Background: Premature infants admitted to the NICU are at a high risk of suffering the consequences of early maternal separation due to their physiological and metabolic immaturity. Bonding processes of mother and infant may also be at risk from early maternal separation. Consequently, infants become vulnerable to a myriad of internal and external events that increase energy loss. Three main factors that may negatively influence the infant’s ability to meet the energy needs after birth are inadequate glycogen stores, immature glucose metabolism and increased ATP degradation due to procedural pain. Processes mediating energy conservation have not been adequately investigated.
Kangaroo mother care (KMC) has been identified as an intervention that activates mechanisms of energy preservation in this population. Direct effects of KMC are improved mortality and morbidity, by stabilization of breathing, thermal regulation, oxygen saturation, heart rate, improved breast-feeding and better parent bonding. Other notable effects are rapid quieting in the infant and analgesic properties. Kangaroo mother care mimics the relaxation found in utero, minimizes dyad separation, and maximizes a battery of physical, physiological, and behavioral effectors that are energy-conserving, and mediated by several different central and peripheral mechanisms. This study links KMC to hypothesized findings of energy conservation as measured by reduced biochemical markers of ATP degradation and oxidative stress. This is the first study that will link physiological biochemical data to the theorized physiological effects of KMC on the infant’s growth, development and response to painful procedures.
Methods: A prospective randomized controlled trial design will be used to test the hypothesis that exposure to KMC will significantly alter biochemical markers of ATP utilization, oxidative stress and cell injury. The study will be conducted at a Level III neonatal intensive care unit in Southern California. The NICU is a tertiary care unit, caring for inborn and out born patients with an average daily census of 84 babies. Potential subjects are premature infants 28-34 weeks gestation who are medically stable as determined by a SNAPPE_II score of less than 9 (Score for Neonatal Acute Physiology- Perinatal extension SNAPPE –II), who have medically required heel lance. Treatment allocation is 1:1. The PI and treatment providers will not be blinded to the treatment due to the nature of this study.
PI will simultaneously collect urine at 3 different intervals for the intervention and the control groups. For the intervention group, urine will be collected on Day 3 at Time 0 - before KMC, Time 1- 3 hours after KMC, and Time 2- 6 hours post KMC. For the control group, urine concentrations of Hx, Xa, and UA will also be collected on Day 3 at Time 0 – before standard NICU incubator care, Time 1- 3 hours after incubator care, and Time 2- 6 hours post incubator care and measured using high performance liquid chromatography (HPLC 100% accuracy) and allantoin will be quantified using gas chromatography/ mass spectroscopy. The effect of KMC on procedural pain (heel lance) will be analyzed from urine samples obtained at Time 0 and Time 1-3 hours after the painful procedure. Subjects randomized to the control (no KMC group) will receive the current standard of care for procedural pain (Sweet-Ease or 24% sucrose).
Bonding will be measured using The Mother-to-Infant Bonding Scale (MIBS). It is a self-report instrument by the mother that has been tested for its psychometric properties in the general and NICU population. It was first devised to screen the general population for postnatal difficulties relating to the maternal emotional behavior towards her baby in the first days (48-72h) postpartum. A principal components and reliability analysis demonstrated an alpha score of 0.71. The instrument is composed of 8 items (adjectives) describing feelings mothers have toward their babies in the first weeks after they are born. The items are scored from 0 to 3 with a total score ranging from 0 to 24 and high scores indicating disturbance in the mother-infant bond. The instrument is a simple questionnaire to administer. In a study validation in the NICU population MIBS satisfactorily detected difficulties in mother child bonding: The area under the ROC curve was 0.93 with a sensitivity of 0.9 and a specificity of 0.8 for a threshold score ≥2. The positive predictive value for this threshold was 40.9% (IC95% (20.36-61.45) and the negative predictive value was 98.1% (IC 95% (89.93-99.95). This is a reliable instrument that generates valid data in the NICU population. Mothers of both the intervention and control groups will be assessed using the MIBS self-rating instrument 72 hours postpartum at 1 hour after incubator care or 1 hour post KMC intervention.
Inclusion and Exclusion criteria: Potential subjects are premature infants 28- 34 weeks gestation and less than 1 day of age postnatal and are medically stable as determined by a SNAPPE_II score of less than 9. All attempts will be made to enroll subjects before DOL 3.
Exclusion criteria will include: 1) requirement for surgery; 2) intraventricular hemorrhage (IVH) > or equal to grade 3; 3) neonates on medication such as morphine, fentanyl, versed, muscle relaxants, phenobarbital, or Dilantin; 4) renal injury (plasma creatinine > 1mg/dl; 5) severe cyanotic heart disease or severe respiratory distress; 6) known abdominal wall or intestinal anomaly or injury (NEC); 7) chromosomal anomaly; and 8) facial anomaly.
Sample size calculation: A convenient sample of 68 potential subjects of premature infants 28-34 weeks gestation will be alternately randomized 34 to the control group and 34 to the intervention group. We expect 25% change in purines to be clinically significant and a SD of 0.5, which would yield an effect size of 0.5, and would require a sample size of approximately 34 subjects in each group. For this ANCOVA approach, we calculated the power to detect differences in purine levels among premature infants 28-34 weeks gestation in terms of a moderate effect size of 0.5. The calculations assumed a single outcome, a Type I error rate (α) of .05, a Type II error rate (ß) of .20 (power of .80), and a two-tailed statistical test, as is appropriate for research purposes. With 68 participants per condition and no effective covariate, this study could detect an effect size of .57. We believe this effect size is small enough that the intervention can produce these differences between conditions, but not so small as to be clinically ad statistically irrelevant.
Statistical Approach:To examine the primary research question, a repeated-measures analysis of covariance (ANCOVA) will be conducted to determine whether significant differences in purine levels (energy expenditure/conservation) exist. Descriptive analysis of all ratio level measurements will be performed to characterize the study sample. All dependent measures will be examined and tested for assumptions of normalcy. Additional tests related to equality of error variances, homogeneity of regression slopes, and multicollinearity will also be conducted. Primary factors in the ANCOVA include time and treatment. Potential covariates and confounders include age, gestational age, ethnicity, FIO2, method of oxygen support, weight, severity of illness, and medications. Appropriate post hoc comparisons will be conducted if warranted. All tests of hypotheses will be two-sided and conducted at an alpha level of 0.05.
Results: Pending
Significance: This study examines the potential biologic mechanism for KMC efficacy through measuring infant energy utilization biomarkers in urine (hypoxanthine, xanthine, and uric acid, and allantoin). Knowledge linking biochemical evidence with physiologic benefits of KMC will further support spread of its practice. Given the prevalence, associated disability and impairment to the premature infant, and the economic burden to both health organizations and families, rigorous measures and assessment of the benefits of kangaroo mother care is imperative.
Implications: To further inform the use of kangaroo mother care in research and clinical settings.
Conclusion: This study will supply the physiological data to further support the benefits of energy conservation from KMC which would allow for recovery, repair, growth and maturation in neonates, and hopefully supply further incentive for NICU nurses to adopt KMC as the primary modality for caring for premies.
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