Skip to main content

Impact of emollient therapy for preterm infants in the neonatal period on child neurodevelopment in Bangladesh: an observational cohort study

Abstract

Background

Topical treatment with sunflower seed oil (SSO) or Aquaphor® reduced sepsis and neonatal mortality in hospitalized preterm infants <33 weeks’ gestational age in Bangladesh. We sought to determine whether the emollient treatments improved neurodevelopmental outcomes during early childhood.

Methods

497 infants were randomized to receive SSO, Aquaphor®, or neither through the neonatal period or hospital discharge. 159 infant survivors were enrolled in the longitudinal follow-up study using a validated Rapid Neurodevelopmental Assessment tool and the Bayley Scales of Infant Development II (BSID II) administered at three-monthly intervals for the first year and thereafter at six-monthly intervals. Lowess smoothing was used to display neurodevelopmental status across multiple domains by age and treatment group, and Generalized Estimating Equations (GEE) were used to compare treatment groups across age points.

Results

123 children completed at least one follow-up visit. Lowess graphs suggest that lower proportions of children who received massage with either SSO or Aquaphor® had neurodevelopmental delays than control infants in a composite outcome of disabilities. In GEE analysis, infants receiving SSO showed a significant protective effect on the development of fine motor skills [odds ratio (OR) 0.92, 95% confidence interval (CI) 0.86–0.98, p=0.006]. The Psychomotor Development Index (PDI) in the BSID II showed significantly lower disability rates in the Aquaphor group (23.6%) compared to the control (55.2%) (OR 0.21, 95% CI 0.06–0.72, p=0.004).

Conclusions

Emollient massage of very preterm, hospitalized newborn infants improved some child neurodevelopmental outcomes over the first 2 years of follow-up. Findings warrant further confirmatory research.

Trial registration

ClinicalTrials.gov (98-04-21-03-2) under weblink https://clinicaltrials.gov/ct2/show/NCT00162747

Background

Among major causes of under 5-year-old child deaths, global progress has been slowest for reducing deaths due to preterm birth [1]. Preterm birth is now the top worldwide cause of death in children before their fifth birthday.

Prematurity is associated with a variety of adverse outcomes among survivors, including chronic pulmonary, cardiovascular, and metabolic disease; deficits in growth, hearing, vision, cognition, and other domains of development; and behavioral problems, learning difficulties, and poor academic performance [2,3,4,5,6,7,8,9]. Moreover, adverse outcomes can persist through adolescence and into adulthood, limiting educational achievement and adult earning potential [5, 6, 10].

Adverse outcomes among very preterm infants are particularly pronounced in developing countries where there are few resources to mitigate risks. Child disability rates are going up in many emerging economies, due primarily to relatively high rates of disability among preterm infants 28 to 32 weeks gestational age who receive poor quality care during pregnancy, childbirth, and the postpartum period [7, 11]. In our follow-up study of a cohort of preterm infants < 33 weeks’ gestational age in Bangladesh, 68% were found to have one or more disabilities or impairments [12].

Postnatal interventions can potentially improve neurodevelopment for preterm infants worldwide [13,14,15,16]. Interventions that begin early, prior to hospital discharge, and continue into early childhood when neurodevelopment is particularly responsive to nurturing interventions [17, 18], might be particularly effective at preventing adverse outcomes [14, 16]. Various strategies to increase weight gain, reduce the length of initial hospital stay, and enhance motor and cognitive development—such as nutritional supplements, physical and sensory stimulation—have been introduced over the past several decades and have met with variable success [13,14,15,16, 19].

Massage therapy is practiced in some neonatal intensive care units or intermediate care units in developed and developing countries [19,20,21,22,23,24,25,26,27,28,29,30,31,32,33], where the most consistently reported benefit among infants receiving massage therapy is greater weight gain for preterm infants [21,22,23,24,25, 29, 34, 35]. Massage may result in a variety of other potential benefits including reduced length of hospital stay and cost savings, increased bone mineralization, and improvement in a variety of functional neurodevelopmental indicators, although with variable results [20, 21, 25, 27,28,29,30, 32, 36].

Oil massage of newborn infants—combining massage with applications of a variety of emollients, particularly natural vegetable oils—is a traditional domiciliary practice utilized in many parts of the world, especially countries in the Mediterranean region, South Asia, and sub-Saharan Africa, with a growing literature on use of this approach to promote newborn and child health [29, 33,34,35, 37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55]. Topical applications of emollients for hospitalized, very preterm infants in low- and middle-income countries (LMICs) have reduced neonatal mortality 27% [relative risk (RR): 0.73, 95% confidence interval (CI): 0.56, 0.94)] and hospital-acquired bloodstream infection by 50% (RR 0.50, 95% CI 0.36, 0.71), and resulted in significant increases in weight (g) [mean difference (MD): 98.04, 95% CI 42.64, 153.45] and weight gain (g/kg/day) (MD 1.57, 95% CI 0.79, 2.36) during the neonatal period compared to control infants [34, 35, 46,47,48]. Evidence for impact of emollient therapy in preterm infants in LMIC settings is strongest for sunflower seed oil (SSO) [35]. The cost per death averted in Bangladesh was $61 for SSO therapy [56], making this a highly cost-effective intervention. Limited data exists on the impact of oil massage therapy on neurodevelopmental outcomes in infants [28,29,30, 33, 37, 38, 54].

This study describes the role of topical emollient therapy of preterm infants < 33 weeks gestational age with SSO or Aquaphor® during hospitalization in the neonatal period on neurodevelopmental outcomes during the first two years of childhood compared to infants who received no oil massage in Bangladesh.

