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Olanrewaju O. Omojokun, MD
Children's National Medical Center
Washington, DC 20010
Mir S. Siadaty, MD, MS
Department of Public Health Sciences
University of Virginia School of Medicine
Charlottesville, VA 22908
We thank the authors for their interest in our article and their thoughtful comments.
We appreciate the updated US Preventive Services Task Force (USPSTF) grading scale and matrix provided by Drs Calonge and Petitti.1 We had not been aware of the newer scale when we conducted our meta-analysis, and thus our use of the 1996 methodology was an unintentional oversight. However, after carefully reviewing the methodology used currently by the USPSTF, we believe that our pacifier recommendation2 as a potential preventive strategy against sudden infant death syndrome (SIDS) would retain the B grading: fair to good strength of evidence of moderate net benefit. As stated in our article, we used the USPSTF taxonomy to classify our recommendation; the task force was in no way involved in the study or its conclusions.
We feel that our review of the evidence was "comprehensive, objective, and attentive to quality."1 We conducted a comprehensive literature search beginning at 1966 and used an analytic framework for evaluating the quality of each study; we excluded from the meta-analysis any studies that were of lower quality. We included studies that measured the associations between pacifier use (the preventive service) and the health outcome of interest (ie, occurrence of SIDS) rather than intermediate outcomes. Because the best studies available used case-control designs, these would be classified under the hierarchy of research design as level II-2. Using the criteria for grading internal validity of individual studies would qualify them as having "good" internal validity.
Next, we examined the quality of the full body of evidence. Here, we found that the evidence for pacifier use at last sleep is highly consistent and internally and externally valid (generalizable). We also believe that the evidence is coherent, that is, makes sense on the basis of hypothesized mechanisms that may explain the apparent protective effect of pacifiers.3,4 However, researchers still do not fully understand the cause of SIDS; thus, the mechanism to explain the observed association between pacifiers and reduced risk of SIDS is currently unknown.
It is difficult to fully assess the existence and magnitude of a causal connection between the preventive service and outcome, because the best evidence available is from observational studies. As noted in our article, "causality" is supported by fulfillment of several of the criteria proposed by Sir Bradford Hill.5 It is unlikely that a randomized, controlled trial of pacifier use and SIDS would or could be conducted.
Finally, the USPSTF methodology calls for assessing the magnitude of the net benefit, that is, weighing the potential benefits against the potential harms of the preventive service. We carefully reviewed the literature that addressed all the potential adverse effects of pacifiers in infants, including breastfeeding duration, otitis media, other infections, and dental malocclusions. Although there has been considerable debate about the potential negative consequences of pacifier use, we feel that, overall, the current literature does not support these fears for pacifiers to be used as we recommended and believe that the benefit may be substantial: "a large impact on an infrequent condition that poses a significant burden at the individual patient level."1
Drs Buzzetti and D'Amico advise against placing value on comparisons based on last sleep, indicating that it is "only 1 particular sleep among many." However, we would posit that last sleep is the more appropriate sleep period to use. SIDS is believed to be a multifactorial disorder requiring a set of circumstances to be present. Various factors contribute to the risk of dying as a result of SIDS; therefore, it is logical that some of these factors may change during different sleep periods on the basis of location of sleep, recent illness, items in the bed, use of pacifiers, sleep position, etc. Thus, proximal or "trigger" factors are likely to be more important in the causal pathway.
Although it is only the case infant in case-control studies who experienced a "last sleep," matching to a similar sleep period for the control infant provides a random sleep period (for that infant), which should appropriately represent a comparison period. "Usual" sleep does not necessarily describe accurately what happened during the sleep period in which the SIDS death occurred. As an example to illustrate this point, if someone is injured in a car accident, it is important to know if that person was wearing his or her seat belt for that car trip, not for "usual" car trips.
As noted in the article that is referenced by Buzzetti and D'Amico in which Dwyer et al analyze possible sources of heterogeneity in the meta-analysis of observational studies, "studies using ‘usual’ sleep position to define exposure had low effect sizes [odds ratios] compared with studies using ‘found’ or ‘placed/put’ positions. This is the pattern of results that would be expected if one sleeping position (eg, the prone position) in fact conveyed higher risk, but it was not used all the time. If the sleeping period varies for a given child, then adopting a ‘usual’ definition of sleeping position in a study would attenuate any observable effect associated with the particular sleeping position that elevates risk."6 In our analysis of the association between pacifiers and SIDS, we examined both usual and last sleep periods and found that the effect size was lower when used for usual sleep compared with last sleep, but it was still present. We believe this result was a result of the variable nature of "usual" practice across studies as well as among individual infants.
Their other concern relates to the reliability of estimates in the primary studies, such as multiple adjustments in "relatively few subjects" and the recruitment of several controls for each case. In calculating the odds ratios in our meta-analysis, the sample sizes of the studies were taken into consideration through weighting on the basis of the confidence intervals. Using multivariate odds ratios provides a more accurate picture, because it takes into account, to the extent possible, other potentially confounding factors. The use of multiple controls for each case, particularly in smaller studies, is a well-accepted methodology in case-control study design specifically intended to increase the precision with which the odds ratio is estimated.7 It will not amplify the effect but, rather, will reduce the chance of a type II error. Some of medicine's greatest discoveries have been based on extremely small case-control studies.8 This would assume, however, that the estimate is correct, and we believe this to be the case on the basis of the following: (1) we included studies in our analysis that met 5 or 6 of the 6 evaluation criteria and passed peer review; and (2) the odds ratios reported, especially for last sleep, were quite consistent.
