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a Child Development Centre, Child Development and Neurology Unit, Dhaka Shishu (Children's) Hospital, Sher-e-Bangla Nagar, Dhaka, Bangladesh
b Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
c Saving Newborn Lives Initiative, Save the Children-US, Washington, DC
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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METHODS. Infants <33 weeks' gestational age were serially assessed for neurodevelopment by physicians and developmental psychologists. An estimate of "low," "moderate," or "high" risk for neurodevelopmental impairments was made at the first visit. At later assessments, neurodevelopmental impairments were graded by severity as "none," "mild," or "serious."
RESULTS. Of the 159 enrolled children, 65% survived, 16% died, and 19% were lost to follow-up. Family income was lowest among those who died, and maternal and paternal literacy was highest among the survivors. At a mean age of 31 months, developmental status of the 85 children followed-up for 
12 months was normal in 32%; 45% had mild and 23% had serious neurodevelopmental impairments. Cognitive impairment was the most common deficit (60%). Final outcome was significantly better than estimated initially. Most serious (85%) but fewer mild (37%) problems were identified independently by both child health physicians and psychologists.
CONCLUSIONS. Parental education and family income had significant influence on postdischarge mortality. Two thirds of infants demonstrated neurodevelopmental impairments. Most mild cognitive impairments would have been missed had either physicians or psychologists alone done the assessments. Preterm infants in this low-resource setting are at high risk for neurodevelopmental impairments, which need to be identified early, preferably by a multidisciplinary team of professionals.
Key Words: disability • follow-up • impairment • low birth weight • mortality • neurodevelopment • preterm
Abbreviations: LBW—low birth weight • SGA—small for gestational age • CDC—Child Development Centre • DSH—Dhaka Shishu Hospital • NDI—neurodevelopmental impairment • NDA—neurodevelopmental assessment • EEG—electroencephalogram • BSID II—Bayley Scales for Infant Development • MDI—Mental Development Index • PDI—Psychomotor Development Index • ROP—retinopathy of prematurity
An estimated 20% of infants are born prematurely in Bangladesh, and 30% have low birth weight (LBW) (ie, <2500 g).1 With a total population of >146 million people, including >20 million children <5 years of age,2 large, unrecognized populations may be at risk for neurodevelopmental morbidity, particularly considering that 85% of deliveries occur at home, often with no skilled care; only 7% of births are ever registered; and primary health care services do not include screening for the developmentally delayed child.3
In an epidemiologic survey of disabilities among 2- to 9-year-old children in Bangladesh, an estimated 68 of 1000 had some form of disability related to motor, vision, hearing, cognitive disabilities, and seizure disorders.4 A more recent survey suggests that, although the overall prevalence of disabilities may not have changed in the past decade, there is a shift from more serious and obvious disabilities to milder problems related to cognitive disability, behavioral problems, hearing impairments, and speech and language delay.5 Methodologic issues remain as to how to identify younger children with impairments and disabilities. Yet, there is a growing awareness among parents of the presence of developmental problems early in the child's life. With fast-declining infant and child mortality rates, smaller family sizes, and increasing emphasis on enrollment into primary schools, the issue of "quality of survival" is gaining ground.
Quality of survival is of particular concern among preterm infants. A recent review of neurocognitive outcomes of very preterm infants concluded that early identification of disabilities and impairments is vital, because a significant proportion are expected to have problems that need follow-up into the preschool and school years.6 There is a paucity of information on neurodevelopmental outcomes of preterm infants in low-resource settings. In a 6-year follow-up of 201 LBW infants in India, those who were preterm and small for gestational age (SGA) had the lowest mean IQ, and all of the LBW infants were poorer in visuomotor perception, preschool skills, and language development compared with normal birth weight controls.7 In the same study cohort, intelligence and academic performance at 12 years of age remained significantly lower than controls, with poor visuomotor perception, motor incompetence, reading, and mathematics learning disabilities. The poorest cognitive outcomes persisted in preterm SGA and very LBW children.8
Comprehensive neurodevelopmental diagnosis and management requires a well-trained team of professionals. Since the early 1990s, progress has been made in using multidisciplinary teams at the tertiary health care level to address neurodevelopmental problems in Bangladesh. The first Child Development Centre (CDC) was established in 1991 within the Dhaka Shishu (Children's) Hospital (DSH), a 350-bed national children's hospital. The CDC works with a core team of professionals, including child health physicians with training in developmental pediatrics, child neurologists, developmental psychologists, and therapists. Since 1997, the CDC has assisted other public hospitals to establish similar centers within their institutions, and >22 such centers are presently in operation throughout the country.9 Demand for more services is being voiced increasingly by parents and service providers alike, indicating that the need for multiprofessional centers is gaining momentum.
