Published online February 29, 2008
PEDIATRICS Vol. 121 No. 3 March 2008, pp. 522-529 (doi:10.1542/10.1542/peds.2007-0213)
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ARTICLE

Effect of Skin Barrier Therapy on Neonatal Mortality Rates in Preterm Infants in Bangladesh: A Randomized, Controlled, Clinical Trial

Gary L. Darmstadt, MD, MSa, Samir K. Saha, PhDb, A.S.M. Nawshad Uddin Ahmed, MBBS, FRCPc, Saifuddin Ahmed, PhDd, M.A.K. Azad Chowdhury, MBBS, FRCPe, Paul A. Law, MD, MPHf, Rebecca E. Rosenberg, MD, MPHa, Robert E. Black, MD, MPHa and Mathuram Santosham, MD, MPHa

a Departments of International Health
d Population and Family Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
b Departments of Microbiology
e Neonatology, Bangladesh Institute of Child Health, Dhaka Shishu Hospital, Dhaka, Bangladesh
c Department of Pediatrics, Kumudini Women's Medical College, Mirzapur, Tangail, Bangladesh
f Department of Medical Informatics, Kennedy Krieger Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. Skin barrier therapy during the neonatal period, when the skin barrier is most highly compromised and the risk of death is greatest, has been shown to have a number of potential benefits, including reduced risk of nosocomial sepsis. Topical application of emollients that augment skin barrier function was evaluated as a strategy for improving survival rates among hospitalized preterm infants in Bangladesh.

METHODS. A prospective, randomized, controlled, clinical trial was conducted in the special care nursery at Dhaka Shishu (Children) Hospital, the largest tertiary care children's hospital in Bangladesh. Preterm infants (gestational age: ≤33 weeks; N = 497) received daily topical applications of sunflower seed oil or Aquaphor ointment. Neonatal mortality rates were compared in an intent-to-treat analysis with a control group that did not receive emollient therapy.

RESULTS. Treatment with sunflower seed oil resulted in a statistically significant 26% reduction in mortality rates, compared with infants not receiving topical emollient therapy. Aquaphor therapy also significantly reduced mortality rates, by 32%.

CONCLUSIONS. Topical therapy with skin barrier-enhancing emollients improved survival rates among preterm hospitalized infants in Bangladesh. This study provides strong evidence for the implementation of topical therapy for high-risk preterm neonates in developing countries.

Key Words: developing country • emollient • low birth weight • mortality • preterm

Abbreviations: SSO—sunflower seed oil • CI—confidence interval

Preterm infants are at increased risk for death and acute and long-term morbidity. In many hospital and community settings in developing countries, the mortality rate for very preterm infants (ie, gestational age of <32 weeks) exceeds 50%.1–3 Although few data on morbidity are available, a recent follow-up study demonstrated that two thirds of a cohort of preterm infants (gestational age: ≤33 weeks) who were hospitalized in Bangladesh developed ≥1 disability or impairment, which placed a large burden on families and the health system.4 Over the past several decades, little progress has been made in reducing rates of preterm births,5 and rates of prematurity have increased in some settings.6 There is an urgent need to develop feasible, acceptable, cost-effective, life-saving interventions for care of these vulnerable newborns.7,8

Evidence has suggested that an important determinant of the high morbidity and mortality rates for very preterm infants is a compromised skin barrier, which results in high rates of transepidermal water loss and concomitant loss of fluid and heat, as well as increased susceptibility to invasive infections.9–15 Malnutrition further compromises skin barrier function.16 Enhancement of the skin barrier through topical emollient therapy during the neonatal period, when the skin barrier is most highly compromised13 and the risk of death is greatest,17 has been shown to reduce transepidermal water loss, stabilizing electrolyte and fluid status and conserving heat and energy, to improve growth,18–25 and to reduce the incidence of nosocomial sepsis.19,26–28 These effects are thought to be mediated through augmentation of the mechanical barrier function of the skin and/or the absorption of essential fatty acids, such as linoleic acid, and their metabolism to form building blocks of the skin barrier.9,29–31 Only one major trial, a multicenter study of extremely preterm infants (birth weight: <1000 g) that was conducted almost exclusively in high-income countries, examined the impact of emollient therapy on mortality rates and found no effect after treatment with Aquaphor (Beiersdorf, Norwalk, CT),32 a proprietary product that primarily augments mechanical skin barrier function.19,33,34

