Parnell Prevost et al. BMC Complementary and Alternative (2019) 19:60 https://doi.org/10.1186/s12906-019-2447-2

RESEARCH ARTICLE Open Access Manual for the pediatric population: a systematic review Carol Parnell Prevost1, Brian Gleberzon2, Beth Carleo1, Kristian Anderson3, Morgan Cark1 and Katherine A. Pohlman4*

Abstract Background: This systematic review evaluates the use of for clinical conditions in the pediatric population, assesses the methodological quality of the studies found, and synthesizes findings based on health condition. We also assessed the reporting of adverse events within the included studies and compared our conclusions to those of the UK Update report. Methods: Six databases were searched using the following inclusion criteria: children under the age of 18 years old; treatment using manual therapy; any type of healthcare profession; published between 2001 and March 31, 2018; and English. Case reports were excluded from our study. Reference tracking was performed on six published relevant systematic reviews to find any missed article. Each study that met the inclusion criteria was screened by two authors to: (i) determine its suitability for inclusion, (ii) extract data, and (iii) assess quality of study. Results: Of the 3563 articles identified, 165 full articles were screened, and 50 studies met the inclusion criteria. Twenty-six articles were included in prior reviews with 24 new studies identified. Eighteen studies were judged to be of high quality. Conditions evaluated were: attention deficit hyperactivity disorder (ADHD), autism, asthma, cerebral palsy, clubfoot, constipation, cranial asymmetry, cuboid syndrome, headache, infantile colic, , obstructive apnea, otitis media, pediatric dysfunctional voiding, pediatric nocturnal enuresis, postural asymmetry, preterm infants, pulled elbow, suboptimal infant breastfeeding, scoliosis, suboptimal infant breastfeeding, temporomandibular dysfunction, torticollis, and upper cervical dysfunction. Musculoskeletal conditions, including low back pain and headache, were evaluated in seven studies. Twenty studies reported adverse events, which were transient and mild to moderate in severity. Conclusions: Fifty studies investigated the clinical effects of manual for a wide variety of pediatric conditions. Moderate-positive overall assessment was found for 3 conditions: low back pain, pulled elbow, and premature infants. Inconclusive unfavorable outcomes were found for 2 conditions: scoliosis (OMT) and torticollis (MT). All other condition’s overall assessments were either inconclusive favorable or unclear. Adverse events were uncommonly reported. More robust clinical trials in this area of healthcare are needed. Trial registration: PROSPERA registration number: CRD42018091835 Keywords: Pediatric, Manual therapy, , Osteopathic, Systematic review

* Correspondence: [email protected] 4Parker University, 2540 Walnut Hill Lane, Dallas, TX 75229, USA Full list of author information is available at the end of the article

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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. Parnell Prevost et al. BMC Complementary and (2019) 19:60 Page 2 of 38

Background Methods Parents consult complementary and alternative medicine This study was registered at the PROSPERA - Center for (CAM) providers for a wide variety of pediatric conditions Reviews and Dissemination, University of York, York, [1, 2]. In addition to botanical and supplements, U.K. on March 28, 2018. Details of the protocol for this some seek manual therapy including soft tissue therapy, systematic review were registered on PROSPERO and mobilization and high velocity low amplitude manipulations can be accessed at https://www.crd.york.ac.uk/prospero/ directed to the spine and peripheral joints. The United display_record.php?RecordID=91835. States (US) Department of Health and Human Services conducts a population-based survey and creates the Na- Search strategy tional Health Interview Statistics (NHIS) reports on the use A comprehensive search of the literature was performed of CAM with children ages 4–17 every 5 years with results by three independent librarians at three different educa- published in 2007 and 2012. Overall, approximately 12% of tional institutions. The databases stated in Table 1 were children used a CAM modality the previous year [1, 2]. searched for English manuscripts published between Manual therapy is a CAM therapy regulated for use 2001 through March 31, 2018. Data mining and refer- among many professions (e.g., doctor of , med- ence tracking of the six previously published systematic ical doctors and physical therapists), but doctors of chiro- reviews were performed for relevant papers. No condi- practic (DCs) are the most likely profession to use manual tion terms were included to keep the search as broad as therapy on a regular basis [3]. According to a recent job possible. The list of search terms and keywords used in analysis of the overall DC profession, 17.1% of chiropractic the search are included in Table 1. patients are 17 years of age or less; this increases to 38.7% among DCs who have specialized in pediatrics [3, 4]. Nde- Eligibility criteria tan et al. conducted a sub-analysis of the 2007 NHIS data Studies were eligible for inclusion if they were full text for chiropractic and/or osteopathic manipulation use and reports of RCTs (no abstracts). Feasibility studies with- found that 3.3% of US children had received chiropractic out outcome measures were not included in this review. or osteopathic manipulation the previous year [5]. Most For observational studies, the Agency for Healthcare Re- commonly, children were between 12 and 18 years of age search and Quality’s (AHRQ) Assessing Risk of Bias and and received care for back or neck pain. Confounding in Observational Studies of Interventions or Concerns regarding manual therapy, specifically ma- Exposures was utilized to determine study type with nipulation [6], have led to complications identified in the non-comparative (case report or case series without pre literature. However, no prospective population-based ac- and post measurements) and cross-sectional studies ex- tive surveillance have been conducted [7]. Serious events cluded [15]. Additional eligibility criteria were that a study are rare, but may be related to high-velocity extension and rotational [8]. The serious events identified in mostly retrospective studies commonly oc- Table 1 Databases searched: PubMed, Cochrane Library, Medline curred with patients that had preexisting underlying path- complete, CINAHL complete, ScienceDirect, McCoy Press, Index to ology, which emphasizes the need for a thorough history Chiropractic Literature, and National Guideline Clearinghouse and physical examination so that abnormal findings are Chiropractic AND pediatric* identified prior to manual therapy in a child [7–9]. Chiropractic AND child* Six systematic reviews have previously been conducted to evaluate the use of manual therapy for pediatric health Chiropractic AND adolescent* conditions [9–14]. These reviews ranged in manual ther- Manipulation, chiropractic AND (pediatric*, child*, adolescent*) (MeSH heading) apy definitions from high-velocity variable amplitude to profession-specific manipulative therapy. Nonetheless, all Manipulation, orthopedic AND (pediatric*, child*, adolescent*) (MeSH heading) reviews concluded that this is a paucity of evidence for the effectiveness of manual therapy for conditions within the Manipulation, osteopathic AND (pediatric*, child*, adolescent*) (MeSH heading) pediatric population, especially for musculoskeletal condi- Osteopath* AND (pediatric*, child*, adolescent*) tions. The purpose of this systematic review was to evalu- ate the use of manual therapy for clinical conditions in the Orthopedic manipulation AND (pediatric*, child*, adolescent*) pediatric population, assess the methodological quality of Orthoped* AND (pediatric*, child*, adolescent*) the studies found, and synthesize findings based on health Pediatric manual therapy AND (pediatric*, child*, adolescent*) condition. We also assessed the reporting and incidence Ped MT AND (pediatric*, child*, adolescent*) of adverse events within the included studies. Additionally, Spinal manipulative therapy AND (pediatric*, child*, adolescent*) we compared conclusions to Clar et al.’s UK Update SMT AND (pediatric*, child*, adolescent*) manuscript [10]. Parnell Prevost et al. BMC Complementary and Alternative Medicine (2019) 19:60 Page 3 of 38

had to include children under the age of 18 who were different assessment tools were utilized to assess the treated with manual therapy (definitions and abbreviations quality of the RCTs and observational studies included shown in Table 2) of any type from any health care profes- in this review. The Cochrane Risk of Bias tool, consisting sional for any condition. of 7 domains, was used to assess the risk of bias of the RCTs [16]. The domains were: Study selection, data extraction, & summary assessment Two independent reviewers evaluated the studies identi-  adequate sequence generation, fied by the searches for potential inclusion in our study.  allocation concealment, They applied the inclusion/exclusion criteria to the studies  patient blinding, identified by first screening the abstracts and then the full  assessor blinding, text of any studies appearing to fulfill the inclusion cri-  addressing of incomplete data, teria. Any discrepancies as to whether or not to include a  selective outcome reporting, and study was resolved by a third independent evaluator. Data  other sources of bias. extraction was conducted by an independent reviewer using an a priori designed data extraction form with a sec- The tool used to assess observational studies was the ond reviewer validating the findings. same used to evaluate the observational study design [15]. An overall result summary assessment was determined This AHRQ tool consists of 9 domains: for each study based on their results as either: “improve- ment” (manual therapy appeared to be effective in the  inclusion/exclusion criteria variances across groups intervention group), “no improvement” (manual therapy (cohort studies only), did not appear to be effective in the intervention group),  recruitment strategies for groups (cohort studies or “no difference” (results appeared to be the same in the only), intervention group as compared to a different interven-  appropriate, selection of comparison groups (cohort tion, sham intervention or control group). studies only),  blinding outcome assessor to intervention, Quality assessment-individual studies  use of valid and reliable outcome tools, The quality assessment process was conducted by an in-  length of follow-up variances across study groups, dependent reviewer and validated by a second randomly  missing important primary outcomes, assigned reviewer. Disagreements for each criterion were  missing harms or adverse events, and settled through discussion with a third reviewer. Two  account of any confounding variables.

Table 2 Abbreviations and definitions used for this study SMT (Spinal Manipulative A procedure involving an high velocity, low amplitude (HVLA) thrust beyond the passive range of motion into the Therapy) para-physiological space, but within the limits of anatomic integrity [71]p10,[72]p142–143,[73]. It is a bimanual motor skill involving various levels of interlimb coordination and postural control combined with a timely weight transfer and is characterized by a HVLA thrust that typically results in joint cavitation [74]. SMT is highly adaptive and context-dependent, meaning the amount of force delivered to the patient must take into account clinically relevant pathologies as well as anthropomorphic differences between the doctor and patient [73].The safe delivery of SMT requires consideration with respect to preload, speed of force production, peak amplitude of force delivered, duration of impulse/thrust delivered, doctor position, patient positioning, and line of drive (direction of thrust) [71, 74]. Mobilization A low velocity, low amplitude (LVLA) oscillation procedure, within the active or passive ranges of motion [71]p18, [72]p142. OMT (Osteopathic Involves physical manipulation of various tissues and parts of the body that includes soft tissue and stretch, Manipulative Therapy) strain-counter-strain, articulation, high velocity thrust, gentle low amplitude mobilizations and neuromuscular techniques [49]p1–2. In some instances OMT is better classified as a mobilization [71]p18 . CST (Cranial-Sacral Therapy) A group of manual procedures directed to the sutures of the skull designed to enhance the functioning of the membranes, tissues, fluids, and bones surrounding or associated with the brain and spinal cord. It is postulated that low-force pressure can influence the vitality of the Cranial Rhythmic Impulse created by the flow of cerebrospinal fluid as it moves from the ventricles of the skull to the sacrum within the spinal cord [71]p123–136. CMT (Chiropractic Synonymous with SMT, but performed by a doctor of chiropractic. Manipulative Therapy) VOMT (Visceral Osteopathic A manual therapy directed to various organs of the body to aid in smooth muscle function, Manipulation) influence somatic biomechanics and body fluid mechanics [49]p251–252. Instrument-assisted The use of any number of different types of hand held instruments used to provide a manipulation-type force. manipulation MT (Manual Therapy) Any of the above. Parnell Prevost et al. BMC Complementary and Alternative Medicine (2019) 19:60 Page 4 of 38

We omitted the following questions from the AHRQ Moderate quality evidence assessment for the following reasons. Questions 4 The evidence comes from at least 1 high-quality RCT (Does the study fail to account for important variations (with sufficient statistical validity) OR at least 2 in the execution of the study from the proposed proto- higher-quality RCTs (with some inconsistency) OR at col?) and 12 (Any attempt to balance the allocation be- least 2 consistent lower-quality RCTs. tween the groups or match groups (e.g., through stratification, matching, propensity scores)?) as these Low quality (inconclusive) evidence were not relevant for our body of literature. Question 8 The available evidence is insufficient to determine effect- (In cases of high loss to follow-up (or differential loss iveness. If all papers showed improvement they are clas- to follow-up), was the impact assessed (e.g., through sified as “Favorable”. If all papers failed to show sensitivity analysis or other adjustment method)?) as improvement they are classified as “Unfavorable”. If all our included studies did not have this level of statistical papers showed a mix of improvement, lack of improve- analysis involved. And question 11 (Are results believ- ment, or no difference they are classified as “Unclear”. able taking study limitations into consideration?) as we Note that observational studies cannot be rated higher felt this question was too subjective [15, 17]. than “Inconclusive (unclear)”, as observational studies The study’s overall quality score was then determined to are not designed to show effectiveness. be: low quality study if the score was between 0 and 33.3%, medium quality, if the score was between 33.4 and Results 66.6%, and high quality if the score was above 66.6%. Search results As shown in Fig. 1, the initial database searches gener- Quality assessment-overall conditions ated a total of 3563 records (2440 after deduplication). We employed the same criteria to summarize the overall Of which, 166 full articles were assessed in detail. One strength of evidence for the studies by conditions to be hundred sixteen of the articles were excluded. Of the 50 consistent with the UK Update/Clar et al. report [10], included articles, 32 were RCTs and 18 were observa- which used an adapted version from the US Preventive tional studies. Table 3 provides a summary of the studies Services Task Force. This report, along with Clar et al. along with the details, sample sizes, quality, results of reports, summarized the overall strength/quality of evi- the study and an overall summary. This table also com- dence as: “high-quality positive/negative”, “medium-qual- pares the overall summary from Clar et al.’s UK Update ity positive/negative”,or“inconclusive evidence favorable/ study [10]. These studies are then summarized by study non-favorable/unclear” [10]. The overall evidence grading design (RCT and observational) in Table 4 and 5, re- system used allows the evidence to be grouped into three spectively, with the individual quality assessment criteria categories based upon its strength: high quality evidence, outlined. moderate quality evidence, or inconclusive evidence. The Overall, we found 23 studies that used OMT (7 of definitions of these three categories are listed below: which specifically used cranial therapies and 1 VOMT); 17 studies used CMT/SMT (including one using Toft- High quality evidence ness technique, one using an upper cervical technique, The evidence comes from at least 2 RCTs and is consid- one using a neuroimpulse instrument, and one using ered high quality due to low risk of bias. As a result, the cranial therapy with CMT), 10 studies used mobiliza- conclusion is unlikely to be affected by future studies. tions (1 also using CST).