A randomized, controlled trial to study the impact of topical emollient therapy on the incidence of nosocomial infections in preterm infants at DSH10 provided the CDC team with an opportunity to ascertain long-term outcomes of preterm infants and to investigate the benefits of multidisciplinary assessments. We report here the postdischarge mortality and neurodevelopmental outcomes of preterm infants who were followed-up by a team of professionals, including child health physicians and child psychologists, up to a mean age of 31 months.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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All of the patients were outborn, because DSH has no maternity ward. The majority of patients are considered poor by Bangladeshi standards, and prevalence of maternal malnutrition and LBW are among the highest in the world. Standards for care at DSH were as described previously.10
Data on family, maternal, and birth history; gestational age; anthropometric measurements; and illnesses during the hospital stay were collected from the original study. During the hospital stay, a health visitor from the CDC at DSH recorded details of the child's home address and counseled the care provider (usually the mother) on the need for careful follow-up of the infant after discharge to optimize their future development. At discharge, informed consent was obtained for enrollment into the neurodevelopmental follow-up study at the CDC.
Study Design
This was a prospective study of a cohort of preterm newborn infant survivors from the emollient trial at DSH who were enrolled on discharge and examined for neurodevelopmental impairments (NDIs) and disabilities by a team of professionals at predetermined intervals.
Subjects
Survivors (n = 159) were recruited from the parent emollient trial from March 1999 to August 2003 into the neurodevelopmental follow-up study. Measures were taken to bring defaulting infants to the CDC by sending out a health volunteer to their homes. Travel allowance was provided to the families whenever required. In case a child expired, attempts were made by the health visitor to conduct a verbal autopsy in the home. The protocol was approved by the Ethical Review Committee of the Bangladesh Institute of Child Health, DSH, and the Committee on Human Research of the Johns Hopkins Bloomberg School of Public Health.
Neurodevelopmental Follow-up
Neurodevelopmental follow-up started at 4 weeks postnatal age, continued at 3-monthly intervals for the first year, and thereafter occurred at 6-monthly intervals. At each visit, a neurodevelopmental assessment (NDA) was done by a child health physician, and a psychological assessment was performed by a developmental psychologist. These assessments were conducted independently of each other.
A developmental therapist assisted the team in counseling mothers at each visit on care practices, including nutrition and sensory-motor and cognitive stimulation. If a problem was identified, steps were taken to conduct appropriate investigations (eg, ultrasonogram, electroencephalogram (EEG), and audiometry) and/or to provide intervention (eg, on movements, positioning, seating, and feeding), advice (eg, medication), and specific counseling to the mother.
NDA
A detailed NDA form was used for data collection, taking into consideration various standardized assessment procedures and techniques,11–19 combined with our own clinical experiences. NDA included family history; antenatal, perinatal, and postnatal history; and a comprehensive neurodevelopmental examination. At every visit, the following components of the NDA were recorded, depending on the chronological age and levels of functional activity: (1) any parental worries about present or past illnesses; (2) general examination; (3) levels of alertness, activity, and responsiveness; (4) primitive reflexes; (5) assessment of near visual acuity; (6) assessment of hearing; (7) evaluation of gross and fine motor tone, posture, movement, and deep tendon reflexes; (8) cognitive functions, (eg, alertness to talking, eye-to-eye contact, social smile, labeling, peek-a-boo, object permanence, and verbal and nonverbal comprehension); (9) speech (eg, vocalization and expressive language); (10) behavior (eg, hyperactivity, attention span, sleep patterns, and communication); (11) seizure history; and (12) funduscopic examination. At every visit, nutritional status, including history of feeding practices and anthropometric measurements, was recorded. At the end of each assessment, impairments (defined as "problems in body function or structure as a significant deviation or loss which may be temporary or permanent" according to the International Classification of Functioning of the World Health Organization19) were recorded on a summary sheet in the following functional domains: motor, vision, hearing, speech, cognition, behavior, and seizures. "Functional activities for chronological age" was considered as the "gold standard," which was adjusted by a minimum of 2 months to take into consideration the prematurity of the subjects. For each type of functional activity limitation, the grades of severity and possible underlying neurodevelopmental diagnoses (eg, diplegia, squint, and sensorineural deafness) were recorded. Interobserver agreement for impairments in any of the developmental domains between study physicians was high (n = 25; r = 0.85).
