Under its Evidence-based Practice Program, the Agency for Healthcare Research and Quality (AHRQ) is developing scientific information for other agencies and organizations on which to base clinical guidelines, performance measures, and other quality improvement tools. Contractor institutions review all relevant scientific literature on assigned clinical care topics and produce evidence reports and technology assessments, conduct research on methodologies and the effectiveness of their implementation, and participate in technical assistance activities.
Overview / Reporting the Evidence / Methodology / Findings / Future Research / Availability of Full Report
Women's health is a major concern in the Nation today, particularly in the areas of maternal health and pregnancy. Within this framework, the American College of Obstetricians and Gynecologists nominated issues for consideration by the Agency for Healthcare Research and Quality (AHRQ) relating to the care of women with preterm labor. Of specific concern are effective strategies for identifying and treating women with symptoms of preterm labor so as to prevent preterm births (i.e., births before 37 full weeks of gestation) and subsequent infant morbidity and mortality.
Definitions of preterm labor vary, but the research criteria commonly hold it to be contractions occurring between 20 and 36 weeks' gestation at a rate of four in 20 minutes or eight in 1 hour with at least one of the following: cervical change over time or dilation greater than or equal to 2.0 cm.
Preterm labor is the most common cause of antenatal hospitalization, but the number of pregnancies in which preterm labor symptoms occur is inadequately documented. Preterm labor is recognized as a prelude to early births, with their attendant burden of infant morbidity and mortality. Although the incidence and prevalence of preterm labor are not well understood, the incidence and burdens of preterm births are. Conservatively, 11 percent of all live births, or approximately 440,000 annually, occur before term in this country, and preterm births are responsible for three-quarters of neonatal mortality and one-half of long-term neurological impairments in children. Preterm births account for one-third of all health care spending on infants and one-tenth of spending for children.
In short, the medical, psychological, and economic burdens of preterm births—and by extension, preterm labor that ends in preterm births—are substantial. Uncertainty persists, however, about the best strategies for managing women in preterm labor. Thus, compelling reasons can be amassed for a systematic review of the literature in this clinical area.
To address these issues, the Research Triangle Institute-University of North Carolina Evidence-based Practice Center (RTI-UNC EPC) undertook a rigorous review of the scientific literature on detection and management of preterm labor. This report addresses four main issues:
The key questions follow:
Biologic Markers: What is the appropriate criteria for a diagnosis of preterm labor? Relatedly, how much positive or negative predictive value does the use of biologic markers add to clinical opinion in diagnosing preterm labor?
Tocolytics: What is the efficacy and/or effectiveness of tocolytics in managing preterm labor? The analysis had two subtopics, one concerning first-line tocolytics (treatment for women having acute symptoms) and the other concerning maintenance therapy for women who have experienced an episode of preterm labor.
Antibiotics: What is the efficacy and/or effectiveness of antibiotics in managing preterm labor? The analysis was limited to women suspected of having occult in utero infections.
Home Uterine Activity Monitoring: What is the efficacy of home uterine activity monitoring in decreasing adverse maternal and neonatal outcomes in women who have experienced an episode of preterm labor in the current pregnancy?
Specifically, we investigated three biologic markers:
Because of a lack of studies regarding E3 in women in labor, the remainder of this summary focuses only on fFN and EVUSD.
We studied five classes of tocolytics:
For these tocolytics, we considered whether they were used as first-line or maintenance regimens; the former applies to acute conditions when a woman's preterm labor symptoms are so significant that a tocolytic agent is used to prevent preterm birth, and the latter applies to use after an episode of acute tocolysis to maintain uterine quiescence.
Our review included numerous antibiotics, which are reviewed as one group. Finally, we considered the literature on home uterine activity monitoring for women with preterm labor.
We conducted a detailed search of the relevant literature using the following databases: MEDLINE; EMBASE; the Cochrane Collaboration and its related York Database; International Pharmaceutical Abstracts; the Health Economic Evaluations Database; Genderwatch; and the Population Index. We also conducted an extensive search of the gray literature, chiefly government documents, with a focus on tocolytics and biologic markers.