Fig. 1 Study selection flow diagram (PRISMA style) Table 3 Overall summary in comparison with the UK Update report Prevost Parnell Clinical condition UK update (1) summary Studies in Intervention Citations Quality Sample Results of study Current study overall current review size summary Gastrointestinal Conditions

Constipation Not evaluated 1 OBS OMT Tarsuslu, 2009 [18] Medium 13 No difference Inconclusive (unclear) Medicine Alternative and Complementary BMC al. et Infantile Colic Inconclusive/ favorable 3 RCT CMT Miller, 2012 [19] High 104 Improvement Inconclusive (unclear) 1OBS Wiberg, 2010 [20] Low 749 No improvement Browning, 2008 [21] High 43 No difference Olafsdottir, 2001 [22] High 86 No difference Infantile Colic Inconclusive/ favorable 1 RCT OMT/CST Hayden, 2006 [23] Medium 28 Improvement Inconclusive (favorable) Pediatric dysfunctional voiding Inconclusive/ favorable 1 RCT OMT Nemett, 2008 [24] Medium 21 Improvement Inconclusive (favorable) Pediatric nocturnal enuresis Inconclusive/ favorable 1 OBS CMT van Poecke, 2009 [25] Medium 33 Improvement Inconclusive (unclear) Suboptimal infant breastfeeding Not evaluated 2 OBS CMT/CST Miller, 2009 [26] Medium 114 Improvement Inconclusive (favorable) Vallone, 2004 [27] Low 25 Improvement Musculoskeletal Conditions Clubfoot Not evaluated 1 RCT MT Nilgun, 2011 [28] Low 29 Improvement Inconclusive (favorable) Cuboid Syndrome Not evaluated 1 OBS MT Jennings, 2005 [29] Medium 2 Improvement Inconclusive (unclear) Headache Not evaluated for pediatrics 1 OBS OMT Przekop, 2016 [30] Medium 83 Improvement Inconclusive (unclear) (2019)19:60 Headache Not evaluated for 1 RCT MT Borusiak, 2010 [31] Medium 52 No difference Inconclusive (unclear) pediatrics Headache Not evaluated for 1 OBS CMT Marchand, 2009 [32] Low 13 Improvement Inconclusive (unclear) pediatrics Low Back Pain Not evaluated 1 RCT CMT Evans, 2018 [33] High 185 Improvement Moderate (favorable) 1OBS Hayden J, 2003 [36] Medium 54 Improvement Low back pain Not evaluated 1 OBS MT Walston, 2016 [34] Medium 3 Improvement Inconclusive (unclear) 1 RCT Selhorst, 2015 [35] Medium 35 No difference Pulled (Nursemaid’s) Elbow Not evaluated 2 RCT MT Garcia-Mata, 2014 [37] Medium 115 Improvement Moderate (favorable) Bek, 2009 [38] Medium 66 Improvement Temporomandibular Joint Not evaluated for pediatrics 1 RCT OMT Monaco, 2008 [39] Low 28 Improvement Inconclusive (favorable) Dysfunction Respiratory Conditions Asthma Not evaluated for pediatrics 1 RCT OMT Guiney, 2005 [40] Medium 140 Improvement Inconclusive (favorable) Asthma Not evaluated for pediatrics 1 RCT CMT Bronfort, 2001 [41] High 34 No improvement Inconclusive (unclear) Obstructive apnea Not evaluated 1 RCT OMT Vandenplas, 2008 [42] Medium 34 Improvement Inconclusive (favorable) Otitis Media Inconclusive/ unclear 3 RCT OMT Steele, 2014 [43] Medium 34 Improvement Inconclusive (favorable) 1OBS Wahl, 2008 [44] High 90 No difference Degenhardt, 2006 [45] Medium 8 Improvement 38 of 5 Page Mills, 2003 [47] High 57 Improvement Otitis Media Not evaluated 1 OBS CMT Zhang, 2004 [46] Medium 22 Improvement Inconclusive (unclear) Table 3 Overall summary in comparison with the UK Update report (Continued) Prevost Parnell Clinical condition UK update (1) summary Studies in Intervention Citations Quality Sample Results of study Current study overall current review size summary Special Needs

ADHD Inconclusive/ unclear 1 RCT OMT Accorsi, 2014 [48] High 28 Improvement Inconclusive (favorable) Medicine Alternative and Complementary BMC al. et Autism Not evaluated 1 OBS VOMT Bramati-Castellarian, Medium 49 Improvement Inconclusive (unclear) 2016 [49] Not evaluated 1 RCT CMT Khorshid, 2006 [50] Low 14 Improvement Inconclusive (favorable) Cerebral Palsy Inconclusive/ unclear 3 RCT OMT Wyatt, 2011 [51] High 142 No improvement Inconclusive (unclear) Duncan, 2008 [53] High 55 Improvement Duncan, 2004 [52] Low 50 Improvement Preterm infants Inconclusive/ unclear 4 RCT OMT/CST Raith, 2015 [54] High 30 No difference Inconclusive/unclear for Cerretelli, 2015 [55] High 695 Improvement general movement Pizzolorusso, 2014 [56] High 110 Improvement Moderate (favorable) Cerretelli, 2013 [57] High 110 Improvement length of stay and hospital costs Structural Conditions Cranial asymmetry Not evaluated 1 RCT MT/CST Cabrera-Martos, 2016 High 46 Improvement Inconclusive (favorable) [58]

Not evaluated 1 OBS OMT Lessard, 2011 [59] Medium 12 Improvement Inconclusive (unclear) (2019)19:60 Postural Asymmetry Not evaluated 1 RCT OMT/CST Phillippi, 2006 [60] High 32 Improvement Inconclusive (favorable) Scoliosis Not evaluated 1 RCT CMT Byun, 2016 [61] Medium 5 Improvement Inconclusive (unclear) 3OBS Rowe, 2006 [62] High 6 No difference Morningstar, 2004 [63] Low 6 Improvement Lantz, 2001 [64] Medium 42 No improvement Scoliosis Not evaluated 1 RCT OMT Hasler, 2010 [65] High 20 No improvement Inconclusive (unfavorable) Torticollis Not evaluated 1 RCT MT Haugen, 2011 [66] Medium 32 No difference Inconclusive (unfavorable) Upper cervical dysfunction Not evaluated 1 OBS MT Saedt, 2017 [67] High 307 Improvement Inconclusive (unclear) ae6o 38 of 6 Page Parnell Prevost et al. BMC Complementary and Alternative Medicine (2019) 19:60 Page 7 of 38

Pediatric clinical conditions infant treated-parent aware; infant treated-parent un- aware; and infant not treated-parent unaware. The out- 1. Gastrointestinal/urinary conditions comes were determined by a decrease in crying time, as assessed by a parent questionnaire and a 24 h crying diary. Table 6 provides a summary of the 10 studies that inves- The study found there was a greater decrease in crying tigated the clinical effects of manual therapy for condi- time in the infants treated with CMT, either parent aware tions categorized as “gastrointestinal/urinary conditions”. or unaware, compared to infants who were not treated, One of the studies investigated the use of manual therapy concluding that parents did not appear to contribute to for constipation [18], five for infantile colic [19–23], one the observed treatment effects in the study. Adverse event for children with dysfunctional voiding [24], one for was reported in one patient in the control (non-treatment) pediatric nocturnal enuresis [25], and two studies for group that reported increased crying [19]. suboptimal infant breastfeeding [26, 27]. Wiberg et al. conducted a low quality interrupted time series without a comparison group observational study 1.1.Constipation that looked at 749 clinical records of infants 0–3 years of age who fulfilled the study’s definition of excessive cry- One study was found that investigated the use of ing. This study investigated if the outcome of excessively OMT for constipation [18]. crying infants treated with CMT was associated with or Tarsuslu et al. conducted a medium quality, inter- partially associated with age in the natural decline in rupted time-series with a comparison group that investi- crying with age in infants. The outcomes were deter- gated the potential effects of OMT on constipation in 13 mined by the parents recording crying in the infants as children ages 2–16 with cerebral palsy. The children “improved”, “uncertain”,or“non-recovery”. These re- were put into one of two groups with no description of searchers concluded that there was no apparent link be- how this allocation happened. The first group received tween the clinical effect of chiropractic treatment and OMT alone and the second group received OMT in improvement in the crying patterns. Limitation of the addition to medical treatment. Both groups showed sig- study was that it was pragmatic, thus not standardized nificant changes from all baseline measures at 3 months. on management or CMT technique. There was no men- The baseline measures included defecation frequency, tion of adverse events in this study [20]. gross motor function, and functional independence Browning and Miller conducted a high quality measure. Group 1 showed significantly favorable changes parent-blind RCT involving 43 infants less than 8 weeks in defecation frequency and constipation scale at 6 of age that presented with infantile colic. The study ob- months. Group 2 showed significantly favorable changes jective was to compare two intervention groups in the from baseline measures at 6 months. The researchers treatment of infantile colic. One intervention group re- suggest advanced additional studies should be con- ceived CMT and the other occipital-sacral decompres- ducted. There was no mention of adverse events made sion. The outcomes were determined by the change in in this study [18]. mean daily hours of crying as recorded in a crying diary Overall Summary: by a parent. Although the mean hours of daily crying Inconclusive (unclear) for use of OMT in treating were statistically significantly reduced in both study constipation. groups, there were no statistically significant differences between them. The researchers noted that although all 1.2.Infantile colic participants’ symptoms improved prior to the normal re- mission age of colic, the natural course of remission Four of the five studies investigated the use of CMT in could not be ruled out. There was no mention of adverse treating infantile colic; three of these studies were high events made in this study [21]. quality RCTs [19, 21, 22] and one low quality retrospect- Olafsdottir et al. conducted the third high quality RCT ive investigation of the clinical records [20]. One that set out to evaluate the effect of CMT on infantile medium quality prospective RCT investigated the use of colic. This study included 86 colicky infants (46 receiving OMT cranial therapy [23]. CMT, 40 in control group) at 3–9 weeks of age. The out- A high quality parent-blinded RCT, authored by Miller come was determined by the parents recording the hours et al., showed favorable results in treating 104 colicky in- of infant crying per 24 h period in a crying diary. The re- fants less than 8 weeks of age with CMT. This study had sults showed no statistically significant improvement in two objectives; the first was to determine the efficacy in the infants in either group. There was no mention of ad- treating colic with CMT and the second was to determine verse events made in this study [22]. if parental reporting bias contributes to the success of the Another medium quality prospective, open-controlled treatment. The infants were randomized into 3 groups: RCT that investigated the impact of cranial osteopathy Table 4 Quality rating of randomized controlled trials Prevost Parnell Author/year Condition sample Results Intervention Selection bias: Selection bias: Performance Detection bias: Attrition bias: Reporting bias: Other bias: Overall size (n) summary random allocation bias: blinding blinding of incomplete selective anything else, quality of personnel outcome outcome data reporting ideally pre- rating and participants assessment specified

Gastrointestinal/Urinary Medicine Alternative and Complementary BMC al. et Miller J, et al. 2012 [19] Infantile Colic Improvement CMT L computer L sealed in L envelopes U-PY two of H per protocol L all outcomes U-PN “parent High (n = 104) generated sequentially revealed to three groups analysis reported diagnosis”, permutated numbered treating provider of parents conducted selective blocks opaque before blinded to nature of diary envelopes treatment, 1 of 3 treatment, data groups parents extractor knew infants blinded to were being teratment treated Browning M & Miller J, Infantile Colic No difference CMT L computer H not stated L blinding of L independent L all outcomes L all outcomes H strict High 2008 [21] (n = 43) generated both parents observer reported reported inclusion and patients binded to criteria, small treatment study size, inexperienced iterns Hayden C & Mullinger B, Infantile Colic Improvement OMT/CST L random U-PY random H patients and H outcome H 2 withdrew L all outcomes U-PN small Medium 2006 [23] (n = 28) number table table number providers not assessors and not reported study size, utilized but blinded unblinded included in lack of not discussed analysis standardized (2019)19:60 treatment Olafsdottir E, et al. 2001 [22] Infantile Colic No difference CMT H “randomized” U-PY “sealed” L parents and L outcome L intention to L all outcomes U-PY small High (n = 86) not described envelopes providers assessor treat analysis reported sample size blinded blinded Musculoskeletal Nemett D, et al. 2008 [24] Pediatric Dysfunctional Improvement OMT U-PY stated H nothing H nothing H only primary H per protocol L all expected L study Medium Voiding (n = 21) “randomized stated stated outcome analysis outcomes appears free assigned” with assessor conducted reported, of other no further blinded secondary sources of description outcome not bias initially evaluated in control group per protocol Nilgun B, et al. 2011 [28] Idiopathic Improvement MT H randomized H not H parents, H outcome L all outcomes L all outcomes H pilot study Low Clubfoot (n = 29) by travel and concealed patients, assessor not reported reported only physical abilities therapists not blinded blinded Borusiak P, et al. 2010 [31] Cervicogenic HA (n = No difference MT L computer L sequentially L parents, U-PY pre- H per protocol L all outcomes H small Medium 52) generated numbered patients and established analysis reported sample size, identical pediatrician analysis plan conducted clinical effect opaque blinded not described of sham,

envelopes observational 38 of 8 Page bias Evans R, et al. 2018 [33] Subacute and Improvement CMT L computerized L sealed in H patients and L outcome L all outcomes L all outcomes L study appears High Chronic LBP dynamic sequentially providers not assessor reported reported free of other (n = 185) allocation numbered blinded blinded sources of bias Table 4 Quality rating of randomized controlled trials (Continued) Prevost Parnell Author/year Condition sample Results Intervention Selection bias: Selection bias: Performance Detection bias: Attrition bias: Reporting bias: Other bias: Overall size (n) summary random allocation bias: blinding blinding of incomplete selective anything else, quality of personnel outcome outcome data reporting ideally pre- rating and participants assessment specified