Previously, we reported that topical therapy with sunflower seed oil (SSO) for hospitalized preterm infants (gestational age: <33 weeks) in Bangladesh reduced the incidence of nosocomial bloodstream infections (ie, sepsis) by 41% (95% confidence interval [CI]: 4%–63%) and treatment with Aquaphor reduced the incidence of sepsis in the highest-risk neonates (weight: <1250 g) by 71% (95% CI: 17%–82%).27 The impact of topical therapy with skin barrier-enhancing emollients on neonatal mortality rates in that trial is reported here.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Site and Population
A randomized, controlled, clinical trial was conducted from December 1998 through July 2003 in the special care nursery at Dhaka Shishu Hospital in Bangladesh. The hospital admits term and preterm newborn infants. It draws patients from throughout Bangladesh but primarily serves an urban poor population. There is no maternity ward at this hospital; therefore, all patients were born at other hospitals or at home.

Newborn infants ≤72 hours after birth and with gestational ages of ≤33 weeks, determined as the average of measures based on criteria described by Ballard et al35 and Dubowitz et al36 and the last menstrual period, were eligible for the study (Fig 1). Infants were excluded by study physicians if they demonstrated the presence of a major congenital anomaly or hydrops fetalis, were admitted for a major surgical procedure (because high rates of infectious complications were expected), or had clinically evident skin infection (confirmed with surface culture), generalized skin disease, or a structural defect involving >5% body surface area that was likely to produce a defect in epidermal barrier function or if the admitting study physician, on the basis of clinical judgment, anticipated that the infant would die within 48 hours after admission.


Figure 1
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  		FIGURE 1 Trial profile. LAMA indicates that the patient left against medical advice.

 
Baseline information was collected on household demographic characteristics and history of the pregnancy, delivery, and immediate postnatal period for each subject. A baseline mortality risk score, based on categories for gestational age, birth weight, and gender, was calculated for each patient by using a newly developed, simplified, age/weight/gender score (G.L.D., unpublished data, 2008).

Study nurses assigned patients to a stratum (gestational age of <30 weeks or ≥30 weeks) and randomly allocated them to a treatment group by referring sequentially to the appropriate randomization list, created by using blocks of 6 with 2 assignments per block for each of the 3 groups (control, Aquaphor, or SSO). The study data manager, who had no patient care responsibilities, periodically reviewed the original randomization sequence for each stratum and compared it with the recorded allocations made by the study nurses. The study physicians were blinded to the randomization procedures.

Informed verbal consent was obtained from each family. The trial was approved by the Johns Hopkins University committee on human research and the Dhaka Shishu Hospital ethical review committee. A data and safety monitoring board met regularly to ensure patient safety.

Clinical Procedures
Patients in the intervention arms received applications of either high-linoleate SSO (Omega Nutrition, Bellingham, WA) or Aquaphor original emollient ointment (Beiersdorf, Norwalk, CT). Emollient was applied by study nurses in a manner that optimized maintenance of product sterility and minimized injury to or contamination of the skin. Before each emollient application, nurses carefully washed their hands with soap and water and allowed their hands to drip-dry, to avoid contamination from towels. Emollient was applied to the entire body surface, except for the scalp and face, 3 times per day for the first 14 days and then 2 times per day until discharge from the hospital. Details of the methods for emollient storage and handling and quality control of emollient application were described previously.27

To maintain the masking of study physicians, they did not have access to the patient randomization lists, study nurses applied emollient when the study physicians were not present on the ward, and study physicians performed routine patient assessments toward the end of the interval between applications (ie, ~8 hours [when emollient was applied 3 times per day] or ~12 hours [when emollient was applied twice per day] after the previous application), when the presence of residual emollient on the skin was minimal. The success of masking was not evaluated formally; however, study physicians generally thought that they could tell which patients were receiving emollient therapy but they could not distinguish between emollients.

Infants in the control group received the standard skin care for the special care nursery, which did not include use of topical emollients or other measures to prevent skin breakdown or to modulate skin barrier function, and they received no massage therapy. Infants in the control and intervention groups otherwise received the same general care, as described previously.27,37 Emphasis was placed on strict hand-washing before each handling of a patient. The routine hand-washing procedure included washing with soap and water and then application of Hexisol hand rub (2.5%, v/v, chlorhexidine gluconate solution in 70%, w/w, isopropyl alcohol; Advanced Chemical Industries, Dhaka, Bangladesh), followed by drip-drying of the hands before contact with the infant; no Hexisol solution was used before emollient applications. Infants were monitored closely by study nurses and physicians, who evaluated the patients clinically at enrollment and ≥3 times per day, as described previously.27

Outcome Measurement
The study was powered to detect hypothesized differences in the primary outcome, that is, rate of nosocomial infections, as reported separately.27 We also hypothesized that mortality rates would be reduced by 40% in infants who received topical therapy with SSO or Aquaphor, from a baseline mortality rate of 30% in control infants. To achieve 80% power in yielding a statistically significant result ({alpha} = .05), we estimated that 200 neonates per group were necessary. Major morbidities (≥1 per patient) contributing to death were identified by the study physicians on the basis of their expert clinical judgment and a synthesis of clinical and laboratory data.