We examined literature meeting the following criteria:
The Medical Subject Headings (MeSH) used for the searches were limited by the subject heading "premature labor." With respect to study designs, we included a variety of terms in "epidemiologic study characteristics" (exploded). In addition, we searched for specific therapies, including "biologic markers," "antibiotics," and "tocolytic agents." We searched the intersection of "premature labor" and "diagnosis," and finally, we searched under "costs and cost analysis and cost-benefit analysis."
Efficacy and Effectiveness Data. Upon completion of the initial literature searches, we subjected lists of titles and article abstracts to a dual, blinded review. We retained those articles that both a clinician and a methodologist reviewer indicated should be included and discarded those that both reviewers indicated should be dropped. In cases of disagreement, the Scientific Director for the project made the final selection. In addition, the Scientific Director reexamined a 20-percent sample of abstracts identified for inclusion and all abstracts identified for exclusion; generally, we erred on the side of inclusion.
We combined all citations into a ProCite database, removing duplicate records and identifying articles to be included in evidence tables and those to be excluded (with reason for exclusion). In all, we retrieved 506 studies of benefit from treatment; of these, we included 101 articles.
We developed, through several iterations, various data extraction forms, specific to each topic. These forms were designed to provide clear and easily accessible information for entering data into evidence tables. Included across all studies were the following variables:
The RTI-UNC EPC used two types of abstractors: individuals with content or clinical expertise and those with strong methodologic skills. The clinician abstractors included several obstetricians, one pediatrician with training in women's health, and a nurse midwife; all had prior research experience. The methods abstractors were all doctoral students in the UNC School of Public Health or the UNC Department of Economics with extensive training in quantitative methods. In addition, reviewers included a health services researcher with expertise in quantitative methods (the Project Director) and an obstetrician with expertise in treating women with preterm labor and conducting clinical research in the topic area (the Scientific Director). We instituted substantial quality control and reliability procedures.
Harms Data. We systematically reviewed evidence about side effects of tocolytics, comparing classes of these drugs and effects on the mother and the fetus or neonate, but we did not distinguish between first-line and maintenance therapies. Rather than developing full evidence tables, we created numerous charts depicting the absolute and relative frequency of various harms associated with tocolytic use.
We first graded the quality of individual articles using a specific scale that considered various aspects of the internal and external validity of each study. It encompassed, among other issues, study design, measurement issues, statistical analyses, and the appropriateness of the conclusions being drawn.
To assess the internal validity of a study (i.e., the likelihood that the design and conduct of the study minimize systematic error [bias]), we evaluated the following:
We evaluated the adequacy of the methods used and whether the investigators assessed the clinical relevancy of the statistical findings. The quality rating instrument assessed whether all three major categories of outcomes were included in a study: delivery, maternal, and infant. With respect to external validity (i.e., whether the findings of the study can be generalized to populations that did not participate in the study), we determined whether the clinical setting was clearly specified and whether conclusions apply to pregnant women in the United States. The quality scores from each abstractor are included in the evidence tables.
We also rated the quality or strength of the collective evidence on each topic according to a categorical, adjudicated rating developed by the Project Director, Scientific Director, and Clinical Methodologist. The quality of the collective evidence takes into account the design quality of the individual studies and the efficacy or effectiveness of reported outcomes. The ratings are as follows:
Good (A): The data or evidence are sufficient for evaluating the quality of the findings. The data are consistent and indicate that the key drug or intervention is superior to alternative treatment or placebo for treating women with preterm labor.
Fair (B): The data are sufficient for evaluating the quality of the findings. The data indicate that inconsistencies exist in the findings between the key drug or intervention and alternative or placebo for treating women with preterm labor.
Poor (C): The data are sufficient for evaluating the quality of the findings. The data do not show that the key drug or intervention is superior to alternative treatment or placebo for treating women with preterm labor.
Incomplete Evidence (I): The data are insufficient for assessing the quality of the key drug or intervention for treating women with preterm labor based on limited sample size or poor methodology.
Efficacy (1): Evidence obtained from well-designed RCTs.
Effectiveness (2): Evidence obtained from well-designed cohort or case-control studies.
We used two designations to grade the overall evidence about harms: "high" if the side effects were life-threatening and their frequency was substantially different from that for alternative treatments or no treatment, and "low" if the side effects were short term and not life-threatening and their frequency was not substantially different from the frequency for an alternative tocolytic treatment or no treatment.