(rank-order opaque Medicine Alternative and Complementary BMC al. et minization) envelopes system Selhorst M & Selhorst B, Mechanical LBP No difference MT H not H not U-PY blinding of L all outcomes H per protocol L all outcomes L study appear Medium 2015 [35] (n = 35) described described patients, exercise patient self- anaylsis reported to be free of therapist, no report blinded conducted other sources of blinding of bias manual therapist Garcia-Mata S & Pulled Elbow Improvement MT H not H not H parents, H outcome L all expected L all outcomes L study appear Medium Hidalgo-Ovejero A, 2014 [37] (n = 115) described described patients, assessors not outcomes reported to be free of therapists not blinded reported other sources o blinded bias Bek B, et al. 2009 [38] Pulled Elbow Improvement MT H not H not H no blinding H outcome L intention to L all outcomes L study appears Medium (n = 66) described described assessors not treat analysis reported free of other blinded source of bias Monaco A, et al. 2008 [39] Non-Specific Improvement OMT H not H not H patients and H outcome H follow up of U-PN sample U-PN small Low Temporomandibular described described providers not assessor not participants response for study size Disorder (n = 28) blinded blinded were not each outcome discussed not provided (2019)19:60 Respiratory Guiney P, et al. 2005 [40] Asthma (n = 140) Improvement OMT U-PY not well H not H provider not H outcome L all patients L all outcomes L study appears Medium described described blinded assessor not accounted for reported free of other “randomization blinded sources of bias based on a 2:1 ratio” Bronfort G et al. 2001 [41] Asthma (n = 34) No CMT L computer L sealed in L blinding of both L outcome L all patients L all outcomes L study appears High improvement generated opaque parents and assessor accounted for reported free of other envelopes patients blinded sources of bias Vandenplas YDE, et al. Obstructive Apnea Improvement OMT H not H not L patients blinded L outcome H per protocol L all outcomes U-PN small study Medium 2008 [42] (n = 34) described described assessors analysis, 6 reported size, imbalance blinded participants in sizes of dropped out control to study and not included in analysis Steele D, et al. 2014 [43] Otitis Media (n = 34) Improvement OMT L study used U-PY H providers not L outcome L all patients L all outcomes H small sample Medium “Research randomized blinded, parents assessors accounted for reported size, pilot study Randomizer” tables blinded but in blinded generated treatment room with unique number assignment ae9o 38 of 9 Page Wahl R, et al. 2008 [44] Otitis Media (n = 90) No difference OMT L randomization L 2 by2 L patients, parents, L outcome L all patients L all outcomes U-PN unequal High in blockes of 8 factorial providers blinded assessor accounted for reported distribution of using random design blinded risk factors in number table treatment group Table 4 Quality rating of randomized controlled trials (Continued) Prevost Parnell Author/year Condition sample Results Intervention Selection bias: Selection bias: Performance Detection bias: Attrition bias: Reporting bias: Other bias: Overall size (n) summary random allocation bias: blinding blinding of incomplete selective anything else, quality of personnel outcome outcome data reporting ideally pre- rating and participants assessment specified

Mills M, et al. 2003 [47] Acute Otitis Media Improvement OMT L computer L independent H parents and L outcome H per protocol L all outcomes L study appears High Medicine Alternative and Complementary BMC al. et (n = 57) generated nurse provider not assessor analysis, 19 reported free of other monitored blinded blinded dropped out sources of bias and disclosed and not by phone included in analysis Special Needs Accorsi A, et al. 2014 [48] Attention-Deficit/ Improvement OMT L permuted- U- PN U -PY patients/ L outcome L all patients U -PN adverse U-PN sample High Hyperactivity block ratio 1:1 allocation parents/providers assessors accounted for events were size not Disorder (n = 28) using R statistical was not blinded but blinded being collected justified program concealed were blinded as to but not reported but not outcomes described Khorshid KA, et al. 2006 [50] Autism (n = 14) Improvement CMT H not described H not H patients and H outcome U-PN L all outcomes U-PN sample Low described providers not assessors not enrollment reported size not blinded blinded number not justified discussed Wyatt K, et al. 2011 [51] Cerebral Palsy No OMT L telephone L allocation H parents and L outcome L all patients L all outcomes U-PN sample High (n = 142) improvement based provided by patients not assessors accounted for reported size not randomization independent blinded blinded justified (2019)19:60 by independent statistician at statistician at remote site remote site Duncan B, et al. 2008 [53] Cerebral Palsy Improvement OMT L draw L blinding of H parents, patients, L outcome H per protocol L all outcomes L study appears High (n = 55) technique concealment providers not assessor analysis reported free of other using blinded blinded conducted sources of bias stratification Duncan B, et al. 2004 [52]CerebralPalsy(n = 50) Improvement OMT H not H not H not described H outcome H per protocol L all outcomes L study appears Low described described assessors not analysis reported free of other discussed conducted sources of bias Raith W, et al. 2016 [54] Prematurity (n = 30) No difference OMT/CST L randomized L sequentially L parents and L outcome L all patients L all outcomes L study appears HIgh using block sealed providers blinded assessors accounted for reported free of other design with opaque blinded sources of bias block size 6 envelopes Cerritelli F, et al. 2015 [55] Prematurity (n = 695) Improvement OMT/CST L randomized L performed in U-PN providers L NICU staff H per protocol L all outcomes L study appears High using block coordinating not blinded blinded analysis reported free of other design with center performed sources of bias block size 10 Pizzolorusso G, et al. Prematurity (n = 110) Improvement OMT/CST L computer L randomized U-PN providers L outcome L all patients L all outcomes L study appears High 2014 [56] generated by IT not blinded assessors accounted for reported free of other permuted consultant blinded sources of bias block Cerritelli F, et al. 2013 [57] Prematurity (n = 110) Improvement OMT/CST L computer L random H parents, patients, L outcome H per protocol L all outcomes L study appears High 38 of 10 Page generated allocation by providers not assessor analysis reported free of other permuted independent blinded blinded conducted sources of bias block consultant Table 4 Quality rating of randomized controlled trials (Continued) Prevost Parnell Author/year Condition sample Results Intervention Selection bias: Selection bias: Performance Detection bias: Attrition bias: Reporting bias: Other bias: Overall size (n) summary random allocation bias: blinding blinding of incomplete selective anything else, quality of personnel outcome outcome data reporting ideally pre- rating and participants assessment specified

Structural Medicine Alternative and Complementary BMC al. et Cabrera-Martos I, et al. Cranial Asymmetry Improvement MT/CST L randomized L sealed H patients and L outcome L all outcomes L all outcomes L study appears High 2016 [58] (nonsynostotic number envelope providers not assessors accounted for reported free of other plagiocephaly) generator in blinded blinded sources of bias (n = 46) blocks of 4 Philippi H, et al. 2006 [60] Postural Asymmetry Improvement OMT/CST L block L sealed in L parents, patients, L outcome L all outcomes L all outcomes L study appears High (n = 32) randomization sequentially provider blinded assessor accounted for reported free of other numbered blinded sources of bias envelopes Hasler C, et al. 2010 [65] Scoliosis (n = 20) No OMT L block U-PY H patients and L outcome L all outcomes L all outcomes U-PN small High improvement randomization consealed provider not assessor accounted for reported sample size envelopes blinded blinded Rowe DE, et al. 2006 [62] Scoliosis (n = 6) No difference CMT L computer L independent L patients and L outcome L all outcomes L all outcomes U-PN small High generated personnel provider blinded assessors accounted for reported sample size provided blinded allocation assignent via e-mail n Haugen E, et al. 2011 [66] Torticollis ( = 32) No difference MT H not U-PY selaed U-PN patients L outcome U-PN patient H not all U-PN sample Medium (2019)19:60 described envelope blinded, providers assessor description and outcomes size not not blinded blinded enrollment reported justified not discussed Legend: H-High risk of bias; L-Low risk of bias; NA-Not applicable; U-Unclear; PN-Probably No (high risk of bias); PY-Probably Yes (low risk of bias). Interventions: CMT Chiropractic Manipulative Therapy, CST , MT Manual Therapy, OMT Osteopathic Manipulative Therapy. ae1 f38 of 11 Page Table 5 Quality rating of observational studies Prevost Parnell Author/year Study Condition sample Result Intervention Include/ Recruitment Comparison Blinded Valid, reliable Length of Missing Missing Missing confounding Overall design type size (n) summary exclude strategy selection outcome measures follow-up outcomes harms/ variables quality assessor(s) adverse rating events

Gastrointestinal/Urinary Medicine Alternative and Complementary BMC al. et Tarsuslu T, et Interrupted Constipation No difference OMT L does H not H not H not U-PN property L consistent L all H U-PN dietary Medium al. 2009 [18] time series and Cerebral not vary described described blinded measurements outcomes adverse (with Palsy (n = 13) not fully discussed events comparison evaluated for not group) children reported Wiberg K & Interrupted Infantile colic No CMT NA NA NA H not U-PN property H not L all H U- PN co-interventions Low Wiberg J, time series (n = 749) improvement blinded measurements discussed outcomes adverse missing 2010 [20] (without a not fully discussed events comparison evaluated for not group) children reported van Poecke A Before-after Nocturnal Improvement CMT NA NA NA H not U-PN property L consistent L all H U- PN dietary Medium & Cunliffe C, Enuresis blinded measurements outcomes adverse 2009 [25] (n = 33) not fully discussed events evaluated for not children reported Miller J, et al. Before-after Suboptimal Improvement CMT NA NA NA H not U-PN property H not L all L adverse L confounding Medium 2009 [26] Infant blinded measurements discussed outcomes events variables Breastfeeding not fully discussed reported accounted for (n = 114) evaluated for (2019)19:60 children Vallone S, Before-after Suboptimal Improvement CMT/CST NA NA NA H not U-PN property H not U-PN H H no confounding Low 2004 [27] Infant blinded measurements discussed different adverse variables included Breastfeeding not fully outcomes events (n = 25) evaluated for for not children participants reported Musculoskeletal Jennings J & Interrupted Cuboid Improvement MT NA NA NA H not U-PN property U-PY not L all H U-PN variables that Medium Davies G, 2005 time series Syndrome blinded measurements different but outcomes adverse may influence [29] (without (n =2) not fully not specified discussed events outcome discussed comparison evaluated for not but no adjustment group) children reported to outcome taken into account Przekop P, et Before-after Chronic Improvement OMT NA NA NA H not U-PN property L consistent L all H L confounding Medium al. 2016 [30] tension-type blinded measurements outcomes adverse variables headache not fully discussed events accounted for (n = 83) evaluated for not children reported Marchand A, Before-after Benign infant Improvement CMT NA NA NA H not U-PN property H not L all H H medication Low et al. 2009 [32] headache blinded measurements discussed outcomes adverse not accounted (n = 13) not fully discussed events for evaluated for not

children reported 38 of 12 Page Table 5 Quality rating of observational studies (Continued) Prevost Parnell Author/year Study Condition sample Result Intervention Include/ Recruitment Comparison Blinded Valid, reliable Length of Missing Missing Missing confounding Overall design type size (n) summary exclude strategy selection outcome measures follow-up outcomes harms/ variables quality assessor(s) adverse rating events

Walston Z & Interrupted Mechanical Improvement MT NA NA NA H not U-PN property Hnot L all L adverse U-PN information Medium Medicine Alternative and Complementary BMC al. et Yake D, 2016 time series Low Back Pain blinded measurements consistent outcomes events not consistently [34] (without (n =3) not fully discussed reported collected comparison) evaluated for children Hayden J, Before-after Mechanical Low Improvement CMT NA NA NA H not U-PN property L consistent U-PN not H U-PY retrospective Medium et al. 2003 [36] Back Pain (n = 54) blinded measurements all cases adverse data, information not fully collected events not consistently evaluated for not collected children reported Respiratory Degenhardt B Before-after Otitis media Improvement OMT/CST NA NA NA H not U-PN property L consistent L all H U-PN natural course Medium &KucheraM, (n =8) blinded measurements outcomes adverse of OM diagnosis, 2006 [45] not fully discussed events differences in AOM evaluated for not and OM, dietary children reported considerations Zhang JQ & Before-after Otitis media Improvement CMT NA NA NA H not U-PN property H not discussed L all L adverse H several confounding Medium Snyder BJ, (n = 22) blinded measurements outcomes events varaibles missing 2004 [46] not fully discussed reported evaluated for (2019)19:60 children Special Needs Bramati- Interrupted Autism (n = 49) Improvement VOMT NA NA NA H not U-PN property L follow up L all H U-PY not all Medium Castellarin I, time series blinded measurements consistent outcomes adverse confounding variables et al. 2016 [49] (without not fully discussed events known comparison) evaluated for not children reported Structural Lessard S, Before-after Cranial asymmetry Improvement OMT NA NA NA L blinded U-PN property L follow-up L all H U-PN natural course Medium et al. 2011 [59] (nonsynostotic measurements consistent outcomes adverse plagiocephaly) not fully discussed events (n = 12) evaluated for not children reported Byun S & Before-after Scoliosis (n = 5) Improvement CMT NA NA NA H not L Cobb angle L follow-up L all H H confounding Medium Han D, blinded consistent outcomes adverse variables not 2016 [61] discussed events accounted for, no not mention of natural discussed course Morningstar M, Before-after Scoliosis (n = 6) Improvement CMT NA NA NA H not L Cobb angle H length of L all H H confounding Low et al. 2004 [63] blinded follow-up similar outcomes adverse variables not but some discussed events accounted for, no patients had not mention of natural received prior reported course 38 of 13 Page Table 5 Quality rating of observational studies (Continued) Prevost Parnell Author/year Study Condition sample Result Intervention Include/ Recruitment Comparison Blinded Valid, reliable Length of Missing Missing Missing confounding Overall design type size (n) summary exclude strategy selection outcome measures follow-up outcomes harms/ variables quality assessor(s) adverse rating events

treatment Medicine Alternative and Complementary BMC al. et Lantz C & Before-after Scoliosis (n = 42) No CMT NA NA NA L blinded L Cobb angle H follow-up not L all H H confounding Medium Chen J, improvement consistent outcomes adverse variables missing, no 2001 [64] discussed events mention of natural not course reported Saedt E, Before-after Upper cervical Improvement MT NA NA NA L blinded U-PN property L follow-up L all L adverse U-PY not all High et al. 2018 [67] dysfunction measurements consistent outcomes events confounding variables (n = 307) not fully discussed discussed known evaluated for children Legend: H-High risk of bias; L-Low risk of bias; NA-Not applicable; U-Unclear; PN-Probably No (high risk of bias); PY-Probably Yes (low risk of bias) Interventions: CMT Chiropractic Manipulative Therapy, CST Craniosacral Therapy, MT Manual Therapy, OMT Osteopathic Manipulative Therapy (2019)19:60 ae1 f38 of 14 Page Table 6 Data extraction for the gastrointestinal/urinary studies Prevost Parnell Condition Author/year Study objective Study design Patient description/ Primary/ main outcome(s) Main results/ conclusions Adverse events Sample size condition Intervention