Statistical Analyses
Data were double-entered in Epi Info 6 (Centers for Disease Control and Prevention, Atlanta, GA), and analyses were conducted by using Stata 9.2 (Stata Corp, College Station, TX). The impact of emollient treatment on rates of neonatal death (ie, death in the first 28 days of life, while hospitalized) was evaluated according to intention to treat by using a parametric survival regression analysis model with Weibull distribution. Our preliminary analysis suggested that proportionality in hazards did not hold; therefore, we did not use Cox's proportional-hazards model, and the Gompertz survival model, which often is used for mortality analysis, does not fit mortality data well at very young ages.38 A cumulative hazard curve was constructed by using the Naelson estimator.39,40


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Patients
Figure 1 outlines the trial profile. A total of 497 newborn infants (11% of all neonates, term and preterm, admitted to the special care nursery) met eligibility and exclusion criteria, were enrolled, and were allocated randomly to 1 of the 3 study arms. All patients were included in the intent-to-treat analysis. Baseline characteristics of patients in the 3 study groups, including baseline risk of death, were comparable (Table 1). No adverse events resulting from treatment were recorded.


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  		TABLE 1 Baseline Characteristics of Enrolled Infants

 
Mortality Rates
The overall mortality rate among all patients enrolled in the trial was 64% (Table 2). The neonatal mortality rate was significantly reduced (P = .042), by 26%, in infants treated with SSO (hazard-adjusted ratio: 0.74; 95% CI: 0.55–0.99) (Table 3). Treatment with Aquaphor also significantly reduced mortality rates, by 32% (hazard-adjusted ratio: 0.67; 95% CI: 0.51–0.92; P = .013). The analysis was adjusted for baseline characteristics of the infants that are known to be significantly associated with risk of death (ie, weight at enrollment, gestational age based on criteria described by Ballard et al,35 and gender), clinical conditions at enrollment or during the hospitalization that are associated with death but were unrelated to treatment effects of emollients (ie, birth asphyxia, apnea, and respiratory distress or failure), and jaundice, a relatively minor condition that reflects admission primarily with physiological hyperbilirubinemia. In very preterm infants (gestational age of <32 weeks; n = 371), mortality rates were reduced by 31% (95% CI: 6%–50%; P = .021) and 38% (95% CI: 13%–55%; P = .005) by SSO and Aquaphor treatment, respectively.


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  		TABLE 2 Survival Rates for Infants According to Treatment Group

 

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  		TABLE 3 Neonatal Mortality Comparisons Between Treatment Groups and Control Group

 
Reductions in mortality rates occurred in the late neonatal period (Table 2 and Fig 2). Serious morbidities identified in neonates who died are shown in Table 4 and included apnea, sepsis, birth asphyxia, hypothermia, necrotizing enterocolitis, and respiratory distress syndrome/respiratory failure (Table 4). Skin infections were identified in 11, 6, and 4 neonates in the comparison, SSO, and Aquaphor groups, respectively.


Figure 2
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  		FIGURE 2 Cumulative hazard probability of neonatal death.

 

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  		TABLE 4 Major Morbidities Among Neonates Who Died

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Few cost-effective, feasible interventions reach very preterm infants in developing countries with high mortality rates,7,8 where the vast majority (99%) of neonatal deaths occur.17 Mortality rates among very preterm infants remain unacceptably high, contributing to a significant proportion (~15%–20%) of overall global neonatal deaths.1–3