Grading of low, moderate, or high risk for each developmental domain was made at the first visit. At each subsequent visit, NDIs were graded according to guidelines provided by International Classification of Functioning,20 as mild, moderate, or severe if functions were >50%, 25% to 50%, or <25% of the gold standard, respectively. A summary of criteria for severity grading at first and subsequent visits, with specific examples, is provided in Table 1.
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42 months of age. The test has been translated into Bangla, and a version that is being adapted for use in Bangladesh (eg, pictures of familiar animals replacing unfamiliar ones) was used (M. Parveen, MSc, doctoral fellow, Dhaka University, verbal communication, 2005). Older children were administered the nonverbal section of the Stanford-Binet Intelligence Scales,22 which has been adapted for Bangladesh.23 For a few visually impaired children (n = 4), the Reynell-Zinkin Scales24 was administered, and the final scores were compared with those standardized for visually impaired children. Before the study began, interobserver agreement between each of the testers and the senior psychologist (M.P.) was high (n = 25; r = 0.98) for the Mental Development Index (MDI) and the Psychomotor Development Index (PDI) of the BSID II.
Severity of cognitive impairments was graded according to the MDI and PDI scores of the BSID II, using the following cutoff points: (1) >85 was considered as normal, (2) 71 to 85 was considered as mild impairment, and (3) 70 was considered as serious impairment. The decision to include scores between –1 SD and –2 SDs as mild impairment rose from a concern about mild cognitive deficits and learning difficulties being a major outcome in follow-up studies of preterm-LBW infants.7,8,25–28 The Behavior Rating Scale results of the BSID II were graded in the following manner: (1) "within normal limits" was considered to be normal, (2) "questionable" was considered mild impairment, and (3) "suboptimal" was serious impairment. For the first assessment, normal, mild, and serious were read as low, moderate, or high risk, respectively. Final scores were corrected for gestational age at every assessment after 3 months of chronological age. For both the Stanford-Binet Scales and the Reynell-Zinkin Scales, that is, the IQ and developmental quotient (DQ), respectively, cutoff points were similar to the ones used for the PDI and MDI scores of the BSID II.
Data Analysis
All of the data were entered and analyzed using SPSSpc (version 11.0 for Windows, SPSS Inc, Chicago, IL) software. Comparisons among expired, defaulting, and alive children were done using analysis of variance for continuous variables; univariate and multivariate analysis using 
2 test was done for categorical variables. Both the physicians' and psychologists' decisions regarding NDIs and psychological test scores, respectively, were taken into consideration to compute a new variable on final neurodevelopmental outcomes. Moderate and severe impairments were collapsed into a serious outcomes category. Differences between mild and serious problems were based on epidemiologic and prognostic considerations (ie, serious impairment being a more stable condition typically leading to a disability and requiring rehabilitation; mild impairment being a more reversible condition amenable to early intervention) from our research experiences.28 Final rating was no impairment, mild impairment, or serious impairment. Initial and final NDIs were cross-tabulated, and significance was determined by using the 2 test.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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12 months, those who were lost to follow-up, and those who died (Table 2). Significant differences were found in mothers' (P = .006) and fathers' (P = .024) literacy rates (defined as "able to read a newspaper"), which were highest among survivors, and in family income (P = .026), which was lowest among those who died.
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12 months up to a mean age of 30.9 months (SD: 13.8). Among these infants, 35 (41%) were from rural areas, and 36 (42%) were females. Mean age at first assessment was 1.2 months (SD: 0.56). Normal development was observed in 32%, mild impairments were found in 45%, and serious impairments in 23%. Final outcome was significantly better than suggested by initial neurodevelopmental status at the first visit (P = .032), which had classified 6% as low risk, 39% as moderate risk, and 55% as high risk. The difference in final outcome compared with initial assessment of risk was more pronounced for older children 2 years of age (n = 59; P = .024), among whom 34% had normal development, compared with younger children <2 years of age (n = 26; P = .076), of whom 27% had normal development. There were also significant gender differences (P = .037) in mean PDI scores on the BSID II at 31 months, that is, 85 (SD: 17.1) for males (n = 49) and 93 (SD: 18.9) for females (n = 36).