Methods

Parent trial

We conducted a prospective, randomized, controlled clinical trial of topical emollient therapy among 497 preterm infants in the Special Care Nursery of Dhaka Shishu Hospital from December 1998 to July 2003, as described previously [47,48,49]. Dhaka Shishu Hospital is the largest pediatric hospital in Bangladesh providing both primary and tertiary care, including comprehensive child developmental and intervention services. The hospital has no delivery facility, and all neonates were out-born.

Eligibility and exclusion criteria

Newborn infants <72-hour old and <33-week gestational age who were admitted to the hospital were eligible for enrollment. Gestational age was calculated as an average determined by three measures: Dubowitz and Ballard criteria and on the basis of maternal dates (time from the first day of the last menstrual period) [57,58,59]. We excluded critically ill babies that the admitting physician, based on clinical judgment, thought would die within 48 h; those who had a major congenital anomaly, hydrops fetalis, or generalized skin disease or a structural defect of >5% body surface area; and those admitted to the hospital for a major surgical procedure.

Parent study procedures

After a study physician had confirmed patient eligibility for enrollment, neonates were allocated to strata based on gestational age [(1) <30 weeks or (2) >30 weeks] and randomly assigned by a study nurse to the untreated control group or one of two treatment groups: topical applications of high-linoleate SSO (Omega Nutrition, Bellingham, Washington) or Aquaphor Original Emollient Ointment® (Beiersdorf, Norwalk, Connecticut), as described in detail previously [47]. Briefly, we created lists for enrollment using blocks of six with two assignments per block for all of the three groups. A data manager periodically reviewed the original randomization sequence for each stratum and compared it with the recorded allocations made by the nurses. Study physicians were not involved in the procedures used to randomize infants and did not have access to the randomization lists. However, it was not possible to identify a control emollient with demonstrated safety yet no effect on epidermal barrier function; thus, masking was not done. Nurses applied the emollients when the doctors where not on the ward. Emollients were absorbed within about an hour of application, and routine physician assessments of patients were conducted toward the end of the interval in between applications when there was little to no residual emollient on the skin.

All neonates received a brief lukewarm bath at enrollment to remove potential exogenous substances on the skin. Study nurses washed their hands with soap and water, followed by Dettol disinfectant before emollient applications. Four grams of emollient per kilogram of body weight was applied three times daily for the first 14 days and then twice daily until hospital discharge, to the entire body surface avoiding the scalp, face, and intravascular catheter sites. Nurses were trained and supervised regularly in gentle application techniques to minimize the risk of skin injury and potential for spread of fecal flora. Nurses demonstrated, instructed, and observed families in the SSO and Aquaphor arms in emollient application before discharge from the hospital-based parent trial and encouraged caretakers to continue emollient practices at home.

To reduce contamination potential and oxidative breakdown, SSO was refrigerated and replaced by fresh products every two months. Additionally, fresh containers of SSO were prepared every 2 to 3 days for use at individual patient bedsides; adherence to sterile procedures during dispensing and application was enforced, and weekly cultures of individual patient SSO samples were evaluated for contamination. Aquaphor was supplied by Beiersdorf in small tubes containing enough ointment for one to two applications, eliminating contamination risk. Neonates in the control group received standard skin care for the Special Care Nursery, which did not include topical emollients, massage, or other skin care measures. Background information on demographic and clinical characteristics of patients and their mothers was obtained, including maternal obstetric history, birth history, and medical history for each subject.

Neurodevelopmental follow-up study design

This was a prospective observational cohort study from January 1999 to July 2005 of the preterm newborn infant survivors from the parent emollient trial at Dhaka Shishu Hospital. Community health workers (CHWs) recorded details of the child’s home address during the hospital stay and counseled the care provider on the need for regular follow-up to assess their child’s neurodevelopment. Subjects were enrolled into the neurodevelopmental follow-up study on discharge and were examined longitudinally for up to two years for neurodevelopmental impairments (NDIs) and disabilities by a multidisciplinary team of child health and development professionals at predetermined intervals at the Child Development Centre (CDC) at Dhaka Shishu Hospital. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for study presentation were followed.

Subjects

Infants who survived to discharge from the parent trial were enrolled. Because newborn infants come to Dhaka Shishu Hospital from throughout Bangladesh, post-discharge follow-up was not feasible for some families who lived too remotely or too far away. Baseline data on socioeconomic status and family demographics, maternal, and birth history; gestational age; anthropometric measures; and illnesses during hospitalization were collected from the parent study records.

Follow-up

Neurodevelopmental follow-up started at four weeks postnatal age, continued at three-monthly intervals for the first year, and thereafter occurred at six-monthly intervals. Travel allowance was provided to families whenever required to ensure attendance at follow-up visits. For infants who failed to appear for a visit, a CHW was sent to the home to accompany the child and guardian(s) to the CDC.

Visits included a neurodevelopmental assessment carried out by a child health physician and a psychological assessment performed by a developmental psychologist. These assessments were conducted independently of each other and each took about 30 min to complete. In addition, a full physical examination was performed by the physician, which took about 15 min. The developmental therapist counseled mothers on nutrition and care practices, including infant massage, sensory-motor, and cognitive stimulation.

Patient and public involvement

Parents and the public were not involved in study design, but participated in ensuring follow-up visits through self-reporting to the CDC.