We presented information from individual studies into pairs of evidence tables-one for study design and the other for outcomes. The content of the study design tables covers the following variables (when available from the publications):
The outcomes tables generally include data on delivery, and maternal and infant outcomes. For the biologic marker outcome tables, we present delivery outcomes in terms of sensitivity, specificity, positive predictive value, and negative predictive value (NPV).
In addition to the systematic review of the literature, we conducted meta-analyses focusing on treatment effects of first-line tocolytics by class, maintenance tocolytics by class, antibiotics, and home uterine activity monitoring. The efficacy of treatment was measured in relation to the following outcomes:
The literature used in the meta-analyses was restricted to RCT studies included in the evidence tables and data concerning women with intact membranes.
The quality of this literature is questionable in many respects, thereby diminishing the confidence with which one can draw conclusions. Among the issues of concern are the definition of preterm labor, the size of the trials, confounding of results because of use of cointerventions, and failure to analyze separately women who have conditions associated with medically indicated preterm births. In addition, we note the absence (except in a few cases) of the use of survival analytic techniques in preference to the use of dichotomous outcomes (e.g., preterm birth or not) or other categorical outcomes that do not adequately reflect how long a pregnancy "survived" without a preterm birth. Survival analysis allows for the stratification of outcomes by such factors as the gestational age at the onset of preterm labor.
Overall, fFN and EVUSD present strong evidence of effectiveness as a diagnostic tool for assessing the risk of preterm birth in women with symptoms of preterm labor. Both tests were only moderately successful in predicting which women with a positive test would deliver before term, but they consistently exhibited strong NPVs, thereby identifying women at low risk of preterm birth. We concluded that these biologic markers offer valuable information that could allow women to avoid unnecessary treatments. These tests can usefully supplement clinical judgment, especially in terms of identifying women who are not likely to experience a preterm birth.
First-Line Tocolytic Therapy. Literature comparing an intervention group of women receiving first-line treatment with tocolytics relative to a control group was available only for beta-mimetics and magnesium sulfate. Results across studies were mixed: for beta-mimetics, we saw evidence of efficacy in terms of estimated gestational age at birth, prolongation of pregnancy for 1 day or more, and improved infant outcomes (birth weight greater than 2,500 g). Significant differences were not found between magnesium sulfate and placebo.
With respect to comparisons among different classes of tocolytics (chiefly in relation to beta-mimetics), results again were mixed. Beta-mimetics had efficacy relative to ethanol treatment in relation to prolonging pregnancy in one (older) study, but other RCTs showed that all other classes of tocolytics had greater or not significantly different effects relative to beta-mimetics on delivery outcomes.
For infant outcomes, results were also mixed, but no study reported that beta-mimetics were a superior treatment. Data from observational studies did not contradict the results of the RCTs.
Meta-analyses suggest that all tocolytics, with the exception of ethanol, were effective in extending pregnancies at or beyond 36-38 weeks gestation compared with a no-treatment group. Beta-mimetics, calcium channel blockers, and magnesium sulfate nearly doubled the odds of term births, relative to control, with potentially small differences in effect sizes between classes.
Overall, the evidence supports the notion that first-line treatment with beta-mimetics, calcium channel blockers, magnesium sulfate, or NSAIDs offers small improvements in prolonging pregnancy. Data concerning relative efficacy are mixed, but they clearly support the conclusion that ethanol is less efficacious than other tocolytic options and support the generally held clinical belief that ethanol is an inappropriate treatment for women with preterm labor symptoms. Concerns that other treatments offer greater efficacy with less risk seem to be warranted in regard to treatment with beta-mimetics as well: the benefits of beta-mimetics never were found to exceed other options, and the maternal harms (see below) were shown to be potentially more severe.
Maintenance Tocolytics. Except for one small study, the efficacy studies showed no difference between treatment and control arms in managing women who had recently experienced an episode of preterm labor, and meta-analysis confirmed these conclusions. In short, for gestational age at birth, prolongation of pregnancy, or birth weight, maintenance treatment conferred no benefits.
Harms of Tocolytics. We graded beta-mimetics as "high" in probability of maternal risk, including serious cardiovascular harms, minor cardiovascular harms, metabolic harms, and psychologic harms. All other classes of tocolytic treatment were graded as "low" in relation to maternal risk. We graded all classes of tocolytics as "low" risk in relation to fetal or neonatal harms: evidence of short-term harms was inconsistent, and evidence of longer term problems was insufficient.