Constipation Tarsuslu T, et al. Investigate potential effects Interrupted Time Children with CP, ages Defecation frequency, gross Both groups showed There was no Medicine Alternative and Complementary BMC al. et 2009 [18] of osteopathic treatment on Series (with 2–16, with constipation motor function classification significant changes mention of adverse constipation in children with comparison group) system, Modified Ashworth from all baseline events made in this cerebral palsy. n =13 scale, functional independence measures at 3 mos. study. OMT measure for children, constipation assessment scale, visual analog scale Infantile Colic Miller JE, Two-fold: 1. Determine efficacy RCT Infants < 8 weeks, Decreased crying (as assessed 1. Greater decrease in One patient in the et al. 2012 [19] of chiropractic manipulation n = 104 diagnosed with colic by parent questionnaire and crying in colicky infants control group noted therapy for infants with colic; CMT 24 h crying diary) treated with CMT increased crying. and compared to infants 2. Parental reporting bias. who were not treated. 2. Unlikely that observed treatment effect is due to bias on part of reporting parent. Wiberg K & Investigate if the outcome of Interrupted Time Healthy, thriving infants, Parent report of crying: No apparent link There was no Wiberg J, 2010 [20] excessively crying infants Series (without ages 0–3 months, who classified as “improved”, between clinical effect mention of adverse “ ” “

treated with chiropractic comparison group) fit diagnostic criteria of uncertain recovery , non of chiropractic treatment events made in this (2019)19:60 manipulation is associated n = 749 infantile colic recovered” and a natural crying study. with age. CMT pattern was found, Slightly older age was found to be linked to crying infants with clinical improvement Browning M & To compare chiropractic RCT Infants < 8 weeks, who Change in group mean Mean hours of crying There was no Miller J, 2008 [21] manual therapy and n =43 cried more than 3 h a daily hours of crying were significantly mention of adverse occipital-sacral decompression CMT day for at least 4 of (recorded in crying diary) reduced in both events made in this in the treatment of infant colic. the previous 7 days groups. Both treatments study. appear to offer benefits to infants with colic. There was no difference between two treatment approaches. Olafsdottir E, To evaluate chiropractic RCT Infants ages 3–9 weeks, 24 h diary of infant’s No difference between There was no et al. 2001 [22] spinal manipulation n =86 diagnosed with infantile crying (crying diary) groups with either mention of adverse management on infantile CMT colic completed by parent; outcome. events made in this colic. Parent report of effect study. after last visit (8–14 days later)

Hayden C & To determine the impact of RCT Infants 1–12 weeks, with Parents record of time No between group There was no 38 of 15 Page Mullinger B, cranial osteopathy on n =28 signs of infantile colic spent crying and comparisons done. mention of adverse 2006 [23] infantile colic. OMT/CST that included; 90 min/ sleeping in a 24-h diary While both groups, events made in this 24 h. of inconsolable demonstrated study. crying on 5 out of decreases, 7 days and additional only the OMT/CST Table 6 Data extraction for the gastrointestinal/urinary studies (Continued) Prevost Parnell Condition Author/year Study objective Study design Patient description/ Primary/ main outcome(s) Main results/ conclusions Adverse events Sample size condition Intervention

clinical signs such as group had significant Medicine Alternative and Complementary BMC al. et borborygmi, knees reduction for time drawn up to chest, fists spent crying and clenched, backward sleeping. bending of head or trunk Pediatric Nemett D, et al. To determine whether RCT Children ages 4–11, Improved dysfunctional Results suggest that There was no dysfunctional 2008 [24] manual - n =21 diagnosed with voiding symptoms; manual physical mention of adverse voiding osteopathic approach added OMT dysfunctional voiding 1. improved or resolved therapy-osteopathic events made in this to standard treatment and symptoms of vesicoureteral reflux approach treatment study. improves dysfunctional daytime incontinence 2. elimination of post-void can improve short-term voiding more effectively and or vesicoureteral urine residuals outcomes in children than standard treatment reflux with dysfunctional alone. voiding, beyond improvements observed with standard treatments. Nocturnal van Poecke A & To evaluate the effect of Before-After Children ages 3–18, Diary of wet night 66.6% resolution rate There was no Enuresis Cunliffe C, 2009 [25] chiropractic treatment on n =33 diagnosis of frequency, diurnal within 1 year, indication mention of adverse

the wet night frequency of CMT nocturnal enuresis urinary output for possible effectiveness events made in this (2019)19:60 patients with nocturnal of chiropractic treatment study. enuresis. (Neuroimpulse instrument) in patients with primary nocturnal enuresis. Suboptimal Miller J, et al. To determine the effect of Before-After Infants ages 2 days - Mother’s report of Exclusively of breastfeeding No negative side infant 2009 [26] chiropractic manipulative n = 114 12 weeks diagnosed exclusivity of was accomplished in 78%. effects were breastfeeding therapy on infants who had CMT by medical provider breastfeeding, rating reported. difficulty breastfeeding. with feeding difficulties of improving and infant weight gain Vallone S, To investigate problems Before-After Infants ages 5 days - Improvement in > 80% of infants experienced There was no 2004 [27] interfering with successful n =25 12 weeks, referred by ability to latch and improvement in latch and mention of adverse breastfeeding and to see if CMT/CST other healthcare ability to breastfeed ability to breastfeed. events made in this proper lactation providers as having study. management can increase difficulty breastfeeding the bonding experience. ae1 f38 of 16 Page Parnell Prevost et al. BMC Complementary and Alternative Medicine (2019) 19:60 Page 17 of 38

on infantile colic in 28 infants was conducted by Hayden excessive suck (grade 4) as objectively determined with a et al. These researchers found a reduction in crying suck grading chart. The results of this study showed fa- times (63%), improved sleeping (11%), and a need for vorable improvement in all the infants after four treat- less parental attention. Due to the favorable findings of ments (78% were able to exclusively breastfeed). this study, the researchers suggested that a larger scale Outcomes included the mother’s report of improved study is warranted. There was no mention of adverse weight gain and a specific list of historical data and clin- events made in this study [23]. ical examination findings including improvements in Overall Summary: suck reflex grading. No negative side effects were re- Inconclusive (unclear) for CMT in treating infantile ported [26]. colic. A low quality before-after case series of 25 infants with Inconclusive (favorable) for OMT/CST in treating SIB set out to determine if proper lactation might increase infantile colic. the bonding experience between mother and infant follow- ing CMT/CST. This study reported improvement in the 1.3.Pediatric dysfunctional voiding ability to latch after the infants received CMT (which in- cluded craniosacral treatment). The study’sauthorsposited A medium quality RCT sought to determine whether CMT/CST in the early stages of neurological imprinting OMT in addition to standard treatment improved dysfunc- appear to safely and effectively address the craniocervical tional voiding in 21 children diagnosed with pediatric dys- dysfunction and help restore natural efficient sucking pat- functional voiding. Improvements in short-term outcomes terns for infants who are unable to latch. There was no in children with dysfunctional voiding were reported be- mention of adverse events made in this study [27]. yond improvements observed with standard treatment. No Overall Summary: mention of adverse events were reported in this study [24]. Inconclusive (favorable) evidence for use of CMT/CST Overall Summary: for children with SIB. Inconclusive (favorable) evidence for use of OMT plus standard treatment to improve dysfunctional voiding. 2. Musculoskeletal conditions

1.4.Pediatric nocturnal enuresis Table 7 summaries the 12 studies that investigated the clinical effects of manual therapy for conditions catego- A medium quality before-after retrospective record rized as “musculoskeletal conditions”. One of these in- review of 33 consecutive patients over a three-year vestigated the use of manual therapy on clubfoot [28] period found somewhat favorable results using CMT, and one on cuboid syndrome [29]. Three of these studies specifically utilizing the Neuroimpulse protocol. The investigated the use of manual therapy for headaches children were between the ages 3–18 with primary [30–32], four for low back pain [33–36], two investigated nocturnal enuresis. The frequency of wet nights was pulled elbow [37, 38], and one study for temporoman- abstracted from the records at 3, 6, 9 and 12 months dibular (TMD) dysfunction [39]. after the commencement of treatment. The records found 22 patients showed complete resolution of pri- 2.1.Clubfoot mary nocturnal enuresis during the 12 months after commencement of chiropractic care. The resolution One study was found that investigated the use of MT rate was 66.6% within 1 year with the mean number on patients with clubfoot [28]. of treatments in the responder’sgroupbeing2.05± A low quality RCT conducted by Nilgun et al. investi- 1.33. There was no mention of adverse events made gated the effectiveness of intensive physical therapy (in- in this study [25]. cluding mobilization technique) as an adjunct to Ponseti Overall Summary: technique in 29 children (average age 15–12 months) with Inconclusive (unclear) evidence for use of CMT to im- idiopathic clubfoot. Using the Dimeglio classification sys- prove nocturnal enuresis. tem they reported a statistically significant improvement in the group that received both MT and the Ponseti tech- 1.5.Suboptimal infant breastfeeding (SIB) nique combined. The study group received the interven- tion once per day, 5 days a week for 1 month. There is no Two case series with pre and post measurements in- mention of adverse events made in this study [28]. vestigated the use of CMT on infants with SIB [26, 27]. Overall Summary: A medium quality before-after case series investigated Inconclusive (favorable) evidence for the use of MT the effect of CMT on 114 infants with SIB, 112 classified combined with Ponseti technique in children with with an ineffective suck (grades 0–2) and 2 having clubfoot. anl Prevost Parnell Table 7 Data extraction for the musculoskeletal studies Condition Author/ year Study objective Study design Patient description/ Primary/main outcome(s) Main results/conclusions Adverse events sample size condition intervention

Clubfoot Nilgun B, To determine efficacy of RCT Children ages 3 and Improvements in passive Treatment procured a There is no mention Medicine Alternative and Complementary BMC al. et et al. 2011 [28] physical therapy, including n =29 under, Dimeglio Score ranges of motion for statistically significant of adverse events manual mobilization, as MT of 17 or under with plantar flexion, inversion, improvements in made in this study. adjunct to Ponseti technique idiopathic clubfoot eversion, rear foot varus ranges of motion, in idiopathic clubfoot. angle and forefoot Dimeglio Score and adduction angle and decrease of rear foot decrease in Dimeglio varus angle in the Score study group. Cuboid Syndrome Jennings J Describe the examination Interrupted 7 patients age range Visual Analog Scale: All patients had There is no mention & Davies D, and treatment of the Time Series 15–36 (2 pediatric Pre- and post-treatment substantial resolution of adverse events 2005 [29] cuboid syndrome following (with patients can be of symptoms following made in this study. lateral ankle sprain. comparison isolated), with cuboid cuboid manipulation. group) syndrome n =2 MT Headache Przekop P, Evaluate and compare Before-After Children ages 13–18, 5 main effects: headache Both approaches There is no mention et al. 2016 a multimodal with n =83 diagnosed with CTTH frequency, pain intensity, showed significant of adverse events [30] pharmacologic OMT general health, pain improvements across made in this study.

treatment for the restriction and number all 5 main effects (2019)19:60 prevention of chronic of tender points outcomes, but tension type headaches multimodal (CTTH) in adolescents. treatments produced more favorable results in headache frequency, general health, and number of tender points. Borusiak P, To investigate the RCT Adolescents ages Assessment of; percentage No difference in any No serious or moderate et al. 2010 [31] efficacy of spinal n=52 7–15, with cervicogenic of days with headache, total outcome measure adverse events were manipulative therapy MT headache duration of headache, days between placebo noted. Minor adverse in adolescents with with school absence due and cervical spine events occurred in both recurrent headache. to headache, consumption manipulation. groups that included; of analgesics, and intensity hot skin in 15 patients of headache (treatment group 6, placebo 9), dizziness in 11 patients (treatment group 7, placebo 4). There was reported transitory increase in headache intensity and

frequency being 38 of 18 Page reported for up to 4 days (treatment group 8, placebo 6). Table 7 Data extraction for the musculoskeletal studies (Continued) Prevost Parnell Condition Author/ year Study objective Study design Patient description/ Primary/main outcome(s) Main results/conclusions Adverse events sample size condition intervention

Marchand A, To conduct a retrospective Before-After Children ages 2 days - Reduction in behavioral All 13 consecutive There is no mention Medicine Alternative and Complementary BMC al. et et al. 2009 [32] file search of infants n =13 8.5 months, with findings recorded verbatim cases had favorable of adverse events presenting with probable CMT benign infant by parents such as; grabbing results based on made in this study. benign infantile headache headache holding face, ineffective parent report of at a chiropractic teaching latching, grimacing and outcomes. clinic. positional discomfort, rapping head against floor, photophobia, and anorexia. Low Back Pain Evans R, et al. To compare 12 weeks RCT Children ages 12–18, Primary outcome - self-reported Chiropractic manipulative Side effects were 2018 [33] of chiropractic n = 185 with chronic lower level of low back pain (11 box therapy plus exercise similar in both groups, manipulative therapy CMT back pain numerical rating scale), Secondary resulted in larger mild and self-limiting combined with exercise outcomes - patient-rated disability reduction in primary and occurred at a therapy to exercise (18 item Roland-Morris Disability outcome of pain severity frequency comparable therapy alone in the questionnaire), quality of life (23 overthecourseof1year. to adult population. treatment of chronic item PedsQL), improvement lower back pain in (9-point scale), frequency of children. medication use for low back pain (days/week), patient satisfaction with care