Rapid Neurodevelopmental Assessment (RNDA)

A detailed RNDA form for children under age 2 years was used for data collection. Details of the development and validation of the methods used for RNDA have been published previously [12, 60]. RNDA included history of feeding practices and seizures and detailed physical and neurological examinations. General, fundoscopic, and primitive reflex examinations were conducted and levels of alertness, activity, responsiveness, near visual acuity, hearing, speech, behavior, and cognitive functions were assessed. Grading of low, moderate, or high risk for each developmental domain was made at the first visit, as described previously [12, 60]. At each subsequent visit, NDIs were identified and graded according to guidelines provided by the International Classification of Functioning [61] as mild, moderate, or severe if functions were >50%, 25 to 50%, or <25% of the gold standard, respectively [12].

Psychological assessment

The Bayley Scales of Infant Development (BSID II) [62] was adapted for Bangladesh [63] and was administered by a developmental psychologist at each follow-up visit for psychological assessment. Older children were administered the nonverbal section of the Stanford-Binet Intelligence Scales [64], which also was adapted for Bangladesh [65]. For a few visually impaired children (n=4), the Reynell-Zinkin Scales [66] was administered and the final scores were compared with those standardized for visually impaired children. Severity of cognitive impairments was graded according to the Mental Development Index (MDI) and Psychomotor Development Index (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 Behavior Rating Scale results of the BSID II, graded as normal, mild, and serious, were read as low, moderate, or high risk, respectively, for the first assessment, as described previously [48]. Assessment after three months of age as (1) “within normal limits” was considered to be normal, (2) “questionable” was considered mild impairment, and (3) “suboptimal” was considered as serious impairment. Details of the methods used for psychological assessments have been described previously [12]. RNDA and psychological assessment outcomes were dichotomised into disability versus no disability.

Statistical analysis

Data were entered into SPSS-PC (Version 11 for Windows; SPSS Inc., Chicago, Illinois) statistical software and then Stat Transfer was used to convert SPSS files into Stata files. The data were analyzed using Stata 9.2 (Stata Corp., College Station, Texas) statistical software. The outcomes of interest were neurodevelopment disabilities including gross motor, fine motor, vision, hearing, speech, cognitive, and behavioral disabilities. Longitudinal data for the outcome measures were originally collected in a scale format ranging from 1 to 4, with 1 = no NDI or disability, 2 = mild, 3 = moderate, and 4 = severe NDI or disability, as described previously [60]. Scores were dichotomized into NDI/disability (score = 2, 3, or 4) vs. no NDI/disability (score = 1) due to the limited sample size. A composite variable was created to examine any disability vs. no disability.

Socio-demographic and control variables were compared across the no treatment, SSO treatment, and Aquaphor treatment groups; sample sizes are shown for each variable and each analysis. Chi-square testing was used for categorical variables, and analysis of variance was used for continuous variables. Exploratory analysis was conducted using cross tabulation and chi-square testing. Additionally, histograms and scatter plots were used to view distributions of socio-demographic and control variables. Lowess graphs examined the relationship between the neurodevelopmental disability outcomes and age, by treatment group [67]. We used Generalized Estimating Equations for longitudinal data (xtgee command in Stata) to account for repeated measures on the same child over time, with a binomial family, logit link, exchangeable correlation and robust variance, adjusted for child age and maternal literacy [68]. Children were assumed to be independent of each other. The main effect in these models is the interaction term between treatment groups and age, which was necessary to compare treatment groups across age points.

Results

Subjects

Of the 216 infants who survived to discharge from the parent study, 159 infants were enrolled in the neurodevelopmental follow-up study. Some infants lived in regions and circumstances of Bangladesh which were infeasible for follow-up. Infants treated with SSO or Aquaphor were similar to control infants in family socio-demographic characteristics and in antecedent risk factors for neurodevelopmental sequelae, including maternal antenatal illness, infant gestational age and anthropometric measures, and conditions including birth asphyxia and seizures (Table 1). There were no statistically significantly differences between study group characteristics except for rural residence.

Table 1 Baseline characteristics of very preterm infants by treatment group (n=123) followed for neurodevelopmental outcomes in Bangladesh

Follow-up

Of the 159 infants enrolled in the follow-up study, 26 infants died and 30 infants were lost to follow-up; 77.4% (n=123) attended at least one follow-up visit and were included in the study analysis, 60.4% (n=96) attended two or more follow-up visits, and 59.7% (n=95) attended follow-up visits through 30 months of age. On average, children were seen 3.7 times during the follow-up period.

Rapid neurodevelopmental assessment

Exploratory analyses suggested that there were several neurodevelopmental outcomes in which treatment groups had lower proportions of developmental delays than the control group, as seen in Lowess graphs for the composite outcome of any disability (Fig. 1a), cognitiion (Fig. 1b), fine motor skills (Fig. 1c), hearing (Fig. 1d), and speech (Fig. 1e). GEE analysis indicated that SSO had a significant protective effect on risk of fine motor skill delays (OR 0.92, 95% CI 0.86–0.98, p=0.006). Additionally, children in the Aquaphor group had reduced odds of having a hearing disability compared to the control group (OR 0.91, 95% CI 0.85–0.97, p=0.030).

