Identifying potential treatment effect modifiers of the effectiveness of chiropractic care to infants with colic through prespecified secondary analyses of a randomised controlled trial

Abstract

Background: A recent trial identified large variation in effect of chiropractic care for infantile colic. Thus, identification of possible effect modifiers could potentially enhance the clinical reasoning to select infants with excessive crying for chiropractic care. Therefore, the aim of this study is to identify potential treatment effect modifiers which might influence the effect of chiropractic care for excessive crying in infancy.

Methods: Design: Prespecified secondary analyses of data from a randomised controlled trial. The analyses are partly confirmative and partly exploratory.

Setting: Four chiropractic clinics in Denmark.

Participants: Infants aged 2-14 weeks with unexplained excessive crying. Of the 200 infants randomised (1:1), 103 were assigned to a chiropractic care group and 97 to a control group.

Intervention: Infants in the intervention group received chiropractic care for 2 weeks, while the control group was not treated. Main analyses: The outcome was change in daily hours of crying. Fifteen baseline variables and 6 general variables were selected as potential effect modifiers, and indices based on these were constructed. Factor analyses, latent class analyses and prognosis were used to construct other potentially modifying variables. Finally, an attempt at defining a new index aiming at optimal prediction of the treatment effect was made. The predictive value for all resulting variables were examined by considering the difference in mean change in crying time between the two treatment groups, stratified by the values of the candidate variables, i.e. interaction analyses.

Results: None of the predefined items or indices were shown to be useful in identifying colicky infants with potentially larger gain from manual therapy. However, more baseline hours of crying (p = 0.029), short duration of symptoms (p = 0.061) and young age (p = 0.089) were all associated with an increased effect on the outcome of hours of crying.

Conclusion: Musculoskeletal indicators were not shown to be predictive of an increased benefit for colicky infants from chiropractic treatment. However, increased benefit was associated with early treatment and a high level of baseline crying, suggesting that the most severely affected infants have the greatest potential of benefiting from manual therapy. This finding requires validation by future studies.

Trial registration: Clinical Trials NCT02595515 , registered 2 November 2015.

Keywords: Chiropractic; Effect modification; Excessive crying; Infantile colic; Manipulative treatment; Randomized controlled trial.

Fig. 1

Distribution of six baseline background variables considered as potential effect modifiers

Fig. 2

The mean change in crying time stratified by absence or presence of the 13 musculoskeletal items in the treatment groups. (red = chiropractic care; blue = control group)

Fig. 3

Estimated treatment effects (difference in mean change) in subgroups defined by absence or presence of the 13 single musculoskeletal items. Negative estimates indicate an advantage for chiropractic treatment. Interactions refer to the difference in treatment effects between presence and absence of the item. Negative interactions indicate a more pronounced advantage of chiropractic care in the case of presence of the item

Fig. 4

The mean change in crying time stratified by the six preselected additional baseline variables. Duration, age and crying hours at baseline were categorised to obtain four groups of roughly equal size. (red = chiropractic care; blue = control group)

Fig. 5

Estimated treatment effects (difference in mean change) at two selected values of each of the six preselected baseline variables. The estimates are based on a model that assumed a linear change in the treatment effect in dependence on the values. Negative estimates indicate an advantage for chiropractic treatment. Interactions refer to the difference in treatment effects between the two selected values. Negative interactions indicate a more distinct advantage of chiropractic care in case of large values. The selected values refer to the 10th and 90th percentile of each variable

Fig. 6

The mean change in crying time stratified by score values for the three predefined scores. The scores were categorised to reach roughly four groups of equal size (red = chiropractic care; blue = control group)

Fig. 7

Estimated treatment effects (difference in mean change) at two selected thresholds of the three predefined scores. The estimates are based on a model that assumed a linear change in the treatment effect in dependence on the score values. Negative estimates indicate an advantage for chiropractic treatment. Interactions refer to the difference in treatment effects between the two selected values. Negative interactions indicate a more pronounced advantage of chiropractic care in the case of larger score values. The selected values refer to the 10th and 90th percentile of each score

Fig. 8

The mean change in crying time stratified by the new index based on all 13 musculoskeletal items. The values of the index refer to the predicted difference in crying time in minutes comparing active treatment with control (red = chiropractic care; blue = control group)