(7-point scale) (2019)19:60 Walston Z & To illustrate the feasibility Interrupted Adolescents ages Pain measured on numerical All outcome showed No adverse reactions Yake D, 2016 and safety of lumbar Time Series 13–15, with pain rating scale and disability improvements (0/10 were reported or [34] manipulation as an (without mechanical low (Oswestry) for each patient on numeric scale and observed with any adjunct to exercise for comparison back pain 0% in the Oswestry episode of treatment of adolescent group) disability index) for manipulation. population with n =3 each patient. mechanical low back MT pain. Selhorst M & To assess efficacy of RCT Adolescents ages Patient Specific Functional Scale, No difference between Two patients in both Selhorst B, lumbar manipulation n =35 13–17, with pain (11-point Numerical Pain groups for Patient the sham and 2015 [35] in addition to a 4-week MT mechanical low Rating Scale), and Global Specific Functional manipulation group physical therapy exercise back pain of Rating of Chance scales Scale, pain, or Global had an adverse program. < 90 days Rating of Chance reaction at 1 week. scales. All patients No patients in either improved. groups reported adverse reactions at either 4 weeks or 6 months. They concluded that no additional risk of having an adverse

reaction were noted 38 of 19 Page in this study. Hayden J, To describe chiropractic Before-After Children ages Subjective assessment of Over a course of Complications from et al. 2003 [36] management, outcomes, n =54 4–18, with acute improvement on a 5-point 4–6 weeks of chiropractic chiropractic patient and factors associated CMT mechanical low rating scale (Pediatric Visual management, 55–62% management were Table 7 Data extraction for the musculoskeletal studies (Continued) Prevost Parnell Condition Author/ year Study objective Study design Patient description/ Primary/main outcome(s) Main results/conclusions Adverse events sample size condition intervention

with outcomes for low back pain Analog Scale) of patients had collected with none Medicine Alternative and Complementary BMC al. et back pain in childhood. improvement that met noted throughout the study’sstringent the study data criteria and 82–87% had collection period. much improvement. Pulled Elbow García-Mata S To determine the RCT Children ages Reduction of pulled elbow Both maneuvers were There is no mention & Hidalgo- relative efficacy of two n = 115 1–5, with pulled verified by observing active effective with a higher of adverse events Ovejero A, pulled elbow reduction MT elbow flexion and extension first-attempt success collected in this 2014 [37] maneuvers, hyper rate with hyper pronation. study. pronation and supination- flexion. Bek D, et al. To compare the reduction RCT Children ages Reduction of pulled elbow Final reduction rates There is no mention 2009 [38] efficiency of hyper n =66 1–5, with pulled indicated by child using similar. Hyper pronation of adverse events pronation to supination- MT elbow the arm maneuver was more collected in this flexion maneuvers for a successful on the first study. pulled elbow. attempt. Temporomandibular Monaco A To evaluate the effects RCT Children average Objective measures pre- Osteopathic manipulation There is no mention Disorder et al. 2008 [39] of osteopathic manipulative n =28 age 12, diagnosed and post-treatment using made significant of adverse events therapy on mandibular OMT with TMD kinesiographic tracings to improvements in maximal made in this study. (2019)19:60 kinematics in patients with assess mandibular movement mouth opening and in temporomandibular maximal mouth opening dysfunction. velocity. ae2 f38 of 20 Page Parnell Prevost et al. BMC Complementary and Alternative Medicine (2019) 19:60 Page 21 of 38

2.2.Cuboid syndrome missing school, percentage of days with necessity of an- algesic medication, and intensity of headache based on a One study was found that investigated the use of MT 10-point numerical analog scale. No significant differ- on patients with cuboid syndrome [29]. ence was reported for any outcome measure. They did A medium quality interrupted time-series without a note that baseline and follow-up frequency of days with comparison group described the proper examination, headache was reduced in both groups however, the dif- evaluation, and treatment of cuboid syndrome with ferences were not significant. Minor adverse events oc- manual manipulation following lateral ankle sprains in 7 curred in both groups with no serious or moderate patients aged 15–36 of which 2 children met our inclu- adverse events reported [31]. sion (ages 15 and 16). Using visual analog scales pre and Marchand et al. conducted a low quality before- post treatment Jennings et al. reported patients’ subject- after case series that investigated the effects CMT for ive pain at rest, during palpation, during midtarsal mo- 13 infants (aged 2 days to 8.5 months) with probable bility testing, with gait, and with single-leg hop. Both benign infant headache. Outcome measures were children were diagnosed with this condition and re- changes noted in behavioral findings as reported ceived a cuboid manipulation. They each required only verbatim by parents including: less grabbing or one treatment and were able to return to competitive ac- holding of the face, improved latching, less grimacing tivity with one treatment without injury recurrence. and positional discomfort, less rapping of the head There is no mention of adverse events made in this against the floor and less photophobia and anorexia. study [29]. They reported that all of the patients responded fa- Overall Summary: vorably to CMT and that a therapeutic trial is war- Inconclusive (unclear) evidence for MT in patients ranted. There is no mention of any adverse events in with cuboid syndrome. this article [32]. Overall Summary: 2.3.Headache Inconclusive (unclear) for the use of OMT for chronic tension-type headaches in adolescents, for the use of MT Three studies investigated the use of manual therapy on for cervicogenic HA, and for the use of CMT for benign pediatric headaches. One medium quality before-after infant headache. study investigated the use of OMT on chronic ten- sion-type headaches in adolescents [30]. One medium 2.4.Low back pain (LBP) quality RCT that was stopped early (before recruit- ment goal based on interim analysis) evaluated the Four studies investigated the use of manual therapy for clinical effectiveness of MT [31]. One low quality LBP in the pediatric population. Two studies looked at the retrospective case series with pre and post measure- use of CMT; one high quality RCT, the other a medium ments looked at the CMT [32]. quality before-after study [33, 36]. The other two looked Przekop et al. conducted a medium quality before-after at the use of MT; a medium quality interrupted observational study that compared multimodal (OMT) time-series, the other a medium quality RCT [34, 35]. and pharmacologic effects on chronic tension-type head- Evans et al. presented a high quality RCT with a compari- aches (CTTH). This study included 83 patients, (67 fe- son group between CMT with exercise against solely focus- males and 16 males), between the ages of 13 and 18. ing on exercise therapy. The patients included a range Outcome measures included: headache frequency, pain of ages between 12 and 18 years, concluding with 185 intensity, general health, pain restriction and the number total patients. They concluded that adolescents of tender points as found by the provider. They reported showed that by adding CMT with exercise therapy, that both multimodal and pharmacologic treatments were resulted in a larger reduction in the primary outcome effective for CTTH; however, results from multimodal (visual analog scale) of pain severity over the course treatment produced more favorable results in headache of 1 year. The study reported minor self-limiting ad- frequency, general health and in the number of tender verseeventsthatwereaboutequalfrequencyinboth points elicited. There was no mention of adverse events in groups [33]. this study [30]. Walston and Yake conducted a medium quality Borusiak et al. conducted a medium quality RCT com- interrupted time- series without a comparison group paring the use of cervical MT to a sham MT in 56 chil- of 3 patients (age range 13 through 15). They showed dren with cervicogenic headaches. Of these, data sets of feasibility and safety of lumbar manipulation with ex- 52 children were analyzed (mean age 11.6 years). Out- ercise in the adolescent population with LBP. Patient comes included: percentage of days with a headache, centered outcomes used included: subjective pain total duration of headache in hours, percentage of days measured on a numeric pain rating scale and the use Parnell Prevost et al. BMC Complementary and Alternative Medicine (2019) 19:60 Page 22 of 38

of Oswestry disability index. All outcomes showed A medium quality RCT compared the efficiency of improvement for all patients with no adverse reac- hyper pronation and supination flexion maneuvers in tions to manipulation [34]. the reduction of pulled elbow on 66 children (34 hyper The medium quality RCT of 35 patients (age range pronation-flexion and 32 supination-flexion) with an 13–17, mean 14.9 years) with mechanical LBP of less average age of 28 months. Successful reduction was con- than 90 days, was conducted to evaluate the clinical ef- sidered by the observation of the child being able to use fects of MT in addition to an exercise program. Eighteen the arm after the reduction. Although the authors con- children received MT and 17 received a sham manipula- cluded that final reduction rates were similar in both tion, which consisted of the child lying on their side and groups they found that the hyper pronation maneuver a therapist passively flexing both hips until slight lumbar was more efficient on the first attempt. There is no men- flexion. Patient centered outcomes utilized included, Pa- tion of adverse events made in this study [38]. tient Specific Functional Scale and Numerical Pain Rat- Overall Summary: ing Scale. Global Rating of Change scales was used to Moderate (positive) evidence for use of CMT/CST for evaluate perceived improvement. Both groups of patients children with SIB. reported improvements in LBP. The authors reported that there was no additional risk for lumbar manipula- 2.6.Temporomandibular dysfunction (TMD) tion, as both groups reported the same number of ad- verse events [35]. One study was found that investigated the use of Hayden et al. conducted a medium quality before- OMT for TMD dysfunction [39]. after cohort study without a control group that investi- A low quality RCT conducted by Monaco et al. evalu- gated the effectiveness of CMT for LBP for 54 patients ated the effects of OMT on mandibular kinematics in 28 ranging in age between 4 and 18 years. They reported children diagnosed with non-specific temporomandibu- that the majority of the patients responded favorably lar disorders. Kinesiographic tracings using K71 mea- and there were no reported adverse events. The re- sured mandibular incisor-point movement in three searchers were quick to point out that a causal relation- dimensions was the only outcome assessed. The results ship between CMT and improvements in pediatric LBP of this study showed a significantly statistical improve- could not be established due to both the small study size ment in the maximal mouth opening velocity in the and the observational design of the study itself. Compli- study group. It was reported that the use of OMT im- cations from chiropractic patient management were col- proved non-specific TMD. There is no mention of ad- lected with none noted throughout the study data verse events made in this study [39]. collection period [36]. Overall Summary: Overall Summary: Inconclusive (favorable) evidence for OMT in Moderate (positive) evidence for the use of CMT for pediatric TMD. adolescent LBP. Inconclusive (unclear) evidence for the use of MT for 3. Respiratory and eyes, ears, nose, and throat (EENT) pediatric mechanical LBP. conditions

2.5.Pulled (nurse’s) elbow Table 8 summarizes the eight studies that investigated respiratory, EENT conditions. In total, there were two Two RCTs met our inclusion criteria and investi- studies that investigated children with asthma [40, 41], gated the effectiveness of two MT maneuvers for the one study that investigated children with obstructive reduction of pulled elbow. It is important to point apnea [42], and five studies investigated children with out that both of these studies compared two different otitis media [43–47]. types of manipulation and both show favorable results on pulled elbow [37, 38]. 3.1.Asthma A medium quality RCT of 115 patients (mean age 2.3 years old) was conducted by Garcia-Mata et al. and Two studies were identified that investigated the use sought to determine which procedure was the most ef- of manual therapy for the treatment of pediatric asthma. fective to reduce a pulled elbow. There were 65 patients One study was a medium quality and investigated OMT allocated to the hyper pronation group and 50 in the [40]. The other study was a high quality pilot RCT and supination-flexion group. The hyper pronation group investigated CMT [41]. was found to be more efficient on reduction at the first Guiney et al. conducted a medium quality RCT and re- attempt. There is no mention of adverse events made in ported favorable results with the use of OMT in 140 pa- this study [37]. tients (90 treatment group, 50 control group), ages 5–17 anl Prevost Parnell Table 8 Data extraction for respiratory studies Condition Author/year Study objective Study design Patient Primary/main outcome(s) Main results/conclusions Adverse events sample size description/ intervention condition

Asthma Guiney P, To demonstrate the RCT Children ages 5– Peak Expiratory Flow Rates There was statistically There was no mention of adverse Medicine Alternative and Complementary BMC al. et et al. 2005 [40] therapeutic relevance of n = 140 17, diagnosed with significant improvement events made in this study. osteopathic manipulation in OMT asthma by of 7 L per minute to 9 L the pediatric asthma guidelines from per minute for peak population. NIH expiratory flow rates in the treatment group. Bronfort G, To determine if chiropractic RCT Children ages 6– Pulmonary function tests, Little to no change in There was no mention of adverse et al. 2001 [41] manipulative therapy in n =34 17, with persistent diary recording peak pulmonary function events made in this study. addition to optimal medical CMT asthma expiratory flow and inhaler tests at 12 weeks and management resulted in use, questionnaires no change in patient, clinically important changes in assessing quality of life, parent/guardian or asthma-related outcomes. asthma severity and pulmonologist rated improvement improvement Obstructive Vandenplas Y, To evaluate if osteopathy can RCT Infants aged 1.5–4 Decrease in the number Infants aged 1.5–4 months, There was no mention of adverse Apnea et al. 2008 [42] influence the incidence of n =34 months, with of obstructive apneas as with obstructive apnea events made in this study. obstructive apnea during sleep OMT obstructive apnea measured by as determined by in infants. as determined by polysomnography. polysomnographic a polysomnographic (2019)19:60 test Otitis Media Steele D, To evaluate the efficacy of an RCT Infant ages 6–24 Tympanometer and Both tympanometer There were no serious adverse events et al.2014 [43] osteopathic manipulative n =52 months, with acute acoustic reflectometer data and acoustic reported during the study. treatment protocol on middle OMT otitis media and reflectometer analysis ear effusion resolution abnormal demonstrated significantly following acute otitis media. tomogram significant improvement in middle ear effusion at visit 3 in the standard care plus osteopathic treatment group. Wahl R, et al. To assess the efficacy of RCT Children aged 12– Reduction in future No interaction was found “One subject withdrew from the study 2008 [44] Echinacea and osteopathic n =90 60 months, with episodes of OM between Echinacea and following an adverse effect (vomiting manipulative treatment for OMT recurrent otitis osteopathic manipulation. after taking the Echinacea placebo). preventing acute otitis media. media Echinacea was associated One additional subject reported adverse with a borderline increased effects (vomiting and non-urticarial rash risk of having at least one 2 days after starting episode of acute otitis Echinacea for a viral upper respiratory media during 6-month illness) but did not withdraw. Neither follow-up compared to adverse effect was considered to have placebo. Osteopathic been caused by the study medication. manipulation did not

significantly affect risk 38 of 23 Page compared to sham. Table 8 Data extraction for respiratory studies (Continued) Prevost Parnell Condition Author/year Study objective Study design Patient Primary/main outcome(s) Main results/conclusions Adverse events sample size description/ intervention condition –