Fig. 1
figure 1

Lowess graphs of disability probability for preterm infants followed-up during early childhood in Bangladesh. a Probability of any disability. b Probability of cognitive disability. c Probability of fine motor disability. d Probability of hearing disability. e Probability of speech disability

Psychological assessment

MDI and PDI scores of the BSID II were comparable at the first assessment at 1 month of follow-up for the treatment groups and the control group (n=121) (Table 2). At up to 30 months of follow-up, 30.5% (29/95) and 36.8% (35/95) of children had disability on the MDI and PDI scales, respectively (Table 3). MDI scores were comparable between the control group and each of the treatment groups (Aquaphor vs. control: OR 0.80, 95% CI 0.23–2.77, p=0.689; SSO vs control: OR 1.16, 95% CI 0.35–3.93, p=0.781). The disability rate based on PDI scores was significantly lower in the Aquaphor group compared to the control group (OR 0.21, 95% CI 0.06–0.72, p=0.004). While the point estimate suggests protection, the SSO group was not significantly different from the control group (OR 0.49, 95% CI 0.15–1.52, p=0.167) (Table 3). Behavior Rating Scales of the BSID revealed ‘questionable’ scores (i.e., mild impairment) which were comparable across all three groups at both the one-month assessment and the assessment at 30 months (data not shown).

Table 2 Psychological assessment using Bayley Scales of Infant Development II at baseline (one month of age)
Table 3 Psychological assessment using Bayley Scales of Infant Development II at 30 months of age

Discussion

These findings build on the parent emollient study that demonstrated benefits of emollient therapy for improved skin barrier function, and prevention of serious infections and mortality of very preterm infants during the neonatal period [47,48,49, 55]. Here, we show that treatment with SSO reduced the risk for development of disability in fine motor skills and Aquaphor reduced the risk of hearing disability, perhaps due to protection from infection. Early acquisition of fine motor skills is important for school readiness and is predictive of later educational achievement, for example in math reading and science [69, 70]. Infants in the Aquaphor group also had significantly improved psychomotor development. Developmental therapists provided education to mothers in all three groups on how to perform massage at home during the follow-up period, which may have attenuated differences between groups.

Previous investigations have shown benefits of massage for preterm infants [29], with improved scores on several clusters on the Brazelton Neonatal Behavior Assessment Scales, including habituation, motor skills, range of state, autonomic stability, excitability, stress behaviors, and more time in active alertness [37]. Better performance on the Brazelton Scales may have facilitated early parent-infant interactions, which in turn, may have benefitted the subsequent development of these preterm infants. In an 8-month follow-up study of preterm infants randomized to massage or no massage while in the Neonatal Intensive Care Unit, massaged infants performed better on the Bayley Mental and Motor Scales [25]. Another study found superior performance on the Bayley Mental Scale later in the first year in preterm infants who received massage interventions, in addition to superior habituation performance noted at the end of the neonatal period [71]. Higher cognitive scores at 12 months of corrected age were also found in infants who received massage, while weight and motor scores did not differ between groups [72].

Limited evidence suggests that benefits of emollient therapy extend beyond those due to massage alone. One study comparing massage with SSO to massage without oil and to no massage showed that weight gain in the SSO massage group was higher compared to the massage only and the no massage groups [37, 51], suggesting that absorption and metabolism of the oil contributed to weight gain [50, 52, 53]. However, there was little statistical difference in the Brazelton Neonatal Behavior Assessment Scales post intervention [37].

SSO is a low-cost, widely available emollient in low-income countries. Topical emollient therapy is a common-to-universal newborn infant and child care practice throughout many low-resource countries [41,42,43,44,45]. A course of SSO treatment of a newborn weighing 1.5 kg costs $0.20 [47]. The higher cost and lack of consistent availability in the marketplace of Aquaphor may prove difficult in low income settings. Moreover, the cost-effectiveness of SSO was superior to Aquaphor in the parent trial to this study [47], which showed that SSO cost US$ 61 per death averted and US$ 2.15 per YLL averted (I$ 6.39, international dollars, per YLL averted) while Aquaphor cost US$ 162 per death averted and US$ 5.74 per YLL averted (I$ 17.09 per YLL averted) [56].

There were several limitations to this study. Our study enrollment and stratification were based on estimates of gestational age—the average of three separate measures—yet we lacked gold-standard ultrasound-based estimates of gestational age. The sample size became prohibitively small as participants were stratified by disability type, age, and treatment groups and were lost to follow-up primarily due to long distances from subjects’ homes to Dhaka Shishu Hospital. This analysis is best viewed as a hypothesis-generating exercise requiring further study in understanding benefits of emollient therapy on long-term neurodevelopment. Additionally, this study was unable to distinguish between the effects of massage and emollients because there was no massage only group. This was deliberate to protect the preterm infants’ skin integrity from the friction of massage without oil.

Conclusion

In conclusion, results show that emollient therapy of preterm infants with SSO or Aquaphor during the neonatal period shows promise for improving child neurodevelopmental outcomes. Resource and income-limited populations may benefit from incorporating improved emollient practices for improved long-term neurodevelopment along with (as shown in prior analyses) improved neonatal weight gain and reduced risk for serious infections and mortality. Further research into impacts and mechanisms of emollient therapy in improving child neurodevelopment is recommended.

Availability of data and materials

Data are available upon reasonable request to the corresponding author, through a data sharing agreement with Stanford University.

Abbreviations

BSID:

Bayley Scales of Infant Development

cm:

Centimeter

CDC:

Child Development Centre

CHWs:

Community health workers

CI:

Confidence interval

GEE:

Generalized Estimating Equations

LMICs:

Low- and middle-income countries

MD:

Mean difference

MDI:

Mental Development Index

NDIs:

Neurodevelopmental impairments

n :

Number

RNDA:

Rapid Neurodevelopmental Assessment

OR:

Odds ratio

PDI:

Psychomotor Development Index

RR:

Relative risk

SD:

Standard deviation

STROBE:

Strengthening the Reporting of Observational Studies in Epidemiology

SSO:

Sunflower seed oil

References

  1. Liu L, Oza S, Hogan D, Perin J, Rudan I, Lawn JE, et al. Global, regional, and national causes of child mortality in 2000-13, with projections to inform post-2015 priorities: an updated systematic analysis. Lancet. 2015;385(9966):430–40. https://doi.org/10.1016/S0140-6736(14)61698-6.