Diagnoses by Physicians and Psychologists
Table 3 shows whether NDIs were diagnosed for a given child by just physicians, just psychologists, or by both professionals. Most (85%) serious impairments were identified by both professionals; 2 children with serious impairments identified by the psychologist had poor BSID II scores, and 1 child diagnosed with serious impairment by the physician had generalized epilepsy. Mild impairments in the following functional domains were identified in 15 children by physicians only: cognition (n = 9), speech (n = 4), vision (n = 3), motor delay (n = 2), hearing (n = 1), and behavior (n = 1). Nine children for whom physicians assigned a normal NDA score had psychological test scores in the mild category.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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One in 6 children died during the course of the study, and an additional 1 in 5 was lost to follow-up. Family income was lowest among those who died and highest among those lost to follow-up, and mothers' and fathers' literacy levels were highest among those who survived. This might signify that educated but comparatively poorer families used the services of DSH, which is a government-sponsored hospital with a sliding scale for hospital charges based on income. All 3 factors, that is, mothers' and fathers' education and family income, have emerged as important determinants of infant and child mortality in Bangladesh.30 From the verbal autopsies, it was surmised that acute infections had preceded most postdischarge deaths. Moreover, 9 of 16 children who were seen at least once at the CDC but subsequently died were found to be at high risk for NDIs. In a study of urban and rural children with cerebral palsy in Bangladesh, mortality was found to be highest among the most severely disabled, and each was preceded by an acute infection.31 From the same study it was found that economic (eg, travel fare), cultural (eg, young mother not allowed to travel alone), and medical (eg, acute illnesses) factors were important barriers to attendance at a rehabilitation service.32 Because the majority of traceable deaths occurred in our cohort within the first 3 months of life, early initiation of evidence-based care in the home and close networking with other health care centers closer to the child's home may have helped to prevent this outcome. In India, Bang et al33 have reported an increase in survival of LBW neonates and reduction of sepsis with home-based supportive care. In Nepal, birth outcomes improved significantly through organization of women's support groups34; and involvement of other members of the family (eg, the mother-in-law) was seen as an important factor to address delays in reaching health facilities.35 More recently, a simple package of essential newborn care, including community-based Kangaroo Mother Care, promoted through community mobilization and behavior change communications by community health workers, substantially reduced neonatal mortality in rural Uttar Pradesh, India.36 These experiences suggest that family, social, and economic empowerment and strengthened linkages between tertiary and primary health care services with each other and with the community are critical for optimum survival and follow-up of high-risk newborns.37
Nearly one third (32%) of study subjects at a mean age of 31 months were developing normally, although another half (45%) still demonstrated minor impairments, and a fourth (23%) were left with serious impairments. Although gestational ages vary, our results are comparable to those of the EPICure study, which monitored the development of infants born in 1995 in the United Kingdom and Ireland before 26 weeks' gestational age.38 At 30 months of follow-up of that cohort, 49% of 308 surviving children had a disability, including 23% with severe disability; and at follow-up at 6 years of age, it was found that severe disability at 30 months had been predictive of later developmental problems. The similarity in outcomes between our study children and those of a lesser gestational age cohort in a higher resource setting is cause for concern. Birth weight, length, and head circumference in our children were between –1 SD and –2 SDs of the mean for gestational age compared with a standard norm.39 This might be an indication of intrauterine growth restriction. Preterm, SGA infants have been found to have the lowest mean IQ in India6; and intrauterine growth restriction and subnormal head size has been found to adversely affect developmental outcomes in LBW infants.40 Studies of children of comparable gestational ages in developed countries suggest that a longer term follow-up of our study cohort is needed to determine school performance. One third of children born between 32 and 35 weeks' gestational age in Oxfordshire, United Kingdom, in 1990 were found to have school problems at 7 years old.41 In the Netherlands, a prospective follow-up of preterm infants (<32 completed weeks of gestation) at 9 years of age found 19% in special education.42 Of the children in mainstream schools, 32% were in a grade below the appropriate level for age, and 38% had special assistance. These are evidence of mild problems reflected as poor academic performance in school. Thus, our data to date may underestimate the total burden of impairments in the cohort, which is just now entering school. We are continuing to follow-up our cohort of preterm infants and believe that by using stringent methods of diagnosis (eg, including IQ cutoff points of >70–85 as mild cognitive impairment), our study findings may be more predictive of the children's future functional and educational outcomes. Furthermore, recognizing impairments earlier might have improved their chances of catch-up development. The higher proportion of those with normal development in the older age group could be one indication of this effect. There were also some gender differences in outcomes, because male children had significantly lower PDI than females at 31 months, a finding that has been reported elsewhere.43 A more detailed risk factor analysis is forthcoming from our data and will be reported separately.