Finally, it would be helpful to investigate the reasons for heterogeneity across studies. We attempted to do this through an improved analysis technique using the proportional odds ratio model.9 In contrast to the fixed-effects model (which pools odds ratios), the proportional odds ratio model estimates effect sizes that are more generalizable. Unfortunately, the necessary data for various covariates were not reported consistently in all the articles, making it impossible to conduct this analysis. In the absence of these data, the fixed-effect model is a valid method.
Drs Stuebe and Lee express several concerns about the relationship between pacifiers and SIDS protection. Some of the same case-control studies that served as the basis for our recommendation have served as the basis for the well-accepted recommendation to place infants supine for sleep.10 This recommendation has proven to be highly successful.11,12 To conduct prospective cohort studies or clinical trials on any of the SIDS risk factors would be highly infeasible, because the occurrence of SIDS is relatively rare (
1 in 2000 live births) and thus would require enormous sample sizes to measure the direct relationship between pacifier use and SIDS. We recognize that causality cannot be proven through case-control design, but it can be inferred by the criteria we used.
We do not believe that differential recall bias played a role on the basis of either the timing of questioning or the parents' perceptions of whether pacifier use is "right." We eliminated from our analysis 1 study in which there was a delay of several years between the infant's death and parental interview.13 However, the timing of interviews in the studies that were included was much closer to the infant's death, and the questions about last sleep for control infants were based generally on a "reference sleep period" (see Table 1 in our article2). That means that the parents of the control infants would have been asked about pacifier use for a very recent sleep period, generally within the last 24 hours. Because there were no official recommendations about pacifier use during the time that any of the studies used in our meta-analysis were conducted, there was no "right" way to respond. If there were any perceptions about pacifiers on the part of the parents of either the case or control infants, it is likely that they would have been random across both groups. In addition, Dwyer et al demonstrated the comparability in magnitude of risk for SIDS associated with prone sleeping between a case-control study and a cohort study.14
It is possible that a variety of factors were involved in the level of risk at last sleep in addition to whether a pacifier was offered and/or accepted by the infant. We know that SIDS is a multifactorial disorder that involves not just environmental risk factors but genetic factors and interactions between them.15 Conducting the meta-analysis using adjusted odds ratios rather than just univariate odds ratios takes into account, as best as possible, many factors that may be potentially confounding the association of interest. It would be impossible in even the best studies to account for and measure every possible contingency, but we agree that additional research should be undertaken to better understand what factors are involved in infants accepting or refusing pacifiers either habitually or on a given day. The consistency across studies, in different countries and populations, and the magnitude of the protective effect, regardless of what factors were controlled for, provide reassurance that this effect is likely to be real. Since our meta-analysis was conducted, 2 other studies, 1 from Germany and 1 from the United States, have also reported reductions in SIDS risk associated with pacifier use at last sleep, further strengthening our conclusions.16,17 In the US study, Li et al17 found a reduction of risk of >90% with pacifier use at last sleep and that reductions in risk were remarkably consistent across different levels of other factors, including thumb-sucking, breastfeeding, and infant sickness during the previous 48 hours.
The findings from McGarvey et al18 raise some questions about whether infants who routinely use pacifiers are at greater risk when not using them compared with infants who do not use them at all. We reviewed the available evidence from studies that conducted similar analyses, and this effect was not found in multivariate analysis, which we find reassuring (refs 19 and 20; R.G. Carpenter, PhD, written correspondence, November 2004). However, it is possible that the protective mechanism involves a "learned" response that makes the infant more vulnerable in the pacifier's absence. Thus, we recommend that pacifiers be used for all sleep periods as a precaution. This effect may be similar to the increased risk associated with unaccustomed prone sleeping, whereby infants who usually sleep nonprone are at greater risk when placed prone than infants who routinely sleep prone.21,22 As a result of this finding, it is recommended that infants be placed supine for every sleep.23 We encourage ongoing surveillance and research to determine if the findings of McGarvey et al are reproducible elsewhere.
There are several mechanisms hypothesized in the literature to explain the association between pacifier use and SIDS. Although not proof, the study by Franco et al,3 in which pacifier users had lower arousal thresholds to auditory challenge, provides support for the arousal hypothesis. The difference among breastfed infants was not significant, but the number in this group was very small. Arousal, however, may not be the only mechanism. Additional research has found that the use of pacifiers modifies cardiac autonomic control during both sucking and nonsucking sleep periods4; autonomic control during sleep-wake processes has also been implicated in SIDS.2 More intense auditory stimuli were needed to arouse infants born to smoking mothers and infants sleeping in the prone position, providing a similar hypothesized causal mechanism among these well-accepted SIDS risk factors.2
The American Academy of Pediatrics made its recommendation for offering pacifiers for sleep periods as a potential way to further reduce the risk of SIDS on the basis of the weight of the evidence and an assessment of the potential benefits and harms.23 Differences of opinions about interpretation of research findings are not unusual. We all agree that it is critical to monitor the outcomes of this recommendation over time to ensure that the net benefits outweigh any unforeseen harms.
REFERENCES
Related articles in Pediatrics:
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