THIS EVIDENCE REPORT IS OUTDATED AND IS NO LONGER VIEWED AS GUIDANCE FOR CURRENT MEDICAL PRACTICE. IT IS MAINTAINED FOR ARCHIVAL PURPOSES ONLY.

Evidence Report/Technology Assessment

Number 18

Prepared for:
Agency for Healthcare Research and Quality

U.S. Department of Health and Human Services
2101 East Jefferson Street
Rockville, MD 20852
http://www.ahrq.gov

Contract No. 290-97-0011

Prepared by:
Research Triangle Institute, Research Triangle Park, NC
Nancy D. Berkman, Ph.D.
Principal Investigator

John M. Thorp, Jr., M.D.
Katherine E. Hartmann, M.D., Ph.D.
Kathleen N. Lohr, Ph.D.
Anjolie E. Idicula, B.A.
Melissa McPheeters, M.P.H.
Norma I. Gavin, Ph.D.
Timothy S. Carey, M.D.
Sue Tolleson-Rinehart, Ph.D.
Anne M. Jackman, M.S.W.
Victor Hasselblad, Ph.D.
Emily C. Puckett, B.A.
Investigators

AHRQ Publication No. 01-E021

December 2000

On December 6, 1999, under Public Law 106-129, the Agency for Health Care Policy and Research (AHCPR) was reauthorized and renamed the Agency for Healthcare Research and Quality (AHRQ). The law authorizes AHRQ to continue its research on the cost, quality, and outcomes of health care, and expands its role to improve patient safety and address medical errors.
This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.

The Agency for Healthcare Research and Quality (AHRQ), formerly the Agency for Health Care Policy and Research, through its Evidence-based Practice Centers (EPCs), sponsors the development of evidence reports and technology assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. The reports and assessments provide organizations with comprehensive, science-based information on common, costly medical conditions and new health care technologies. The EPCs systematically review the relevant scientific literature on topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to developing their reports and assessments.

To bring the broadest range of experts into the development of evidence reports and health technology assessments, AHRQ encourages the EPCs to form partnerships and enter into collaborations with other medical and research organizations. The EPCs work with these partner organizations to ensure that the evidence reports and technology assessments they produce will become building blocks for health care quality improvement projects throughout the Nation. The reports undergo peer review prior to their release.

AHRQ expects that the EPC evidence reports and technology assessments will inform individual health plans, providers, and purchasers as well as the health care system as a whole by providing important information to help improve health care quality.

We welcome written comments on this evidence report. They may be sent to: Director, Center for Practice and Technology Assessment, Agency for Healthcare Research and Quality, 6010 Executive Blvd., Suite 300, Rockville, MD 20852.

John M. Eisenberg, M.D.	Douglas B. Kamerow, M.D.
Director Agency for Healthcare Research and Quality	Director, Center for Practice and Technology Assessment Agency for Healthcare Research and Quality

The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services of a particular drug, device, test, treatment, or other clinical service.

Objectives. Preterm labor is often a prelude to early births and the significant attendant burden of infant morbidity and mortality. To address the question of how best to manage women in preterm labor, the Research Triangle Institute-University of North Carolina Evidence-based Practice Center undertook a rigorous review of the scientific literature on: (1) appropriate criteria for diagnosing preterm labor and use of three biologic markers, fetal fibronectin (fFN), endovaginal ultrasound (EVUSD), and salivary estriol; (2) efficacy and effectiveness of tocolytics-pharmaceutical agents including beta-mimetics, calcium channel blockers, magnesium sulfate, nonsteroidal antiinflammatory disease drugs (NSAIDs), and ethanol that arrest preterm labor symptoms); (3) efficacy and effectiveness of antibiotics for treating covert infections that might have prompted preterm labor; and (4) efficacy of home uterine activity monitoring.

Search Strategy. We conducted a detailed search of the relevant literature using MEDLINE; EMBASE; the Cochrane Collaboration and its related York Database, International Pharmaceutical Abstracts; the Health Economic Evaluations Database; Genderwatch; and the Population Index. The Medical Subject Headings included premature labor, diagnosis, epidemiologic study characteristics, terms for specific therapies (biologic markers, antibiotics, and tocolytic agents) and costs, cost analysis, and cost-benefit analysis. We conducted an extensive search of the gray literature, chiefly government documents, with a focus on tocolytics and biologic markers.