    Article  PubMed  Google Scholar 

  2. Dammann O, Leviton A, Gappa M, Dammann CE. Lung and brain damage in preterm newborns, and their association with gestational age, prematurity subgroup, infection/inflammation and long term outcome. BJOG. 2005;112(Suppl 1):4–9. https://doi.org/10.1111/j.1471-0528.2005.00576.x.

    Article  PubMed  Google Scholar 

  3. Stjernqvist K, Svenningsen NW. Ten-year follow-up of children born before 29 gestational weeks: health, cognitive development, behavior and school achievement. Acta Paediatr. 1999;88(5):557–62. https://doi.org/10.1111/j.1651-2227.1999.tb00175.x.

    Article  CAS  PubMed  Google Scholar 

  4. Wolke D, Meyer R. Cognitive status, language attainment, and prereading skills of 6-year-old very preterm children and their peers: the Bavarian Longitudinal Study. Dev Med Child Neurol. 1999;4:94–109.

    Article  Google Scholar 

  5. Taylor H, Klein N, Minich N, Hack M. Middle-school-age outcomes in children with very low birth weight. Child Dev. 2000;71:1495–511.

    Article  CAS  Google Scholar 

  6. Conley D, Bennett N. Comment: outcomes in young adulthood for very-low-birth weight infants. New Engl J Med. 2002;347:141–3.

    Article  Google Scholar 

  7. Lawn JE, Blencowe H, Darmstadt GL, Bhutta ZA. Beyond newborn survival: the world you are born into determines your risk of disability-free survival. Pediatr Res. 2013;74(Suppl 1):1–3. https://doi.org/10.1038/pr.2013.202.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Luu TM, Rehman Mian MO, Nuyt AM. Long-term impact of preterm birth: neurodevelopmental and physical health outcomes. Clin Perinatol. 2017;44(2):305–14. https://doi.org/10.1016/j.clp.2017.01.003.

    Article  PubMed  Google Scholar 

  9. Spittle A, Orton J, Anderson PJ, Boyd R, Doyle LW. Early developmental intervention programmes provided post hospital discharge to prevent motor and cognitive impairment in preterm infants. Cochrane Database Syst Rev. 2015;(11):CD005495. https://doi.org/10.1002/14651858.CD005495.pub4.

  10. Conley D, Bennett NG. Is biology destiny? Birth weight and life chances. Am Sociol Rev. 2000;65(3):458–67. https://doi.org/10.2307/2657467.

    Article  Google Scholar 

  11. Lawn JE, Blencowe H, Oza S, You D, Lee AC, Waiswa P, et al. Progress, priorities, and potential beyond survival. Lancet. 2014;384(9938):189–205. https://doi.org/10.1016/S0140-6736(14)60496-7.

    Article  PubMed  Google Scholar 

  12. Khan NZ, Ahmed HM, Parveen M, Bhattacharya M, Begum N, Chowdhury S, et al. Neurodevelopmental outcomes of preterm infants in Bangladesh. Pediatrics. 2006;118(1):280–9. https://doi.org/10.1542/peds.2005-2014.

    Article  PubMed  Google Scholar 

  13. Leib SA, Benfield G, Guidubaldi J. Effects of early intervention and stimulation on the preterm infant. Pediatrics. 1980;66:83–9.

    CAS  PubMed  Google Scholar 

  14. Maulik PK, Darmstadt GL. Community-based interventions to optimize early childhood development in low resource settings. J Perinatol. 2009;29(8):531–42. https://doi.org/10.1038/jp.2009.42.

    Article  CAS  PubMed  Google Scholar 

  15. Darmstadt GL, Sutton P. Preterm birth and neurodevelopment: a review of outcomes and recommendations for early identification and cost-effective interventions. J Trop Pediatr. 2013;59(4):258–65.

    Article  Google Scholar 

  16. Hernandez-Reif M, Field T. Preterm infants benefit from early interventions. In: Osofsky J, Fitzgerald H, editors. WAIMH Handbook of Infant Mental Health. New York: Wiley; 2000. p. 296–325.

    Google Scholar 

  17. Black MM, Walker SP, Fernald LCH, Andersen CT, DiGirolamo AM, Lu C, et al. Early childhood development coming of age: science through the life course. Lancet. 2016;389(10064):77–90. https://doi.org/10.1016/S0140-6736(16)31389-7.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Britto PR, Lye SJ, Proulx K, Yousafzai AK, Matthews SG, Vaivada T, et al. Nurturing care: promoting early childhood development. Lancet. 2016;389(10064):91–102. https://doi.org/10.1016/S0140-6736(16)31390-3.

    Article  PubMed  Google Scholar 

  19. Ottenbacher KJ, Muller L, Brandt D, Heintzelman A, Hojem P, Sharpe P. The effectiveness of tactile stimulation as a form of early intervention: a quantitative evaluation. J Dev Behav Pediatr. 1987;8(2):68–76.

    Article  CAS  Google Scholar 

  20. Vickers A, Ohlsson A, Lacy JB, Horsley A. Massage for promoting growth and development of preterm and/or low birth-weight infants. Cochrane Database Syst Rev. 2008;(4). https://doi.org/10.1002/14651858.CD000390.pub2.