This is the first developing-country trial of the impact of topical emollient therapy on mortality rates. The results suggest that rates of survival of very preterm newborns in a low-resource setting such as Bangladesh can be improved significantly through topical application of emollients that have skin barrier-enhancing properties.19,29,41 The mechanism of the effect is unproven but seems to involve improvements in mechanical skin barrier function, which is thought to be the primary mode of action of Aquaphor in improving skin barrier function. This ointment contains inert materials (ie, petrolatum, mineral oil, and mineral wax) that intercalate into stratum corneum spaces to reduce transepidermal loss of water and heat and to prevent the invasion of pathogens.9,19,20,26,27 The long-chain hydrocarbons (ie, n-alkanes) of petrolatum, mineral oil, and mineral wax do not penetrate beyond the stratum corneum; therefore, they act locally and do not enter the systemic circulation.30,31,33,34 In this low-resource setting, in which the majority of children are malnourished and the low birth weight rate is among the highest in the world,42 there may also be a contribution from the absorption of lipid components of the emollients and their metabolism into building blocks of the skin barrier. Aquaphor, for example, also contains purified lanolin alcohol, which is rich in cholesterol and other epidermal lipid building blocks of the epidermal barrier (eg, fatty acids), and the effect of Aquaphor may also be mediated in part through the metabolism of these components into a structurally enhanced skin barrier.

Although the effect of SSO may be attributable in part to the mechanical barrier function of the oil within the stratum corneum, this emollient, in contrast to Aquaphor, is an especially rich source of essential fatty acids, particularly linoleic acid, which seems to be responsible for some of the beneficial effects of SSO.43–45 Highly active lipid metabolism in the epidermis and the presence of a linoleic acid transporter on keratinocytes makes it possible for the epidermis to use this lipid from topically applied SSO in the formation of a functional epidermal barrier.29–31,46,47 Furthermore, activation by linoleic acid of the nuclear hormone receptors, peroxisome proliferator-activated receptors, and farnesoid X-activated receptor involved in skin barrier development may hasten development of the skin barrier, provided other essential building blocks of the skin barrier are made available.48,49 The reason for the observed lag in reduction in mortality rates beyond the early neonatal period may reflect the time required for the topically applied products to exert such in vivo effects on skin barrier metabolism and/or development, including the uptake of essential fatty acids and their utilization in the skin barrier matrix46; however, this requires additional research. Emollients with a balanced composition of epidermal lipids, particularly balanced molar ratios of cholesterol, ceramide, palmitate, and linoleate, have been shown to promote skin barrier function most effectively.29 New research continues to identify products with optimal compositions for use with newborn infants.

Although SSO may not have the optimal balance of lipids sought in state-of-the-art products under development for use with newborn infants, it is an inexpensive and widely available natural oil. Oil massage of newborn infants is a nearly universal practice in southern Asian communities,50,51 although limited data in a mouse model suggest that the usual practice of mustard oil application does not improve skin barrier function and, moreover, is potentially toxic.41 If families and physicians could be convinced to adopt healthful skin care practices with emollients (such as SSO) that promote skin barrier function, as our preliminary investigations suggest,51,52 then the public health impact could be substantial.

Although emollient therapy is not currently promoted for use with premature infants in neonatal care units in high-income countries, this study adds to the accumulating evidence that emollient therapy has several potential benefits for the care of preterm infants in developing countries that could improve survival rates. Reduced transepidermal water loss reduces the risk for hypothermia22 and, by reducing fluid requirements and simplifying fluid management, could potentially modulate factors such as hydration status, blood pressure, and serum sodium concentrations, which place preterm infants at risk for intracranial hemorrhage.53 Reduced mortality rates, however, apparently are attributable primarily to the decreased incidence of sepsis.27,28 Recent analysis of the relationship between the skin flora and the invasion of pathogens into the blood of our study subjects showed that the odds of finding a pathogen contained on the skin but unable to gain access to the blood was elevated in the SSO and Aquaphor groups, by 72% (95% CI: 1.06–2.81; P = .031) and 50% (95% CI: 0.87–2.60; P = .149), respectively, relative to the control group.54 This supports the hypothesis that a life-saving mechanism of topical emollient therapy is to block the entry of pathogens from the skin into the bloodstream.

Another potential mediator of some of the beneficial effects of emollient therapy could be the tactile stimulation that occurs in the process of the treatments. There is some evidence that neonatal massage promotes weight gain and may improve neurodevelopmental outcomes, possibly through decreased cortisol levels, increased metabolic efficiency, or increased vagal activity.55–57 Additional research is needed, however, to define the neurophysiological and neurodevelopmental effects and to differentiate the biochemical effects of the oil from the benefits of the physical stimulation and potentially increased psychological bonding that occurs in the process of treatment.55