Selection Criteria. Our inclusion criteria were randomized controlled trials (RCTs) and cohort or case-control studies on biologic markers, tocolytics, and antibiotics that met the following specifications: published from 1966 to 1999 in English, French, or German; including pregnant females of any age with signs and symptoms of preterm labor; involving inpatient and outpatient settings; and measuring delivery, maternal morbidities, and infant health outcomes. Home uterine activity monitoring was further restricted to RCTs published in English since 1980.

Data Collection and Analysis. We conducted dual and blinded reviews of abstracts of articles and pulled full articles. Those articles meeting inclusion criteria were given a detailed dual review and abstraction onto four (topic-specific) data extraction forms. We judged the quality of the individual articles (on internal validity, statistical considerations, clinical relevance of findings, an external validity) and the strength of the evidence overall in each topic area (considering consistency of findings over all studies, quality rating of each study, magnitude of important outcomes, and meta-analysis results). In addition to the systematic reviews of the literature, we conducted meta-analyses of treatment effects from first-line and maintenance tocolytics, antibiotics, and home uterine activity monitoring.

Main Results. The quality of this literature is questionable in many respects, including the definition of preterm labor, the size of the trials, confounding of results because of use of cointerventions, reliance on bivariate analyses without including stratified analyses such as would be available through survival analysis, and failure to separately analyze women who have conditions that culminate in medically indicated preterm births.

Both fFN and EVUSD present strong evidence of effectiveness from cohort studies as diagnostic tools for assessing the risk of preterm birth in women with preterm labor, mainly in terms of their negative predictive value. Both can identify women who are not likely to experience a preterm birth and thus help clinicians avoid unneeded therapy. The efficacy of these findings from RCTs is not yet available.

First-line treatment with certain tocolytics offers small improvements in pregnancy prolongation. Whether this prolongation is beneficial in improving neonatal outcomes has not been established. Tocolytics other than beta-mimetics offer greater efficacy at less risk; the benefits of beta-mimetics never exceeded other options, and their harms were potentially more severe than for other options. Ethanol is less efficacious than other tocolytic options and is an inappropriate treatment for women with preterm labor symptoms. In terms of gestational age at birth, prolongation of pregnancy, or birth weight, maintenance treatment with tocolytics conferred no benefits. Evidence of harms was high for beta-mimetics in relation to the probability of maternal risk (serious cardiovascular harms, minor cardiovascular harms, metabolic harms, and psychologic harms); harms for other tocolytics were regarded as low for maternal risk. All classes of tocolytics posed low short-term risk for fetal or neonatal outcomes. Long-term risk to the infant was not evaluated.

Therapy with antibiotics for occult in utero infections believed to be associated with preterm labor had mixed results, but meta-analysis indicated marginally significant improvements in two maternal outcomes (length of pregnancy and gestational age). Significant increases in birth weight were not found.

No RCT of home uterine activity monitoring that controlled for the cointervention of nursing support found a significant effect from use of this device. Meta-analysis confirmed this "no- effect" conclusion in relation to gestational age at birth and birth weight.

Conclusions. Based on the literature reviewed, two biologic markers (fFN and EVUSD) are found to be quite useful in identifying women in preterm labor who are at low risk of experiencing a preterm birth. Although the evidence remains mixed, certain tocolytics-beta- mimetics, calcium channel blockers, magnesium sulfate, and NSAIDs-appear effective in prolonging pregnancy when used as first-line agents in arresting preterm labor, but beta- mimetics in comparison with other tocolytics seem to present a higher risk of maternal harms. Ethanol is not found to be an appropriate tocolytic agent. Tocolytics are not useful as maintenance interventions. Antibiotics for suspected genital tract infections may be useful. Home uterine activity monitoring was found to confer no maternal or fetal/neonatal benefits.

The literature concerning the management of preterm labor is flawed in several ways relating largely to definitions of preterm labor, appropriate measures of outcomes, and use of survival analysis. Epidemiologic research as well as additional efficacy and effectiveness studies of the two biologic markers, selected tocolytics, and antibiotics are warranted.

