This Phase II randomized controlled trial was conducted by The Osteopathic Research Center at the University of North Texas Health Science Center. Recruitment was open from July 2003 through December 2005 within the Department of Obstetrics and Gynecology at the University of North Texas Health Science Center. All study procedures were approved by the Institutional Review Board for Protection of Human Subjects. The study was also registered with ClinicalTrials.gov
Obstetrical clinic patients were screened up to the 30th week of pregnancy for eligibility and willingness to participate in the study. Exclusion criteria included either of the following: (1) intent to deliver at a non-designated hospital or (2) high risk pregnancy as determined by the attending obstetrician. The latter criterion included, but was not limited to gestational diabetes, preeclampsia, placenta previa, and abruptio placentae. Clinic patients who met the eligibility criteria and provided informed consent were enrolled as subjects between the 28th and 30th weeks of pregnancy and were then randomized as trial subjects.
Each subject was randomized to one of three treatment groups: (1) usual obstetrical care and OMT (UOBC+OMT); (2) usual obstetrical care and sham ultrasound treatment (UOBC+SUT); or (3) usual obstetrical care only (UOBC only). In this trial, “usual obstetrical care” refers to conventional prenatal care during pregnancy exclusive of OMT, which is generally considered a CAM therapy (10
). Subjects were stratified by age and gravida number on the theoretical basis that these factors may influence response to OMT. Twenty-four years was estimated to be the median age of clinic patients seeking obstetrical care based on previous records, and we arbitrarily stratified subjects as primigravida or multigravida. Hence, the four age- and gravida-specific strata were as follows: (1) age ≤24 years and primigravida; (2) age ≤24 years and multigravida; (3) age ≥25 years and primigravida; and (4) age ≥25 years and multigravida. Blocked treatment assignments were then made within each of the four age- and gravida-specific strata (11
). Blocks of six subjects were used to randomly assign two subjects to each of the three treatment groups within each age- and gravida-specific stratum. Assuming continued eligibility and pregnancy, the UOBC+OMT and UOBC+SUT groups were scheduled to receive treatments at the 30th
week (visit 1), 32nd
week (visit 2), 34th
week (visit 3), 36th
week (visit 4), 37th
week (visit 5), 38th
week (visit 6), and 39th
week (visit 7). Each treatment visit was scheduled to last 30 minutes.
The OMT protocol consisted of a standardized approach whereby each assigned subject received treatment provided by licensed physician faculty within the Department of Osteopathic Manipulative Medicine at the University of North Texas Health Science Center. The study protocol included any of the following treatment modalities: soft tissue, myofascial release, muscle energy, and range-of-motion mobilization (12
). These modalities were used in a systematic manner within a protocol that enabled the physician to identify and treat specific somatic dysfunctions in the following anatomical regions: cervical, thoracic, and lumbar spine; thoracic outlet and clavicles; ribcage and diaphragm; and pelvis and sacrum. Treatment providers met regularly to ensure consistency in the duration, type, anatomic location, and manner of manipulation provided throughout the trial. The study protocol prohibited use of high velocity, low amplitude (HVLA) techniques because the increasing ligamentous laxity that occurs in late pregnancy may pose a theoretical risk in performing such maneuvers. A cranial technique known as compression of the fourth ventricle (CV-4) was also prohibited on theoretical grounds that it may potentially induce premature labor, although the small uncontrolled study suggesting that CV-4 may initiate uterine contractions involved only postdate women (13
The SUT protocol was adapted from that described in a previous randomized controlled trial of manual therapy (14
). The SUT treatments were provided by the same physicians who provided OMT. In addition to controlling for physician attention during the treatment visit, the SUT used a nonfunctional ultrasound therapy unit that was modified for research purposes to provide both visible and auditory cues that could potentially elicit a placebo response. The physician provided the SUT by placing the applicator head over the subject's clothing and applying sufficient pressure for tactile stimulation of the skin and underlying tissues in the same anatomical distributions as would generally be addressed if the subject were being treated with OMT.