Degenhardt B Does osteopathic Before-After Infants ages 7 35 Decreased incidence 5 participants had no There is no mention of adverse events Medicine Alternative and Complementary BMC al. et & Kuchera M, manipulation decrease the n =8 months, with of acute otitis media recurrence after 1 year made in this study. 2006 [45] recurrence of otitis media? OMT/CST recurrent otitis follow-up. 1 participant had 1 media recurrence. 2 participants had a short-term of no recurrence only. Zhang J & To study the effect of Toftness Before-After Children ages 9 Tympanic Membrane After Toftness chiropractic “During the study protocol, no side Snyder B, chiropractic adjustment for n =22 months −9 years, visualization via adjustment, red and bulging effects or deterioration of clinical 2004 [46] acute otitis media. CMT with acute otitis otoscopic exam and tympanic membrane presentations were found among media oral temperature returned to normal in 21 children with otitis media.” 95% of children. A decrease in average oral temperature was noted. Mills M, et al. To evaluate the effect of usual RCT Children ages 6 Decreased frequency of Intervention group had fewer There were no adverse events reported 2003 [47] care and osteopathic n =57 months - 6 years, acute otitis media, episodes of acute otitis during the study. manipulation for children with OMT with recurrent antibiotic us, surgical media, fewer surgical acute otitis media. otitis media interventions, and procedures and an increased improved tympanometric frequency of more normal

and audiometric tympanogram readings. (2019)19:60 performance ae2 f38 of 24 Page Parnell Prevost et al. BMC Complementary and Alternative Medicine (2019) 19:60 Page 25 of 38

with asthma. The primary outcome was improved peak technique) for acute otitis media [46]. All but one of the expiratory flow rates. Their results show a statistically OMT studies showed favorable results on the use of MT significant improvement from 7 L/min to 9 L/min for for acute otitis media. peak expiratory flow rates. No mention of adverse events Steele et al. conducted a medium quality prospective, was noted in this study [40]. pilot RCT (stopped before it reached its recruitment Bronfort et al. conducted a high quality pilot RCT goal of 80 patients) that evaluated 52 infants ages 6–24 that investigated if CMT in addition to medical man- months with acute otitis media and abnormal tomo- agement would result in clinically important changes grams. The primary outcome was measured with a tym- in asthma-related outcomes. This study included an panometer and an acoustic reflectometer. They observation component, but no actual data was avail- determined there was faster resolution in middle ear ef- able to include in this review. Their study included fusion in 2 weeks with what they described as “standard- 34 children aged 6–17 years of age with persistent ized OMT”. There were no serious adverse events asthma. The main outcomes were determined by pul- reported during this study [43]. monary technicians at baseline and at 12 weeks. They A high quality RCT evaluated the use of Echinacea looked at diaries of recording peak expiratory flow purpurea and OMT on 90 (84 completed the study) in- and inhaler use, questionnaires assessing quality of fants aged 12–60 months with recurrent otitis media. life, asthma severity, and improvements. They found The main outcome of the study was a reduction in the little to no change in pulmonary function tests at 12 incidence of recurrent otitis media. As reported in weeks and no change in patient or pulmonologist monthly telephone interviews and at the 3- and rated improvement with the use of CMT. However, 6-month visits, there was no statistically significant dif- Bronfort et al. did report improvement in patient-cen- ference in reporting of any side effects between placebo tered outcomes such as quality of life, even 1 year and treatment groups for either echinacea or OMT. One after the last treatment. No mention of adverse events participant withdrew from the study following adverse was noted in this study [41]. events (vomiting after taking the echinacea placebo). Overall Summary: One additional participant reported adverse events Inconclusive (favorable) for OMT in treating asthma. (vomiting and non-urticarial rash 2 days after starting Inconclusive (unclear) for CMT in treating asthma. echinacea for a viral upper respiratory illness) but did not withdraw [44]. 3.2.Obstructive apnea A medium quality before-after cohort, practice basedstudyevaluated8infantsages7–35 months One study was found that investigated the use of with recurrent acute otitis media was undertaken by OMT on obstructive apnea [42]. Degenhardt et al. The main outcome was a decreased A medium quality pilot RCT by Vandenplas et al. incidence of otitis media. The results of this study sought to investigate if OMT can influence the incidence were that 5 of the 8 children had no recurrence after of obstructive apnea during sleep in infants. This study 1 year follow up, one had 1 recurrence, and 2 of the of 34 infants, ages 1.5–4 months diagnosed with ob- 8 children had a short period of no recurrence after structive apnea showed a significant decrease in the receiving OMT. In the method section of this study, number of observed apnea episodes in the OMT group the OMT used met the description of craniosacral compared to the control group. The main outcome mea- therapy (CST). It is also important to note that all sured was a decrease in the incidence of apnea with the participants in this study were also under concurrent suggestion for additional research. No mention of ad- medical care. No mention of adverse events was noted in verse events was noted in this study [42]. this study [45]. Overall Summary: A medium quality study before-after case series in- Inconclusive (favorable) evidence for OMT in treating vestigated 22 children ages 9 months to 9 years with obstructive apnea. acute otitis media showed favorable results utilizing Toftness chiropractic technique, a type of low force 3.3.Otitis media technique chiropractic system. The primary outcome measures utilized in the study was otoscopic Five studies investigated the clinical effectiveness of visualization and oral temperature. The researchers of manual therapy on otitis media that met our inclusion this study state that otitis media may benefit from criteria. Four of the studies investigated the use of OMT. Toftness CMT and that the data justified a clinical Of these, two were of high quality and two were of trial be undertaken. During the study, no side effects medium quality [43–45, 47]. One medium quality study or deterioration of clinical presentations were noted looked at the use of CMT (specifically Toftness among the pediatric participants [46]. Parnell Prevost et al. BMC Complementary and Alternative Medicine (2019) 19:60 Page 26 of 38

A second high quality RCT investigated the use of Inconclusive (favorable) evidence for OMT in treating OMT for 57 children with acute otitis media. In this ADHD in children. study, Mills et al. grouped 25 participants into the treat- ment group that received OMT in addition to routine 4.2.Autism pediatric care and 32 subjects in the control group who received only routine pediatric care. The average age Two studies were found that investigated the use of was 26 months in the treatment group and 20 months in manual therapy on patients with autism. One looked at the control group. Decreased symptoms and improved the use of visceral osteopathic manual therapy (VOMT) tympanogram scores were only reported in the OMT the other CMT [49, 50]. group. The researchers stated there were no adverse A medium quality interrupted time-series without events reported during the study [47]. comparison was conducted by Bramati-Casterllarian et Overall Summary: al. They investigated the influence of VOMT on behav- Inconclusive (favorable) evidence for OMT in treating ior and GI symptoms on children with autism. Their acute otitis media. study included 49 autistic children ages 3 1/2 to 8 years Inconclusive (unclear) evidence for CMT (Toftness of age with GI symptoms and impaired social interac- technique) in treating acute otitis media. tions and communication. The primary outcome meas- ure they utilized was parental completion of the 4. Special needs Modified Autism Research Institute survey and secretin assessment to assess the GI signs and symptoms. Overall Table 9 summarizes the ten studies investigating the significant symptomatic improvement for social behav- use of manual therapy for pediatric conditions catego- iors and communication, as well as improvement in di- rized as special needs that met our inclusion criteria. gestive issues such as vomiting and poor appetite, were One study investigated OMT on children with Attention reported. They concluded VOMT could have a signifi- Deficit Hyperactive Disorder (ADHD) [48], two studies cant improvement in quality of life and well-being for investigated the use of manual therapy for autistic chil- children suffering from both autism and GI signs and dren [49, 50], (one used VOMT and the other used symptoms. There was no mention of adverse events CMT). Three studies investigated the use of OMT on made in this study [49]. children with cerebral palsy [51–53] and four of the A low quality RCT without a control group intended studies investigated the use of OMT on premature in- to identify the differences in efficacy between Upper fants [54–57]. Cervical CMT and Full Spine (Diversified) CMT in 14 autistic children. The clinical effects of the autistic chil- 4.1.Attention deficit hyperactive disorder (ADHD) dren were evaluated using the Autism Treatment Evalu- ation Checklist, a questionnaire that assessed the One study was found that investigated the use of children’s development and progress that is answered by OMT on patients with ADHD [48]. the parents. Although autistic children in both groups Accorsi et al. conducted a high quality RCT evaluat- demonstrated improvements in their autistic behaviours, ing the efficacy of OMT in the treatment of 28 children the ATEC score for the upper cervical group was 32% ages 5 to 15 years old with ADHD. One half of the par- versus 19% for the full spine group. The authors con- ticipants (n=14) were placed in a treatment group, cluded autistic children receiving Upper Cervical CMT which received OMT plus conventional treatment, and experienced better improvement in their autistic behav- one half of participants (n = 14) were placed in the con- iors compared to autistic children receiving Diversified trol group, receiving conventional therapy alone. The CMT. There is no mention of adverse events in this outcome measures were better accuracy and rapidity study [50]. scores on the Biancardi-Stroppa Modified Cancellation Overall Summary: test, a test that is used to measure visual-spatial atten- Inconclusive (unclear) evidence for VOMT in treating tion. Accorsi et al. reported the children in the inter- autism. vention group demonstrated statistically significant Inconclusive (favorable) evidence for CMT in treating improvement in selective and sustained attentive per- autism. formances, as measured using the Biancardi-Stroppa Modified Cancellation Test. These findings prompted 4.3.Cerebral palsy the researchers to recommend a larger study be under- taken. There is no mention of adverse events in this Three RCT’s were found that met our criteria investi- study [48]. gated the use of OMT on children with cerebral palsy Overall Summary: [51–53]. Table 9 Data extraction for the special needs studies Prevost Parnell Condition Author/year Study objective Study design Patient description/ Primary/main outcome(s) Main results/conclusions Adverse events sample size condition intervention –

ADHD Accorsi A, et al. To evaluate efficacy of RCT Children ages 5 15, Biancardi-Stroppa Modified Osteopathic manipulative There was no mention Medicine Alternative and Complementary BMC al. et 2014 [48] osteopathic manipulative n =28 with primary diagnosis Bell Cancellation Test, treatment was positively of adverse events treatment of children OMT of ADHD accuracy and rapidity associated with changes made in this study. with ADHD. scores in the Biancardi-Stroppa Test accuracy and rapidity scores. Autism Bramati-Castellarin I, Investigate the influence Interrupted Autistic children ages Parental completion of the Significant improvements “There was no et al. 2016 [49] of visceral osteopathic Time Series 3 1/2–8, with GI Modified Autism Research reported in “social behavior mention of adverse technique on the (without symptoms, impaired Institute outcomes survey and communication” and events made in this behaviour and GI control group) social interactions form (9 S.O.S. questionnaires) “digestive signs” subscale study.” symptoms of children n =49 and communication and secretin assessment of the questionnaire and with autism. VOMT used to assess GI signs and in vomiting and poor symptoms appetite comparing before and after VOMT. Khorshid K, et al. Identify the differences RCT Children diagnosed ATEC average scores and Clinical improvements Clinical deterioration 2006 [50] in efficacy between n =14 with autism parental observations observed through parental was shown in one of upper cervical and full CMT observations and through the children of the full spine adjustment in a decrease in the ATEC spine group, but only

autistic children scores in both groups. Upper marginal in one child (2019)19:60 cervical group had improved of the upper cervical ATEC average scores of 32%. Full group. spine group had improved ATEC scores of 19%. Cerebral Wyatt K, et al. Evaluate the general RCT Children with CP, Gross Motor Function Measure - No statistical change in No serious adverse Palsy 2011 [51] health and wellbeing n = 142 ages 5–12 (GMFMM-66) Quality of life GMFM-66 or CHQ. PF50 events were reported. effect of cranial Cranial Child Health Questionnaire- Parents (unblinded) osteopathy on cerebral Osteopathy (CHQ) PF50 reported better global health. palsy children. Duncan B, et al. Evaluate effectiveness RCT Children with spastic Parent reporting of changes 96% reported improvements. There was no mention 2004 [52] of osteopathic manipulation n =50 CP, ages 20 months observed (open-ended Most frequent seen in use of adverse events or as a OMT - 12 years questions) of arms and legs (61 and made in this study. supplemental therapies 68%) and more restful sleep for children with spastic (39 and 68%) in osteopathic cerebral palsy. and acupuncture respectively. Additional improvements also noted in mood and bowel functions. Duncan B, et al. Evaluate effectiveness RCT Children with CP, 11 outcomes used: Primary- Osteopathic manipulation There was no mention 2008 [53] of osteopathic n =55 ages 20 months - GMFCS, GMFM total percent, was associated with of adverse events manipulation (cranial OMT/ 12 years PEDI mobility, PEDI self-care, improvements in 2 of 11 made in this study.

field, Acupuncture WeeFIM mobility, WeeFIM self- outcomes; GMFM total 38 of 27 Page or both) vs. acupuncture care; Secondary- DO rating of percent and WeeFIM in spastic cerebral palsy spasticity, MAS biceps, MAS Mobility. Acupuncture patients. hamstring, parent/guardian was not associated with rating of arched back, parent/ improvements in any guardian rating of startle reflex of the outcomes variables. Table 9 Data extraction for the special needs studies (Continued) Prevost Parnell Condition Author/year Study objective Study design Patient description/ Primary/main outcome(s) Main results/conclusions Adverse events sample size condition intervention