  21. Dieter J, Field T, Hernandez-Reif M, Emory E, Redzepi M. Stable preterm infants gain more weight and sleep less after five days of massage therapy. J Pediatr Psychol. 2003;28(6):403–11.

    Article  Google Scholar 

  22. Ferber SG, Kuint J, Weller A, Feldman R, Dollberg S, Arbel E, et al. Massage therapy by mothers and trained professionals enhances weight gain in preterm infants. Early Hum Dev. 2002;67(1-2):37–45. https://doi.org/10.1016/S0378-3782(01)00249-3.

    Article  PubMed  Google Scholar 

  23. Lahat S, Mimouni FB, Ashbel G, Dollberg S. Energy expenditure in growing preterm infants receiving massage therapy. J Am Coll Nutr. 2007;26(4):356–9. https://doi.org/10.1080/07315724.2007.10719623.

    Article  PubMed  Google Scholar 

  24. Scafidi FA, Field TM, Schanberg SM, Bauer CR, Tucci K, Roberts J, et al. Massage stimulates growth in preterm infants: a replication. Infant Behav Dev. 1990;13(2):167–88. https://doi.org/10.1016/0163-6383(90)90029-8.

    Article  Google Scholar 

  25. Field T, Scafidi FA, Schanberg S. Massage of preterm newborns to improve growth and development. Pediatr Nurs. 1987;13:385–7.

    Google Scholar 

  26. Scafidi FA, Field T, Schanberg SM. Factors that predict which preterm infants benefit most from massage therapy. J Dev Behav Pediatr. 1993;14(3):176–80.

    Article  CAS  Google Scholar 

  27. Rice RD. Neurophysiological development in premature neonates following stimulation. Dev Psychol. 1977;13(1):69–76. https://doi.org/10.1037/0012-1649.13.1.69.

    Article  Google Scholar 

  28. Field T, Diego M, Hernandez-Reif M. Preterm infant massage therapy research: a review. Infant Behav Dev. 2010;33(2):115–24. https://doi.org/10.1016/j.infbeh.2009.12.004.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Kulkarni A, Kaushik JS, Gupta P, Sharma H, Agrawal R. Massage and touch therapy in neonates: the current evidence. Indian Pediatr. 2010;47(9):771–6.

  30. Badr LK, Abdallah B, Kahale L. A meta-analysis of preterm infant massage: an ancient practice with contemporary applications. MCN Am J Matern Child Nurs. 2015;40(6):344–58. https://doi.org/10.1097/NMC.0000000000000177.

    Article  PubMed  Google Scholar 

  31. Trivedi D. Cochrane Review Summary: massage for promoting mental and physical health in typically developing infants under the age of six months. Prim Health Care Res Dev. 2015;16(1):3–4. https://doi.org/10.1017/S1463423614000462.

    Article  PubMed  Google Scholar 

  32. Kumar J, Upadhyay A, Dwivedi AK, Gothwal S, Jaiswal V, Aggarwal S. Effect of oil massage on growth in preterm neonates less than 1800 g: a randomized control trial. Indian J Pediatr. 2013;80(6):465–9. https://doi.org/10.1007/s12098-012-0869-7.

    Article  PubMed  Google Scholar 

  33. Wang L, He JL, Zhang XH. The efficacy of massage on preterm infants: a meta-analysis. Am J Perinatol. 2013;30(9):731–8. https://doi.org/10.1055/s-0032-1332801.

    Article  PubMed  Google Scholar 

  34. Salam RA, Darmstadt GL, Bhutta ZA. Effect of emollient therapy on clinical outcomes in preterm neonates in Pakistan: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2015;100(3):F210–5. https://doi.org/10.1136/archdischild-2014-307157.

    Article  PubMed  Google Scholar 

  35. Salam RA, Das JK, Darmstadt GL, Bhutta ZA. Emollient therapy for preterm newborn infants – evidence from the developing world. BMC Public Health. 2013;13(Suppl 3):S31. https://doi.org/10.1186/1471-2458-13-S3-S31.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Moyer-Mileur L, Luetkemeier M, Boomer L, Chan GM. Effect of physical activity on bone mineralization in premature infants. J Pediatr. 1995;127(4):620–5. https://doi.org/10.1016/S0022-3476(95)70127-3.

    Article  CAS  PubMed  Google Scholar 

  37. Arora J, Kumar A, Ramji S. Effect of oil massage on growth and neurobehavior in very low birth weight preterm neonates. Indian Pediatr. 2005;42:1092–100.

    PubMed  Google Scholar 

  38. Vaivre-Douret L, Oriot D, Blossier P, Py A, Kasolter-Péré M, Zwang J. The effect of multimodal stimulation and cutaneous application of vegetable oils on neonatal development in preterm infants: a randomized controlled trial. Child Care Health Dev. 2009;35(1):96–105. https://doi.org/10.1111/j.1365-2214.2008.00895.x.

    Article  CAS  PubMed  Google Scholar 

  39. Bhatia S. Traditional childbirth practices: implications for a rural MCH program. Stud Fam Plan. 1981;12(2):66–75. https://doi.org/10.2307/1966274.

    Article  CAS  Google Scholar 

  40. Iyengar SD, Bhakoo ON. Prevention of neonatal hypothermia in Himalayan villages. Trop Geogr Med. 1991;43(3):293–6.

    CAS  PubMed  Google Scholar 

  41. Ahmed ASMNU, Saha SK, Chowdhury MAKA, Law P, Black RE, Santosham M, et al. Acceptability of oil massage with skin barrier enhancing emollients in young neonates in Bangladesh. J Health Popul Nutr. 2007;25:236–40.