This document is in the public domain and may be used and reprinted without permission except those copyrighted materials noted for which further reproduction is prohibited without the specific permission of copyright holders.

Suggested Citation:
Berkman, ND, Thorp, JM Jr, Hartmann, KE, et al. Management of preterm labor. Evidence Report/Technology Assessment No. 18 (Prepared by Research Triangle Institute under Contract No. 290-97-0011). AHRQ Publication No. 01-E021. Rockville (MD) Agency for Healthcare Research and Quality. December 2000.

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: (1) the appropriate criteria for diagnosing preterm labor, specifically with respect to the use of three biologic markers and their positive and negative predictive value; (2) the efficacy and effectiveness of tocolytics (pharmaceutical agents that arrest uterine contractions); (3) the efficacy and effectiveness of antibiotics (with respect to covert infections that might prompt preterm labor); and (4) the efficacy of home uterine activity monitoring in decreasing adverse outcomes in women who are experiencing preterm labor.

The key questions are:

Biologic Markers: What are 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: fetal fibronectin (fFN), endovaginal ultrasound (EVUSD), and salivary estriol (E3); because of a lack of studies regarding E3 in laboring women, the remainder of this summary focuses only on fFN and EVUSD. We studied five classes of tocolytics: beta-mimetics, calcium channel blockers, magnesium sulfate, nonsteroidal anti-inflammatory disease drugs (NSAIDs), and ethanol. 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 literatures 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:

• Study populations: humans; pregnant females.
• Condition: signs and symptoms of preterm labor, not including articles in which all research subjects experienced preterm premature rupture of membranes, medically indicated preterm delivery, or multiple gestation.
• Interventions: biologic markers as noted, tocolytics, antibiotics, and home uterine activity monitoring.
• Study settings: essentially all inpatient and outpatient settings including patients' homes.
• Outcomes: three major categories of outcomes-birth, maternal morbidities, and infant health.
• Time period: for pharmacotherapies and biologic markers, 1966 through 1999, depending on the date of approval; for home uterine activity monitoring, 1980 through 1999.
• Languages and geographic sites: English, French, and German (English only for home uterine activity monitoring), and excluding locations based on language of publication other than these.
• Admissible evidence: efficacy studies in which health care is delivered under ideal settings, identified as randomized controlled trials (RCTs) (double and single blinded); effectiveness studies (non-RCTs, prospective and retrospective cohort studies, and case control studies) in which health care is delivered under ordinary circumstances; only RCTs were used for home uterine activity monitoring; other information included meta-analyses, review articles for reference lists, and cost-effectiveness studies; finally, sample sizes of 40 or more subjects.

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."

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:

• Study designs.
• Description of patient population, including maternal age and race, and clinical inclusion/exclusion criteria, such as condition of membranes (ruptured or intact), estimated gestational age, how gestational age was defined, and maternal and fetal indications for birth.
• Definition of preterm labor.
• Description of the test, treatment, or intervention.
• Description of adjunct therapies.
• Outcomes measured such as prolongation of pregnancy, gestational age at delivery, rate of preterm births, maternal morbidities, and infant birth weight.
• Description of any secondary analyses performed.

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.

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: recruitment strategy; masking of the treating clinician and patient; inclusion of baseline measurements (e.g., contraction frequency, cervical dilation, effacement, and estimated gestational age); and definition of outcome measures, attrition rates, and confounding variables. 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): statement of the research objective, definition of preterm labor used by the authors, patient inclusion/exclusion criteria, patient demographic characteristics, description of the experimental intervention, total number of participants, and number of participants in each arm of the study at its conclusion. 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.

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: (1) prolongation of pregnancy, (2) estimated gestational age at delivery, and (3) birth weight. 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 general 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 only moderately were successful in predicting which women with a positive test would deliver before term, but they consistently exhibited strong negative predictive values, thereby identifying women at low risk of preterm birth.

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 2500 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 to 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.

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.

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: a marginally significant increase in length of pregnancy of about 6 days; a marginally significant increase of about 0.60 of a week in gestational age resulting from antibiotic treatment; and a small increase in birth weight that was not statistically significant. 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 that result in preterm birth, modifiable risk factors for preterm birth, and a better understanding of these basic facts among 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 (in their capacity 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.