Prematurity Raith W, et al. Investigate neurological RCT Preterm infants ages Primary outcome: General No difference in the general There was no mention Medicine Alternative and Complementary BMC al. et 2016 [54] short term effects of n =30 25–33 weeks, free movement assessment movement could be observed of adverse events craniosacral therapy on OMT/CST from medical tool. Secondary outcomes: between the groups. No made in this study. general movements in complications in General movement change in general movement preterm infants. NICU optimality score optimality score was noted. Cerretelli F, et al. Investigate whether RCT Preterm infants ages 1. Reducing length of Osteopathic treatment There were no 2015 [55] osteopathic manipulation n = 695 29–37 weeks, without hospital stay reduced days hospital complications reduces the length of OMT/CST congenital complications 2. Weight gain and hospital (3.9 days) and reduced associated to the hospital stay, costs, and in NICU savings costs by 1250.65€ per intervention. weight gain for preterms. newborn per length of stay. No change in weight gain was noted. Pizzolorusso G, Investigate whether RCT Preterm infants ages 1. Reducing length of hospital Sooner osteopathic There were no et al. 2014 [56] osteopathic manipulation n = 110 32–37 weeks, free stay and impact on length manipulation introduced, complications reduces length of hospital OMT/CST from medical of stay of timing of shorter length of stay. There associated to the stay, what effect the timing complications in introduction of osteopathic is a positive association of intervention. of introduction of osteopathic NICU manipulation osteopathic manipulation with treatment may have on the 2. Reducing hospital cost overall reduction in cost

outcome and hospital costs of care. (2019)19:60 in preterm infants. Cerretelli F, et al. Determine effectiveness of RCT Preterm infants ages 1. Decreased length of Osteopathic manipulation No serious adverse 2013 [57] osteopathic manipulative n = 110 >28 and <38 weeks, hospital stay reduced length of stay events were reported. therapy in reducing the OMT/CST free from medical 2. Improved weight gain and hospital costs but length of hospital stay, complications in and reduced NICU costs not effect weight gain. hospital costs and weight NICU gain in preterm infants. ae2 f38 of 28 Page Parnell Prevost et al. BMC Complementary and Alternative Medicine (2019) 19:60 Page 29 of 38

A high quality pragmatic RCT evaluated the effect of in the use of arms or legs (61 and 68%) and more OMT using cranial therapy on the general health and restful sleep (39 and 68%) in the OMT and the acu- well-being of 142 children ages 5–12 with cerebral palsy. puncture groups, respectively. Improvement in mood In this study, Wyatt et al. placed 71 children in treatment and improved bowel function were also very common group, who received 6 OMT sessions over 6 months and benefits noted by the parents in both groups. There 71 children in a control group, which they referred to as is no mention of adverse events in this study [52]. “waiting list”. Primary outcome measures included: Gross Overall Summary: Motor Function Measure 66 (GMFMM-66) and Quality Inconclusive (unclear) evidence for OMT in treating of Life Child Health Questionnaire (CHQ) PF50. Second- children with cerebral palsy. ary outcomes measures used in this study included: Paren- tal Assessment of Global Health and Sleep at 6 months, 4.4.Prematurity Pain and Sleep Questionnaire at 10 weeks and 6 months, CHQ PF50 at 10 weeks and the Quality of Life Short Four high quality RCTs were found, that investigated Form-36. This trial showed no statistically significant evi- the use of OMT on various clinical outcomes of children dence that OMT led to sustained improvement in motor born preterm [54–57]. function, pain, sleep, quality of life of the subjects or in A high quality RCT was conducted by Raith et al. on the quality of life of their caretakers. No serious adverse 30 preterm infants between 25 and 33 weeks in the neo- events were reported and none of the children withdrew natal intensive care unit, free from medical complica- from the study due to side effects of the treatment [51]. tions, with OMT/CST. The aim was to investigate Duncan et al. conducted a high quality assessor blinded neurological short term effects of craniosacral therapy wait-list controlled pilot RCT that investigated the effect- on general movement in preterm infants. The primary iveness of OMT (cranial therapy), myofascial release or outcome utilized was improvement in general move- both versus acupuncture on 55 cases of children ages 20 ment assessment tool. Secondary outcomes included months to 12 years with moderate to severe spastic cere- improvement in general movement optimality score. bral palsy. Participants were grouped into one of three They found no differences between the control or groups: OMT (which included osteopathy, myofascial re- study group for all outcome measures and at all time lease or both) (n =15),acupuncture(n =19)andwait-list points. There was no mention of adverse events made control (non-therapeutic attention) (n = 22). The six pri- in this study [54]. mary outcome measures were: Gross Motor Functional Cerretelli et al. conducted a high quality RCT in 2015 Classification, Gross Motor Measurement Total percent- that investigated the effectiveness of OMT/CST on age, Pediatric Evaluation of Disability Inventory mobility length of hospital stay, hospitalization costs, and weight and self-care, and Functional Independent Measure for gain in 695 preterm infants’ ages 29–37 weeks. (Study Children mobility and self-care. Duncan et al. reported group, n = 352; control group, n = 343) The primary ob- that OMT resulted in an improvement in the child’sgross jective was in determining the effect of OMT/CST in re- motor function as indicated by the outcome measures in ducing the length of the hospital stay. Secondary children with moderate to severe spastic cerebral palsy. objectives evaluated the effect on weight gain and NICU There was no mention of adverse events in this study [53]. cost savings. They found a reduction in days in hospital A low quality RCT evaluated the effectiveness of (3.9 days) and associated cost savings, but no significant OMT, acupuncture or both for 50 children aged 11 change in weight gain after OMT/CST compared to the months to 2 years with spastic cerebral palsy. Partici- control group. Similar to the Pizzolorusso et al. 2014 pants were grouped into four groups: OMT (n = 23), study, the description of the intervention listed as “ma- acupuncture (n = 19), both OMT and acupuncture nipulation” met the characteristics of cranial/craniosacral (n = 8) and wait-list control (n = 19). Multiple out- therapy. No complications were associated with the inter- come variables were used to determine if these inter- vention [55]. ventions would decrease muscle tone, improve Pizzolorusso et al. investigated whether OMT (cra- function and quality of life. Evaluation in this study nial sacral) reduced the length of the hospital stay in included parental interviews to assess perceptions and 110 preterm infants ages 32–37 weeks in a high qual- changes observed. Only 2 of 17 parents reported posi- ity RCT. Fifty-five infants were placed in the study tive gains while their child was in a wait-list control group who received routine pediatric care and OMT/ period, but all 17 parents reported gains while in the CST and compared to 55 infants in the control group treatment phase of the study. Improvement was who received routine pediatric care only. The primary claimed by 96% (48 of 50) of the parents while their objective of the study was to determine the effect of child was receiving treatments, but the gains varied. OMT/CST on reducing the length of stay and what The most frequent gains were seen in improvement effect the timing of introduction OMT/CST may have Parnell Prevost et al. 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on the outcome. The secondary objective was to esti- positional changes and the use of an orthotic helmet. mate the potential savings in terms of hospital costs. The study group included 23 infants who received Pizzolorusso et al. reported that length of stay and CST in addition to standard treatment to evaluate neonatal intensive care unit costs were improved after treatment duration and motor development. The pri- introduction of OMT. It was also concluded that the mary outcome utilized was the Alberta Infant Motor earlier the OMT/CST had the shorter the hospital stay. Scale at baseline and at discharge of the patients. The No adverse events were recorded in this study [56]. results of the study showed that CST added to usual Lastly, Cerretelli et al. conducted another high treatment for severe nonsynostotic plagiocephaly re- quality RCT that sought to determine the clinical ef- sulted in significant improvement in asymmetry, less fects of OMT in 110 preterm infants ages range 29– treatment duration, and improved motor behavior. 37 weeks. The treatment group had 55 assigned to There were no adverse events seen during the treat- receive OMT/CST plus routine pediatric care. They ment period [58]. were compared to 55 infants in the control group One medium quality pilot before-after study re- who received only routine pediatric care. The pri- ported favorable results utilizing OMT (the most fre- mary outcome measure was to determine the effect- quently used techniques used in the study were iveness of OMT/CST in reducing the length of the described as “cranial” work) on 12 infants with cranial hospital stay. Secondary objectives included deter- asymmetry. Twelve infants with cranial asymmetries mining the effect of OMT/CST on weight gain and received four OMT treatments over 2 weeks. An- in reducing NICU costs. The results of this study thropometric, plagiocephalometric, and qualitative show that OMT reduced the length of stay (− 5.9 measures were administered pre-intervention, during days) and NICU costs, but did not impact weight the third treatment and 2 weeks after the fourth treat- gain. They suggested that further studies based on ment. The study group showed a significant decrease multi-center design are required to confirm these re- in cranial vault asymmetry, skull base asymmetry, and sults. No adverse or side effects were shown in ei- trans-cranial vault asymmetry. The researchers con- ther group [57]. cluded that OMT contributes to improvements in cra- Overall Summary: nial asymmetries in infants younger than 6.5 months Moderate (favorable) evidence for OMT/CST in redu- presenting with nonsynostotic occipital plagiocephaly cing length of stay and hospital costs for preterm infants. characteristics. There was no mention of adverse Inconclusive (unclear) evidence for OMT/CST in im- events in this study [59]. proving general movement in preterm infants. Overall Summary: Inconclusive (favorable) evidence for both OMT and 5. Structural conditions MT/CST in treating cranial asymmetry in children.

Table 10 provides a summary of ten studies that 5.2.Postural asymmetry were categorized as “structural” conditions. Two stud- ies assessed changes to cranial asymmetry [58, 59], One high quality RCT reported improved infant pos- one evaluated postural asymmetry [60], five studies tural asymmetry utilizing OMT/CST on 32 infants, investigated scoliosis [61–65], one study evaluated (18 males, 14 females) with gestational age of at least torticollis [66], and one study evaluated upper cervical 36 weeks. Infants were assigned to intervention (n =16)or dysfunction [67]. sham (n = 16) groups. Outcomes were measured using a standardized video-based asymmetry scale from 5.1.Cranial asymmetry (non-synostotic plagiocephaly) baseline to final visit. In the control group, the mean improvement was 1.2 points. In the treatment group, Two studies investigated the use of manual therapy on the mean improvement was 5.9 points. The re- cranial asymmetry. searchers concluded that OMT/CST in the first One high quality RCT evaluated the use of MT/CST months of life is beneficial for infants with idiopathic [58], the other a medium quality before-after observa- asymmetry. At least two of the seven vegetative symp- tional study looked at OMT [59]. toms aggravated for 2 days after the intervention in six Cabrera-Martos conducted a high quality RCT that patients of the control group and in four patients of evaluated the effects of CST in infants with severe the treatment group. No other adverse events were nonsynostotic plagiocephaly. Forty-six children meet- described [60]. ing eligibility were randomized into control and study Overall Summary: groups. Twenty-three children allocated to the control Inconclusive (favorable) evidence for OMT/CST in group received standard treatment which included treating postural asymmetry in children. Table 10 Data extraction for structural studies Prevost Parnell Condition Author/year Study objective Study design Patient description/ condition Primary/main outcome(s) Main results/conclusions Adverse events sample size intervention – Cranial Cabrera-Martos I, Evaluate the effects of RCT Infants ages 4 8 months, Treatment duration and Treatment duration was Study reported no adverse Medicine Alternative and Complementary BMC al. et Asymmetry et al. 2016 [58] manual therapy as an n =46 with severe nonsynostotic motor development significantly reduced in effects were seen during adjuvant option on MT/CST plagiocephaly assessed with Alberta manual therapy group the treatment period. treatment duration Infant Motor Scale (109.84 +/− 14.45) and motor compared to the control development in group (148.65 +/− 11.53) infants with severe days. Asymmetry after the nonsynostotic treatment was minimal plagiocephaly. Type 0 or Type 1. Motor behaviour was normal in all the infants after treatment. Lessard S, et al. Does osteopathic Before-After Infants ages < 6.5 months, Anthropometric changes Osteopathic treatment There is no mention of 2011 [59] manipulation alter n =12 diagnosed with nonsynostotic led to improvements in adverse events made in cranial asymmetry OMT plagiocephaly cranial asymmetry. this study. in infants. Postural Philippi H, et al. To assess the RCT Infant ages 6–12 weeks, with Video-based Significant improvement “At least two of the seven Asymmetry 2006 [60] therapeutic efficacy n =32 postural asymmetry measurements in postural asymmetry vegetative symptoms

of osteopathic OMT/CST (mean 5.9 points) aggravated for 2 days after (2019)19:60 manipulation in observed with the interventions in six infants with postural osteopathic manipulation. patients of the control asymmetry. group and in four patients of the treatment group. Otherwise no adverse effects were seen.” Scoliosis Byun S & Han D, Examine whether Before-After Children ages 10–13, with Reduction in Cobb No significant difference in There is no mention of 2016 [61] chiropractic n =5 Cobb angles > 10 degrees angle Cobb angle was noted adverse events made in techniques would CMT after the 4th week of this study. reduce the curvature chiropractic manipulation. of idiopathic scoliosis. Hasler C, et al. Test to see if RCT Post-pubertal females Trunk morphology, Repeat measurements “No intervention-related 2010 [65] osteopathy alters n =20 ages 12–18, with Cobb spine flexibility and revealed no therapeutic side effects or complications trunk morphology, OMT angles 20–40 scoliometer effect on rib hump, were noted” to unload the measurements lumbar prominence, concave side of the plumb line, sagittal scoliosis to halt curve profile and global progression. flexibility. ae3 f38 of 31 Page Table 10 Data extraction for structural studies (Continued) Prevost Parnell Condition Author/year Study objective Study design Patient description/ condition Primary/main outcome(s) Main results/conclusions Adverse events sample size intervention Rowe D, et al. To conduct a pilot RCT Children ages 10–16, with Reduction in Cobb Feasible to recruit AIS CMT delivered on 52 visits ta.BCCmlmnayadAtraieMedicine Alternative and Complementary BMC al. et 2006 [62] (feasibility) study n =6 Cobb angles 20–40 degrees angle patients for a randomized resulted in two benign and explore issues CMT clinical trial to compare reactions one with of patient safety, chiropractic care and moderate pain lasting patient recruitment standard medical 24 h; the other produced and compliance, treatment. mild pain lasting 6 h. treatment standardization, sham treatment refinement, interprofessional cooperation, quality assurance, and outcome measure selection. Morningstar M, Evaluate of scoliosis Before-After Scoliotic patients aged Reduction in Cobb Reduction in Cobb angles There is no mention of et al. 2004 [63] treatment using a n =19(6 15–65 (6 patients 18 angle in all patients. adverse events made combination of pediatrics) and under- identified in this study. manipulative and CMT in Table 3 of study)

rehabilitative therapy. (2019)19:60 Lantz C & Effect of chiropractic Before-After Children aged 6–17, Reduction in Cobb No overall reduction in There is no mention of Chen J, 2001 [64] manipulation on small n =42 with Cobb angles 6–25 angle Cobb angle after adverse events made in scoliotic curves in CMT 6.5–28.5 months of care. this study. younger subjects. Torticollis Haugen E, Evaluate measurement RCT Infant aged 3–6 months, Primary outcome: No significant difference There is no mention of 2011 [66] methods and examine n =32 diagnosed with torticollis Videoclip recordings, in primary outcome. adverse events made in short-time effect of MT Secondary outcomes: Found non-significant this study. manual therapy in 12 parameters of body tendency to greater addition to function, activity, improvement in lateral physiotherapy in participation flexion and head infants with torticollis. righting in intervention group. Upper Cervical Saedt E, et al. To gain insight into Before-After Infants aged < 27 weeks, Improved flexion-rotation Flexion- rotation test No serious adverse Dysfunction 2018 [67] the patient n = 295 with positional preference, test and lateral flexion tests decreased from 78.8 to events were reported characteristics and MT restlessness, abnormal Parental perception of 6.8%. Lateral flexion test during this study. reasons for seeking head position, excessive treatment effects Pre- decreased from 91.5% tp care in infants with crying and post treatment 6.2%. All parents indications of upper self-reported perceived positive cervical dysfunction questionnaires treatment effects. referred for manual therapy. ae3 f38 of 32 Page Parnell Prevost et al. BMC Complementary and Alternative Medicine (2019) 19:60 Page 33 of 38