    PubMed  PubMed Central  Google Scholar 

  42. Mullany LC, Darmstadt GL, Khatry SK, Tielsch JM. Traditional massage of newborns in Nepal: implications for trials of improved practice. J Trop Pediatr. 2005;51(2):82–6. https://doi.org/10.1093/tropej/fmh083.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Darmstadt GL, Saha SK. Neonatal oil massage. Indian Pediatr. 2003;40(11):1098–9.

    PubMed  Google Scholar 

  44. Darmstadt GL, Saha SK. Traditional practice of oil massage of neonates in Bangladesh. J Health Popul Nutr. 2002;20:175–9.

    Google Scholar 

  45. Duffy JL, Ferguson RM, Darmstadt GL. Opportunities for improving, adapting and introducing emollient therapy and improved newborn skin care practices in Africa. J Trop Pediatr. 2012;58(2):88–95. https://doi.org/10.1093/tropej/fmr039.

    Article  PubMed  Google Scholar 

  46. Darmstadt GL, Badrawi N, Law PA, Alam A, Ahmed S, Husein MH, et al. Topical therapy with sunflower seed oil prevents nosocomial infections and mortality in premature babies in Egypt: a randomized, controlled clinical trial. Pediatr Infect Dis J. 2004;23(8):719–25. https://doi.org/10.1097/01.inf.0000133047.50836.6f.

    Article  PubMed  Google Scholar 

  47. Darmstadt GL, Saha SK, Ahmed ASMNU, Chowdhury MAKA, Law PA, Ahmed S, et al. Effect of topical treatment with skin barrier-enhancing emollients on nosocomial infections in preterm infants in Bangladesh: a randomized controlled trial. Lancet. 2005;365(9464):1039–45. https://doi.org/10.1016/S0140-6736(05)71140-5.

    Article  CAS  PubMed  Google Scholar 

  48. Darmstadt GL, Saha SK, Ahmed ASMNU, Ahmed S, Chowdhury MAKA, Law P, et al. Effect of skin barrier therapy on neonatal mortality rates in preterm infants in Bangladesh: a randomized, controlled, clinical trial. Pediatrics. 2008;121(3):522–9. https://doi.org/10.1542/peds.2007-0213.

    Article  PubMed  Google Scholar 

  49. Darmstadt GL, Saha SK, Ahmed ASMNU, Choi Y, Chowdhury MAKA, Law PA, et al. Effect of topical emollient treatment of preterm neonates in Bangladesh on invasion of pathogens into the bloodstream. Pediatr Res. 2007;61(5, Part 1):588–93. https://doi.org/10.1203/pdr.0b013e3180459f75.

    Article  CAS  PubMed  Google Scholar 

  50. Prottey C, Hartop PJ, Press M. Correction of the cutaneous manifestation s of essential fatty acid deficiency in man by application of sunflower seed oil to the skin. J Invest Dermatol. 1975;64(4):228–34. https://doi.org/10.1111/1523-1747.ep12510667.

    Article  CAS  PubMed  Google Scholar 

  51. Fallah R, Akhavan Karbasi S, Golestan M, Fromandi M. Sunflower oil versus no oil moderate pressure massage leads to greater increases in weight in preterm neonates who are low birth weight. Early Hum Dev. 2013;89(9):769–72. https://doi.org/10.1016/j.earlhumdev.2013.06.002.

    Article  CAS  PubMed  Google Scholar 

  52. Taheri PA, Goudarzi Z, Shariat M, Nariman S, Matin EN. The effect of a short course of moderate pressure sunflower oil massage on the weight gain velocity and length of NICU stay in preterm infants. Infant Behav Dev. 2018;50:22–7. https://doi.org/10.1016/j.infbeh.2017.11.002.

    Article  PubMed  Google Scholar 

  53. Jabraeile M, Rasooly AS, Farshi MR, Malakouti J. Effect of olive oil massage on weight gain in preterm infants: a randomized controlled clinical trial. Niger Med J. 2016;57(3):160–3. https://doi.org/10.4103/0300-1652.184060.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Li Z, Zhong Q, Tang L. A meta-analysis of the efficacy and safety of using oil massage to promote infant growth. J Pediatr Nurs. 2016;31(5):e313–22. https://doi.org/10.1016/j.pedn.2016.04.003.

    Article  PubMed  Google Scholar 

  55. Saedi R, Ghorbani Z, Shapouri MA. The effect of massage with medium-chain triglyceride oil on weight gain in premature neonates. Acta Med Iran. 2015;53(2):134–8.

    Google Scholar 

  56. Lefevre A, Shilcutt SD, Saha SK, Ahmed ASMNU, Ahmed S, Chowdhury MAKA, et al. Cost effectiveness of skin barrier enhancing emollients among preterm neonates in Bangladesh. Bull World Health Organ. 2010;88(2):104–12. https://doi.org/10.2471/BLT.08.058230.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Dubowitz L, Dubowitz V, Goldberg C. Clinical assessment of gestational age in the newborn infant. J Pediatr. 1970;77(1):1–10. https://doi.org/10.1016/S0022-3476(70)80038-5.

    Article  CAS  PubMed  Google Scholar 

  58. Ballard J, Khoury J, Wedig K, Wang L, Ellers-Walsman B, Lipp R. New Ballard Score, expanded to include extremely premature infants. J Pediatr. 1991;119(3):417–23. https://doi.org/10.1016/S0022-3476(05)82056-6.