Our results are in general agreement with those of an earlier trial in Egypt that showed a trend toward reduced mortality rates among preterm infant (gestational age: <34 weeks) treated with SSO (adjusted odds ratio: 0.72; 95% CI: 0.39–1.34; P = .30) of a magnitude similar to that reported here, although the statistical power of that study was insufficient to detect an impact on neonatal mortality rates.28 In contrast, a United States-based, multicenter/multicountry trial among extremely preterm infants (<1000 g) showed no difference in mortality rates attributable to Aquaphor therapy.32 A number of differences in trial design, study populations, and environmental factors may account for the differences in impact. Our study population had a much higher overall mortality rate, and the special care nursery had limited to no capacity to provide many life-saving interventions available in western NICUs, such as assisted ventilation and parenteral nutrition, and had less ability to manage fluid/electrolyte and thermal status precisely. The burden of environmental contamination was also exceedingly high in Bangladesh, and sepsis, which was prevented by emollient therapy in Bangladesh27 but not in the United States-based trial,28 was a more-dominant factor in mortality rates for our study population. This may reflect the differences in profiles of the infecting organisms; the primary agent of sepsis in the United States-based trial was coagulase-negative staphylococcus, whereas highly virulent Gram-negative organisms predominated in our trial in Bangladesh. Because coagulase-negative staphylococci invade the bloodstream primarily at sites of instrumentation, and emollient therapy would be expected to have limited to no impact on preventing bacterial entry at these sites of gross skin barrier compromise, the impact of emollient therapy would be expected to be limited relative to the study population in Bangladesh, where invasive procedures that breach the skin barrier (other than intravenous catheter placement) were unavailable. In our trial, direct bacterial invasion of the skin barrier seemed to be a function much more of the integrity and function of the entire skin surface, rather than localized sites of instrumentation, and to be more amenable to emollient therapy.54

This study had sufficient but limited power to detect differences in neonatal mortality rates among treatment groups. Further investigation of this intervention is warranted, including phase 4 studies to evaluate the implementation of this intervention in several developing-country hospitals. Also needed are trials to evaluate the potential for emollient therapy to improve health and survival rates for all newborn infants, regardless of gestational age, in developing-country community settings, where effects on mortality rates may be greater, in part because of limitations in care-seeking and in the availability of quality health care. Use of behavior-change interventions to foster the adoption of more-healthful skin care practices seems to be promising, but acceptability remains to be proven among physicians and families.52 Use of other emollients, particularly locally available products, also needs to be studied.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Both SSO and Aquaphor significantly reduced mortality rates among preterm hospitalized infants with gestational ages of ≤33 weeks in Bangladesh, by ~25% to 30%. This study provides the first evidence that emollient therapy may be life-saving. Taken in combination with other evidence of benefits resulting from emollient therapy in hospitalized preterm infants, it indicates that this intervention, particularly SSO treatment (because of its low cost and availability), may be implemented in very preterm hospitalized newborns in low-resource settings. The results should be confirmed in other hospital-based studies, and evaluation should be extended to all newborns in community settings in developing countries.


   ACKNOWLEDGMENTS
 
This study was supported by the Thrasher Research Fund; the Office of Health, Infectious Diseases, and Nutrition, Global Health Bureau, US Agency for International Development (award HRN-A-00-96-90006-00); Save the Children-US through a grant from the Bill and Melinda Gates Foundation; and the Society for Pediatric Dermatology. The funders had no input regarding study design or conduct, data analysis or interpretation, manuscript preparation, or the decision to submit the results for publication.

SSO was kindly provided by Omega Nutrition (Bellingham, WA), and Aquaphor original emollient ointment was donated by Beiersdorf (Norwalk, CT). We thank Kim Mulholland, Barbara Stoll, and William Blackwelder for their guidance as members of the study's data and safety monitoring board. We also thank Dr Mahmuda Khatun for her clinical care and evaluation of the study patients and the study nurses for their attention to aseptic technique and proper emollient application.


   FOOTNOTES
 
Accepted Aug 20, 2007.

Address correspondence to Gary L. Darmstadt, MD, MS, Department of International Health E8153, Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe St, Baltimore, MD 21205. E-mail: gdarmsta{at}jhsph.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.

The opinions expressed herein are those of the authors and do not necessarily reflect the views of US Agency for International Development.

This trial has been registered at www.clinicaltrials.gov (identifier 98-04-21-03-2).


What's Known on this Subject

Preterm infants in developing countries are at increased risk for death from infection and complications of prematurity. Few feasible, cost-effective interventions exist for these vulnerable newborns. Emollient therapy in low-resource settings has been shown to protect hospitalized neonates from infection.

 

What This Study Adds

Topical emollient therapy with sunflower seed oil or Aquaphor significantly reduced mortality rates for hospitalized premature neonates, by 26% and 32%, respectively. Additional research is warranted to evaluate the implementation of this intervention in developing-country hospitals and community settings.

 


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics

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