The subjects assigned to the UOBC only group did not receive any study treatments beyond conventional obstetrical care; however, they were expected to complete data collection forms on the same schedule as all other trial subjects. As with the UOBC+OMT and UOBC+SUT subjects, the UOBC only subjects were allowed to receive conventional obstetrical care with the exception of OMT, massage therapy, physical therapy, chiropractic manipulation, or therapeutic ultrasound intended to treat musculoskeletal disorders.
Data for subjects in each of the three treatment groups were collected by blinded clinical research personnel at the time of randomization and during third trimester visits 1 through 7. At each treatment visit, the blinded attending obstetrician confirmed the subject's continuing eligibility during the prenatal visit immediately before the provision of the study treatment (i.e., OMT or SUT in the applicable treatment groups). The two outcome domains included: (1) back pain, as measured by an 11-point scale (0, 1, 2, … 10) for the average level of back pain; and (2) back-specific functioning, as measured by the Roland-Morris Disability Questionnaire (RMDQ) (15
). The back pain scale included interval ratings from 0 (“no pain”) to 10 (“worst possible pain”) with no temporal frame of reference. Responses to this item were analyzed as if obtained from a 10-cm visual analogue scale for pain. The RMDQ was scored as the total number of affirmative responses to each of its 24 back-related items based on the day of data collection. A higher score was indicative of poorer back-specific functioning and a greater level of disability.
All analyses were based on the intention-to-treat principle (11
). Thus, once a particular treatment was started, each subject was included in that treatment group regardless of her adherence to the seven-visit treatment protocol during the third trimester. Subjects may have missed their assigned treatments for various reasons, including withdrawing from the study without cause, being lost to follow-up, being withdrawn by their attending obstetrician for development of a high risk condition, or other miscellaneous reasons. Additionally, subjects may have “missed” scheduled treatment visits because of delivery prior to visit 7 at the 39th
week. Missing data were imputed using the last observation carried forward method. If a subject delivered prior to visit 7, to maximize statistical power, the carry-forward method was used to impute missing data for censored observations during the remaining obstetrical visits that were obviated by the delivery. Because back pain was likely to increase and back-specific functioning to deteriorate as pregnancy progressed, this approach to imputation may have biased the results in favor of treatment groups with more missed visits. We analyzed the differences in frequency of missed visits among treatment groups to determine if supplemental analyses were needed to further address this potential source of bias.
The baseline characteristics of subjects were summarized using descriptive statistics. Differences among the three treatment groups were assessed using the χ2
test for categorical variables and analysis of variance (ANOVA) for continuous variables. Life table methods were used to assess subject flow through the trial, including the cumulative distributions of treatment-eligible subjects, treatment-withdrawn subjects because of development of high risk status, and treatment-censored subjects because of delivery prior to visit 7. Treatment outcomes were assessed with repeated measures analyses of covariance (ANCOVA) using the baseline measures as covariates. The ANCOVA considered both treatment group and time (as proxied by visit number) main effects and the treatment group X time interaction. Additional analyses were performed to measure effect sizes for treatment outcomes. The latter were computed such that positive effect sizes reflected treatment outcomes in the desired directions (i.e., lower pain levels and lower RMDQ scores). Effect size thresholds for minimally important benefits and harms attributable to OMT were used to supplement the conventional statistical interpretation of the results of this exploratory trial (16
). Minimally important benefits were defined by effect sizes ≥ 0.2 based on a commonly accepted standard for small effects. Minimally important harms were more conservatively defined by effect sizes ≤ −0.1. All hypotheses were assessed at the α=.05 level of statistical significance using two-tailed tests. The treatment group sample sizes were estimated to achieve a statistical power of 70% in conventional independent group comparisons based on a hypothesized moderate and clinically relevant effect size of 0.5 for back pain (ability to detect differences of 1.25 cm among treatment groups on a 10-cm visual analogue scale for back pain) and back-specific functioning (ability to detect differences of 3 units among treatment groups on the 24-unit RMDQ) (17
). Data management was performed with the SPSS Version 14.0 software package (Chicago, IL).