The majority (85%) of serious NDIs were identified by both physicians and psychologists independently. A considerable number of children, however, would have remained unrecognized had only 1 professional done the assessment. The strength of the team approach was that the child was evaluated on multiple developmental constructs, which is reflected in the wide range of developmental problems that were found in the study children (see Table 4). Each type of problem (eg, cerebral palsy, cognitive delay, and ROP) requires specific types of management and rehabilitation. In most developing countries, a traditional "medical paradigm" of health care exists wherein physicians are usually the only professionals available. Our study reflects the qualitative changes that may occur within health services with multiprofessional involvement. Training of professionals, such as physicians, as well as psychologists and therapists, has been a key focus of the Child Development (Shishu Bikash) Network in Bangladesh, which has assisted in establishing a number of CDCs within the country.8
This study had several limitations. It did not include a matched control group to which outcomes could have been compared. Being a small but protracted study (eg, time gap from first to last enrollment was 4 years) of discharged preterm infants who had already been part of a randomized, controlled trial on the prevention of sepsis, we found it unethical to randomize them further for NDA, particularly because intervention was provided when indicated. Other discharged term infants from the same ward could not be included because of lack of logistic support. Also, the examiners were not blind to the child's neurodevelopmental status, which may have produced study bias. These factors need to be taken into consideration when interpreting the data.
At present, prospectively planned neurodevelopmental follow-up studies of preterm neonates, such as ours, do not have well-established methodologies for evaluating outcomes.44 More standardized and universally acceptable evaluation measures need to be developed. We believe that the epidemiologic tools that we used to diagnose and grade impairments could be developed into a valid tool that can be used across sites and cultures. Larger multicenter studies might have to be undertaken for this purpose.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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ACKNOWLEDGMENTS |
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We are greatful to the Bangladeshi families who willingly participated in this follow-up study to the emollient trial. We thank Kim Mulholland, Barbara Stoll, and William Blackwelder for their guidance as members of the parent study’s Data and Safety Monitoring Board (New York, NY). We also acknowledge the tireless efforts of Drs Samir K. Saha, A.S.M. Nawshad Uddin Ahmed and M.A.K. Azad Chowdhury at Dhaka Shishu Hospital in managing the parent emollient trial.
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FOOTNOTES |
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Address correspondence to Naila Z. Khan, MBBS, FCPS, PhD, Child Development and Neurology Unit, Dhaka Shishu (Children's) Hospital, Sher-e-Bangla Nagar, Dhaka 1207, Bangladesh. E-mail: zakhan{at}bangla.net; or Gary L. Darmstadt, Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205. E-mail: gdarmsta{at}jhsph.edu
This work was presented in part at the First International Perinatal Congress; February 3, 2003; Dhaka, Bangladesh; Bangladesh National Congress on Cerebral Palsy, October 2, 2003; Dhaka, Bangladesh; and Bangladesh Neonatal Forum, November 24, 2004; Dhaka, Bangladesh.
The opinions expressed herein are those of the authors and do not necessarily reflect the views of the US Agency for International Development.
The authors have indicated they have no financial relationships relevant to this article to disclose.
1 Drs Khan and Darmstadt contributed equally to this work. 
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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800g) schoolchildren: multiple areas of hidden disability.
Arch Dis Child Fetal Neonatal Ed. 1997;77
:F85
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 G. L. Darmstadt, S. K. Saha, A.S.M. N. U. Ahmed, S. Ahmed, M.A.K. A. Chowdhury, P. A. Law, R. E. Rosenberg, R. E. Black, and M. Santosham Effect of Skin Barrier Therapy on Neonatal Mortality Rates in Preterm Infants in Bangladesh: A Randomized, Controlled, Clinical Trial Pediatrics, March 1, 2008; 121(3): 522 - 529. [Abstract] [Full Text] [PDF]
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