5.3.Scoliosis in scoliotic curvature. The authors reported no overall improvement in scoliotic curves using CMT. No men- Five studies looked at the use of manual therapy in the tion of adverse events was made in this study [64]. treatment of scoliosis. Four looked at the use of CMT Hasler et al. conducted a high quality prospective RCT [61–64]. Of these, one was a high quality RCT, three that sought to determine if OMT altered trunk morph- before-after, two medium and one of low quality. The ology to unload the concave side of the scoliosis in order fifth study was a high quality RCT that looked at the use to halt curve progression. The study included 20 of OMT [65]. pre-pubertal women with curves that ranged from 20 to A medium quality before-after observational study by 40 degrees. The primary outcomes was trunk morph- Byun and Han examined whether chiropractic tech- ology and spine flexibility. The authors concluded that niques would reduce the curve of adolescent idiopathic there was no evidence to support the use of OMT in the scoliosis in 5 healthy children with an average age of treatment of mild idiopathic scoliosis. No 11.8 years with Cobb angles greater than 10 degrees intervention-related side effects or complications were (average 11.2 degrees). The primary outcome was the noted [65]. change in the Cobb angle that was measured after 4 and Overall Summary: at 8 weeks of treatment. The results of this study were Inconclusive (unclear) evidence for use of CMT in that the Cobb angle was noticeably decreased after 4 childhood scoliosis. weeks, but no further reduction in Cobb angle was Inconclusive (unfavorable) evidence for use of OMT noted after 8 weeks, except in one male. They concluded in childhood scoliosis. that chiropractic techniques effectively reduced the Cobb angle in adolescent idiopathic scoliosis after 4 5.4.Torticollis weeks. There was no mention of adverse events made in this study [61]. One medium quality pilot RCT investigated whether Rowe et al. conducted a high quality pilot RCT that in- MT improved torticollis in 32 patients between the ages vestigated the clinical effects of CMT on children with of 3–6 months. There were 15 infants in the study group scoliosis. This was a feasibility study whose purpose was who received MT plus physiotherapy (PT) and 16 in- to explore issues of safety, patient recruitment, patient fants in the control group who received child physio- compliance, treatment standardization, sham treatment therapy alone. The study did not describe the type of refinement, inter-professional cooperation, quality assur- MT provided. The primary outcome measured was ance, and outcome measure selection. The primary out- evaluating the torticollis symptoms via videotape footage come measured was the Cobb angle. Secondary outcome of the child using a 4-point scale in which the child was was the Scoliosis Quality of Life Index (SQLI). The re- rated as “much better”, “better”, “no significant change” searchers reported improved Cobb angles in 5 of the 6 or “worse”. Secondary outcomes included 12 measure- patients that received CMT and an improved SQLI in 1 ment parameters that involved body function, activity, of the 6. Due to the small sample size, no conclusions and participation corresponding to the International could be made regarding effectiveness. Regarding ad- Classification of Function The study reported no signifi- verse events, CMT delivered on 52 visits resulted in two cant improvement in the MT and PT group in the pri- benign reactions; 1 with moderate pain lasting 24 h, the mary outcome, but improvement in two of the other produced mild pain lasting 6 h [62]. secondary outcome measures of improved passive and Morningstar et al. conducted a low quality before-after active lateral flexion of the neck. No mention of adverse case series that reviewed the clinical files of 22 patients, events were noted in this study [66]. 6 of whom were 18 years or younger, who received a Overall Summary: combination of CMT and rehabilitative therapy. The au- Inconclusive (unfavorable) evidence for MT for thors found reductions in Cobb angle (average 17 degree torticollis. reduction) in all the patients, including the patients under the age of 18 years. No mention of any adverse 5.5.Upper cervical dysfunction events was noted in this study [63]. Lantz et al. conducted a medium quality before-after A high quality before-after observational study by Saedt case series of 42 children, 16 males, 26 females, with et al. sought to gain insight into the patient characteris- scoliotic curves ranging from 4 to 22 degrees, ages 6–17 tics and reasons for seeking care in infants with upper years, to determine the clinical effects of full spine CMT, cervical dysfunction (UCD). A group of 295 infants use of heel lifts, and lifestyle counseling on the progres- (mean age of 11.2 weeks) with positional preference, rest- sion of the curves. Participants were treated for between lessness, abnormal head position and excessive crying 6.5 to 28.5 months. The main outcome was a reduction were treated with mobilization. The primary outcomes Parnell Prevost et al. BMC Complementary and Alternative Medicine (2019) 19:60 Page 34 of 38

were assessed with pre- and post-treatment self-reported  ADHD (using OMT); questionnaires used to assess diagnostics, treatment pro-  Autism (using CMT); cedures, outcomes, and harms from parents and manual  Asthma (using OMT); therapists. The questionnaires consisted of two sections:  Clubfoot (using MT); one collected at baseline; the other posttreatment by  Cranial Asymmetry (using MT/CST); both the parents and the manual therapists. The re-  Dysfunctional Voiding (using OMT); searchers concluded that the majority of infants with  Infantile Colic (using OMT/CST); upper cervical dysfunction showed positional preference  Obstructive Apnea (using OMT); oftheheadandreducedtheactiveandpassivemobility  Otitis Media (using OMT); of the upper cervical spine. After gentle upper cer-  Postural Asymmetry (using OMT/CST); vical mobilization techniques, active and passive cer-  Suboptimal Infant Breastfeeding (using CMT/CST); and vical mobility increased. They also reported that the  Temporomandibular Joint Dysfunction (using OMT). parents reported a reduction in symptoms. No serious adverse events were reported during this study [67]. Pediatric conditions assessed to be ‘inconclusive- Overall Summary: unclear’ were: Inconclusive (unclear) evidence for the use of MT in infants with upper cervical dysfunction.  Asthma (using CMT);  Autism (using VOMT); Discussion  Cerebral Palsy (using OMT); This review identified 50 RCTs and observational ori-  Constipation (using OMT); ginal studies that evaluate manual therapy for pediatric  Cranial Asymmetry (using OMT); conditions, which updates several previously published  Cuboid Syndrome (using MT); systematic reviews. Of particular importance, our review  Headache (using CMT, OMT, and MT); included studies investigating the effects of manual ther-  Infantile Colic (using CMT); apy on musculoskeletal conditions, including pediatric  Low Back Pain (using MT); low back pain and headache. Other conditions not previ-  Otitis Media (using CMT); ously reported in some previous systematic reviews in-  Nocturnal Enuresis (using CMT); clude: constipation, suboptimal infant breastfeeding,  Preterm Infants (using OMT/CST for general clubfoot, cuboid syndrome, headache, pulled (nurse’s) movement); elbow, asthma, obstructive apnea, autism, cranial asym-  Scoliosis (using CMT); and metry, postural asymmetry, scoliosis, torticollis, and  Upper Cervical Dysfunction (using MT). upper cervical dysfunction. Of the 50 studies, 32 were RCTs (18 high-quality, 10 Pediatric conditions assessed to be ‘inconclusive-unfa- medium-quality, and 4 low-quality). The remaining 18 stud- vorable’ were: ies were observational (1 high-quality, 13 medium-quality, and 4 low-quality). Observational studies were further  Scoliosis (using OMT) and broken down by study design (13-before-after, 4 interrupted  Torticollis (using MT). time-series without comparison group, and 1 interrupted times-series with comparison group). Thirty-six studies re- Our findings had a few notable updates from prior sys- ported ‘favorable’ results, five showed ‘no improvement,and’ tematic reviews, especially the UK Update, of which nine showed ‘no difference’ between study groups. In five of “inconclusive-unclear” or “inconclusive-favorable” was the nine ‘no difference’ studies, ‘favorable’ results were noted the outcome for all conditions [10]. The UK Update was in both groups, of which two of these studies had MT in unable to review any musculoskeletal conditions because both groups. no studies were available at that time [10]. Evans et al. Pediatric conditions assessed as ‘moderate-favorable’ published the first high-quality RCT on adolescent low were: back pain, which allowed for this review to report a “moderate-positive” evidence for low back pain using  Low Back Pain (using CMT); CMT [33]. Another musculoskeletal condition that has an  Pulled (or Nurse’s) Elbow (using MT); and ongoing study is headaches (ClinicalTrials.gov Identifier:  Preterm Infants (using OMT/CST to reduce days NCT02684916); we anticipate the results of this study will and costs in hospital). allow for better practitioner guidance because of the high rigor described in the protocol. Pulled (Nurse’s) elbow Pediatric conditions assessed to be ‘inconclusive- using MT was also not in the UK Update, and was found favorable’ were: to have a “moderate-positive” result in this study [37, 38]. Parnell Prevost et al. BMC Complementary and Alternative Medicine (2019) 19:60 Page 35 of 38

Additional evidence ratings changed in a positive direc- report that adverse events are rare, but that the true inci- tion in our study from the UK Update for preterm infants dence is unknown as they have not been evaluated pro- (reducing length of stay and hospital costs) using OMT/ spectively. The current “Best Practices for Chiropractic CST. Three new high-quality RCT’s not previously identi- Care of Children: A Consensus Update” report states that fied by the UK Update were identified showing favorable the best way to minimize adverse events is by conducting results, which accounted for this modification [55–57]. a thorough history and examination, as the majority of ad- We were able to change the evidence ratings from “incon- verse event cases in the literature are often due to under- clusive-unclear” to “inconclusive-favorable” for two add- lying pre-existing pathology that was not diagnosed [9]. itional conditions: otitis media, based on data gathered Our review is in agreement with previous studies in from two medium quality RCT’s[43, 45], reporting favor- recommending that prospective-population-based studies able results and for ADHD, based on the results of a high should be conducted to identify the true incidence of ser- quality RCT showing favorable results [48]. ious adverse events due to MT in the pediatric population. We amended the evidence from “inconclusive-favor- Such a clinical trial is currently ongoing (ClinicalTrials.gov able” to “inconclusive-unclear” for infantile colic and Identifier: NCT02268331). pediatric enuresis using CMT. Regarding the change for Additionally the “Best Practice” report states that manual infantile colic, our study included four studies, the most procedures should be modified when treating children to recent of which is a high-quality with improved out- take into account the differences in patient size, structural comes [19]. However, the remaining studies showed ei- development and flexibility of the joints [9]. Modifications ther “no improvement” or “no difference” [20–22]. Our should include using gentler, lighter biomechanical forces evidence rating is similar to the recent 2018 systematic proportioned to the size and structural development of the review and meta-analysis of infantile colic and manual child. Both Triano et al. and Todd et al. [8, 70]. have posited therapy conducted by Carnes et al. [68]. Carnes et al. that healthcare providers using SMT are able to modulate concluded that while small benefits were found for the the amount of forces used. We agree this ability to modu- overall outcome, the benefit of manual therapy for in- late for pediatric, geriatric, and other special populations fantile colic is still unclear [68]. For pediatric enuresis, ought to be included in undergraduate training programs our search identified only one observational study show- or during continuing education workshops for field ing favorable results; however, this level of evidence was practitioners. not enough to substantiate a “favorable” rating [25]. The UK Update conclusion was based off the Huang et al. Limitations systematic review, which included clinical trials that did Aside from using rigorous methodology in this system- not meet our eligibility criteria for manual therapy and atic review and conducting a comprehensive search, it is year of publication [69]. possible that our search failed to identify every relevant Similar to the previous systematic review on this topic, study, especially considering the restriction of the search and despite using only recent literature, this review con- to English-language studies. Our knowledge of unpub- tinued to find serious methodological limitations within lished trials have influenced our conclusions; unpub- the included studies. Our most common methodological lished trials may be more likely to produce negative or concern was the lack of standardization of the interven- equivocal results. Although the independent reviewers tion, which varied across the professions and even be- performed this review, and in spite of utilizing system- tween studies within the same profession. Many studies atic strategies for assessing the quality of the included failed to adequately describe the methods used by the studies, there is still room for subjective interpretation. practitioner; most of the studies also failed to describe While we deliberately chose widely accepted recommen- the number of treatments the patients received and over dations for assessing quality and determining bias, our what duration of time. In addition, the provider’sexperi- adaptation of some recommendations to better fit our ence, training, and type of intervention used in the same study design may have impacted our conclusions. Also, study varied considerably. Another notable methodo- each reviewer has varying degrees of familiarity with the logical concern was small sample size, which was not assessment tools a priori, which could influence the accounted for in the quality assessment. Finally, many inter-reviewer reliability of the primary quality and bias studies failed to report on the incidence of adverse events. assessments. Finally, all six reviewers are chiropractors; Adverse events were addressed in only 20 of the 50 in- this expertise, as well, may be considered a source of cluded studies reviewed. No lasting or significant adverse bias. events were reported for children receiving any form of MT. Two previous systematic reviews have been pub- Conclusions lished regarding the incidence of adverse events associated Favorable, albeit inconclusive, results were reported in 36 with pediatric spinal manipulation [7]. These reviews of the 50 studies we assessed that used different types of Parnell Prevost et al. 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