Results of our review concerning therapy with antibiotics for treating occult in utero infections associated with preterm labor were mixed. Two RCTs found improvements in all three delivery outcomes of interest—prolongation of pregnancy, mean gestational age at birth, and birth at a particular number of weeks—but all other RCT studies showed mixed results or no significant difference from placebo/control group assignment.
Results from survival analyses included in three RCTs were also mixed. Meta-analysis showed the following:
The array of agents, routes of administration, and durations of therapy preclude us from making a generalization about the optional antibiotic regimen to achieve these benefits.
Of the four RCTs reviewed, none of the three that controlled for nursing support as an element of the monitoring approach found a significant effect from home uterine activity monitoring; meta-analysis confirmed this "no-effect" conclusion in relation to gestational age at birth and birth weight. A fourth RCT reported that home uterine activity monitoring significantly prolonged delivery to 37 weeks, but the approach in this study included nursing support; the separate effect of monitoring was not analyzed.
We encountered numerous difficulties in reviewing this literature, arriving at concrete conclusions, or drawing appropriate inferences about the efficacy or effectiveness of these drugs and other interventions. Methodologic issues included explicit definitions of preterm labor, clarity about cointerventions, and no separate analysis of women who had medically indicated preterm births. We urge investigators to be more precise in their design and description of efficacy and effectiveness studies.
Moreover, researchers differed in their definitions of even standard outcomes, and we have noted already the infrequent use of survival analysis (or related techniques). Our recommendation is that investigators, to the extent possible, supplement and integrate the use of dichotomous outcomes measures (e.g., preterm or term birth) and variables involving specific cutoff points for gestational age and include concepts such as the length of time a pregnancy was extended (i.e., prolongation as a form of survival of the pregnancy). We specifically advocate survival analysis stratified by gestational age at enrollment as the analytic technique of choice in view of its clinical and biologic relevance.
The dearth of reliable epidemiologic information about preterm labor is significant. The areas that require special attention include biologic mechanisms that result in birth before term, incidence and prevalence of preterm labor and the proportion of pregnancies that result in preterm birth, modifiable risk factors for preterm birth, and a better understanding of these basic facts among racial/ethnic minorities.
Further study on risk factors is important because clinicians and researchers must be able to assess accurately the risk of preterm birth in women with symptoms of preterm labor and to exclude women at low risk of early birth from intervention trials. Biologic markers (such as fFN and EVUSD), by virtue of being objective and reproducible, are superior to purely clinical assessment or prognostication of preterm delivery. Nonetheless, we advocate more direct experimental investigation of the predictive characteristics of these two biologic markers. Meanwhile, we recommend that investigators studying tocolytics and antibiotics as part of a medical regimen for women with preterm labor use biologic marker negativity as an exclusion criterion.
Our results from both the systematic review and meta-analysis for the first-line tocolytics and for antibiotics suggested that further trials of these modalities are justified, although we note that investigators must now attend to the deficits of the efficacy and effectiveness studies to date. Future research should focus on the benefits (and harms) of beta-mimetics, calcium channel blockers, magnesium sulfate, and NSAIDs, in comparison with no treatment and in comparisons with one another.
Finally, we advise against further research on maintenance tocolytics or home uterine activity monitoring. The research to date has made adequately clear that the use of tocolytics in a maintenance capacity following an episode of acute tocolysis has no proven efficacy or effectiveness and that the use of home uterine activity monitoring confers no maternal, fetal, or neonatal benefits.
The full evidence report from which this summary was derived was prepared for the Agency for Healthcare Research and Quality by the Research Triangle Institute, University of North Carolina, Chapel Hill, under contract No. 290-97-0011. Printed copies may be obtained free of charge from the AHRQ Publications Clearinghouse by calling 800-358-9295. Requesters should ask for Evidence Report/Technology Assessment Number 18, Management of Preterm Labor (AHRQ Publication No. 01-E021).
The Evidence Report is also online on the National Library of Medicine Bookshelf, or can be downloaded as a zipped file.
AHRQ Publication No. 01-E020
Current as of October 2000
Internet Citation:
Management of Preterm Labor. Summary, Evidence Report/Technology Assessment: Number 18. AHRQ Publication No. 01-E020, October 2000. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/epcsums/pretermsum.htm
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