From the Department of Obstetrics and Gynecology and the Department of Biostatistics and Epidemiology, Leonard Davis Institute of Health Economics, University of Pennsylvania School of Medicine, Philadelphia, PA (e-mail: gmacones{at}mail.obgyn.upenn.edu).
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INTRODUCTION |
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First, is preterm labor itself a clinically important health outcome? If not, is it a reasonable surrogate for another clinically important outcome? Dayan et al. make the argument that preterm labor is itself a clinically important outcome, based mainly on maternal considerations, such as the need for maternal hospitalization and the use of tocolytic medications. Certainly, there is a risk of thrombosis in pregnant women placed on bed rest, given the lower extremity venous stasis and hypercoagulability associated with pregnancy. In addition, the most commonly used tocolytic agents (beta agonists and magnesium sulfate) have both been associated with serious cardiopulmonary morbidity (24
). Fortunately, the risk of thromboses and the risk of cardiopulmonary complications with tocolytic agents are exceedingly low. Given the low rate of maternal complications arising from preterm labor, the clinical importance of preterm labor is largely determined by its relation with preterm birth (infants born preterm are at substantially increased risk for many complications, including death, chronic lung disease, intraventricular hemorrhage, necrotizing enterocolitis, and others). If one agrees with this thinking, the next question becomes whether preterm labor is a reasonable surrogate for preterm birth. The answer to this is unquestionably "no." As Dayan et al. point out, women diagnosed and treated for preterm labor often will deliver at term. This fact is borne out in the many clinical trials of tocolytic agents (where relatively strict diagnostic criteria were used), in which approximately 50 percent of women randomized to placebo delivered at or beyond 37 weeks (5
). In clinical practice, where less stringent diagnostic criteria for preterm labor are likely used, the proportion of women "diagnosed" with preterm labor who ultimately deliver at term may be substantially higher than that seen in the clinical trials. It would certainly be interesting to know what proportion of women diagnosed with preterm labor in this study actually went on to deliver at term. Still, it is clear that preterm labor is not a surrogate for preterm birth.
Why, then, is preterm labor so poorly associated with preterm birth? The answer to this has to do with the methods by which preterm labor is defined. Traditionally, the diagnosis of preterm labor has been based on the observation of "frequent" uterine contractions (various definitions have been used) and the presence of cervical "change" (defined as a change in cervical dilation and/or effacement from a prior examination). Dayan et al. in this study use a similar definition. Unfortunately, the measurement and interpretation of both uterine contractions and cervical dilation are fraught with difficulty. There are three components of the assessment of uterine contractions, namely, frequency, duration, and intensity. Prior to the onset of ruptured amniotic membranes, contractions are measured with an external tocodynamometer, which senses changes in the maternal abdominal contour that occur as the uterus contracts. These monitors yield reliable information on the frequency and duration of uterine contractions, but they allow no information on the intensity of contractions. The intensity of contractions (prior to ruptured amniotic membranes) is usually assessed by a health care provider (usually an obstetric nurse). Health care professionals will often gauge contraction intensity by feeling the top of the fundus of the uterus during the peak of the contraction and applying a grading system to its firmness. There are few data to support an acceptable inter- and intraobserver reliability of this method. In addition, while all of these measures are easily obtainable in women of average weight, they are more difficult to obtain and interpret in women who are obese. The assessment of the cervix is even more problematic. The two main components of the cervical examination are its dilation and effacement (also called shortening). Traditionally, the cervix has been assessed by digital examination by a trained health care professional. Prior work suggests that digital cervical assessment is neither reliable nor reproducible. Phelps et al. (6), in a classic study, mounted polyvinyl chloride pipe of known diameter (from 1 to 10 cm) in a box (to simulate digital cervical examination). They obtained 1,574 measurements from a total of 102 examiners. The overall accuracy of these digital examinations was approximately 50 percent. Allowing for an error of ±1 cm, the accuracy improved to approximately 90 percent. The intraobserver variability was approximately 50 percent (improving to 10 percent if an error of ±1 cm is allowed). Unfortunately, the diagnosis of preterm labor is often made clinically on a change in cervical dilation of less than 1 cm. Because of the difficulties in digital assessment of the cervix, obstetricians began to investigate transvaginal measurements of the cervix. Indeed, these ultrasound measures are more reproducible than digital examinations (7
). However, ultrasound measurement of the cervix takes significant skill and training, and it necessitates the presence of specialized equipment. Thus, it is unclear whether transvaginal ultrasonographic cervical assessment will ever become a part of routine obstetric practice.
In addition to measurement error of uterine contractions and cervical dilation/effacement (which would lead to misclassification of preterm labor, likely decreasing the specificity of the clinical diagnosis), temporal changes in both uterine contraction frequency and cervical status during pregnancy further complicate the use of preterm labor as a definable endpoint. Specifically, as pregnancy advances, the frequency of uterine contractions increases (early in pregnancy, contractions are uncommon). Thus, if monitored, many women destined to deliver at term would be noted to have contractions prior to term (8, 9
). Likewise, although the cervix is normally closed and long early in pregnancy, as pregnancy advances it softens, effaces, and dilates. For these reasons, it can be difficult at times for a clinician to differentiate between expected changes in uterine contractions and cervical dilation/effacement from those changes that represent pathologic preterm labor (especially later in pregnancy). This difficulty is compounded by the fact that often the diagnosis of cervical change needs to be made by comparing the results of a digital examination performed in the first trimester with one performed much later in pregnancy (since it is uncommon to have serial cervical assessments during pregnancy). These factors also contribute to a poor specificity of the diagnosis of preterm labor.
Finally, in the study by Dayan et al. (1), the "diagnosis" of preterm labor was presumably given only to women who had "complaints" of contractions that necessitated a visit to the obstetrician. Given the different pain thresholds among women, it is probable that the likelihood of complaints would vary from person to person. For the association addressed in this study, I am concerned that "anxious" women would be more likely to complain of uterine contractions than women who were not anxious. This could certainly bias the association between anxiety/depression and preterm labor (falsely increasing the magnitude of the association). The authors address this possibility and provide some reassuring clinical information, though I am still concerned about the potential for this bias.
Given the difficulties in the clinical diagnosis of preterm labor, which leads to its variable association with preterm birth, we should all question whether this is an appropriate endpoint in perinatal research. I believe that there are more quantifiable endpoints that we can choose, depending on the question. For example, from a biologic/etiologic perspective, it would be valuable to understand the relation between maternal stress/anxiety and the frequency of both symptomatic and asymptomatic uterine contractions. Although uterine contractions themselves are certainly not an important "health outcome," such work could yield interesting biologic information. Alternatively, if one is more interested in assessing the relation between stress/anxiety and clinically important outcomes, then I believe a more quantifiable endpoint would be spontaneous preterm birth (<37 weeks' gestation), which is much more reliably ascertained than preterm labor. However, it is essential to remember that even preterm birth is a surrogate outcome. The most relevant clinical endpoints in perinatal epidemiologic research are those that relate to short- and long-term infant outcomes. Given that rates of morbidity are gestational age dependent, it is clear that not all preterm births are equal. For this reason, many, myself included, believe that research efforts should be focused on predicting and preventing "early" preterm births, those occurring prior to 32 weeks' gestation.
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ACKNOWLEDGMENTS |
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NOTES |
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REFERENCES |
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Related articles in Am. J. Epidemiol.: