Significant improvements in neonatal technology utilized in neonatal intensive care units (NICUs) over the last 2 decades, along with evidence-based care guidelines, have significantly improved hospitalization and survival for both low birth weight (LBW) infants and the residual preterm population, albeit at a high cost. A major proportion of pediatric hospital stays in the United States is attributable to neonatal conditions that rank among the most expensive items in the list of services provided for children [1]. The average cost per infant is highest for preterm newborns with gestational age (GA) between 24-31 weeks, and next highest for those between 32-36 weeks, as opposed to the general population [2]. Costs per surviving infant generally decrease with increasing GA. In the United States, preterm/LBW infants account for half the hospitalization costs of all newborns and one quarter of overall pediatric costs [3].

Length of stay (LOS) in NICUs is strongly associated with GA and birth weight [4]. Infants delivered at the earliest GA have the longest hospital stays, partly because of the higher incidence of medical complications in very low birth weight (VLBW) infants.

However, compared to term infants, premature infants are unique in their need to attain not only medical stability but also physiologic maturity, including adequate temperature control, cessation of apnea and bradycardia, and adequate feeding behavior, before they are safely discharged to home [5, 6].

Patterns of hospitalization of preterm infants are also associated with the presence of clinical symptoms of abnormal gastrointestinal function. In particular, vomit and regurgitation were found to be associated with increased esophageal acid occurrence among NICU patients [7], as well as gastric residuals (GR) [8], which can be linked to feeding behaviors and definitely improved by targeted feeding strategies.

In VLBW infants, feeding tolerance algorithms are based on pre-prandial GR volume measurement. High pre-prandial volumes of GR are regarded as significant markers of feeding intolerance [9]. Previous studies in NICUs show that neonates under stress have a higher incidence of stress-induced gastric mucosal damage [10, 11]. Functional constipation and hard stools are common conditions in both term and preterm infants, usually leading to changes in feeding formulas [12] and use of enemas in specific settings [13].

Non invasive treatments to improve feeding tolerance and to reduce clinical complications of premature infants may represent a convenient option in the absence of standard procedures for specific subgroups of patients.

The present report describes the activity of a research team investigating the effects of Osteopathic Manipulative Treatment (OMT) in preterm infants, including monitoring of physiological functions of the gastrointestinal system and LOS.

The main objective of this exploratory study was to investigate the effects of OMT in a population of premature infants in terms of gastrointestinal functions and LOS.

The medical literature lacks information of any potential benefits of complementary treatments in this area. To the best of the authors' knowledge, OMT in premature newborns has never been documented by pediatric specialty journals. Studies carried out in pediatric patients suggested positive effects of OMT in very young children [17–19]. In the broader field of manual therapy, specialists of massage therapy and kinesthetic stimulation showed positive results in premature infants [20]. However, such findings were inconsistent and obtained with heterogeneous methods, showing only minimal differences in terms of clinical significance [20, 21].

The present study suggests that OMT may reduce the occurrence of frequent symptoms of abnormal gastrointestinal functionality.

Precise mechanisms for such positive effects generated by OMT are difficult to specify, but several hypotheses can be offered on the basis of neurological, tissue and neuroendocrine factors.

In terms of neurology, there is evidence of an association between autonomic nervous system function and OMT, showing a significant direct relation between myofascial release technique and modifications in the autonomic nervous system activity [22].

Regarding the interaction between OMT and tissue modification, in-vitro models highlight a possible decrease in the production of inflammatory factors [23].

A possible role of neuroendocrine factors can be hypothesized as indicated by the evidence of the effect of OMT on pain biomarker modification in patients affected by low back pain [24].

This study also shows that a significantly higher rate of premature infants receiving osteopathic care can be discharged before 28 days regardless of gender, GA, birth weight and oral feeding at admission.

Such a result may have important implications for the optimization of health care in premature infants. Focusing on the percentage of patients discharged before a given threshold, rather than looking at the average reduction in LOS, may be very relevant for health optimization and cost control. Reducing the rate of long stays would reduce the number of patients in the NICU, allowing for more cribs to become simultaneously available for those infants who require specialized care.

From an epidemiological point of view, the potential benefit may also spread beyond discharge, considering that hospitalization can influence nutrition [25] and morbidity of gastrointestinal infections [26].

An understanding of the differential advantage of OMT on specific subgroups, in particular within specified classes of GA, will require ad hoc studies with an adequate sample size. In the present study, it was not possible to perform subgroups analyses on subjects with very low GA, due to the very limited number of patients available for enrollment.

Finally, some intrinsic limitations of the present study need to be outlined.

This report is based on measurements implemented at the local NICU at the start of the study. Additional relevant confounding variables such as maternal/delivery factors (including breast feeding), respiratory support, method of feeding and gastric emptying time could not be included in this study.

Treatment allocation was neither randomized nor structured, as it was based on matters of convenience within the constraints of the proposed two days per week of osteopathic care. Furthermore, due to the current logistics and procedures it was not possible to "blind" nurses and neonatologists to treatment regimen.

This study, which was conducted in only one NICU, cannot capture the intrinsic variability of organizational strategies across multiple clinical centers managing the complexities of the overall population of newborn infants.

From a methodological point of view, sample size was not based on formal power estimation, treatment was not allocated using a random procedure, and the population of preterm infants may not be representative of the entire population of cases.

The above limitations affect our ability to check for bias and duly rely on the precision of our estimates. In other terms, both the size of the effect of OMT (point estimate) and its level of uncertainty (95% confidence interval) are more likely to be inconsistent with further results obtainable under more general conditions.

To evaluate the efficacy of OMT more studies are required using formal experimental methods, such as randomized and placebo controlled clinical trials. The best endpoint of a well designed three armed study would be the difference between the sham and the actual treatment. However, to make it possible, osteopaths should collaborate with NICU managers to revise the application of operational procedures, so that OMT can be smoothly applied on large populations, across multiple clinical sites.

Despite the above limitations, and given the current lack of information on the possible effects of OMT in preterm infants, the finding of this report sets an interesting ground for new developments. Among these, the standard measurement of all relevant parameters represents an essential aspect that deserves attention for future investigations. Key characteristics and outcomes that can be easily monitored on a daily basis by clinicians, nurses and even parents of preterm infants have been identified. Their adoption for the construction of electronic data base registers can offer a sustainable means to improve both analysis and management of NICU activity, allowing to carry out more detailed exploratory studies while providing a basis for ongoing trials.

The study suggests that osteopathic treatment may reduce a high occurrence of gastrointestinal symptoms and the rates of long-term stays.

Randomized control studies are needed to confirm these results and to generalize them to a broader population of high risk newborns.