    Article  CAS  PubMed  Google Scholar 

  59. Rosenberg RE, Ahmed S, Ahmed ASMNU, Saha SK, Chowdhury MAKA, Black RE, et al. Determining gestational age in a low-resource setting: validity of last menstrual period. J Health Popul Nutr. 2009;27:332–8.

    PubMed  PubMed Central  Google Scholar 

  60. Khan NZ, Muslima H, Begum D, Shilpi AB, Akhter S, Bilkis K, et al. Validation of rapid neurodevelopmental assessment instrument for under-two-year-old children in Bangladesh. Pediatrics. 2010;125(4):e755–62. https://doi.org/10.1542/peds.2008-3471.

    Article  PubMed  Google Scholar 

  61. World Health Organization. International Classification of Functioning, Disability and Health. Geneva: World Health Organization; 2001.

    Google Scholar 

  62. Bayley N, Psychological Corporation. Bayley Scales of Infant Development. New York: Psychological Corp; 1969.

    Google Scholar 

  63. Parveen M, Rahman S, Islam S, Zaman S, Hamadani J, Khan N. Adaptation of items of bayley scales of infant development-II (BSID-II) suitable for Bangladeshi infants. Dhaka Univ J Biological Sci. 2014;23(2):187–95. https://doi.org/10.3329/dujbs.v23i2.20099.

    Article  Google Scholar 

  64. Thorndike RL, Hagen EP, Sattler JM. The Stanford-Binet Intelligence Scale. 4th ed. Chicago: Riversham Publishing Company; 1986.

    Google Scholar 

  65. Sultana N, Huq S, Khan M. Adaptation of the five nonverbal subtests of Stanford-Binet Intelligence Scale Fifth Edition for use in urban Bangladesh. Int J Soc Sci. 2012;5(1):45–62.

    Google Scholar 

  66. Reynell J. The Reynell-Zinkin Scales. Developmental scales for young visually handicapped children: part i mental development. Windsor: NFER-Nelson Publishing Co; 1981.

    Google Scholar 

  67. Cleveland W. Robust locally weighted regression and smoothing scatterplots. J Am Stat Assoc. 1979;74(368):829–36. https://doi.org/10.1080/01621459.1979.10481038.

    Article  Google Scholar 

  68. Zeger S, Liang K, Albert P. Models for longitudinal data: a generalized estimating equation approach. Biometrics. 1988;44(4):1049–60. https://doi.org/10.2307/2531734.

    Article  CAS  PubMed  Google Scholar 

  69. Cameron CE, Brock LL, Murrah WM, Bell LH, Worzalla SL, Grissmer D, et al. Fine motor skills and executive function both contribute to kindergarten achievement. Child Dev. 2012;83(4):1229–44. https://doi.org/10.1111/j.1467-8624.2012.01768.x.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Grissmer D, Grimm KJ, Aiyer SM, Murrah WM, Steele JS. Fine motor skills and early comprehension of the world: two new school readiness indicators. Dev Psychol. 2010;46(5):1008–17. https://doi.org/10.1037/a0020104.

    Article  PubMed  Google Scholar 

  71. Field T. Preterm infant massage therapy studies: an American approach. Semin Neonatol. 2002;7(6):487–94. https://doi.org/10.1053/siny.2002.0153.

    Article  PubMed  Google Scholar 

  72. Abdallah B, Badr LK, Hawwari M. The efficacy of massage on short and long term outcomes in preterm infants. Infant Behav Dev. 2013;36(4):662–9. https://doi.org/10.1016/j.infbeh.2013.06.009.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the community health workers who made every effort to reach and facilitate follow-up with each family for each visit. We are deeply grateful to the families of our study patients who made extraordinary efforts to attend follow-up visits.

Funding

This study was supported by the Thrasher Research Fund; the Office of Health, Infectious Diseases and Nutrition, Global Health Bureau, United States Agency for International Development (USAID; award HRN-A-00-96-90006-00); Save the Children/USA through a grant from the Bill & Melinda Gates Foundation; and the Society for Pediatric Dermatology. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data and had final responsibility to submit the paper for publication.

Author information

Authors and Affiliations

Authors

Contributions

GLD conceived the study and was principle investigator of the parent trial. SKS was the site principle investigator for the parent study, and ASMNUA and AC were responsible for clinical care of the subjects. NZK and GLD designed the neurodevelopmental follow-up study. NZK led the neurodevelopmental assessments and provided oversight to assessments by HM and MP. SR conducted the analysis with oversight from SZ. WM led the literature review. GLD wrote the first draft of the paper. The authors reviewed and approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to Gary L. Darmstadt.

Ethics declarations

Ethics approval and consent to participate

Informed verbal consent for enrollment in the parent trial was obtained from each family, as approved by study institutional review boards. Verbal informed consent was also obtained for enrollment into the neurodevelopmental follow-up study. The parent and the follow-up study protocols were approved and progress monitored by the Johns Hopkins Committee for Human Research and the Ethical Review Committee of Dhaka Shishu Hospital. The parent trial was registered at clinicaltrials.gov (98-04-21-03-2) under weblink https://clinicaltrials.gov/ct2/show/NCT00162747.

Consent for publication

Not applicable.

Competing interests

The authors have indicated they have no potential conflicts of interest to disclose. The authors have indicated they have no financial relationships relevant to this article to disclose.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Darmstadt, G.L., Khan, N.Z., Rosenstock, S. et al. Impact of emollient therapy for preterm infants in the neonatal period on child neurodevelopment in Bangladesh: an observational cohort study. J Health Popul Nutr 40, 24 (2021). https://doi.org/10.1186/s41043-021-00248-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s41043-021-00248-9

Keywords