriate stimulation activities with their infants.
Neurodevelopmental assessment performed by a masked trained evaluator using a modified Bayley Scales of Infant Development (BSID)  at 18-24 months, documented mental development index (MDI) for asphyxiated infants of 105 ± 15 in the EDI group vs. 91 ± 11 in the conventional care group (p < 0.001). Normal term infants who received conventional care and obtained a MDI of 100 ± 13. The BSID psychomotor development index (PDI) did not differ significantly between the groups. This trial suggests that a program of EDI, at a level of intensity lower than evaluated in high-income countries, may effectively promote cognitive development in infants with birth asphyxia. The effect size was about 1.0 standard deviation (SD). Nonetheless, it is unknown if the cognitive benefits are reproducible and generalizable because of the limited scope of the trial and the small sample size.
Several trials of EDI with other risk groups of infants and young children conducted in different L/LMIC, uniformly document its positive effects on child development. This has included groups at risk for neurodevelopmental disability due to prematurity or low birth weight in China  and Jamaica [26, 27]; growth retardation or stunting in Jamaica [28–30]; malnourishment in Colombia [31, 32], Jamaica [33–36], India , and Bangladesh [38, 39]; as well as socioeconomic deprivation in Jamaica , Brazil  and Vietnam . Follow-up evaluations as long as 18 years have shown significant positive effects for those who received EDI during the first two years of life on measures of intelligence, reading comprehension, mental health, and self-esteem [43, 44].
While several studies have suggested positive effects on the development of children at risk for neurodevelopmental disabilities in a number of L/LMIC, most enrolled relatively small samples. Thus, a larger, multi-site study is needed to evaluate EDI in L/LMIC.
Background information on the trial
The Brain Research to Ameliorate Impaired Neurodevelopment - Home-based Intervention Trial (BRAIN-HIT) was conducted in communities in India, Pakistan, and Zambia that participated the Global Network for Women's and Children's Health Research and are sites of the FIRST BREATH (FB) Trial. The FB Trial was the first randomized trial to test the effectiveness of standard educational programs for resuscitation interventions (initial steps of resuscitation and bag and mask ventilation) to reduce mortality from birth asphyxia (ClinicalTrials.gov). The FB Trial was developed to answer the question of whether increased resuscitation efforts would be associated with an increase of survivors at-risk for neurodevelopmental disability in societies least able to provide for their care. Therefore, BRAIN-HIT is a follow-up trial of a sub-set of the FB Trial infants who were resuscitated by bag and mask ventilation. BRAIN-HIT is designed to evaluate whether EDI can improve neurodevelopment in infants at-risk for poor neurodevelopment outcome due to birth asphyxia.
BRAIN-HIT is implemented at sites in India (Jawaharlal Nehru Medical College, Belgaum), Pakistan (The Aga Khan University, Karachi), and Zambia (University Teaching Hospital/University of Zambia School of Medicine, Lusaka). In addition, RTI International serves as the data coordinating center for the trial. Sites in India, Pakistan, and Zambia were selected for the BRAIN-HIT because these countries have well organized primary care health systems yet a high proportion of home deliveries attended by traditional birth attendants and a majority of home deliveries. Birth asphyxia is a major cause of neonatal mortality and neurodevelopmental disability in all three countries. The study sites in India, Pakistan and Zambia are relatively rural and have a high perinatal mortality rate. The India site was located in Karnataka State; in Pakistan, the site was in Thatta, about 100 kilometers from Karachi; and in Zambia, the site was located in Chongwe and Kafue Districts, about 100 kilometers from Lusaka.
Formative and feasibility research
Prior to embarking on BRAIN-HIT, investigators tested the feasibility of the methods over a two-year period in Zambia. Funded with a planning grant from the NIH Fogarty International Center, pilot work included perinatal data collection, identification of infants with birth asphyxia (Ellis neurological exam and Apgar scoring), recruitment of at risk infants, administration of the EDI program, and neurodevelopmental testing. Indicated modifications in the methods were made before implementation of the current RCT.
Aim, objectives, and hypotheses
The overall aim of BRAIN-HIT is to evaluate the effects of an EDI program on the development of children in L/LMIC who are at-risk for neurodevelopmental disability because of birth asphyxia. A group of children without perinatal complications are evaluated in the same protocol to compare the effects of the EDI in healthy infants in the same communities. If the study shows positive results, the long-term aim is to empower local health systems with training and logistic support to sustain an EDI program that can reduce morbidity for children in L/LMIC with high rates of birth asphyxia as well as stimulate further research and implementation of comparable programs worldwide.
The specific objectives are to: (1) Evaluate the effects of a home-based EDI plus health and safety counseling (HSC) compared to HSC alone on the cognitive, social-emotional, and motor development at 12, 24 and 36 months in children with birth asphyxia; (2) Determine whether children with birth asphyxia who receive EDI demonstrate cognitive, social-emotional and motor development at 12, 24 and 36 months of age that is indistinguishable from that of children without perinatal complications from the same communities; and (3) Examine whether the effects of EDI on children with birth asphyxia are moderated by child, parent, and family characteristics.
The primary hypothesis is that home-based EDI and HSC will improve cognitive development (as indicated by a difference in BSID MDI scores of 10 points [0.67 SD]) at 36 months of age compared to HSC only, in children with mild to moderate birth asphyxia and normal post-natal neurological exam. This hypothesis is also tested in groups of children without perinatal complications from the same communities. The following secondary hypotheses are also tested in children with and without birth asphyxia: (1) Improvements will be observed in children who receive EDI in social-emotional and motor development at 36 months of age compared to those who do not; (2) Improvements will be observed in children who receive EDI in all developmental domains at 12 and 24 months of age; compared to those who do not (3) The improvements in cognitive, social-emotional, and motor development related to EDI will be larger in the children with birth asphyxia compared to those without perinatal complications; (4) The effects of EDI in children with and without birth asphyxia will be moderated by child, parent, and family characteristics; and (5) Children who receive a higher EDI dose (i.e., are exposed to more EDI home visits by a parent trainer) will experience greater developmental improvements than those who receive a lower dose.